Breast Cancer Treatment (PDQ®)
General Information About Breast Cancer
This summary discusses primary epithelial breast cancers in women. The breast is rarely affected by other tumors such as lymphomas, sarcomas, or melanomas. Refer to the following PDQ summaries for more information on these cancer types:
Breast cancer also affects men and children and may occur during pregnancy, although it is rare in these populations. Refer to the following PDQ summaries for more information:
- Male Breast Cancer Treatment
- Breast Cancer Treatment and Pregnancy
- Unusual Cancers of Childhood Treatment
Incidence and Mortality
Estimated new cases and deaths from breast cancer (women only) in the United States in 2015:
- New cases: 231,840.
- Deaths: 40,290.
Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 60,290 cases of in situ disease, 231,840 new cases of invasive disease, and 40,290 deaths expected in 2015. Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 71,660 American women will die of lung cancer in 2015. Men account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section in the PDQ summary on Breast Cancer Screening for more information).
Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). (Refer to the Ductal Carcinoma In Situ section in the Breast Cancer Diagnosis and Pathology section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States and the United Kingdom demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.
Risk and Protective Factors
Increasing age is the most important risk factor for breast cancer. Other risk factors for breast cancer include the following:
- Family health history.
- Major inheritance susceptibility.
- Germline mutation of the genes BRCA1 and BRCA2, and other breast cancer susceptibility genes.
- Alcohol intake.
- Breast tissue density (mammographic).
- Estrogen (endogenous):
- Menstrual history (early menarche/late menopause).
- Older age at first birth.
- Hormone therapy history:
- Combination estrogen plus progestin hormone replacement therapy (HRT).
- Oral contraception.
- Personal history of breast cancer.
- Personal history of proliferative forms of benign breast disease.
- Radiation exposure to the breast/chest.
Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer.
Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2. Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as high as 5% per year. Male BRCA2 mutation carriers also have an increased risk of breast cancer.
Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer or other primary cancers. Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Breast Cancer Prevention; and Breast Cancer Screening for more information.)
(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that increase the risk of breast cancer.)
Protective factors and interventions to reduce the risk of female breast cancer include the following:
- Estrogen use (after hysterectomy).
- Early pregnancy.
- Breast feeding.
- Selective estrogen receptor modulators (SERMs).
- Aromatase inhibitors or inactivators.
- Risk-reducing mastectomy.
- Risk-reducing oophorectomy or ovarian ablation.
(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that decrease the risk of breast cancer.)
Clinical trials have established that screening asymptomatic women using mammography, with or without clinical breast examination, decreases breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.)
When breast cancer is suspected, patient management generally includes the following:
- Confirmation of the diagnosis.
- Evaluation of the stage of disease.
- Selection of therapy.
The following tests and procedures are used to diagnose breast cancer:
- Breast magnetic resonance imaging (MRI), if clinically indicated.
Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. At 10 years after diagnosis, the risk of a primary breast cancer in the contralateral breast ranges from 3% to 10%, although endocrine therapy decreases that risk. The development of a contralateral breast cancer is associated with an increased risk of distant recurrence. When BRCA1/BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.
Patients who have breast cancer will undergo bilateral mammography at the time of diagnosis to rule out synchronous disease. To detect either recurrence in the ipsilateral breast in patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast, patients will continue to have regular breast physical examinations and mammograms.
The role of MRI in screening the contralateral breast and monitoring women treated with breast-conserving therapy continues to evolve. Because an increased detection rate of mammographically occult disease has been demonstrated, the selective use of MRI for additional screening is occurring more frequently despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation before treatment is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.
Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):
- The menopausal status of the patient.
- The stage of the disease.
- The grade of the primary tumor.
- The estrogen receptor (ER) and progesterone receptor (PR) status of the tumor.
- Human epidermal growth factor type 2 receptor (HER2/neu) overexpression and/or amplification.
- The histologic type. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. For example, favorable histologic types include mucinous, medullary, and tubular carcinomas.
The use of molecular profiling in breast cancer includes the following:
- ER and PR status testing.
- HER2/neu receptor status testing.
- Gene profile testing by microarray assay or reverse transcription-polymerase chain reaction (e.g., MammaPrint, Oncotype DX).
On the basis of these results, breast cancer is classified as:
- Hormone-receptor positive.
- HER2 positive.
- Triple negative (ER, PR, and Her2/neu negative).
Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting; these women are at greater risk of developing contralateral breast cancer.
Hormone replacement therapy
After careful consideration, patients with severe symptoms may be treated with hormone replacement therapy. For more information, refer to the following PDQ summaries:
Other PDQ summaries containing information related to breast cancer include the following:
- Breast Cancer Prevention
- Breast Cancer Screening
- Breast Cancer Treatment and Pregnancy
- Genetics of Breast and Gynecologic Cancers
- Male Breast Cancer Treatment
- Unusual Cancers of Childhood Treatment (breast cancer in children)
- American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed April 1, 2015.
- Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online. Last accessed April 1, 2015.
- Johnson A, Shekhdar J: Breast cancer incidence: what do the figures mean? J Eval Clin Pract 11 (1): 27-31, 2005.
- Haas JS, Kaplan CP, Gerstenberger EP, et al.: Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med 140 (3): 184-8, 2004.
- Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996.
- Colditz GA, Kaphingst KA, Hankinson SE, et al.: Family history and risk of breast cancer: nurses' health study. Breast Cancer Res Treat 133 (3): 1097-104, 2012.
- Malone KE, Daling JR, Doody DR, et al.: Family history of breast cancer in relation to tumor characteristics and mortality in a population-based study of young women with invasive breast cancer. Cancer Epidemiol Biomarkers Prev 20 (12): 2560-71, 2011.
- Cybulski C, Woko��orczyk D, Jakubowska A, et al.: Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol 29 (28): 3747-52, 2011.
- Goodwin PJ, Phillips KA, West DW, et al.: Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 30 (1): 19-26, 2012.
- Mavaddat N, Barrowdale D, Andrulis IL, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21 (1): 134-47, 2012.
- Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994.
- Futreal PA, Liu Q, Shattuck-Eidens D, et al.: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182): 120-2, 1994.
- Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.
- Hamajima N, Hirose K, Tajima K, et al.: Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 87 (11): 1234-45, 2002.
- Boyd NF, Martin LJ, Rommens JM, et al.: Mammographic density: a heritable risk factor for breast cancer. Methods Mol Biol 472: 343-60, 2009.
- McCormack VA, dos Santos Silva I: Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15 (6): 1159-69, 2006.
- Key TJ, Appleby PN, Reeves GK, et al.: Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 105 (5): 709-22, 2011.
- Kaaks R, Rinaldi S, Key TJ, et al.: Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12 (4): 1071-82, 2005.
- Kaaks R, Berrino F, Key T, et al.: Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 97 (10): 755-65, 2005.
- Endogenous Hormones and Breast Cancer Collaborative Group: Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94 (8): 606-16, 2002.
- Collaborative Group on Hormonal Factors in Breast Cancer: Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 13 (11): 1141-51, 2012.
- Ritte R, Lukanova A, Tjønneland A, et al.: Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study. Int J Cancer 132 (11): 2619-29, 2013.
- Kampert JB, Whittemore AS, Paffenbarger RS Jr: Combined effect of childbearing, menstrual events, and body size on age-specific breast cancer risk. Am J Epidemiol 128 (5): 962-79, 1988.
- Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350 (9084): 1047-59, 1997.
- Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.
- Chlebowski RT, Anderson GL, Gass M, et al.: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304 (15): 1684-92, 2010.
- Chlebowski RT, Hendrix SL, Langer RD, et al.: Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289 (24): 3243-53, 2003.
- Chlebowski RT, Manson JE, Anderson GL, et al.: Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study. J Natl Cancer Inst 105 (8): 526-35, 2013.
- Nelson HD, Zakher B, Cantor A, et al.: Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med 156 (9): 635-48, 2012.
- Wolin KY, Carson K, Colditz GA: Obesity and cancer. Oncologist 15 (6): 556-65, 2010.
- Morimoto LM, White E, Chen Z, et al.: Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative (United States). Cancer Causes Control 13 (8): 741-51, 2002.
- Kotsopoulos J, Chen WY, Gates MA, et al.: Risk factors for ductal and lobular breast cancer: results from the nurses' health study. Breast Cancer Res 12 (6): R106, 2010.
- Goldacre MJ, Abisgold JD, Yeates DG, et al.: Benign breast disease and subsequent breast cancer: English record linkage studies. J Public Health (Oxf) 32 (4): 565-71, 2010.
- Kabat GC, Jones JG, Olson N, et al.: A multi-center prospective cohort study of benign breast disease and risk of subsequent breast cancer. Cancer Causes Control 21 (6): 821-8, 2010.
- Worsham MJ, Raju U, Lu M, et al.: Risk factors for breast cancer from benign breast disease in a diverse population. Breast Cancer Res Treat 118 (1): 1-7, 2009.
- Pearlman MD, Griffin JL: Benign breast disease. Obstet Gynecol 116 (3): 747-58, 2010.
- Vogel VG: Epidemiology, genetics, and risk evaluation of postmenopausal women at risk of breast cancer. Menopause 15 (4 Suppl): 782-9, 2008 Jul-Aug.
- Degnim AC, Visscher DW, Berman HK, et al.: Stratification of breast cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol 25 (19): 2671-7, 2007.
- Worsham MJ, Abrams J, Raju U, et al.: Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population. Breast J 13 (2): 115-21, 2007 Mar-Apr.
- Razzaghi H, Troester MA, Gierach GL, et al.: Mammographic density and breast cancer risk in White and African American Women. Breast Cancer Res Treat 135 (2): 571-80, 2012.
- Pfeiffer RM, Mitani A, Matsuno RK, et al.: Racial differences in breast cancer trends in the United States (2000-2004). J Natl Cancer Inst 100 (10): 751-2, 2008.
- Andrieu N, Easton DF, Chang-Claude J, et al.: Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group. J Clin Oncol 24 (21): 3361-6, 2006.
- Bhatia S, Robison LL, Oberlin O, et al.: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334 (12): 745-51, 1996.
- Claus EB, Risch N, Thompson WD: Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer 73 (3): 643-51, 1994.
- Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.
- Blackwood MA, Weber BL: BRCA1 and BRCA2: from molecular genetics to clinical medicine. J Clin Oncol 16 (5): 1969-77, 1998.
- Offit K, Gilewski T, McGuire P, et al.: Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 347 (9016): 1643-5, 1996.
- Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998.
- Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.
- Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.
- Biesecker BB, Boehnke M, Calzone K, et al.: Genetic counseling for families with inherited susceptibility to breast and ovarian cancer. JAMA 269 (15): 1970-4, 1993.
- Berry DA, Parmigiani G, Sanchez J, et al.: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89 (3): 227-38, 1997.
- Hoskins KF, Stopfer JE, Calzone KA, et al.: Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 273 (7): 577-85, 1995.
- Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.
- Anderson GL, Limacher M, Assaf AR, et al.: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291 (14): 1701-12, 2004.
- LaCroix AZ, Chlebowski RT, Manson JE, et al.: Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 305 (13): 1305-14, 2011.
- Anderson GL, Chlebowski RT, Aragaki AK, et al.: Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol 13 (5): 476-86, 2012.
- Bernstein L, Henderson BE, Hanisch R, et al.: Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst 86 (18): 1403-8, 1994.
- Thune I, Brenn T, Lund E, et al.: Physical activity and the risk of breast cancer. N Engl J Med 336 (18): 1269-75, 1997.
- Adams-Campbell LL, Rosenberg L, Rao RS, et al.: Strenuous physical activity and breast cancer risk in African-American women. J Natl Med Assoc 93 (7-8): 267-75, 2001 Jul-Aug.
- Pike MC, Krailo MD, Henderson BE, et al.: 'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer. Nature 303 (5920): 767-70, 1983.
- Lambe M, Hsieh C, Trichopoulos D, et al.: Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331 (1): 5-9, 1994.
- Col: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360 (9328): 187-95, 2002.
- Cuzick J, Sestak I, Bonanni B, et al.: Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 381 (9880): 1827-34, 2013.
- Goss PE, Ingle JN, Alés-Martínez JE, et al.: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364 (25): 2381-91, 2011.
- Cuzick J, Sestak I, Forbes JF, et al.: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383 (9922): 1041-8, 2014.
- Hartmann LC, Schaid DJ, Woods JE, et al.: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340 (2): 77-84, 1999.
- Rebbeck TR, Levin AM, Eisen A, et al.: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91 (17): 1475-9, 1999.
- Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.
- Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.
- Kauff ND, Domchek SM, Friebel TM, et al.: Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 26 (8): 1331-7, 2008.
- Rosen PP, Groshen S, Kinne DW, et al.: Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol 11 (11): 2090-100, 1993.
- Abbott A, Rueth N, Pappas-Varco S, et al.: Perceptions of contralateral breast cancer: an overestimation of risk. Ann Surg Oncol 18 (11): 3129-36, 2011.
- Nichols HB, Berrington de González A, Lacey JV Jr, et al.: Declining incidence of contralateral breast cancer in the United States from 1975 to 2006. J Clin Oncol 29 (12): 1564-9, 2011.
- Heron DE, Komarnicky LT, Hyslop T, et al.: Bilateral breast carcinoma: risk factors and outcomes for patients with synchronous and metachronous disease. Cancer 88 (12): 2739-50, 2000.
- Graeser MK, Engel C, Rhiem K, et al.: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (35): 5887-92, 2009.
- Garber JE, Golshan M: Contralateral breast cancer in BRCA1/BRCA2 mutation carriers: the story of the other side. J Clin Oncol 27 (35): 5862-4, 2009.
- Lehman CD, Gatsonis C, Kuhl CK, et al.: MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med 356 (13): 1295-303, 2007.
- Solin LJ, Orel SG, Hwang WT, et al.: Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. J Clin Oncol 26 (3): 386-91, 2008.
- Morrow M: Magnetic resonance imaging in the breast cancer patient: curb your enthusiasm. J Clin Oncol 26 (3): 352-3, 2008.
- Simpson JF, Gray R, Dressler LG, et al.: Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 18 (10): 2059-69, 2000.
- Rosen PP, Groshen S, Kinne DW: Prognosis in T2N0M0 stage I breast carcinoma: a 20-year follow-up study. J Clin Oncol 9 (9): 1650-61, 1991.
- Diab SG, Clark GM, Osborne CK, et al.: Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas. J Clin Oncol 17 (5): 1442-8, 1999.
- Rakha EA, Lee AH, Evans AJ, et al.: Tubular carcinoma of the breast: further evidence to support its excellent prognosis. J Clin Oncol 28 (1): 99-104, 2010.
- Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001.
Histopathologic Classification of Breast Cancer
Table 1 describes the histologic classification of breast cancer based on tumor location. Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.Table 1. Tumor Location and Related Histologic SubtypeTumor Location Histologic SubtypeNOS = not otherwise specified.Carcinoma, NOSDuctalIntraductal (in situ) Invasive with predominant component Invasive, NOS ComedoInflammatory Medullary with lymphocytic infiltrate Mucinous (colloid) Papillary Scirrhous Tubular Other LobularInvasive with predominant in situ componentInvasive NipplePaget disease, NOSPaget disease with intraductal carcinomaPaget disease with invasive ductal carcinoma Other Undifferentiated carcinomaMetaplastic
The following tumor subtypes occur in the breast but are not considered typical breast cancers:
- Phyllodes tumor.
- Primary lymphoma.
- Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
- Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 222 (4): 549-59; discussion 559-61, 1995.
- Chaney AW, Pollack A, McNeese MD, et al.: Primary treatment of cystosarcoma phyllodes of the breast. Cancer 89 (7): 1502-11, 2000.
- Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004.
Stage Information for Breast Cancer
The American Joint Committee on Cancer (AJCC) staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to the following:
- Tumor size.
- Lymph node status.
- Estrogen-receptor and progesterone-receptor levels in the tumor tissue.
- Human epidermal growth factor receptor 2 (HER2/neu) status.
- Menopausal status.
- General health of the patient.
Definitions of TNM and AJCC Stage Groupings
The AJCC has designated staging by tumor, node, and metastasis (TNM) classification to define breast cancer. When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III. As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.Table 2. Primary Tumor (T)a,b DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ. *Information about LCIS is not included in this summary.aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76. bThe T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size. cInvasion of the dermis alone does not qualify as T4. TXPrimary tumor cannot be assessed. T0No evidence of primary tumor. TisCarcinoma in situ. Tis (DCIS)DCIS. Tis (LCIS)LCIS.* Tis (Paget)Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted. T1Tumor ≤20 mm in greatest dimension. T1miTumor ≤1 mm in greatest dimension. T1aTumor >1 mm but ≤5 mm in greatest dimension. T1bTumor >5 mm but ≤10 mm in greatest dimension. T1cTumor >10 mm but ≤20 mm in greatest dimension. T2Tumor >20 mm but ≤50 mm in greatest dimension. T3Tumor >50 mm in greatest dimension. T4Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules).c T4aExtension to the chest wall, not including only pectoralis muscle adherence/invasion. T4bUlceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma. T4cBoth T4a and T4b. T4dInflammatory carcinoma. Table 3. Regional Lymph Nodes (N)a Clinical aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76. bClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine-needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine-needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment. NXRegional lymph nodes cannot be assessed (e.g., previously removed). N0No regional lymph node metastases. N1Metastases to movable ipsilateral level I, II axillary lymph node(s). N2Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted. OR Metastases in clinically detectedb ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases. N2aMetastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures. N2bMetastases only in clinically detectedb ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases. N3Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement. OR Metastases in clinically detectedb ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases. OR Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement. N3aMetastases in ipsilateral infraclavicular lymph node(s). N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s). N3cMetastases in ipsilateral supraclavicular lymph node(s). Table 4. Pathologic (pN)a,b AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse transcriptase/polymerase chain reaction. aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76. bClassification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN). c"Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination. d"Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination. pNXRegional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study). pN0No regional lymph node metastasis identified histologically. Note: ITCs are defined as small clusters of cells ≤0.2 mm, or single tumor cells, or a cluster of <200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by IHC methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated. pN0(i–)No regional lymph node metastases histologically, negative IHC. pN0(i+)Malignant cells in regional lymph node(s) ≤0.2 mm (detected by H&E or IHC including ITC). pN0(mol–)No regional lymph node metastases histologically, negative molecular findings (RT-PCR). pN0(mol+)Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC. pN1Micrometastases. OR Metastases in 1–3 axillary lymph nodes. AND/OR Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected.c pN1miMicrometastases (>0.2 mm and/or >200 cells but none >2.0 mm). pN1aMetastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm. pN1bMetastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c pN1cMetastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected. pN2Metastases in 4–9 axillary lymph nodes. OR Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases. pN2aMetastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2 mm). pN2bMetastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases. pN3Metastases in ≥10 axillary lymph nodes. OR Metastases in infraclavicular (level III axillary) lymph nodes. OR Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes. OR Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c OR Metastases in ipsilateral supraclavicular lymph nodes. pN3aMetastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm). OR Metastases to the infraclavicular (level III axillary lymph) nodes. pN3bMetastases in clinically detectedd ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes. OR Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c pN3cMetastases in ipsilateral supraclavicular lymph nodes. Posttreatment ypN –Posttreatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above. The modifier "SN" is used only if a sentinel node evaluation was performed after treatment. If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND. –The X classification will be used (ypNX) if no yp posttreatment SN or AND was performed. –N categories are the same as those used for pN. Table 5. Distant Metastases (M)a aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76. M0No clinical or radiographic evidence of distant metastases. cM0(i+)No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of metastases. M1Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm. Table 6. Anatomic Stage/Prognostic Groupsa,b Stage T N MIllustration aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76. bT1 includes T1mi. cT0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB. –M0 includes M0(i+). –The designation pM0 is not valid; any M0 should be clinical. –If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy. –Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy. –Postneoadjuvant therapy is designated with "yc" or "yp" prefix. No stage group is assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, for example, ypT0ypN0cM0. 0 Tis N0 M0 IA T1b N0 M0 IB T0 N1mi M0 T1b N1mi M0 IIA T0 N1c M0 T1b N1c M0 T2 N0 M0 IIB T2 N1 M0 T3 N0 M0 IIIA T0 N2 M0 T1b N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0 IIIB T4 N0 M0 T4 N1 M0 T4 N2 M0 IIIC Any T N3 M0 IV Any T Any N M1 References:
- Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
- Singletary SE, Allred C, Ashley P, et al.: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20 (17): 3628-36, 2002.
- Woodward WA, Strom EA, Tucker SL, et al.: Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol 21 (17): 3244-8, 2003.
Ductal Carcinoma In Situ
Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to become invasive cancer, but estimates of the likelihood of this vary widely. Some people include DCIS in breast cancer statistics. The frequency of the diagnosis of DCIS has increased markedly in the United States since the widespread use of screening mammography. In 1998, DCIS accounted for about 18% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.
Very few cases of DCIS present as a palpable mass; 80% are diagnosed by mammography alone. DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into several subtypes based primarily on architectural pattern: micropapillary, papillary, solid, cribriform, and comedo. Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.
Treatment Option Overview
Until recently, the customary treatment of DCIS was mastectomy. The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy following wide excision alone, and a 25% to 50% incidence of breast recurrence following limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma. The combined local and distant recurrence rate following mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation are available.
In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy.
Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[Level of evidence: 1iiDii] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.
Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates.[Level of evidence: 1iiDii] In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy. In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.
The results of these two trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41–0.58; P < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; P = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; P = .03).[Level of evidence: 1iiD]
Given that lumpectomy and radiation therapy are generally applicable for most patients with DCIS, can a subset of patients be identified with such a low risk of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.
The Van Nuys Prognostic Index, which combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification), was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy. Using this prognostic index, patients with favorable lesions, who received surgical excision alone, had a low recurrence rate (i.e., 2% with a median follow-up of 79 months). A subsequent analysis of these data was performed to determine the influence of margin width on local control. Patients whose excised lesions had margin widths 10 mm or larger in every direction had an extremely low probability of local recurrence with surgery alone (4% with a mean follow-up of 8 years). These reviews are retrospective, noncontrolled, and are subject to substantial selection bias. By contrast, no subset of patients was identified in the prospective NSABP trial that did not benefit from the addition of radiation therapy to lumpectomy in the management of DCIS.
To determine if tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24) of 1,804 women. Patients were randomly assigned to lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation therapy, and tamoxifen (20 mg/day for 5 years). Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured not larger than 1 cm, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on a placebo (8.2% vs. 13.4%; P = .009).[Level of evidence: 1iDii] With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03). Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01). The benefit of tamoxifen extended to those patients with positive or uncertain margins. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
Treatment Options for Patients With DCIS
- Breast-conserving surgery and radiation therapy with or without tamoxifen.
- Total mastectomy with or without tamoxifen.
- Breast-conserving surgery without radiation therapy. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed due to poor accrual, and results are pending.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with ductal breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References:
- Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997.
- Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999.
- Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982.
- Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998.
- Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001.
- Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000.
- Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006.
- Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001.
- Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev 11: CD000563, 2013.
- Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995.
- Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75 (6): 1223-1227, 1995.
- Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994.
- Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996.
- Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999.
- Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast--a systematic review of the randomised trials. Breast 18 (3): 143-9, 2009.
- Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999.
- Houghton J, George WD, Cuzick J, et al.: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362 (9378): 95-102, 2003.
Early/Localized/Operable Breast Cancer
Treatment Option Overview for Early/Localized/Operable Breast Cancer
Standard treatment options for early, localized, or operable breast cancer may include the following:
- Breast-conserving surgery (lumpectomy) and sentinel node biopsy with or without axillary lymph node dissection for positive sentinel lymph nodes (SLNs).
- Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.
- Axillary node–negative breast cancer (postmastectomy):No additional therapy.Radiation therapy.
- Axillary node–positive breast cancer (postmastectomy):For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.For four or more nodes or extranodal involvement, regional radiation therapy is advised.
- Axillary node–negative or positive breast cancer (post–breast-conserving therapy):Whole-breast radiation therapy.
- Therapy depends on many factors including stage, grade, molecular status of the tumor (e.g., estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2/neu], or triple-negative [ER-negative, PR-negative, and HER2/neu-negative] status). Adjuvant treatment options may include the following:Tamoxifen.Aromatase inhibitor (AI) therapy.Ovarian function suppression. Chemotherapy.
- HER2 targeted therapy.
- Endocrine therapy.
Stage I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:
- Biopsy. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy.
- Surgical procedure. After the presence of a malignancy is
confirmed by biopsy, the following surgical treatment options can be discussed
with the patient before a therapeutic procedure is selected:
- Breast-conserving surgery.
- Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction.
To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.
Selection of a local therapeutic approach depends on the following:
- Location and size of the lesion.
- Analysis of the mammogram.
- Breast size.
- Patient's desire to preserve the breast.
Options for surgical management of the primary tumor include the following:
- Breast-conserving surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy. However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.
- Mastectomy with or without breast reconstruction.
Surgical staging of the axilla should also be performed.
Survival is equivalent with any of these options, as documented in the European Organization for Research and Treatment of Cancer's trial (EORTC-10801) and other prospective randomized trials. Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER-positive or PR-positive; ER-negative and PR-negative but HER2/neu-positive; and triple-negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.
The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated. However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:
- Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.
- More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.
- There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.
Axillary lymph node management
Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%. Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[Level of evidence: 3iiiA]
The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients. These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.
On the basis of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.
Evidence (SLN biopsy):
- A randomized trial of 1,031 women compared SLN biopsy followed by ALND when the SLN was positive with ALND in all patients.[Level of evidence 1iiC]Quality of life at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% vs. 35% deteriorating in the SLN biopsy vs. ALND groups, respectively; P = .001). Arm function was also better in the SLN group.
- The National Surgical Adjuvant Breast and Bowel Project's NSABP-B-32 (NCT00003830) multicenter phase III trial randomly assigned women (N = 5,611) to either SLN plus ALND or SLN resection alone, with ALND only if the SLNs were positive.[Level of evidence: 1iiA]The study showed no detectable difference in overall survival (OS), disease-free survival (DFS), and regional control. OS was 91.8% for SLN plus ALND versus 90.3% for SLN resection alone (P = .12).
On the basis of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.
Evidence (ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer):
- A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1 or T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND or no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast radiation therapy, and appropriate systemic therapy; OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms.[Level of evidence: 1iiA] At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone.The secondary endpoint of 5-year DFS was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.
- In a similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to ALND or no ALND.[Level of evidence: 1iiA]Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11).No difference in OS was observed.
- The AMAROS (NCT00014612) trial studied ALND and axillary radiation therapy after identification of a positive sentinel node.[Level of evidence: 1iiA]ALND and axillary radiation therapy provided excellent and comparable axillary control for patients with T1 or T2 primary breast cancer and no palpable lymphadenopathy who underwent breast-conserving therapy or mastectomy.The use of axillary radiation therapy was also associated with significantly less morbidity.
For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.
For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction). Breast contour can be restored by the following:
- Submuscular insertion of an artificial implant (silicone- or saline-filled). If an immediate implant cannot technically be performed, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's [FDA's] Web site for more information on breast implants.)
- Rectus muscle or other flap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.
After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.
Postoperative Radiation Therapy
Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.
For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women. Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death. Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.
Evidence (breast-conserving surgery followed by radiation therapy):
- A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.[Level of evidence: 1iiA] Whole-breast radiation therapy resulted in a significant reduction in the 10-year risk of recurrence compared with breast-conserving surgery alone (19% for whole-breast radiation therapy vs. 35% for breast-conserving surgery alone; relative risk (RR), 0.52; 95% CI, 0.48–0.56) and a significant reduction in the 15-year risk of breast cancer death (21% for whole-breast radiation therapy vs. 25% for breast-conserving surgery alone; RR, 0.82; 95% CI, 0.75–0.90).
With regard to radiation dosing and schedule, the following has been noted:
- Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.
- Radiation boost. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001).[Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.[Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.
Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.
- A noninferiority trial of 1,234 randomly assigned patients with node-negative invasive breast cancer analyzed local-regional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule. The 10-year local-regional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% for a shorter fractionation schedule vs. 6.7% for whole-breast radiation therapy with absolute difference, 0.5 percentage points; 95% CI, −2.5 to 3.5).[Level of evidence: 1iiDii
- Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early-stage breast cancer after breast-conserving surgery to conventional whole-breast radiation therapy dosing or shorter fractionation, revealed no difference in a 10-year local-regional relapse rate.[Level of evidence: 1iiDii]
Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.
Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for local-regional failure after mastectomy. Patients at highest risk for local recurrence have one or more of the following:
- Four or more positive axillary nodes.
- Grossly evident extracapsular nodal extension.
- Large primary tumors.
- Very close or positive deep margins of resection of the primary tumor.
In this high-risk group, radiation therapy can decrease local-regional recurrence, even among those patients who receive adjuvant chemotherapy.
Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.
Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):
- The 2005 EBCTCG meta-analysis of 42,000 women in 78 randomized treatment comparisons indicated that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[Level of evidence: 1iiA]For women with node-positive disease postmastectomy and axillary clearance (removal of axillary lymph nodes and surrounding fat), radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain, 17%; 95% CI, 15.2%–18.8%). This translated into a significant reduction (P = .002) in breast cancer mortality, 54.7% versus 60.1%, with an absolute gain of 5.4% (95% CI, 2.9%–7.9%).In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence (2P < .00001), overall recurrence (RR, 0.68; 95% CI, 0.57–0.82; 2P = .00006), and breast cancer mortality (RR, 0.80; 95% CI, 0.67–0.95; 2P = .01).[Level of evidence: 1iiA]In contrast, for women at low-risk of local recurrence with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality (absolute gain, 1.0%; P > .1; 95% CI, -0.8%–2.8%).
Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated local-regional recurrence was low enough (7.1%) that routine local-regional radiation therapy was not warranted.
Timing of postoperative radiation therapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.
Evidence (timing of postoperative radiation therapy):
- In a randomized trial, patients received one of the following regimens:[Level of evidence: 1iiA]Chemotherapy first (n = 122), consisting of cyclophosphamide, methotrexate, fluorouracil (5-FU), and prednisone (CMFP) plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation.Breast radiation first (n = 122), followed by the same chemotherapy.The following results were observed:With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).The 5-year crude rate of first recurrence by site was 5% in the radiation-first group and 14% in the chemotherapy-first group for local recurrence and 32% in the radiation-first group and 20% in the chemotherapy-first group for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07).Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those who had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses was low.Potential explanations for the increase in distant recurrence noted in the radiation-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages because of increased myelosuppression.
- Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information. In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of CMF (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of doxorubicin and cyclophosphamide (AC) (n = 199) followed by radiation therapy.[Level of evidence: 1iiA]No differences in DFS, distant DFS, and OS were observed between these two arms.The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy and reported results similar to NSABP-B-15.
These studies showed that delaying radiation therapy for 2 to 7 months after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.[Level of evidence: 1iiA]
In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu-positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab. Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.
Late toxic effects of radiation
Late toxic effects of radiation therapy are uncommon, and can be minimized with current radiation delivery techniques and with careful delineation of the target volume. Late effects of radiation include the following:
- Radiation pneumonitis. In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months. The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[Level of evidence: 3iii]
Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer. This was probably caused by the radiation received by the left myocardium.
Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.
An analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[Level of evidence: 3iB]
- Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy. (Refer to the PDQ summary on Lymphedema for more information.)
- Brachial plexopathy. Radiation injury to the brachial plexus after adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were monitored for 5.5 years to assess the rate of brachial plexus injury. The diagnosis of such injury was made clinically with computerized tomography (CT) to distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0%, compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.
- Contralateral breast cancer. One report suggested an increase in contralateral breast cancer for women younger than 45 years who received chest wall radiation therapy after mastectomy. No increased risk of contralateral breast cancer occurred in women aged 45 years and older who received radiation therapy. Techniques to minimize the radiation dose to the contralateral breast are used to keep the absolute risk as low as possible.
- Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with a long-term risk of 0.2% at 10 years. In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.
Postoperative Systemic Therapy
Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.
An international consensus panel proposed a risk classification system and systemic therapy treatment options. This classification, with some modification, is described below:Table 7. Systemic Treatment for Early Breast Cancer by SubtypeaSubtype Treatment Options Comments CT = computed tomography; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; LN = lymph node; PR = progesterone receptor.aModified from Senkus et al.Luminal A–like– Hormone receptor–positiveEndocrine therapy alone in most casesConsider chemotherapy if:– HER2-negative– High tumor burden (≥4 LNs, T3 or higher)– PR >20%– Ki67 low– Grade 3Luminal B–like– Hormone receptor–positiveEndocrine therapy plus chemotherapy in most cases– HER2-negative– Either Ki67 high or PR lowHER2-positive Chemotherapy plus anti-HER2 therapyUse endocrine therapy, if also hormone receptor–positiveMay consider omitting chemotherapy plus anti-HER2, for small node-negative tumorsTriple-negativeChemotherapyMay consider omitting CT, for small node-negative tumors
The selection of therapy is most appropriately based upon knowledge of an individual's risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their particular situation. The treatment options described below should be modified based upon both patient and tumor characteristics.Table 8. Adjuvant Systemic Treatment Options for Women With Stages I, II, IIIA, and Operable IIIC Breast CancerPatient Group Treatment OptionsER = estrogen receptor; PR = progesterone receptor.Premenopausal, hormone receptor–positive (ER or PR)No additional therapyTamoxifenTamoxifen plus chemotherapyOvarian function suppression plus tamoxifen Ovarian function suppression plus aromatase inhibitorPremenopausal, hormone receptor–negative (ER or PR)No additional therapyChemotherapyPostmenopausal, hormone receptor–positive (ER or PR)No additional therapyUpfront aromatase inhibitor therapy or tamoxifen followed by aromatase inhibitor with or without chemotherapyPostmenopausal, hormone receptor–negative (ER or PR)No additional therapyChemotherapy
Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus CMF
The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate and fluorouracil). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women.
Evidence (anthracycline-based regimens):
- The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of fluorouracil, epirubicin, and cyclophosphamide [FEC] or fluorouracil, doxorubicin, and cyclophosphamide [FAC]) with CMF (either oral or intravenous [IV]) in approximately 14,000 women, 64% of whom were younger than 50 years. Compared with CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[Level of evidence: 1iiA]Of note, few women older than 70 years were studied, and specific conclusions could not be reached for this age group.Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to hormone-receptor status, and the trials were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy. As a result, the data may not reflect treatment outcomes based on evolving treatment patterns.
Study results suggest that particular tumor characteristics (i.e., node-positive breast cancer with HER2/neu overexpression) may predict anthracycline-responsiveness.
Evidence (anthracycline-based regimen in women with HER2/neu amplification):
- Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF), or the addition of doxorubicin to the adjuvant regimen, is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA]
- A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF).[Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods. The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in relapse-free survival (RFS) and OS.In patients with HER2/neu amplification, the RFS and OS were increased by CEF.In the absence of HER2/neu amplification, CEF and CMF were similar with regard to RFS (HR for relapse, 0.91; 95% CI, 0.71–1.18; P = .049) and OS (HR for death, 1.06; 95% CI, 0.83–1.44; P = .68).
- Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with nonanthracycline-containing regimens.
Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy
A number of trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.
Evidence (adding a taxane to an anthracycline-based regimen):
- A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001).[Level of evidence: 1iiA] Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens.There were no differences in benefit observed in patient subsets defined by nodal status, hormone-receptor status, or age/menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies that were reviewed involved a direct comparison between paclitaxel and docetaxel.
- A U.S. intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC (doxorubicin and cyclophosphamide) chemotherapy, patients were randomly assigned for a second time to paclitaxel (175 mg/m2) every 3 weeks for four cycles or no further therapy, and women with hormone receptor–positive tumors also received tamoxifen for 5 years.[Level of evidence: 1iiA]Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).
- The NSABP-B-28 trial randomly assigned 3,060 women with node-positive breast cancer to four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. Women younger than 50 years with receptor-positive disease and all women older than 50 years received tamoxifen.[Level of evidence: 1iiA] DFS was significantly improved by the addition of paclitaxel (HR, 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS, 76% vs. 72%).The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).
- In the Breast Cancer International Research Group's trial (BCIRG-001), the FAC regimen was compared with the docetaxel plus doxorubicin and cyclophosphamide (TAC) regimen in 1,491 women with node-positive disease. Six cycles of either regimen were given as adjuvant postoperative therapy.[Level of evidence: 1iiA] There was a 75% DFS rate at 5 years in the TAC group, compared with a 68% DFS rate in the FAC group (P = .001).TAC was associated with a 30% overall lower risk of death (5% absolute difference) than was FAC (HR, 0.70; 98% CI, 0.53–0.91; P < .008).Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group. (Refer to the PDQ summary on Fatigue for information on anemia.)
An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.[Level of evidence: 1iiA] Study findings include the following:
- There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).
- There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).
- Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).
- Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.
Chemotherapy schedule: Dose-density
Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.
Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):
- A U.S. intergroup trial (CLB-9741) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[Level of evidence: 1iiA] At a median follow-up of 68 months, dose-dense treatment improved DFS, the primary end point, in all patient populations (HR, 0.80; P =.018), but not OS (HR, 0.85; P =.12).[Level of evidence: 1iiA]There was no interaction between density and sequence.Severe neutropenia was less frequent in patients who received the dose-dense regimens.[Level of evidence: 1iiA]
- A meta-analysis of dose-dense versus standard dosing included data from ten trials and over 11,000 women. In three trials that evaluated similar dosing in the treatment arms, dose-dense treatment was associated with an improvement in DFS (HR, 0.83; 95% CI, 0.73–0.94) and OS (HR, 0.84; 95% CI, 0.72–0.98).In seven trials in which modified doses or regimens were evaluated, improvement in DFS (HR, 0.81; 95% CI, 0.73–0.88) and OS (HR, 0.85; 95% CI, 0.75–0.96) was also seen. The benefit in DFS was seen in women with hormone receptor–negative disease (HR, 0.71; 95% CI, 0.56–0.98), but not in women with hormone receptor–positive disease (HR, 0.92; 95% CI, 0.75–1.12).
Docetaxel and cyclophosphamide
Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.
Evidence (docetaxel and cyclophosphamide):
- The regimen of docetaxel and cyclophosphamide (TC) compared with AC (doxorubicin and cyclophosphamide) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy.[Level of evidence: 1iiA] At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS. DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033). OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032).Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia.
Timing of postoperative chemotherapy
The optimal time to initiate adjuvant therapy is uncertain. A retrospective, observational study has reported the following:
- A single-institution study of early-stage breast cancer patients diagnosed between 1997 and 2011 revealed that delays in initiation of adjuvant chemotherapy adversely affected survival outcomes.[Level of evidence: 3iiiA] Initiation of chemotherapy 61 days or more after surgery was associated with adverse outcomes among patients with stage II breast cancer (distant relapse-free survival [DRFS]: HR, 1.20; 95% CI, 1.02–1.43) and stage III breast cancer (OS: HR, 1.76; 95% CI, 1.26–2.46; RFS: HR, 1.34; 95% CI, 1.01–1.76; and DRFS: HR, 1.36; 95% CI, 1.02–1.80).Patients with triple-negative breast cancer (TNBC) tumors and those with HER2-positive tumors treated with trastuzumab who started chemotherapy 61 days or more after surgery had worse survival (TNBC: HR, 1.54; 95% CI, 1.09–2.18; HER2-positive: HR, 3.09; 95% CI, 1.49–6.39) than did those who initiated treatment in the first 30 days after surgery.Because of the weaknesses and limitations of this study design, the optimal time to initiate adjuvant chemotherapy remains uncertain.
Toxic effects of chemotherapy
Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen. Common toxic effects include the following:
- Nausea and vomiting.
Less common, but serious, toxic effects include the following:
- Heart failure (if an anthracycline is used).
- Thromboembolic events.
- Premature menopause.
- Second malignancy (leukemia).
Refer to the PDQ summary on Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.
The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years. This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).
Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens. However, data on this topic from prospective, randomized studies are lacking.
The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer. This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy.
HER2/neu-negative breast cancer
For HER2/neu-negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.
Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.
Triple-negative breast cancer (TNBC)
TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.
Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.
Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):
- A prospective analysis studied 1,118 patients who received neoadjuvant chemotherapy at a single institution, of whom 255 (23%) had TNBC.[Level of evidence: 3iiDiv] The study observed that patients with TNBC had higher pathologic complete response (pCR) rates than did non-TNBC patients (22% vs. 11%; P = .034). Improved pCR rates may be important because in some studies, pCR is associated with improved long-term outcomes.
Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[Level of evidence: 3iiiDiv] A randomized clinical trial, CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The Triple Negative Trial (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.
Poly (ADP-ribose) polymerase (PARP) inhibitor agents
The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.
HER2/neu-positive breast cancer
Treatment options for HER2-positive early breast cancer:
Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.
Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.
Evidence (duration of trastuzumab therapy):
- The HERA (BIG-01-01 [NCT00045032]) trial examined whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus local-regional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms: Observation (n = 1,693).1 year of trastuzumab (n = 1,694).2 years of trastuzumab (n = 1,694).Of the patients in the comparison of 1 year of trastuzumab versus observation group, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)–negative disease.[Level of evidence: 1iiA]One year of trastuzumab versus observation:Patients who were treated with 1 year of trastuzumab experienced a 46% lower risk of a first event (HR, 0.54; 95% CI, 0.43–0.67; P < .001), corresponding to an absolute DFS benefit of 8.4% at 2 years (95% CI, 2.1–14.8). The updated results at 23.5 months of follow-up showed an unadjusted HR for the risk of death with trastuzumab compared with observation of 0.66 (95% CI, 0.47–0.91; P = .0115), corresponding to an absolute OS benefit of 2.7%.There were 218 DFS events reported in the trastuzumab group, compared with 321 DFS events reported in the observation group. The unadjusted HR for the risk of an event with trastuzumab was 0.64 (0.54–0.76; P < .001), corresponding to an absolute DFS benefit of 6.3%.The benefit of 1 year of trastuzumab over observation persisted, despite crossover of 52% of the patients on observation (HR, 0.76; 95% CI, 0.65–0.88; P = .0005).One year versus 2 years of trastuzumab:After a median follow-up of 8 years, the results of the comparison of 1 year versus 2 years of trastuzumab were analyzed. No difference in DFS was found between the groups (HR, 0.99; 95% CI, 0.85–1.14; P = .86).
- In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[Level of evidence: 1iiA] The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients. A highly statistically significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%) was observed, as was a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% in the trastuzumab group vs. 91.7% in the control group; 4-year OS, 91.4% in the trastuzumab group vs. 86.6% in the control group).Patients treated with trastuzumab experienced a longer DFS, with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence in patients treated with trastuzumab was 53% lower (HR, 0.47; 95% CI, 0.37–0.61; P < .001), and the risk of death was 33% lower (HR, 0.67; 95% CI, 0.48–0.93; P = .015).
- In the BCIRG-006 (NCT00021255) trial, 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a nonanthracycline-containing regimen).[Level of Evidence: 1iiA] A significant DFS and OS benefit was seen in both groups treated with trastuzumab compared with the control group that did not receive trastuzumab. For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04). The control group had a 5-year DFS rate of 75% and an OS rate of 87%.The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens.The rates of congestive heart failure (CHF) and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P < .001).These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH.This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.
- The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[Level of evidence: 1iiA]At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR, 0.41; P = .01; 95% CI, 0.21–0.83; 3-year DFS, 89% vs. 78%).The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).
- In contrast, another study failed to demonstrate that 6 months of adjuvant trastuzumab was noninferior to 12 months of treatment.[Level of evidence: 1iiA]A 2-year DFS rate was 93.8% (95% CI, 92.6–94.9) in the 12-month group and 91.1% (89.7–92.4) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29). Therefore, 12 months should remain the standard duration of trastuzumab adjuvant therapy.
A number of studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.
Cardiac toxic effects with adjuvant trastuzumab
Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:
- In the HERA (BIG-01-01) trial, severe CHF (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab. Symptomatic CHF occurred in 1.7% of patients in the trastuzumab arm and 0.06% of patients in the observation arm.
- In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm. The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%).
- In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events was 0.35% in arm A (no trastuzumab), 3.5% in arm B (trastuzumab after paclitaxel), and 2.5% in arm C, (trastuzumab concomitant with paclitaxel).
- In the AVENTIS-TAX-GMA-302 (BCIRG 006) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC/docetaxel (AC-D) arm, 1.87% of patients in the AC/docetaxel/trastuzumab (AC-DH) arm, and 0.37% of patients in the docetaxel/carboplatin/trastuzumab (DCbH) arm. There was also a statistically significant higher incidence of asymptomatic and persistent decrease in left ventricular ejection fraction (LVEF) in the AC-DH arm than with either the AC-D or DCbH arms.
- In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.
Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu-positive breast cancer.
Evidence (against the use of lapatinib for HER2 positive early breast cancer):
- In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison with, or as an alternative to trastuzumab) in the adjuvant setting was investigated.Results presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting revealed that in a comparison of concurrently administered lapatinib and trastuzumab versus trastuzumab alone, the HR for DFS reached 0.84 (97.5% CI, 0.70–1.02) with a p-value of .048, which failed to meet the p ≤ .025 threshold for establishing statistical superiority.Similarly, sequential use of trastuzumab and lapatinib did not meet the noninferiority criteria compared with trastuzumab alone on the basis of an HR for DFS of 0.96 (97.5% CI, 0.80–1.15); p-value of .610, with a p-value of .025 required for significance.Combination therapy with lapatinib and trastuzumab also resulted in worsened diarrhea (75% vs. 20%), rash (55% vs. 20%), and hepatobiliary adverse events (23% vs. 16%) compared with trastuzumab alone.Publication in a peer-reviewed journal is awaited.
Hormone receptor–positive therapy
Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an ASCO guideline that describes several options for the management of these patients.
Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.
Evidence (tamoxifen for hormone receptor–positive early breast cancer):
- The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. An analysis published in 2005 included information on 80,273 women in 71 trials of adjuvant tamoxifen.[Level of evidence: 1iiA]In this analysis, the benefit of tamoxifen was found to be restricted to women with hormone receptor–positive or hormone receptor–unknown breast tumors. In these women, the 15-year absolute reduction associated with 5 years of use was 12% for recurrence and 9% for mortality.Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, ≥70 years), PR status, or other tumor characteristics.The meta-analysis also confirmed the benefit of adjuvant tamoxifen in hormone receptor–positive premenopausal women. Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the node-positive breast cancer group (5.3% vs. 12.5% with 5 years of use).
- Similar results were found in the IBCSG-13-93 trial. Of 1,246 women with stage II disease, only the women with hormone receptor–positive disease benefited from tamoxifen.
The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials. Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.
Evidence (duration of tamoxifen therapy):
- The EBCTCG meta-analysis demonstrated that 5 years of tamoxifen was superior to shorter durations. The following results were reported:A highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction, 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction, 7.9%; P = .01) was observed.
- Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial demonstrated that 10 years of tamoxifen therapy was superior to 5 years of tamoxifen therapy. Between 1996 and 2005, 12,894 women with early breast cancer were randomly assigned to 10 years or 5 years of tamoxifen therapy. The following results were reported:[Level of Evidence: 1iiA]Study results revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences for 10 years of tamoxifen vs. 711 recurrences for 5 years of tamoxifen; P = .002), reduced breast-cancer mortality (331 deaths for 10 years of tamoxifen vs. 397 deaths for 5 years of tamoxifen; P = .01), and reduced overall mortality (639 deaths for 10 years of tamoxifen vs. 722 deaths for 5 years of tamoxifen; P = .01).Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% at 10 years and 12.2% at 5 years. Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following: Pulmonary embolus RR, 1.87 (95% CI, 1.13–3.07; P = .01). Stroke RR, 1.06 (0.83–1.36). Ischemic heart disease RR, 0.76 (0.6–0.95; P = .02). Endometrial cancer RR, 1.74 (1.30–2.34; P = .0002). Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.The results of the ATLAS trial indicated that for women who remained premenopausal after 5 years of adjuvant tamoxifen, continued tamoxifen for 5 more years was beneficial. Women who have become menopausal after 5 years of tamoxifen may also be treated with AI. (Refer to the Aromatase inhibitors section in the Hormone–receptor positive therapy section of this summary for more information.)
Tamoxifen and chemotherapy
Based on the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy. However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.
Ovarian ablation, tamoxifen, and chemotherapy
Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies. Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.
Evidence (tamoxifen plus ovarian suppression):
- The largest study (SOFT [NCT00066690]) to examine the addition of ovarian ablation to tamoxifen with or without chemotherapy randomly assigned 2,033 premenopausal women (53% of whom had received previous chemotherapy) to tamoxifen or tamoxifen plus ovarian suppression with triptorelin or ablation with surgery or radiation therapy.[Level of evidence: 1iiDii]Overall, there was no significant difference in the primary outcome, DFS, (HR 0.83; 95% CI, 0.66–1.04; P = .10); 5-year DFS was 86% in the tamoxifen plus ovarian suppression group versus 84.7% in the tamoxifen alone group.The authors also reported results from two secondary analyses. In a multivariable Cox proportional hazards model, the tamoxifen plus ovarian suppression arm was statistically superior to the tamoxifen alone arm with respect to DFS (HR 0.78; 95% CI, 0.62–0.98; P = .03), but the variables included in this analysis were not stated to be prespecified. In a subgroup analysis addressing a secondary endpoint (OS), patients who had previously received chemotherapy were found to have a significantly better outcome if they received tamoxifen plus ovarian ablation (interaction P = .03). The P values in these two secondary analyses were not corrected for multiple comparisons.
Aromatase inhibitors (AI)
In postmenopausal women, the use of AI in sequence with or as a substitute for tamoxifen has been shown to improve DFS, but not OS. These drugs have been studied in several settings.
Evidence (AI as initial therapy in postmenopausal women):
- A large, randomized trial of 9,366 patients compared the use of the AI anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative or node-positive disease. Most (84%) of the patients in the study were hormone–receptor positive. Slightly more than 20% had received chemotherapy.; [Level of evidence: 1iDii]With a median follow-up of 33.3 months, no benefit in DFS was observed for the combination arm relative to tamoxifen alone.Patients on anastrozole, however, had a significantly longer DFS (HR, 0.83) than those on tamoxifen. In an analysis conducted after a median follow-up of 100 months among hormone receptor–positive patients, DFS was significantly (P = .003) longer in patients on anastrozole (HR, 0.85; 95% CI, 0.76–0.94), but OS was not improved (HR, 0.97; 95% CI, 0.86–1.11; P = .7).Patients on tamoxifen more frequently developed endometrial cancer and cerebrovascular accidents, whereas patients on anastrozole had more fracture episodes. The frequency of myocardial infarction was similar in both groups. Except for a continued increased frequency of endometrial cancer in the tamoxifen group, these differences did not persist in the posttreatment period.
- A large double-blinded randomized trial of 8,010 postmenopausal women with hormone receptor–positive breast cancer compared the use of letrozole with tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years. An updated analysis from the Breast International Group (IBCSG-1-98) reported results on the 4,922 women who received tamoxifen or letrozole for 5 years at a median follow-up of 51 months.[Level of evidence: 1iDii]DFS was significantly superior in patients treated with letrozole (HR, 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS, 84.0% vs. 81.1%).OS was not significantly different in patients treated with letrozole (HR, 0.91; 95% CI, 0.75–1.11; P = .35). In an updated analysis with 8.7 years of median follow-up, the following results were reported:[Level of evidence: 1iiA] DFS remained significantly superior in patients treated with letrozole (HR, 0.86; 95% CI, 0.78–0.96; P = .007) and there was a marginally significant difference in OS (HR, 0.87; 95% CI, 0.77–0.999; P = .048).The authors point out that the results of long-term follow-up are confounded because patients on tamoxifen were permitted to take letrozole when the trial was unblinded and, thus, the benefit of letrozole may be underestimated in the intent-to-treat analysis described above.
- The mild androgen activity of exemestane prompted a randomized trial to evaluate whether exemestane might be preferable to anastrozole, in terms of its efficacy (event-free survival [EFS]) and toxicity, as upfront therapy for postmenopausal women diagnosed with hormone receptor–positive breast cancer.[Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole or exemestane.At a median follow-up of 4.1 years, no difference in efficacy was seen (HR, 1.02; 95% CI, 0.87–1.18, P = .86).[Level of evidence: 1iiD]There was also no significant difference in the impact of the two therapies on bone mineral density or fracture rates.[Level of evidence: 1iiD]
AI versus tamoxifen therapy
AI have also been compared with tamoxifen in premenopausal women whose ovarian function was suppressed or ablated. The results of these studies have been conflicting.
Evidence (comparing an AI with tamoxifen in premenopausal women):
- In one study, 1,803 women receiving goserelin were randomly assigned to a 2 × 2 factorial design trial comparing anastrozole and tamoxifen, with or without zoledronic acid.At a median follow-up of 62 months, there was no difference in DFS (HR, 1.08; 95% CI, 0.81–1.44; P = .59).OS was superior with tamoxifen (HR, 1.75; 95% CI 1.08–2.83; P = .02).
- Exemestane has also been compared with tamoxifen in premenopausal women who underwent ovarian ablation in an unblinded study that enrolled 4,690 women.[Level of evidence: 1iDii]The use of exemestane resulted in a significant difference in DFS (HR, 0.72; 95% CI, 0.60–0.85; P < .001; 5-year DFS, 91.1% in the exemestane-ovarian suppression group vs. 87.3% in the tamoxifen-ovarian suppression group).No difference in OS (HR, 1.14 for death in the exemestane-ovarian suppression group; 95% CI, 0.86–1.51; P = .37; 5-year OS, 95.9% in the exemestane/ovarian suppression group vs. 96.9% in the tamoxifen-ovarian suppression group) was reported.[Level of evidence: 1iiA]
Sequential tamoxifen and AI versus 5 years of tamoxifen
Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen. The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.
Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):
- One study, which included 448 patients, demonstrated a statistically significant reduction in DFS (HR, 0.35; 95% CI, 0.18–0.68; P = .001) but no difference in OS in the anastrozole group.[Level of evidence: 1iiA]
- Two other trials were reported together. A total of 3,224 patients were randomly assigned after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed in the anastrozole group.
- A meta-analysis of these three studies showed the following:Patients who switched to anastrozole had significant improvements in DFS (HR, 0.59; 95% CI, 0.48–0.74; P < .001), EFS (HR, 0.55; 95% CI, 0.42–0.71; P < .001), distant DFS (HR, 0.61; 95% CI, 0.45–0.83; P = .002), and OS (HR, 0.71; 95% CI, 0.52–0.98; P = .04) compared with the patients who remained on tamoxifen.
- A large, double-blinded, randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[Level of evidence: 1iDii] After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR, 0.68) favoring the exemestane arm.After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[Level of evidence: 1iA]At 2.5 years after random assignment, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).
- A meta-analysis that included the previous trial along with three other studies found the following:[Level of evidence: 1iA]Switching to an AI resulted in a significant improvement in DFS (HR, 0.71; 95% CI, 0.64–0.77; P < .001; approximately 5-year DFS, 95% vs. 91.9%) and OS (HR, 0.79; 95% CI, 0.72–0.86; P = .004; approximately 5-year OS, 96.7% vs. 95.6%).
Sequential tamoxifen and AI for 5 years versus 5 years of an AI
The evidence indicates there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.
Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):
- A large, randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years. The primary endpoints were DFS at 2.75 years and 5.0 years.[Level of evidence: 1iDii]Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR, 0.97; 95% CI, 0.88–1.08; P = .60).
- Similarly in the IBCSG 1-98 (NCT00004205) trial, two sequential arms were compared with 5 years of letrozole.[Level of evidence: 1iDii]There was no difference in DFS when the two sequential arms were compared with 5 years of letrozole (letrozole to tamoxifen HR, 1.06; 95% CI, 0.91–1.23; P = .45 and tamoxifen to letrozole HR, 1.07; 95% CI, 0.92–1.25; P = .36).
Switching to an AI after 5 years of tamoxifen
The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.
- A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years.[Level of evidence: 1iDii]After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57) favoring the letrozole arm.After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.An updated analysis including all events before unblinding confirmed the results of the interim analysis. In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no statistically significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), although the P value was not corrected for multiple comparisons.
- The NSABP B-33 (NCT00016432) trial that was designed to compare 5 years of exemestane with placebo after 5 years of tamoxifen was stopped prematurely when the results of CAN-NCIC-MA17 became available. At the time of analysis, 560 of the 783 patients who were randomly assigned to exemestane remained on that drug and 344 of the 779 patients who were randomly assigned to receive placebo had crossed over to exemestane.[Level of evidence: 1iDii]An intent-to-treat analysis of the primary study endpoint (DFS) demonstrated a nonsignificant benefit of exemestane (HR, 0.68; P = .07).
The role of bisphosphonates as part of adjuvant therapy for early-stage breast cancer is unclear.
Evidence (bisphosphonates in the treatment of early breast cancer):
- The ABCSG-12 (NCT00295646) trial was a 2 × 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with hormone receptor–positive breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second random assignment to receive zoledronic acid (4 mg IV every 6 months) or no zoledronic acid.[Level of evidence: 1iiA] The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy alone, resulted in a relative reduction of 36% in the risk of disease progression (HR, 0.64; P = .01) but did not significantly reduce the risk of death.Results were unchanged in an analysis conducted 2 years after treatment completion.
- Similar results were obtained in the NCT00171340 trial in which 1,065 postmenopausal women received letrozole and were randomly assigned to receive zoledronic acid (4 mg IV every 6 months) immediately or only after the development of bone loss or fractures.[Level of evidence: 1iiA]Immediate administration of zoledronic acid resulted in a 34% improvement in DFS (HR, 0.66; 95% CI, 0.44–0.97; P = .035) but did not affect OS.
- While bisphosphonates appear to improve DFS in a population with low-to-intermediate-risk breast cancer, this benefit does not appear to be seen in all patients with breast cancer. The AZURE trial was a randomized, phase III trial that assigned 3,660 patients with stage II or stage III breast cancer to receive chemotherapy and/or hormone therapy with or without zoledronic acid.[Level of evidence: 1iiA] At a median follow-up of 59 months, there was no significant benefit in DFS in both groups (77% in each group; HR, 0.98; P = .79).OS was also similar, at 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted HR, 0.85; P = .07).In a final analysis with a median follow-up of 84 months, the results were unchanged for DFS (adjusted HR, 0.94; 95% CI, 0.82–1.06; P = .30), OS (0.93, 0.81–1.08; P = .37), and distant DFS (0.93; 0.81–1.07; P = .29).[Level of evidence: 1iiA]
These three studies, plus several others, have been included in three meta-analyses addressing the question of whether the use of zoledronic acid in the adjuvant setting prolongs survival. The results of these meta-analyses are conflicting. One study found no significant impact on survival (relative risk [RR], .90; 95% CI, 0.61–1.33; P = .61). A second study found a significant effect on survival (HR, .81; 95% CI, .70–.94; P = .007). The third study found a borderline significant effect on survival (RR, .88; 95% CI, 0.77– 1.01; P = .06).[Level of evidence: 1iiA]
Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III breast cancer.
Preoperative Systemic Therapy
Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer in an attempt to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple randomized clinical trials has demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[Level of evidence: 1iiDiv]
A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation, and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains. Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.
Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.
Patient selection, staging, treatment, and follow-up
Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:
- Patient selection.
- Choice of systemic therapy.
- Management of the axilla and surgical approach.
- Decision to administer adjuvant radiation therapy.
The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone–receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline/taxane based) may be avoided.
Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:
- CT scan of the chest and abdomen and a bone scan.
- Positron-emission tomography.
Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes may be biopsied before initiation of systemic treatment.
The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:
- If suspicious nodes are positive for malignancy at baseline, an SLN biopsy may be performed after preoperative therapy but is associated with a high false-negative rate. If the procedure is performed with both radiocolloid and blue dye and at least two nodes are sampled (provides 10.8% false-negative rate) and are negative, then axillary lymph node dissection (ALND) may be omitted.[Level of evidence: 2Div]; [Level of evidence: 3iiD]; [Level of evidence: 3iiDiv] Alternatively, it is acceptable in this circumstance to perform ALND based on the possibility of undetected positive nodes.
- In patients with clinically negative nodes, SLN biopsy may be performed before preoperative therapy because of the false-negative rates observed when performed after preoperative therapy. If the SLN biopsy is negative, ALND can be omitted.
- If SLN biopsy is performed after preoperative chemotherapy, the baseline clinical and postchemotherapy pathological nodal status should be taken into consideration when deciding whether ALND is necessary. ALND is usually performed in the setting of node-positivity.
When considering preoperative therapy, treatment options include the following:
- For HER2-negative breast tumors, an anthracycline-taxane based chemotherapy regimen.
- For HER2-positive disease, chemotherapy and HER2-targeted therapy.
- Ideally, the entire treatment regimen is administered before surgery.
- For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.
- For premenopausal women with hormone–responsive cancer, the use of preoperative endocrine therapy is under investigation.
Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible. Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.
HER2/neu-negative breast cancer
Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.
Evidence (preoperative anthracycline-based regimen):
- A randomized clinical trial (NSABP-B-18) was designed to determine whether the preoperative combination of four cycles of AC would more effectively prolong DFS and OS than the same chemotherapy given in the adjuvant setting.[Level of evidence: 1iiA] After preoperative therapy, 36% of the patients had a complete clinical response.More patients treated with preoperative chemotherapy were able to have breast-conserving procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%; P = .001).No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.
- An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS, but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[Level of evidence: 1iiA]
In an effort to improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.
Evidence (anthracycline/taxane-based chemotherapy regimen):
- In an effort to improve on the results observed with AC alone, the NSABP B-27 trial was conducted.[Level of evidence: 1iiD] The administration of preoperative AC followed by docetaxel was associated with a higher clinical complete response rate compared with the administration of AC alone (63.6% for AC followed by docetaxel and 40.1% for AC alone; P < .001); a higher pCR rate was also observed (26.1% for AC followed by docetaxel and 13.7% for AC alone; P < .001).
- Data from NSABP B-27 and the Aberdeen Breast Group Trial support the use of anthracycline- and taxane-based regimens in women with initial response or with relative resistance to anthracyclines.
- Alternative anthracycline/taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above.[Level of evidence: 1iiDiv]
The incorporation of many additional cytotoxic agents to anthracycline- and taxane-based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[Level of evidence: 1iiDiv]
Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.
Evidence (adding carboplatin to an anthracycline-taxane based chemotherapy regimen in patients with TNBC):
- In the GeparSixto (NCT01426880) trial, carboplatin was added to an anthracycline/taxane-based backbone.[Level of evidence: 1iiDiv] Higher pCR rates were observed with the addition of carboplatin to an anthracycline/taxane-based backbone compared with anthracycline/taxane alone (36.9% vs. 53.2%; P = .005) in patients with TNBC.The more intensive regimen was also associated with increased toxicity and treatment discontinuations (39% vs. 48%).
- The CALGB 40603 (NCT00861705) trial compared an anthracycline/taxane backbone alone with an anthracycline/taxane backbone plus carboplatin in patients with stage II and stage III TNBC.[Level of evidence: 1iiDiv] The pCR rate for the breast and axilla was 54% for the anthracycline/taxane backbone plus carboplatin group versus 41% for the anthracycline/taxane backbone alone group (P = .0029)
Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).[Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.
HER2/neu-positive breast cancer
After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline- and taxane-based regimens.[Level of evidence: 1iiDiv] This has been confirmed in phase III studies.
- A phase III study (NOAH) randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to preoperative chemotherapy with or without 1 year of trastuzumab therapy.[Level of evidence:1iiA]Study results confirmed that the addition of trastuzumab to preoperative chemotherapy resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (breast and axilla, 38% vs. 19%) but also in EFS, the primary outcome.[Level of evidence:1iiA]After a median follow-up of 5.4 years, the EFS benefit was 58% with the addition of trastuzumab to chemotherapy (95% CI, 48–66) and 43% (95% CI, 34–52) in patients in the chemotherapy group. The unadjusted HR for EFS between the two randomized HER2-positive treatment groups was 0.64 (95% CI, 0.44–0.93; two-sided log-rank P = .016). EFS was strongly associated with pCR in patients who received trastuzumab. Symptomatic cardiac failure occurred in two patients who received concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of LVEF and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (Refer to the Cardiac toxic effects with adjuvant trastuzumab section in this summary for more information.)[Level of evidence: 1iiD]
- A phase III (Z1041 [NCT00513292]) trial randomly assigned patients with operable HER2-positive breast cancer to receive trastuzumab sequential to or concurrent with the anthracycline component (fluorouracil, epirubicin, cyclophosphamide) of the preoperative chemotherapy regimen.[Level of evidence: 1iiDiv] There was no significant difference in pCR rate in the breast between the arms (56.5% sequential, 54.2% concurrent; difference, 2.3% with 95% CI, -9.3–13.9).In addition, asymptomatic declines in LVEF during preoperative chemotherapy were identified in similar proportions of patients in each arm.The conclusion was that concurrent administration of trastuzumab with anthracyclines is not warranted based on these findings.
A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to preoperative chemotherapy (anthracycline/taxane-based), concurrent with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[Level of evidence: 1iiD] The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. Data regarding the DFS and OS differences between the arms are not yet available.
An ongoing trial, SafeHer (NCT01566721), is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early- and late-stage breast cancer.
Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.
Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials in an attempt to improve on the pCR rates observed with trastuzumab and chemotherapy.
- In the open-label, randomized, phase II NeoSPHERE (NCT00545688) trial, 417 women with tumors that were larger than 2 cm or node-positive, and who had HER2-positive breast cancer, were randomly assigned to one of four preoperative regimens:[Level of evidence: 1iiDiv]Docetaxel plus trastuzumab.Docetaxel plus trastuzumab and pertuzumab.Pertuzumab plus trastuzumab.Docetaxel plus pertuzumab. The following results were observed:The pCR rates were 29%, 46%, 17%, and 24%, respectively. Therefore, the highest pCR rate was seen in the preoperative treatment arm with dual HER2 blockade plus chemotherapy. The addition of pertuzumab to the docetaxel plus trastuzumab combination did not appear to increase toxic effects, including the risk of cardiac adverse events.
- The open-label, randomized, phase II TRYPHAENA (NCT00976989) trial sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab.[Level of evidence: 1iiDiv] All 225 women with tumors that were larger than 2 cm or node-positive, and who had operable, locally advanced, or inflammatory HER2-positive breast cancer, were randomly assigned to one of three preoperative regimens: Concurrent FEC plus trastuzumab plus pertuzumab (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab.FEC alone (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab (×3). Concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab (×6). The following results were observed:The pCR rate was equivalent across all three treatment arms (62%, 57%, and 66%, respectively).All three arms were associated with a low incidence of cardiac adverse events of 5% or less.
On the basis of these studies, the FDA granted accelerated approval for the use of pertuzumab as part of preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive. The FDA approved no more than three to six cycles of pertuzumab. Thus, a pertuzumab-based regimen as outlined above is a new treatment option for patients with HER2-positive breast cancer who are candidates for preoperative therapy. There is insufficient evidence to recommend concomitant anthracycline/pertuzumab or sequential use of doxorubicin with pertuzumab.
The ongoing APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, is the confirmatory trial for this accelerated approval. Results are expected in 2016.
Cardiac toxic effects with pertuzumab
A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[Level of evidence: 3iiiD]
- Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5–10.2), 3.4% of patients receiving pertuzumab in combination with a nonanthracycline-containing chemotherapy (n = 175; 95% CI, 1.3–7.3), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4–13.5).
- Symptomatic heart failure was observed in 1 (0.3%), 2 (1.1%), and 1 (1.1%) patients, respectively.
Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.
- The role of lapatinib in the preoperative setting was examined in the GeparQuinto [NCT00567554] trial. This phase III trial randomly assigned women with HER2-positive early-stage breast cancer to receive chemotherapy with trastuzumab or chemotherapy with lapatinib, with pCR as the primary endpoint.[Level of evidence: 1iiDiv] pCR in the chemotherapy and lapatinib arm was significantly lower than it was with chemotherapy and trastuzumab (22.7% vs. 30.3%; P = .04).Other endpoints of DFS, RFS, and OS have not been reported.
- Preoperative therapy with dual HER2 inhibition was studied in the NeoALTTO [NCT00553358] trial.[Level of evidence: 1iiDiv] This phase III trial randomly assigned 455 women with HER2-positive early-stage breast cancer (tumor size >2 cm) to receive preoperative lapatinib, preoperative trastuzumab, or preoperative lapatinib plus trastuzumab. This anti-HER2 therapy was given alone for 6 weeks and then weekly paclitaxel was added to the regimen for an additional 12 weeks for all enrolled patients. The primary endpoint of this study was pCR. pCR was significantly higher in the lapatinib plus trastuzumab combination arm (51.3%; 95% CI, 43.1–59.5) than in the trastuzumab alone arm (29.5%; 95% CI, 22.4–37.5).No significant difference in pCR was seen between the lapatinib (24.7%, 95% CI, 18.1–32.3) and trastuzumab groups (difference, -4.8%, -17.6–8.2; P = .34).
More definitive efficacy data were provided by the phase III ALLTO (NCT00490139) trial that randomly assigned women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting. The trial did not meet its primary endpoint of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.
Preoperative endocrine therapy
Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor–positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.[Level of Evidence: 1iDiv]
Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients. A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, P-value for trend < .04).[Level of Evidence: 1iiDiv]
The AI have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months preoperative therapy were either statistically significantly improved in the AI-treated women or comparable to tamoxifen-associated outcomes. An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.
The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.
There is currently no clear role for adjuvant chemotherapy in cases in which pCR is not obtained after receipt of an anthracycline/taxane combination chemotherapy regimen. Clinical trials of novel therapies should be considered in these individuals (after neoadjuvant or preoperative trials).
Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of local-regional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.
Other adjuvant systemic treatments may be administered either postoperatively or during/after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor–positive disease and adjuvant trastuzumab for those with HER2-positive disease.
The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.
Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations. Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected. On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:
- Physical examination.
- Annual mammography.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I breast cancer, stage II breast cancer, stage IIIA breast cancer and stage IIIC breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References:
- Fisher B, Fisher ER, Redmond C, et al.: Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer. Breast Cancer Res Treat 7 (3): 147-60, 1986.
- Thor AD, Berry DA, Budman DR, et al.: erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90 (18): 1346-60, 1998.
- Paik S, Bryant J, Park C, et al.: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90 (18): 1361-70, 1998.
- Simpson JF, Gray R, Dressler LG, et al.: Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 18 (10): 2059-69, 2000.
- Hutchins LF, Green SJ, Ravdin PM, et al.: Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23 (33): 8313-21, 2005.
- Abrams JS, Phillips PH, Friedman MA: Meeting highlights: a reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst 87 (24): 1837-45, 1995.
- Weiss MC, Fowble BL, Solin LJ, et al.: Outcome of conservative therapy for invasive breast cancer by histologic subtype. Int J Radiat Oncol Biol Phys 23 (5): 941-7, 1992.
- van Dongen JA, Voogd AC, Fentiman IS, et al.: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92 (14): 1143-50, 2000.
- Fisher B, Anderson S, Bryant J, et al.: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347 (16): 1233-41, 2002.
- Blichert-Toft M, Rose C, Andersen JA, et al.: Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr (11): 19-25, 1992.
- van Dongen JA, Bartelink H, Fentiman IS, et al.: Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr (11): 15-8, 1992.
- Sarrazin D, Lê MG, Arriagada R, et al.: Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14 (3): 177-84, 1989.
- Jacobson JA, Danforth DN, Cowan KH, et al.: Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 332 (14): 907-11, 1995.
- Veronesi U, Cascinelli N, Mariani L, et al.: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347 (16): 1227-32, 2002.
- Veronesi U, Salvadori B, Luini A, et al.: Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 31A (10): 1574-9, 1995.
- Freedman GM, Anderson PR, Li T, et al.: Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 115 (5): 946-51, 2009.
- Schmidt-Ullrich R, Wazer DE, Tercilla O, et al.: Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int J Radiat Oncol Biol Phys 17 (4): 733-8, 1989.
- Solin LJ, Fowble BL, Schultz DJ, et al.: The significance of the pathology margins of the tumor excision on the outcome of patients treated with definitive irradiation for early stage breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 279-87, 1991.
- Wazer DE, Schmidt-Ullrich RK, Schmid CH, et al.: The value of breast lumpectomy margin assessment as a predictor of residual tumor burden. Int J Radiat Oncol Biol Phys 38 (2): 291-9, 1997.
- Moran MS, Schnitt SJ, Giuliano AE, et al.: Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. J Clin Oncol 32 (14): 1507-15, 2014.
- Barth RJ Jr, Danforth DN Jr, Venzon DJ, et al.: Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival. Arch Surg 126 (5): 574-7, 1991.
- Rivadeneira DE, Simmons RM, Christos PJ, et al.: Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients. J Am Coll Surg 191 (1): 1-6; discussion 6-8, 2000.
- Greco M, Agresti R, Cascinelli N, et al.: Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis. Ann Surg 232 (1): 1-7, 2000.
- Kern KA: Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg 189 (6): 539-45, 1999.
- Rubio IT, Korourian S, Cowan C, et al.: Sentinel lymph node biopsy for staging breast cancer. Am J Surg 176 (6): 532-7, 1998.
- Veronesi U, Paganelli G, Galimberti V, et al.: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 349 (9069): 1864-7, 1997.
- Albertini JJ, Lyman GH, Cox C, et al.: Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276 (22): 1818-22, 1996.
- Krag D, Weaver D, Ashikaga T, et al.: The sentinel node in breast cancer--a multicenter validation study. N Engl J Med 339 (14): 941-6, 1998.
- Veronesi U, Paganelli G, Viale G, et al.: Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 91 (4): 368-73, 1999.
- Mansel RE, Fallowfield L, Kissin M, et al.: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial. J Natl Cancer Inst 98 (9): 599-609, 2006.
- Krag DN, Anderson SJ, Julian TB, et al.: Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 11 (10): 927-33, 2010.
- Giuliano AE, Hunt KK, Ballman KV, et al.: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305 (6): 569-75, 2011.
- Galimberti V, Cole BF, Zurrida S, et al.: Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol 14 (4): 297-305, 2013.
- Donker M, van Tienhoven G, Straver ME, et al.: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 15 (12): 1303-10, 2014.
- Cunningham BL: Breast reconstruction following mastectomy. In: Najarian JS, Delaney JP, eds.: Advances in Breast and Endocrine Surgery. Chicago, Ill: Year Book Medical Publishers, 1986, pp 213-226.
- Scanlon EF: The role of reconstruction in breast cancer. Cancer 68 (5 Suppl): 1144-7, 1991.
- Hang-Fu L, Snyderman RK: State-of-the-art breast reconstruction. Cancer 68 (5 Suppl): 1148-56, 1991.
- Feller WF, Holt R, Spear S, et al.: Modified radical mastectomy with immediate breast reconstruction. Am Surg 52 (3): 129-33, 1986.
- Kuske RR, Schuster R, Klein E, et al.: Radiotherapy and breast reconstruction: clinical results and dosimetry. Int J Radiat Oncol Biol Phys 21 (2): 339-46, 1991.
- Clarke M, Collins R, Darby S, et al.: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366 (9503): 2087-106, 2005.
- Eifel P, Axelson JA, Costa J, et al.: National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 93 (13): 979-89, 2001.
- Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011.
- Romestaing P, Lehingue Y, Carrie C, et al.: Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol 15 (3): 963-8, 1997.
- Bartelink H, Horiot JC, Poortmans P, et al.: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345 (19): 1378-87, 2001.
- Bartelink H, Maingon P, Poortmans P, et al.: Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 16 (1): 47-56, 2015.
- Wazer DE, Kramer B, Schmid C, et al.: Factors determining outcome in patients treated with interstitial implantation as a radiation boost for breast conservation therapy. Int J Radiat Oncol Biol Phys 39 (2): 381-93, 1997.
- Whelan TJ, Pignol JP, Levine MN, et al.: Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 362 (6): 513-20, 2010.
- Haviland JS, Owen JR, Dewar JA, et al.: The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 14 (11): 1086-94, 2013.
- Ragaz J, Jackson SM, Le N, et al.: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337 (14): 956-62, 1997.
- Overgaard M, Hansen PS, Overgaard J, et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337 (14): 949-55, 1997.
- Fowble B, Gray R, Gilchrist K, et al.: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6 (7): 1107-17, 1988.
- Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 355 (9217): 1757-70, 2000.
- McGale P, Taylor C, Correa C, et al.: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383 (9935): 2127-35, 2014.
- Taghian AG, Jeong JH, Mamounas EP, et al.: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 24 (24): 3927-32, 2006.
- Recht A, Come SE, Henderson IC, et al.: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334 (21): 1356-61, 1996.
- Fisher B, Brown AM, Dimitrov NV, et al.: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8 (9): 1483-96, 1990.
- Wallgren A, Bernier J, Gelber RD, et al.: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35 (4): 649-59, 1996.
- Hickey BE, Francis DP, Lehman M: Sequencing of chemotherapy and radiotherapy for early breast cancer. Cochrane Database Syst Rev 4: CD005212, 2013.
- Halyard MY, Pisansky TM, Dueck AC, et al.: Radiotherapy and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG Phase III Trial N9831. J Clin Oncol 27 (16): 2638-44, 2009.
- Lingos TI, Recht A, Vicini F, et al.: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21 (2): 355-60, 1991.
- Paszat LF, Mackillop WJ, Groome PA, et al.: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 16 (8): 2625-31, 1998.
- Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61 (6): 866-8, 1990.
- Darby SC, McGale P, Taylor CW, et al.: Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6 (8): 557-65, 2005.
- Højris I, Overgaard M, Christensen JJ, et al.: Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 354 (9188): 1425-30, 1999.
- Nixon AJ, Manola J, Gelman R, et al.: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16 (4): 1374-9, 1998.
- Giordano SH, Kuo YF, Freeman JL, et al.: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97 (6): 419-24, 2005.
- Harris EE, Correa C, Hwang WT, et al.: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24 (25): 4100-6, 2006.
- Meek AG: Breast radiotherapy and lymphedema. Cancer 83 (12 Suppl American): 2788-97, 1998.
- Larson D, Weinstein M, Goldberg I, et al.: Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys 12 (9): 1575-82, 1986.
- Swedborg I, Wallgren A: The effect of pre- and postmastectomy radiotherapy on the degree of edema, shoulder-joint mobility, and gripping force. Cancer 47 (5): 877-81, 1981.
- Powell S, Cooke J, Parsons C: Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol 18 (3): 213-20, 1990.
- Boice JD Jr, Harvey EB, Blettner M, et al.: Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326 (12): 781-5, 1992.
- Storm HH, Andersson M, Boice JD Jr, et al.: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84 (16): 1245-50, 1992.
- Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11 (3): 485-97, 1985.
- Taghian A, de Vathaire F, Terrier P, et al.: Long-term risk of sarcoma following radiation treatment for breast cancer. Int J Radiat Oncol Biol Phys 21 (2): 361-7, 1991.
- Inskip PD, Stovall M, Flannery JT: Lung cancer risk and radiation dose among women treated for breast cancer. J Natl Cancer Inst 86 (13): 983-8, 1994.
- Senkus E, Kyriakides S, Penault-Llorca F, et al.: Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24 (Suppl 6): vi7-23, 2013.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 (9472): 1687-717, 2005.
- Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352 (9132): 930-42, 1998.
- Pritchard KI, Shepherd LE, O'Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354 (20): 2103-11, 2006.
- Gennari A, Sormani MP, Pronzato P, et al.: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100 (1): 14-20, 2008.
- De Laurentiis M, Cancello G, D'Agostino D, et al.: Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 26 (1): 44-53, 2008.
- Henderson IC, Berry DA, Demetri GD, et al.: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21 (6): 976-83, 2003.
- Mamounas EP, Bryant J, Lembersky B, et al.: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23 (16): 3686-96, 2005.
- Martin M, Pienkowski T, Mackey J, et al.: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352 (22): 2302-13, 2005.
- Perez EA: TAC--a new standard in adjuvant therapy for breast cancer? N Engl J Med 352 (22): 2346-8, 2005.
- Sparano JA, Wang M, Martino S, et al.: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358 (16): 1663-71, 2008.
- Citron ML, Berry DA, Cirrincione C, et al.: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21 (8): 1431-9, 2003.
- Hudis C, Citron M, Berry D, et al.: Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-41, 2005.
- Citron ML, Berry DA, Cirrincione C, et al.: Dose-dense (DD) AC followed by paclitaxel is associated with moderate, frequent anemia compared to sequential (S) and/or less DD treatment: update by CALGB on Breast Cancer Intergroup Trial C9741 with ECOG, SWOG, & NCCTG. [Abstract] J Clin Oncol 23 (Suppl 16): A-620, 33s, 2005.
- Bonilla L, Ben-Aharon I, Vidal L, et al.: Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102 (24): 1845-54, 2010.
- Jones SE, Savin MA, Holmes FA, et al.: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24 (34): 5381-7, 2006.
- Jones S, Holmes FA, O'Shaughnessy J, et al.: Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 27 (8): 1177-83, 2009.
- Gagliato Dde M, Gonzalez-Angulo AM, Lei X, et al.: Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol 32 (8): 735-44, 2014.
- Pritchard KI, Paterson AH, Paul NA, et al.: Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 14 (10): 2731-7, 1996.
- Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19 (14): 3306-11, 2001.
- Smith RE, Bryant J, DeCillis A, et al.: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 21 (7): 1195-204, 2003.
- Crump M, Tu D, Shepherd L, et al.: Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21 (16): 3066-71, 2003.
- Praga C, Bergh J, Bliss J, et al.: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23 (18): 4179-91, 2005.
- Schagen SB, Muller MJ, Boogerd W, et al.: Change in cognitive function after chemotherapy: a prospective longitudinal study in breast cancer patients. J Natl Cancer Inst 98 (23): 1742-5, 2006.
- Peto R, Davies C, Godwin J, et al.: Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379 (9814): 432-44, 2012.
- Mehta RS: Dose-dense and/or metronomic schedules of specific chemotherapies consolidate the chemosensitivity of triple-negative breast cancer: a step toward reversing triple-negative paradox. J Clin Oncol 26 (19): 3286-8; author reply 3288, 2008.
- Liedtke C, Mazouni C, Hess KR, et al.: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26 (8): 1275-81, 2008.
- Silver DP, Richardson AL, Eklund AC, et al.: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28 (7): 1145-53, 2010.
- Anders CK, Winer EP, Ford JM, et al.: Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res 16 (19): 4702-10, 2010.
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353 (16): 1659-72, 2005.
- Smith I, Procter M, Gelber RD, et al.: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369 (9555): 29-36, 2007.
- Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al.: 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 382 (9897): 1021-8, 2013.
- Romond EH, Perez EA, Bryant J, et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353 (16): 1673-84, 2005.
- Perez E, Romond E, Suman V, et al.: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patiens with HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): 512, 6s, 2007.
- Slamon D, Eiermann W, Robert N, et al.: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365 (14): 1273-83, 2011.
- Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al.: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354 (8): 809-20, 2006.
- Pivot X, Romieu G, Debled M, et al.: 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 14 (8): 741-8, 2013.
- Tan-Chiu E, Yothers G, Romond E, et al.: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23 (31): 7811-9, 2005.
- Slamon D, Eiermann W, Robert N, et al.: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-52, 2006.
- Piccart-Gebhart MJ, Holmes AP, Baselga J, et al.: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). [Abstract] J Clin Oncol 32 (Suppl 5): A-LBA4, 2014.
- Burstein HJ, Temin S, Anderson H, et al.: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol 32 (21): 2255-69, 2014.
- Colleoni M, Gelber S, Goldhirsch A, et al.: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol 24 (9): 1332-41, 2006.
- Fisher B, Dignam J, Bryant J, et al.: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93 (9): 684-90, 2001.
- Stewart HJ, Prescott RJ, Forrest AP: Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst 93 (6): 456-62, 2001.
- Tormey DC, Gray R, Falkson HC: Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst 88 (24): 1828-33, 1996.
- Davies C, Pan H, Godwin J, et al.: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381 (9869): 805-16, 2013.
- Albain KS, Barlow WE, Ravdin PM, et al.: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet 374 (9707): 2055-63, 2009.
- Eisen A, Messersmith J, Franek M, et al.: Adjuvant ovarian ablation in the treatment of premenopausal women with early stage invasive breast cancer. Ontario, Canada: Cancer Care, 2010. Evidence-based Series # 1-9: Section 1. Available online. Last accessed April 1, 2015.
- Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Lancet 341 (8856): 1293-8, 1993.
- Schmid P, Untch M, Kossé V, et al.: Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol 25 (18): 2509-15, 2007.
- Ejlertsen B, Mouridsen HT, Jensen MB, et al.: Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer. J Clin Oncol 24 (31): 4956-62, 2006.
- Wolff AC, Davidson NE: Still waiting after 110 years: the optimal use of ovarian ablation as adjuvant therapy for breast cancer. J Clin Oncol 24 (31): 4949-51, 2006.
- Boccardo F, Rubagotti A, Amoroso D, et al.: Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. email@example.com. J Clin Oncol 18 (14): 2718-27, 2000.
- Winer EP, Hudis C, Burstein HJ, et al.: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 20 (15): 3317-27, 2002.
- Tevaarwerk AJ, Wang M, Zhao F, et al.: Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 32 (35): 3948-58, 2014.
- Francis PA, Regan MM, Fleming GF, et al.: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372 (5): 436-46, 2015.
- The ATAC Trialists' Group. Arimidex, tamoxifen alone or in combination: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359 (9324): 2131-9, 2002.
- Howell A, Cuzick J, Baum M, et al.: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 (9453): 60-2, 2005.
- Thürlimann B, Keshaviah A, Coates AS, et al.: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26): 2747-57, 2005.
- Coates AS, Keshaviah A, Thürlimann B, et al.: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25 (5): 486-92, 2007.
- Regan MM, Leyland-Jones B, Bouzyk M, et al.: CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst 104 (6): 441-51, 2012.
- Goss PE, Ingle JN, Pritchard KI, et al.: Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol 31 (11): 1398-404, 2013.
- Goss PE, Hershman DL, Cheung AM, et al.: Effects of adjuvant exemestane versus anastrozole on bone mineral density for women with early breast cancer (MA.27B): a companion analysis of a randomised controlled trial. Lancet Oncol 15 (4): 474-82, 2014.
- Gnant M, Mlineritsch B, Stoeger H, et al.: Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 12 (7): 631-41, 2011.
- Pagani O, Regan MM, Walley BA, et al.: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371 (2): 107-18, 2014.
- Boccardo F, Rubagotti A, Guglielmini P, et al.: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 17 (Suppl 7): vii10-4, 2006.
- Jakesz R, Jonat W, Gnant M, et al.: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366 (9484): 455-62, 2005 Aug 6-12.
- Boccardo F, Rubagotti A, Aldrighetti D, et al.: Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer 109 (6): 1060-7, 2007.
- Jonat W, Gnant M, Boccardo F, et al.: Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol 7 (12): 991-6, 2006.
- Coombes RC, Hall E, Gibson LJ, et al.: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350 (11): 1081-92, 2004.
- Coombes RC, Kilburn LS, Snowdon CF, et al.: Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 (9561): 559-70, 2007.
- Dowsett M, Cuzick J, Ingle J, et al.: Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 28 (3): 509-18, 2010.
- van de Velde CJ, Rea D, Seynaeve C, et al.: Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377 (9762): 321-31, 2011.
- Regan MM, Neven P, Giobbie-Hurder A, et al.: Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol 12 (12): 1101-8, 2011.
- Goss PE, Ingle JN, Martino S, et al.: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349 (19): 1793-802, 2003.
- Bryant J, Wolmark N: Letrozole after tamoxifen for breast cancer--what is the price of success? N Engl J Med 349 (19): 1855-7, 2003.
- Burstein HJ: Beyond tamoxifen--extending endocrine treatment for early-stage breast cancer. N Engl J Med 349 (19): 1857-9, 2003.
- Goss PE, Ingle JN, Martino S, et al.: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97 (17): 1262-71, 2005.
- Mamounas EP, Jeong JH, Wickerham DL, et al.: Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol 26 (12): 1965-71, 2008.
- Gnant M, Mlineritsch B, Schippinger W, et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360 (7): 679-91, 2009.
- Coleman R, de Boer R, Eidtmann H, et al.: Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24 (2): 398-405, 2013.
- Coleman RE, Marshall H, Cameron D, et al.: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 365 (15): 1396-405, 2011.
- Coleman R, Cameron D, Dodwell D, et al.: Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 15 (9): 997-1006, 2014.
- Yan T, Yin W, Zhou Q, et al.: The efficacy of zoledronic acid in breast cancer adjuvant therapy: a meta-analysis of randomised controlled trials. Eur J Cancer 48 (2): 187-95, 2012.
- Valachis A, Polyzos NP, Coleman RE, et al.: Adjuvant therapy with zoledronic acid in patients with breast cancer: a systematic review and meta-analysis. Oncologist 18 (4): 353-61, 2013.
- He M, Fan W, Zhang X: Adjuvant zoledronic acid therapy for patients with early stage breast cancer: an updated systematic review and meta-analysis. J Hematol Oncol 6 (1): 80, 2013.
- Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 97 (3): 188-94, 2005.
- Bear HD, Anderson S, Brown A, et al.: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21 (22): 4165-74, 2003.
- Smith IE, Dowsett M, Ebbs SR, et al.: Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23 (22): 5108-16, 2005.
- Carlson RW, Allred DC, Anderson BO, et al.: Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 7 (2): 122-92, 2009.
- Boughey JC, Suman VJ, Mittendorf EA, et al.: Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA 310 (14): 1455-61, 2013.
- Kuehn T, Bauerfeind I, Fehm T, et al.: Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 14 (7): 609-18, 2013.
- Alvarado R, Yi M, Le-Petross H, et al.: The role for sentinel lymph node dissection after neoadjuvant chemotherapy in patients who present with node-positive breast cancer. Ann Surg Oncol 19 (10): 3177-84, 2012.
- Lyman GH, Temin S, Edge SB, et al.: Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 32 (13): 1365-83, 2014.
- Smith IC, Heys SD, Hutcheon AW, et al.: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20 (6): 1456-66, 2002.
- von Minckwitz G, Kümmel S, Vogel P, et al.: Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst 100 (8): 552-62, 2008.
- Fisher B, Bryant J, Wolmark N, et al.: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16 (8): 2672-85, 1998.
- Fisher ER, Wang J, Bryant J, et al.: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95 (4): 681-95, 2002.
- Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008.
- van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19 (22): 4224-37, 2001.
- Vriens BE, Aarts MJ, de Vries B, et al.: Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer 49 (15): 3102-10, 2013.
- von Minckwitz G, Rezai M, Loibl S, et al.: Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 28 (12): 2015-23, 2010.
- von Minckwitz G, Schneeweiss A, Loibl S, et al.: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15 (7): 747-56, 2014.
- Sikov WM, Berry DA, Perou CM, et al.: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33 (1): 13-21, 2015.
- Rastogi P, Buyse ME, Swain SM, et al.: Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group. Clin Breast Cancer 11 (4): 228-34, 2011.
- Untch M, Loibl S, Bischoff J, et al.: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13 (2): 135-44, 2012.
- Buzdar AU, Ibrahim NK, Francis D, et al.: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23 (16): 3676-85, 2005.
- Untch M, Rezai M, Loibl S, et al.: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28 (12): 2024-31, 2010.
- Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010.
- Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15 (6): 640-7, 2014.
- Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14 (13): 1317-25, 2013.
- Ismael G, Hegg R, Muehlbauer S, et al.: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13 (9): 869-78, 2012.
- Gianni L, Pienkowski T, Im YH, et al.: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13 (1): 25-32, 2012.
- Baselga J, Bradbury I, Eidtmann H, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379 (9816): 633-40, 2012.
- Schneeweiss A, Chia S, Hickish T, et al.: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24 (9): 2278-84, 2013.
- Lenihan D, Suter T, Brammer M, et al.: Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 23 (3): 791-800, 2012.
- Eiermann W, Paepke S, Appfelstaedt J, et al.: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12 (11): 1527-32, 2001.
- Preece PE, Wood RA, Mackie CR, et al.: Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. Br Med J (Clin Res Ed) 284 (6319): 869-70, 1982.
- Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271 (20): 1587-92, 1994.
- Rosselli Del Turco M, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271 (20): 1593-7, 1994.
- Khatcheressian JL, Wolff AC, Smith TJ, et al.: American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 24 (31): 5091-7, 2006.
Stage IIIB, Inoperable IIIC, IV, Recurrent, and Metastatic Breast Cancer
Inoperable Stage IIIB or IIIC or Inflammatory Breast Cancer
Multimodality therapy delivered with curative intent is the standard of care for patients with clinical stage IIIB disease. In a retrospective series, approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined modality therapy. Although these results have not been replicated in another series, this result suggests such patients should be treated with the same intent.
Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen-receptor (ER) and progesterone-receptor (PR) levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression. Initial treatment with anthracycline-based chemotherapy and/or taxane-based therapy is standard. In one series of 178 patients with inflammatory breast cancer, DFS was 28% at 15 years with a combined-modality approach.[Level of evidence: 3iiiDii] For patients who respond to neoadjuvant chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered in patients with a good partial or complete response to neoadjuvant chemotherapy. Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy should be administered to patients whose tumors are ER-positive or unknown. All patients should be considered candidates for clinical trials to evaluate the most appropriate fashion in which to administer the various components of multimodality regimens.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer and inflammatory breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Stage IV, Recurrent, and Metastatic Breast Cancer
Recurrent breast cancer is often responsive to therapy, though treatment is rarely curative at this stage of disease. Patients with localized breast or chest wall recurrences, however, may be long-term survivors with appropriate therapy. Prior to treatment for recurrent or metastatic cancer, restaging to evaluate extent of disease is indicated. Cytologic or histologic documentation of recurrent or metastatic disease should be obtained whenever possible. The ER levels and PR levels, HER2/neu positivity at the time of recurrence, and previous treatment should be considered, if known, when selecting therapy. ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence. Patients in this study had no interval treatment. If ER and PR status is unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in selecting chemotherapy or hormone therapy.
Recurrent local-regional breast cancer
Patients with local-regional breast cancer recurrence may become long-term survivors with appropriate therapy. A clinical trial indicated that between 10% and 20% of patients will have locally recurrent disease in the breast between 1 and 9 years after breast-conserving surgery plus radiation therapy. Nine percent to 25% of these patients will have distant metastases or locally extensive disease at the time of recurrence. Patients with local-regional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%. A phase III, randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[Level of evidence: 1iiDiii]
Local chest wall recurrence following mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative. Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater than 2-year disease-free interval prior to recurrence have the best chance for prolonged survival. The 5-year disease-free survival DFS rate in one series of such patients was 25%, with a 10-year rate of 15%. The local-regional control rate was 57% at 10 years. Systemic therapy should be considered in patients with local regional recurrence because of the high risk of subsequent metastases. No randomized controlled studies are available to guide patient care in this situation.
Stage IV and metastatic disease
Treatment for systemic disease is palliative in intent. Goals of treatment include improving quality of life and prolongation of life. Although median survival has been reported to be 18 to 24 months, some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[Level of evidence: 3iiDiii]
Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. Radiation therapy and/or surgery may be indicated for patients with limited symptomatic metastases. All patients with metastatic or recurrent breast cancer should be considered candidates for ongoing clinical trials.
Surgery may be indicated for selected patients. Examples include patients who need mastectomies for fungating/painful breast lesions, parenchymal brain or vertebral metastases with spinal cord compression, isolated lung metastases, pathologic (or impending) fractures, or pleural or pericardial effusions. (Refer to the PDQ summary on Pain for more information and for information on pleural and pericardial effusions, refer to the PDQ summary on Cardiopulmonary Syndromes.)
Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications include painful bony metastases, unresectable central nervous system metastases (i.e., brain, meningeal, and spinal cord), bronchial obstruction, and fungating/painful breast or chest wall lesions. Radiation therapy should also be given following surgery for decompression of intracranial or spinal cord metastases and following fixation of pathologic fractures. Clinical trials (including the completed Radiation Therapy Oncology Group's (RTOG) trial [RTOG-9714]) are exploring the optimal radiation fractionation schedule. Strontium 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases. (Refer to the PDQ summary on Pain for more information.)
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV breast cancer and recurrent breast cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The use of bisphosphonates to reduce skeletal morbidity in patients with bone metastases should be considered. Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate. (Refer to the PDQ summary on Pain for more information on bisphosphonates.)
Hormone therapy should generally be considered as initial treatment for a postmenopausal patient with newly diagnosed metastatic disease if the patient's tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is especially indicated if the patient's disease involves only bone and soft tissue and the patient has either not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year. While tamoxifen has been used in this setting for many years, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the aromatase inhibitors (AIs) compared with tamoxifen.[Level of evidence: 1iiDiii] In a meta-analysis that included randomized trials in patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HR] for death, 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[Level of evidence: 1iA]
Several randomized but underpowered trials have tried to determine if combined hormone therapy (luteinizing hormone-releasing hormone [LHRH] agonists + tamoxifen) is superior to either approach alone in premenopausal women. Results have been inconsistent. The best study design compared buserelin (an LHRH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors. Patients receiving buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those receiving tamoxifen or buserelin who survived 2.9 and 2.5 years, respectively (P = .01).[Level of evidence: 1iiA] Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.
Women whose tumors are ER-positive or unknown, with bone or soft tissue metastases only, who have received an antiestrogen within the past year, should be given second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective AIs, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens; and the ER down-regulator, fulvestrant. In comparison to megestrol acetate, all three currently available AIs have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability. In a meta-analysis that included randomized trials of patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[Level of evidence: 1iA] Two randomized trials that enrolled 400 and 451 patients who had progressed after receiving tamoxifen demonstrated that fulvestrant yielded similar results to anastrozole in terms of its impact on PFS. The proper sequence of these therapies is currently not known. While there is a biologic rationale for combining fulvestrant with a third-generation AI for patients with recurrent or metastatic disease, the benefits of such combination therapy have not been established.
Premenopausal women should undergo oophorectomy (surgically, with external-beam radiation therapy or with an LHRH agonist). Patients with lymphangitic pulmonary metastases, major liver involvement, and/or central nervous system involvement should not receive hormone therapy as a single modality. Patients with structural compromise of weight-bearing bones should be considered for surgical intervention and/or radiation in addition to systemic therapy. Patients with vertebral body involvement should be evaluated for impending cord compression even in the absence of neurologic symptoms. Increasing bone pain and increasing alkaline phosphatase within the first several weeks of hormone therapy does not necessarily imply disease progression. Patients with extensive bony disease are at risk for the development of symptomatic hypercalcemia early in the course of hormone therapy. Early failure (e.g., <6 months) on hormone therapy suggests that cytotoxic chemotherapy should be the next modality employed.
Endocrine therapy is recommended for patients with metastatic hormone receptor-positive (HR+) disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mammalian target of rapamycin (mTOR) inhibitors might enhance the efficacy of endocrine therapies.
The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) , is a randomized, phase III, placebo-controlled trial, of randomly assigned patients with HR+ metastatic breast cancer resistant to nonsteroidal aromatase inhibition who received the mTOR inhibitor everolimus plus exemestane versus placebo plus exemestane.[Level of Evidence: 1iDiii] At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001). The addition of everolimus to exemestane was more toxic with the most common grade 3 or 4 adverse events (AEs) being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). The results of this study report a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy but there were more side effects. Final overall survival (OS) outcomes on this trial are awaited.
Evidence of mTOR inhibitor activity in HER2-positive breast cancer was shown in the phase III BOLERO-3 (NCT01007942) trial.[Level of evidence: 1iDiii] In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine or placebo plus trastuzumab plus vinorelbine. At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067). Serious AEs were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group. Final OS outcomes for this trial have not yet been reported.
Approximately 25% of patients with breast cancer have tumors that overexpress HER2/neu. Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy and trastuzumab. Patients treated with chemotherapy plus trastuzumab had an OS advantage as compared with those receiving chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[Level of evidence: 1iiA] When combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity. Consequently, patients with metastatic breast cancer with substantial overexpression of HER2/neu are candidates for treatment with the combination of trastuzumab and paclitaxel or for clinical studies of trastuzumab combined with taxanes and other chemotherapeutic agents.
Clinical trials comparing multiagent chemotherapy plus trastuzumab versus single-agent chemotherapy have yielded conflicting results. In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time-to-progression, compared with trastuzumab and paclitaxel alone.[Level of evidence: 1iDiii] However, a phase III Breast Cancer International Research Group (BCIRG) trial (BCIRG-007 [NCT00047255]) comparing carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer showed no difference in OS, time to progression, or response rate.[Level of evidence: 1iiA] Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer should consist of single-agent chemotherapy plus trastuzumab.
Pertuzumab is a humanized, monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3. Given their potentially complementary mechanisms of action, the phase III CLEOPATRA [NCT00567190] trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2+ metastatic setting.[Level of evidence: 1iA] With a median follow-up of 50 months, the median OS was 40.8 months in the control group and 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months with the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80). The toxicity profile was similar in both treatment groups with no increase in cardiac toxic effects seen in the pertuzumab combination arm.
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2–targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue. The phase III EMILIA or TDM4370g (NCT00829166) study was a randomized, open-label trial enrolling 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[Level of evidence: 1iiA]
Patients were randomly assigned between T-DM1 versus lapatinib plus capecitabine. Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P < .001). Median OS at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; HR, 0.68; 95% CI, 0.55–0.85; P < .001). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar syndrome were higher in patients who received lapatinib plus capecitabine.
Further evidence of T-DM1's activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.[Level of evidence: 1iiDiii] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting. At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97). T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 AE, (46.4% vs. 90.9%), AE leading to treatment discontinuations (7.2% vs. 40.9%), and serious AE (20.3% vs. 25.8%). Preliminary OS results were similar between treatment arms.
Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized, phase III, TH3RESA (NCT01419197) study of T-DM1 versus physician's choice of treatment.[Level of evidence: 1iiA] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician's choice) and allowed crossover to T-DM1. At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician's choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician's choice group (HR, 0.528; 95% CI, 0.422–0.661); P < .0001). Interim OS analysis showed a trend favoring T-DM1, but the stopping boundary was not crossed (HR, 0.552; 95% CI, 0.369–0.826; P = .003).
Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor.
Lapatinib plus capecitabine
Lapatinib has shown activity in combination with capecitabine in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab. A nonblinded, randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab. At the first planned interim analysis of the trial, a highly significant difference was found that favored the combination arm with respect to the primary study endpoint and time to progression (median time to progression 8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34–0.71; P < .001). There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[Level of evidence: 1iiA] Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. No data on quality of life or treatment after progression are available. (Refer to the PDQ summary on Gastrointestinal Complications for more information on diarrhea.)
Lapatinib plus trastuzumab
The combination of lapatinib and trastuzumab has been evaluated for patients with HER2-positive metastatic breast cancer whose disease progressed while they were being treated with trastuzumab in a phase III trial.[Level of evidence: 1iiA] A total of 291 patients were randomly assigned to treatment with lapatinib alone or in combination with trastuzumab. Compared with lapatinib alone, the combination of lapatinib and trastuzumab significantly improved PFS (HR, 0.74; 95% CI, 0.58–0.94; median, 11 weeks vs. 8 weeks) and OS (HR, 0.74; 95% CI, 0.57–0.97; median, 14 months vs. 10 months). The control arm of lapatinib alone is a nonstandard treatment arm. These data offer heavily pretreated metastatic HER2-positive breast cancer patients an alternative chemotherapy-free treatment regimen using dual HER2 blockade.
Lapatinib plus paclitaxel
A double-blind, randomized phase III study compared paclitaxel and lapatinib with paclitaxel plus placebo as first-line therapy in patients with metastatic breast cancer. In the intention-to-treat population, no benefit was found with the combination treatment. However, specimens were evaluated retrospectively to determine HER2/neu status. When used in HER2/neu-positive patients, treatment with paclitaxel and lapatinib showed improvement in time to progression, event-free survival, response rate, and clinical benefit rate; OS did not increase. Toxicities, specifically alopecia, diarrhea, and rash were higher in the HER2/neu-positive lapatinib group. A series of AE were low and existed in both arms.[Level of evidence: 1iDiii]
Patients whose tumors have progressed on hormone therapy are candidates for cytotoxic chemotherapy. Patients with hormone receptor–negative tumors and those with visceral metastases are also candidates for cytotoxic agents.
Single agents that have shown activity in metastatic breast cancer include the following:
- Liposomal doxorubicin.
- Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).
- Alkylating agents.
- Vinca alkaloids.
- Mitomycin C.
- Eribulin mesylate.
Combination regimens that have shown activity in metastatic breast cancer:
- CA: cyclophosphamide and doxorubicin.
- Docetaxel and doxorubicin.
- CAF: cyclophosphamide, doxorubicin, 5-fluorouracil.
- CMF: cyclophosphamide, methotrexate, 5-fluorouracil.
- Doxorubicin and paclitaxel.
- Docetaxel and capecitabine.
- Vinorelbine and epirubicin.
- Capecitabine and ixabepilone.
Whether single-agent chemotherapy or combination chemotherapy is preferable for first-line treatment is unclear. An Eastern Cooperative Oncology Intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin given both as a combination and sequentially. Although response rate and time-to-progression were both better for the combination, survival was the same in both groups.[Level of evidence: 1iiA]; The rate of disease progression, the presence or absence of comorbid medical conditions, and physician/patient preference will influence the choice of therapy in individual patients. At this time, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents. A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[Level of evidence: 1iiA]
The optimal treatment duration for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS from immediate treatment with a different chemotherapy regimen compared to observation with treatment upon relapse.[Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment, and in one of these studies, survival was actually worse in the immediately treated group. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomized to receive either a different chemotherapy versus observation or a different chemotherapy regimen given at higher versus lower doses.[Level of evidence: 1iiA] These four studies indicate that different combination regimens of additional chemotherapy immediately following a patient's best response to an induction chemotherapy regimen does not improve OS. In view of the lack of a standard approach, patients requiring second-line regimens are good candidates for clinical trials.
The potential for doxorubicin-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for an individual patient. Recognized risk factors for cardiac toxicity include advanced age, prior chest-wall radiation therapy, prior anthracycline exposure, hypertension, diabetes, and known underlying heart disease. The cardioprotective drug, dexrazoxane, has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive greater cumulative doses of doxorubicin and allowed patients with cardiac risk factors to receive doxorubicin. Dexrazoxane has a similar protective effect in patients receiving epirubicin. The risks of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.
Studies comparing high-dose chemotherapy with stem cell support to conventional chemotherapy in patients with metastatic disease indicate no OS or relapse-free survival benefit for patients receiving high-dose chemotherapy with stem cell support.[Level of evidence: 1iiA] In the absence of data suggesting a benefit from high-dose chemotherapy with stem cell support, this remains an area of clinical evaluation.
Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor-A. Its role in the treatment of metastatic breast cancer remains controversial. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial. The study enrolled 462 patients who had received prior anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab. The study failed to demonstrate a statistically significant effect on PFS (4.86 months vs. 4.17 months; HR, 0.98) or OS (15.1 months vs. 14.5 months).[Level of Evidence: 1iiA]
ECOG-2100 (NCT00028990), a completed, open-label, randomized, phase III trial, demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 months vs. 5.9 months; HR, 0.60; P <.001).[Level of Evidence: 1iiA] However, the addition of bevacizumab did not improve OS (26.7 months vs. 25.2 months, P = .16). Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe hypertension, proteinuria, cerebrovascular ischemia, and infection.
The AVADO (NCT00333775) trial randomly assigned 736 patients to docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer. The combination of bevacizumab at 15 mg/kg, but not 7.5 mg/kg, with docetaxel modestly improved median PFS compared with placebo (10.1 months vs. 8.1 months) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[Level of Evidence: 1iiA] Again, more toxic effects were seen in patients in the bevacizumab-containing arms with significantly higher rates of bleeding and hypertension compared with the placebo arms.
Similarly, the RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo. Median PFS was longer for each bevacizumab-containing combination (Cape cohort: increased from 5.7 mo. to 8.6 mo.; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and Taxane/Anthracycline cohort: increased from 8.0 mo. to 9.2 mo.; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[Level of Evidence: 1iiA] However, no statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed. Toxicities associated with bevacizumab were similar to those seen in prior bevacizumab clinical trials.
The RIBBON-2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer. This trial randomly assigned 684 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo. Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). However, no statistically significant difference in OS was seen (16.4 months vs. 18.0 months for chemotherapy plus placebo vs. chemotherapy plus bevacizumab, respectively, P = .3741).[Level of evidence: 1iA] Toxicities associated with bevacizumab were again similar to those seen in prior clinical trials.
In November 2011, based on the consistent finding that bevacizumab only modestly improved PFS but not OS, and given bevacizumab's considerable toxicity profile, the Food and Drug Administration revoked approval of bevacizumab for the treatment of metastatic breast cancer.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer and metastatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References:
- Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001.
- Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997.
- Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994.
- Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996.
- Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987.
- Lichter AS, Lippman ME, Danforth DN Jr, et al.: Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol 10 (6): 976-83, 1992.
- Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986.
- Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993.
- Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991.
- Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001.
- Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991.
- Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992.
- Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990.
- Waeber M, Castiglione-Gertsch M, Dietrich D, et al.: Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol 14 (8): 1215-21, 2003.
- Honig SF: Hormonal therapy and chemotherapy. In: Harris JR, Morrow M, Lippman ME, et al., eds.: Diseases of the Breast. Lippincott-Raven Publishers: Philadelphia, Pa, 1996, pp 669-734.
- Greenberg PA, Hortobagyi GN, Smith TL, et al.: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14 (8): 2197-205, 1996.
- Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993.
- Quilty PM, Kirk D, Bolger JJ, et al.: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31 (1): 33-40, 1994.
- Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21 (21): 4042-57, 2003.
- Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11 (1): 59-65, 1993.
- Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16 (6): 2038-44, 1998.
- Powles T, Paterson A, McCloskey E, et al.: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8 (2): R13, 2006.
- Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003.
- Bonneterre J, Thürlimann B, Robertson JF, et al.: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol 18 (22): 3748-57, 2000.
- Nabholtz JM, Buzdar A, Pollak M, et al.: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18 (22): 3758-67, 2000.
- Mouridsen H, Gershanovich M, Sun Y, et al.: Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21 (11): 2101-9, 2003.
- Mauri D, Pavlidis N, Polyzos NP, et al.: Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 98 (18): 1285-91, 2006.
- Boccardo F, Rubagotti A, Perrotta A, et al.: Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol 5 (4): 337-42, 1994.
- Jonat W, Kaufmann M, Blamey RW, et al.: A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer 31A (2): 137-42, 1995.
- Klijn JG, Blamey RW, Boccardo F, et al.: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 19 (2): 343-53, 2001.
- Klijn JG, Beex LV, Mauriac L, et al.: Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 92 (11): 903-11, 2000.
- Buzdar AU, Jones SE, Vogel CL, et al.: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group. Cancer 79 (4): 730-9, 1997.
- Dombernowsky P, Smith I, Falkson G, et al.: Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol 16 (2): 453-61, 1998.
- Jonat W, Howell A, Blomqvist C, et al.: A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A (3): 404-12, 1996.
- Gershanovich M, Chaudri HA, Campos D, et al.: Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol 9 (6): 639-45, 1998.
- Peethambaram PP, Ingle JN, Suman VJ, et al.: Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis. Breast Cancer Res Treat 54 (2): 117-22, 1999.
- Kaufmann M, Bajetta E, Dirix LY, et al.: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18 (7): 1399-411, 2000.
- Kvinnsland S, Anker G, Dirix LY, et al.: High activity and tolerability demonstrated for exemestane in postmenopausal women with metastatic breast cancer who had previously failed on tamoxifen treatment. Eur J Cancer 36 (8): 976-82, 2000.
- Buzdar A, Douma J, Davidson N, et al.: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19 (14): 3357-66, 2001.
- Gibson LJ, Dawson CK, Lawrence DH, et al.: Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev (1): CD003370, 2007.
- Howell A, Robertson JF, Abram P, et al.: Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol 22 (9): 1605-13, 2004.
- Perey L, Paridaens R, Hawle H, et al.: Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol 18 (1): 64-9, 2007.
- Henderson IC: A rose is no longer a rose. J Clin Oncol 20 (16): 3365-8, 2002.
- Osborne CK, Pippen J, Jones SE, et al.: Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20 (16): 3386-95, 2002.
- Howell A, Robertson JF, Quaresma Albano J, et al.: Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20 (16): 3396-403, 2002.
- Flemming J, Madarnas Y, Franek JA: Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review. Breast Cancer Res Treat 115 (2): 255-68, 2009.
- Buzdar AU: Combination endocrine treatments unproven in breast cancer. Lancet Oncol 14 (10): 917-8, 2013.
- Bajetta E, Zilembo N, Buzzoni R, et al.: Goserelin in premenopausal advanced breast cancer: clinical and endocrine evaluation of responsive patients. Oncology 51 (3): 262-9, 1994 May-Jun.
- Clarysse A: Hormone-induced tumor flare. Eur J Cancer Clin Oncol 21 (5): 545-7, 1985.
- Baselga J, Campone M, Piccart M, et al.: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366 (6): 520-9, 2012.
- André F, O'Regan R, Ozguroglu M, et al.: Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 15 (6): 580-91, 2014.
- Pegram MD, Pauletti G, Slamon DJ: HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res Treat 52 (1-3): 65-77, 1998.
- Cobleigh MA, Vogel CL, Tripathy D, et al.: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17 (9): 2639-48, 1999.
- Slamon DJ, Leyland-Jones B, Shak S, et al.: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344 (11): 783-92, 2001.
- Seidman A, Hudis C, Pierri MK, et al.: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20 (5): 1215-21, 2002.
- Burstein HJ, Kuter I, Campos SM, et al.: Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19 (10): 2722-30, 2001.
- Robert N, Leyland-Jones B, Asmar L, et al.: Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24 (18): 2786-92, 2006.
- Valero V, Forbes J, Pegram MD, et al.: Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol 29 (2): 149-56, 2011.
- Baselga J, Cortés J, Kim SB, et al.: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366 (2): 109-19, 2012.
- Swain SM, Baselga J, Kim SB, et al.: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372 (8): 724-34, 2015.
- Verma S, Miles D, Gianni L, et al.: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367 (19): 1783-91, 2012.
- Hurvitz SA, Dirix L, Kocsis J, et al.: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31 (9): 1157-63, 2013.
- Krop IE, Kim SB, González-Martín A, et al.: Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (7): 689-99, 2014.
- Geyer CE, Forster J, Lindquist D, et al.: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (26): 2733-43, 2006.
- Blackwell KL, Burstein HJ, Storniolo AM, et al.: Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 30 (21): 2585-92, 2012.
- Di Leo A, Gomez HL, Aziz Z, et al.: Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26 (34): 5544-52, 2008.
- Wilcken N, Dear R: Chemotherapy in metastatic breast cancer: A summary of all randomised trials reported 2000-2007. Eur J Cancer 44 (15): 2218-25, 2008.
- Ranson MR, Carmichael J, O'Byrne K, et al.: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 15 (10): 3185-91, 1997.
- Harris L, Batist G, Belt R, et al.: Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94 (1): 25-36, 2002.
- Keller AM, Mennel RG, Georgoulias VA, et al.: Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22 (19): 3893-901, 2004.
- Sparano JA, Makhson AN, Semiglazov VF, et al.: Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol 27 (27): 4522-9, 2009.
- Seidman AD, Berry D, Cirrincione C, et al.: Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26 (10): 1642-9, 2008.
- Gonzalez-Angulo AM, Hortobagyi GN: Optimal schedule of paclitaxel: weekly is better. J Clin Oncol 26 (10): 1585-7, 2008.
- Gradishar WJ, Tjulandin S, Davidson N, et al.: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23 (31): 7794-803, 2005.
- Ibrahim NK, Samuels B, Page R, et al.: Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 23 (25): 6019-26, 2005.
- Blum JL, Jones SE, Buzdar AU, et al.: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17 (2): 485-93, 1999.
- Blum JL, Dieras V, Lo Russo PM, et al.: Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92 (7): 1759-68, 2001.
- Venturini M, Paridaens R, Rossner D, et al.: An open-label, multicenter study of outpatient capecitabine monotherapy in 631 patients with pretreated advanced breast cancer. Oncology 72 (1-2): 51-7, 2007.
- Degardin M, Bonneterre J, Hecquet B, et al.: Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer. Ann Oncol 5 (5): 423-6, 1994.
- Carmichael J, Walling J: Advanced breast cancer: investigational role of gemcitabine. Eur J Cancer 33 (Suppl 1): S27-30, 1997.
- Vahdat LT, Pruitt B, Fabian CJ, et al.: Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 27 (18): 2954-61, 2009.
- Cortes J, O'Shaughnessy J, Loesch D, et al.: Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377 (9769): 914-23, 2011.
- Tranum BL, McDonald B, Thigpen T, et al.: Adriamycin combinations in advanced breast cancer. A Southwest Oncology Group Study. Cancer 49 (5): 835-9, 1982.
- Misset JL, Dieras V, Gruia G, et al.: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10 (5): 553-60, 1999.
- Buzdar AU, Kau SW, Smith TL, et al.: Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol 12 (2): 123-8, 1989.
- Tormey DC, Gelman R, Band PR, et al.: Comparison of induction chemotherapies for metastatic breast cancer. An Eastern Cooperative Oncology Group Trial. Cancer 50 (7): 1235-44, 1982.
- Jassem J, Pie��kowski T, P��uza��ska A, et al.: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19 (6): 1707-15, 2001.
- Biganzoli L, Cufer T, Bruning P, et al.: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial. J Clin Oncol 20 (14): 3114-21, 2002.
- O'Shaughnessy J, Miles D, Vukelja S, et al.: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20 (12): 2812-23, 2002.
- Serin D, Verrill M, Jones A, et al.: Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study. Br J Cancer 92 (11): 1989-96, 2005.
- Thomas ES, Gomez HL, Li RK, et al.: Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25 (33): 5210-7, 2007.
- Sledge GW, Neuberg D, Bernardo P, et al.: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21 (4): 588-92, 2003.
- Seidman AD: Sequential single-agent chemotherapy for metastatic breast cancer: therapeutic nihilism or realism? J Clin Oncol 21 (4): 577-9, 2003.
- Overmoyer B: Combination chemotherapy for metastatic breast cancer: reaching for the cure. J Clin Oncol 21 (4): 580-2, 2003.
- Perez EA: Current management of metastatic breast cancer. Semin Oncol 26 (4 Suppl 12): 1-10, 1999.
- Jones D, Ghersi D, Wilcken N: Addition of drug/s to a chemotherapy regimen for metastatic breast cancer. Cochrane Database Syst Rev 3: CD003368, 2006.
- Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16 (5): 1669-76, 1998.
- Peters WP, Jones RB, Vrendenburgh J, et al.: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-149, 121, 1996.
- Muss HB, Case LD, Richards F 2nd, et al.: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 325 (19): 1342-8, 1991.
- Falkson G, Gelman RS, Glick J, et al.: Metastatic breast cancer: higher versus low dose maintenance treatment when only a partial response or a no change status is obtained following doxorubicin induction treatment. An Eastern Cooperative Oncology Group study. Ann Oncol 3 (9): 768-70, 1992.
- Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15 (4): 1333-40, 1997.
- Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997.
- Hensley ML, Schuchter LM, Lindley C, et al.: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17 (10): 3333-55, 1999.
- Marty M, Espié M, Llombart A, et al.: Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17 (4): 614-22, 2006.
- Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996.
- Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63 (1): 37-45, 1989.
- Stadtmauer EA, O'Neill A, Goldstein LJ, et al.: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 342 (15): 1069-76, 2000.
- Schmid P, Schippinger W, Nitsch T, et al.: Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol 23 (3): 432-40, 2005.
- Berry DA, Broadwater G, Klein JP, et al.: High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 20 (3): 743-50, 2002.
- Farquhar C, Marjoribanks J, Basser R, et al.: High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database Syst Rev (3): CD003142, 2005.
- Miller KD, Chap LI, Holmes FA, et al.: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23 (4): 792-9, 2005.
- Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357 (26): 2666-76, 2007.
- Miles DW, Chan A, Dirix LY, et al.: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28 (20): 3239-47, 2010.
- Robert NJ, Diéras V, Glaspy J, et al.: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29 (10): 1252-60, 2011.
- Brufsky AM, Hurvitz S, Perez E, et al.: RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29 (32): 4286-93, 2011.