Breast Cancer Treatment: A Review

Importance Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer. Observations Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; formerly HER2): hormone receptor positive/ERBB2 negative (70% of patients), ERBB2 positive (15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%). More than 90% of breast cancers are not metastatic at the time of diagnosis. For people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer–specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive and ERBB2 positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor–positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients with ERBB2-positive tumors receive ERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed. Increasingly, some systemic therapy is delivered before surgery. Tailoring postoperative treatment based on preoperative treatment response is under investigation. Metastatic breast cancer is treated according to subtype, with goals of prolonging life and palliating symptoms. Median overall survival for metastatic triple-negative breast cancer is approximately 1 year vs approximately 5 years for the other 2 subtypes. Conclusions and Relevance Breast cancer consists of 3 major tumor subtypes categorized according to estrogen or progesterone receptor expression and ERBB2 gene amplification. The 3 subtypes have distinct risk profiles and treatment strategies. Optimal therapy for each patient depends on tumor subtype, anatomic cancer stage, and patient preferences.

[1]  Sung-Bae Kim,et al.  Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. , 2015, The New England journal of medicine.

[2]  A. Giobbie-Hurder,et al.  Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. , 2009, The New England journal of medicine.

[3]  Gideon Blumenthal,et al.  Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis , 2014, The Lancet.

[4]  C. Hudis,et al.  MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2− Metastatic Breast Cancer , 2017, Clinical Cancer Research.

[5]  T. Julian,et al.  Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. , 2007, The Lancet. Oncology.

[6]  M. Morrow,et al.  Axillary Nodal Management Following Neoadjuvant Chemotherapy: A Review , 2017, JAMA oncology.

[7]  D. Cameron,et al.  Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. , 2015, The Lancet. Oncology.

[8]  T. Julian,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. , 2010, The Lancet. Oncology.

[9]  EBCTCG (Early Breast Cancer Trialists' Collaborati 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 , 2014, The Lancet.

[10]  M. Hurlbert,et al.  Increasing Black:White disparities in breast cancer mortality in the 50 largest cities in the United States. , 2014, Cancer epidemiology.

[11]  Anna L. Brown,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 Bowe , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  P. Kumthekar,et al.  Medical management of brain metastases and leptomeningeal disease in patients with breast carcinoma. , 2018, Future oncology.

[13]  E. Winer,et al.  Atezolizumab and Nab‐Paclitaxel in Advanced Triple‐Negative Breast Cancer , 2018, The New England journal of medicine.

[14]  T. Whelan,et al.  Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. , 2016, The New England journal of medicine.

[15]  Sung-Bae Kim,et al.  Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. , 2012, The New England journal of medicine.

[16]  Laurence Collette,et al.  Impact of a Higher Radiation Dose on Local Control and Survival in Breast-Conserving Therapy of Early Breast Cancer: 10-Year Results of the Randomized Boost Versus No Boost EORTC 22881-10882 Trial , 2007 .

[17]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[18]  R. Peto,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 , 2014, The Lancet.

[19]  P. Fasching,et al.  Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  R Peto,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 , 2011, The Lancet.

[21]  C. Caldas,et al.  PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. , 2018 .

[22]  F. Holmes,et al.  Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  I. Ellis,et al.  Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial , 2017, The Lancet.

[24]  Ian Krop,et al.  Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

[26]  A. Amini,et al.  The 21-Gene Recurrence Score Assay for Node-Positive, Early-Stage Breast Cancer and Impact of RxPONDER Trial on Chemotherapy Decision-Making: Have Clinicians Already Decided? , 2017, Journal of the National Comprehensive Cancer Network : JNCCN.

[27]  J. Baselga,et al.  Trastuzumab emtansine for HER2-positive advanced breast cancer. , 2012, The New England journal of medicine.

[28]  J. Berlin,et al.  Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  A. Ruíz,et al.  Adjuvant docetaxel for high-risk, node-negative breast cancer. , 2010, The New England journal of medicine.

[30]  E. Winer,et al.  International Guidelines for Management of Metastatic Breast Cancer: Combination vs Sequential Single-Agent Chemotherapy , 2009, Journal of the National Cancer Institute.

[31]  Sung-Bae Kim,et al.  Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy , 2017, The New England journal of medicine.

[32]  Ming-Feng Hou,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 , 2013, The Lancet.

[33]  M. Buyse,et al.  Adjuvant Trastuzumab in HER 2-Positive Breast Cancer , 2011 .

[34]  K. Holli,et al.  Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  M. Press,et al.  Molecular Oncology of Breast Cancer , 2018 .

[36]  Anthony Fyles,et al.  Long-term results of hypofractionated radiation therapy for breast cancer. , 2010, The New England journal of medicine.

[37]  C. Lawton Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial , 2012 .

[38]  Mike Clarke,et al.  Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials , 2018, The Lancet. Oncology.

[39]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[40]  E. Winer,et al.  Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. , 2016, The New England journal of medicine.

[41]  H. Earl,et al.  aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  Jorma Isola,et al.  Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. , 2006, The New England journal of medicine.

[43]  D. Cutter,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 , 2012, The Lancet.

[44]  H. Struikmans,et al.  Regional Nodal Irradiation in Early-Stage Breast Cancer. , 2015, The New England journal of medicine.

[45]  Joanne S Haviland,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. , 2013, The Lancet. Oncology.

[46]  Virginia G Kaklamani,et al.  Adjuvant Chemotherapy Guided by a 21‐Gene Expression Assay in Breast Cancer , 2018, The New England journal of medicine.

[47]  H. Gómez,et al.  Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  Marc Buyse,et al.  Adjuvant trastuzumab in HER2-positive breast cancer. , 2011, The New England journal of medicine.

[49]  Kathleen A Cronin,et al.  US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. , 2014, Journal of the National Cancer Institute.

[50]  B. E. F. Isher,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. , 2002 .

[51]  S. Loibl,et al.  Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  R Peto,et al.  Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials , 2011, The Lancet.

[53]  M. Robson,et al.  Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation , 2017, The New England journal of medicine.

[54]  S. Shak,et al.  West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  A. Giobbie-Hurder,et al.  Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. , 2014, The New England journal of medicine.

[56]  C. Denkert,et al.  Molecular alterations in triple-negative breast cancer—the road to new treatment strategies , 2017, The Lancet.

[57]  Virginia G Kaklamani,et al.  Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. , 2015, The New England journal of medicine.

[58]  E. Winer,et al.  Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain? , 2018, Clinical Cancer Research.

[59]  Jay R. Harris,et al.  Diseases of the Breast , 2014 .

[60]  S. Loi,et al.  Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. , 2015, The New England journal of medicine.

[61]  M. Ellis,et al.  Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). , 2017 .

[62]  L. V. van't Veer,et al.  70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. , 2016, The New England journal of medicine.

[63]  N. Campioni [The physical examination of the breast]. , 1967, Il Policlinico. Sezione pratica.

[64]  Jorge S Reis-Filho,et al.  Triple-negative breast cancer. , 2010, The New England journal of medicine.

[65]  K. Hunt,et al.  Incorporating Tumor Characteristics to the American Joint Committee on Cancer Breast Cancer Staging System. , 2017, The oncologist.

[66]  R. Peto,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. , 2012, Lancet.

[67]  M. Ellis,et al.  HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor. , 2015, Journal of the National Comprehensive Cancer Network : JNCCN.

[68]  E. Perez,et al.  Weekly paclitaxel in the adjuvant treatment of breast cancer. , 2008, The New England journal of medicine.

[69]  Marion Procter,et al.  Adjuvant Pertuzumab and Trastuzumab in Early HER2‐Positive Breast Cancer , 2017, The New England journal of medicine.

[70]  R. Mansel,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. , 2014, The Lancet. Oncology.

[71]  A. Giuliano,et al.  Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. , 2011, JAMA.

[72]  Anthony Rhodes,et al.  American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. , 2010, Archives of pathology & laboratory medicine.

[73]  M. Duffy,et al.  Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). , 2017, European journal of cancer.

[74]  Li Ding,et al.  Activating HER2 mutations in HER2 gene amplification negative breast cancer. , 2013, Cancer discovery.

[75]  P. Neven,et al.  MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  Sung-Bae Kim,et al.  Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[77]  S. Paik,et al.  Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  Alphonse G. Taghian,et al.  Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. , 2017, Practical radiation oncology.

[79]  M. Goetz,et al.  MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  A. Jemal,et al.  Factors That Contributed to Black-White Disparities in Survival Among Nonelderly Women With Breast Cancer Between 2004 and 2013. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  W. Eiermann,et al.  Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation , 2018, The New England journal of medicine.

[82]  E. Winer,et al.  Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer , 2018, The New England journal of medicine.

[83]  David Cameron,et al.  11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial , 2017, The Lancet.

[84]  F. Holmes,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. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[85]  K. Gelmon,et al.  Palbociclib and Letrozole in Advanced Breast Cancer. , 2016, The New England journal of medicine.

[86]  Daniel F. Hayes,et al.  20‐Year Risks of Breast‐Cancer Recurrence after Stopping Endocrine Therapy at 5 Years , 2017, The New England journal of medicine.

[87]  Ruth Etzioni,et al.  Estimation of the Number of Women Living with Metastatic Breast Cancer in the United States , 2017, Cancer Epidemiology, Biomarkers & Prevention.

[88]  John M S Bartlett,et al.  Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[89]  Barbara L. Smith,et al.  Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[90]  G. Bonadonna,et al.  Combination chemotherapy as an adjuvant treatment in operable breast cancer. , 1976, The New England journal of medicine.

[91]  B. Henderson,et al.  Intersection of Race/Ethnicity and Socioeconomic Status in Mortality After Breast Cancer , 2015, Journal of Community Health.

[92]  Laurence Collette,et al.  Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. , 2015, The New England journal of medicine.

[93]  J. Forbes,et al.  Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials , 2015, The Lancet.

[94]  Robert B Livingston,et al.  Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. , 2010, The Lancet. Oncology.

[95]  Barbara L. Smith,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. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  P. Park,et al.  A molecular portrait of microsatellite instability across multiple cancers , 2016, Nature Communications.

[97]  D. Berry,et al.  Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance) , 2016 .

[98]  M. Dowsett,et al.  Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[99]  M. Espié,et al.  6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. , 2013, The Lancet. Oncology.

[100]  T. Braun,et al.  The Effect of the 2009 USPSTF breast cancer screening recommendations on breast cancer in Michigan: A longitudinal study , 2018, The breast journal.

[101]  R. Bast,et al.  Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  B. Fisher,et al.  National Surgical Adjuvant Breast and Bowel Project , 2020, Definitions.

[103]  John M S Bartlett,et al.  Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. , 2014, Archives of pathology & laboratory medicine.

[104]  Early Breast Canc Trialists Collab 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 , 2011 .