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Updates in the Evaluation and Management of Breast Cancer

      Abstract

      Breast cancer is the most commonly diagnosed cancer worldwide. More than 200,000 new cases of invasive breast cancer are diagnosed annually in the United States; approximately 40,000 patients die of the disease. The etiology of most breast cancer cases is unknown, although multiple factors predisposing to the disease have been identified. Apart from increasing age and female sex, these other factors account for only a minority of breast cancer diagnoses. This article provides an overview of the management of noninvasive and invasive breast cancer, which is often complex and varies according to patient factors, disease stage, and breast cancer subtype. Although much progress has been made, continued research endeavors are ongoing; enrollment of eligible patients in prospective clinical trials is an essential way to improve patient outcomes.

      Abbreviations and Acronyms:

      AI (aromatase inhibitor), ASCO (American Society of Clinical Oncology), CDK4/6 (cyclin-dependent kinase 4/6), DCIS (ductal carcinoma in situ), DFS (disease-free survival), ER (estrogen receptor), FDA (Food and Drug Administration), HER2 (human epidermal growth factor receptor 2), HR (hormone receptor), OS (overall survival), PFS (progression-free survival), PR (progesterone receptor), TNBC (triple negative breast cancer)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) list risk factors and protective factors associated with breast cancer, (2) recognize the prognostic and therapeutic significance of tumor estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression for breast cancer, (3) describe the current trends in the locoregional and systemic management of operable early-stage breast cancer, and (4) recall the current goals and standard of care management of metastatic breast cancer.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation. In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Loprinzi has a consulting/advisory role with Lpath and Mundipharma and receives research funding from Janssen and Bristol-Myers Squibb. Dr Haddad has a consulting/advisory role with TerSera Therapeutics and receives research funding from Takeda.
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      Questions? Contact [email protected]
      Breast cancer is the most frequently diagnosed cancer and is a common cause of cancer-related death in women, accounting for 25% of cancer cases and 15% of cancer-related deaths worldwide.
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      Global cancer in women: burden and trends.
      As breast cancer is a heterogeneous disease, it is challenging to diagnose and treat.
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      Breast cancer: updates and advances in 2016.
      Global incidence patterns are influenced by risk factors and the availability of mammography.
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      • Ward E.M.
      • Jemal A.
      Global cancer in women: burden and trends.
      The highest breast cancer incidence rates are in North America, Australia, New Zealand, and Northern and Western Europe. Mortality rates are influenced by the occurrence of the disease and the availability of screening programs and appropriate treatment. Despite lower breast cancer incidence, breast cancer mortality rates are higher in many low-income countries, for example, in sub–Saharan Africa, because of later stage at diagnosis, suboptimal access to treatment, more aggressive biological subtypes, and younger age at diagnosis.
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      Breast cancer in Africa: prevalence, treatment options, herbal medicines, and socioeconomic determinants.
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      Breast cancer in sub-Saharan Africa: how does it relate to breast cancer in African-American women?.
      Factors associated with an increased risk of breast cancer include older age, female sex, positive family history, deleterious gene sequence variations (BRCA1, BRCA2, CHEK2, PALB2, and others; for expansion of gene symbols, use search tool at www.genenames.org),
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      Systemic treatment strategies for patients with hereditary breast cancer syndromes.
      increased mammographic breast density, reproductive factors (eg, nulliparity, early age at menarche, late age at menopause, and late age at first full-term pregnancy), a sedentary lifestyle, alcohol consumption, excess body weight (postmenopausal women), menopausal hormone therapy (combined estrogen- and progesterone-based treatments), and prior medical radiation therapy to the thorax, especially during childhood.
      • Colditz G.A.
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      Priorities for the primary prevention of breast cancer.
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      Risk-based breast cancer screening: implications of breast density.
      • Marsden J.
      Hormonal contraception and breast cancer, what more do we need to know?.
      Prospective studies have also found an association between smoking and breast cancer.
      • Mullooly M.
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      • Dallal C.M.
      • et al.
      Epidemiologic risk factors for in situ and invasive breast cancers among postmenopausal women in the National Institutes of Health–AARP Diet and Health Study.
      Conversely, physical activity and breastfeeding are associated with a reduction in breast cancer risk.
      Collaborative Group on Hormonal Factors in Breast Cancer
      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.
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      • Metsios G.S.
      • Nevill A.M.
      • Carmichael A.R.
      Physical activity, risk of death and recurrence in breast cancer survivors: A systematic review and meta-analysis of epidemiological studies.
      Breast cancer can be classified by molecular and histopathological features. The most common histologic subtype comprising 80% to 85% of all invasive breast cancers is infiltrating ductal carcinoma. Infiltrating lobular carcinoma accounts for approximately 10% to 15% of cases, whereas other rarer histologic subtypes account for 1% or less.
      • Dillon D.
      • Guidi A.J.
      • Schnitt S.J.
      Pathology of invasive breast cancer.
      Approximately 75% of patients with breast cancer have hormone receptor (HR)–positive disease, that is, estrogen receptor (ER) and/or progesterone receptor (PR) expression of 1% or more.
      • Giordano S.B.
      • Gradishar W.
      Breast cancer: updates and advances in 2016.
      Endocrine therapy targeting ER is a fundamental component of treatment in both adjuvant and metastatic settings for these patients. Furthermore, 15% to 20% of breast cancers are human epidermal growth factor receptor 2 (HER2)–positive as determined by HER2 protein overexpression measured by immunohistochemistry or gene amplification measured by fluorescence in situ hybridization.
      • Wolff A.C.
      • Hammond M.E.
      • Hicks D.G.
      • et al.
      American Society of Clinical Oncology; College of American Pathologists
      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.
      Human epidermal growth factor receptor 2 is 1 of 4 transmembrane human epidermal growth factor receptors belonging to the ErbB family involved in signal transduction pathways that mediate cell growth and differentiation. Tumors with overexpression/amplification of HER2 were associated with poor outcomes before the advent of the HER2-directed monoclonal antibody trastuzumab. Trastuzumab, typically administered in conjunction with chemotherapy, has dramatically improved disease-free survival (DFS) and overall survival (OS) clinical outcomes.
      • Slamon D.
      • Eiermann W.
      • Robert N.
      • et al.
      Breast Cancer International Research Group
      Adjuvant trastuzumab in HER2-positive breast cancer.
      • Slamon D.J.
      • Leyland-Jones B.
      • Shak S.
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      Finally, triple negative breast cancer (TNBC) describes tumors that do not express ER and PR and do not overexpress HER2. Triple negative breast cancer is heterogeneous in that it can be classified by several molecular subtypes with variable prognoses.
      • Lehmann B.D.
      • Bauer J.A.
      • Chen X.
      • et al.
      Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
      The eighth edition of the American Joint Committee on Cancer breast cancer staging manual was clinically implemented in 2018. Notably, traditional tumor/node/metastasis anatomic staging was preserved; however, staging further incorporates prognostic biomarkers including tumor grade, ER, PR, HER2, and Oncotype DX Breast Recurrence Score. Breast cancer staging has now become quite complex with more than 150 combinations of anatomic and prognostic staging groups. The full citation can be referenced for complete staging information.
      • American Joint Committee on Cancer (AJCC)
      Cancer Staging Manual for Breast Cancer, Eighth Edition.
      Landmark studies have classified breast cancer into at least 4 distinct intrinsic subtypes by molecular phenotype,
      • Perou C.M.
      • Sørlie T.
      • Eisen M.B.
      • et al.
      Molecular portraits of human breast tumours.
      • Sørlie T.
      • Perou C.M.
      • Tibshirani R.
      • et al.
      Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
      for example, luminal A, luminal B, HER2-enriched, and basal-like. Luminal A and B breast carcinomas are positive for ER and/or PR expression. The luminal B subtype is distinguished by less prominent HR expression, higher rates of proliferation, and/or HER2/neu gene amplification.
      • Cheang M.C.
      • Chia S.K.
      • Voduc D.
      • et al.
      Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer.
      Tumors with the HER2-enriched phenotype are negative for ER and PR expression and positive for HER2 gene amplification. Most breast carcinomas belong to one of these groups, and therapies targeting these receptors are available.
      • Li X.
      • Oprea-Ilies G.M.
      • Krishnamurti U.
      New developments in breast cancer and their impact on daily practice in pathology.
      The basal-like subtype, commonly negative for ER, PR, and HER2, is characterized by high expression of keratin 5, 6, and 17, higher frequency of p53 sequence variations, higher proliferative index, higher tumor grade, and worse prognosis. This subtype is most commonly seen in blacks.
      • O'Brien K.M.
      • Cole S.R.
      • Tse C.K.
      • et al.
      Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study.
      In addition, most patients with BRCA1-mutant breast carcinomas fall into this subgroup.
      • Gonzalez-Angulo A.M.
      • Timms K.M.
      • Liu S.
      • et al.
      Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer.

      Ductal Carcinoma In Situ

      Ductal carcinoma in situ (DCIS) of the breast refers to noninvasive lesions comprising malignant epithelial cells contained within the basal membrane of the terminal duct lobular units.
      • Wellings S.R.
      • Jensen H.M.
      On the origin and progression of ductal carcinoma in the human breast.
      Since the clinical implementation and prominent use of screening mammography, there has been a sharp increase in the incidence of DCIS.
      • Martínez-Pérez C.
      • Turnbull A.K.
      • Ekatah G.E.
      • et al.
      Current treatment trends and the need for better predictive tools in the management of ductal carcinoma in situ of the breast.
      Ductal carcinoma in situ has variable outcomes in that approximately 40% of lesions never become clinically apparent if untreated whereas other precursor lesions progress to invasive disease.
      The treatment approach for DCIS, although not well standardized, consists of surgery alone or combined with radiation therapy or endocrine therapy or both.
      • Zujewski J.A.
      • Harlan L.C.
      • Morrell D.M.
      • Stevens J.L.
      Ductal carcinoma in situ: trends in treatment over time in the US.
      • Morrow M.
      • O'Sullivan M.J.
      The dilemma of DCIS.
      Surgery, the mainstay of care, can be either mastectomy or lumpectomy, depending on patient- and disease-specific factors.
      • Sue G.R.
      • Lannin D.R.
      • Au A.F.
      • Narayan D.
      • Chagpar A.B.
      Factors associated with decision to pursue mastectomy and breast reconstruction for treatment of ductal carcinoma in situ of the breast.
      Clear surgical margins are the goal, as this reduces the risk of recurrence by approximately 50%.
      • Morrow M.
      • Van Zee K.J.
      • Solin L.J.
      • et al.
      Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma In Situ.
      Sentinel lymph node surgery for axillary staging is often performed in patients at high risk for invasive disease upstaging (the discovery of invasive breast cancer when DCIS is surgically excised). Five randomized trials reported that adjuvant radiation therapy after lumpectomy reduces the risk of local recurrence by approximately 50%.
      • Fisher B.
      • Land S.
      • Mamounas E.
      • Dignam J.
      • Fisher E.R.
      • Wolmark N.
      Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience.
      • Cuzick J.
      • Sestak I.
      • Pinder S.E.
      • et al.
      Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial.
      • Bijker N.
      • Meijnen P.
      • Peterse J.L.
      • et al.
      EORTC Breast Cancer Cooperative GroupEORTC Radiotherapy Group
      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.
      • Houghton J.
      • George W.D.
      • Cuzick J.
      • Duggan C.
      • Fentiman I.S.
      • Spittle M.
      UK Coordinating Committee on Cancer ResearchDuctal Carcinoma in situ Working PartyDCIS trialists in the UK, Australia, and New Zealand
      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.
      • Emdin S.O.
      • Granstrand B.
      • Ringberg A.
      • et al.
      Swedish Breast Cancer Group
      SweDCIS: radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening.
      However, it is unclear whether adjuvant radiation therapy for DCIS is always required.
      • Narod S.A.
      • Iqbal J.
      • Giannakeas V.
      • Sopik V.
      • Sun P.
      Breast cancer mortality after a diagnosis of ductal carcinoma in situ.
      There is no role for radiation therapy after mastectomy. Approximately 60% and 75% of DCIS is ER-positive. In this setting, the selective estrogen receptor modulator tamoxifen, when administered for 5 years after lumpectomy and radiotherapy, reduces the relative risk of subsequent ipsilateral and contralateral cancer.
      • Allred D.C.
      • Anderson S.J.
      • Paik S.
      • et al.
      Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP protocol B-24.
      The International Breast Cancer Intervention Study II (IBIS-II) study found that the aromatase inhibitor (AI) anastrozole was noninferior to tamoxifen in this adjuvant setting,
      • Forbes J.F.
      • Sestak I.
      • Howell A.
      • et al.
      IBIS-II investigators
      Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial.
      whereas in the National Surgical Adjuvant Breast and Bowel Project B-35 (NSABP B-35) trial, anastrozole was more effective than tamoxifen in preventing recurrences in postmenopausal women 60 years and younger who had completed lumpectomy and radiation therapy.
      • Ganz P.A.
      • Cecchini R.S.
      • Julian T.B.
      • et al.
      Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial.
      Outcomes were similar in those older than 60 years. As both radiation therapy and endocrine therapy may cause short- and long-term adverse effects, tailoring treatment is important, although challenging, given the difficulties in accurately identifying high-risk lesions. Although nomograms and molecular prognostic tools have been developed to aid risk stratification (eg, Memorial Sloan Kettering DCIS nomogram and Oncotype DX Breast DCIS score), these have limitations and are not routinely used in the clinic.
      • Martínez-Pérez C.
      • Turnbull A.K.
      • Ekatah G.E.
      • et al.
      Current treatment trends and the need for better predictive tools in the management of ductal carcinoma in situ of the breast.
      Current research is focused on developing better prognostic indices by integrating different types of predictive factors.

      Operable Stage I to III Breast Cancer

      Diagnostic Considerations

      Invasive breast cancer is commonly detected on a screening mammogram.
      Kiluk JV, ed. Breast cancer workup.
      Features worrisome for malignant tumor include a mass, architectural distortion, asymmetry, and microcalcifications, which require further work-up with a diagnostic mammogram, ultrasound, core needle biopsy, and sometimes breast magnetic resonance imaging. For persons who present with a palpable mass, the evaluation consists of a “triple assessment” of clinical examination, breast imaging (diagnostic mammography and ultrasound), and core needle biopsy. Systemic staging to evaluate for distant metastases is indicated only for patients with clinical stage III disease.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2017.
      • Puglisi F.
      • Follador A.
      • Minisini A.M.
      • et al.
      Baseline staging tests after a new diagnosis of breast cancer: further evidence of their limited indications.
      The complexity and nuances of the breast cancer work-up are beyond the scope of the article, but are described in the referenced guidelines.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2017.

      Treatment Considerations

      The treatment of breast cancer encompasses local treatment (ie, surgery, radiotherapy, or both) and systemic therapy.

      Local-Regional Therapy Considerations

      Breast and Axillary Surgery

      Breast conservation is the preferred approach for most patients with breast cancer and is possible for an increasing number of patients with the advent of newer surgical techniques
      • Yoon J.J.
      • Green W.R.
      • Kim S.
      • et al.
      Oncoplastic breast surgery in the setting of breast-conserving therapy: a systematic review.
      and the use of preoperative systemic therapy.
      • Harbeck N.
      • Gnant M.
      Breast cancer.
      However, the rates of patient-requested mastectomy, including contralateral prophylactic mastectomies, are increasing, although there is no evidence that this approach reduces breast cancer–related mortality.
      • Kurian A.W.
      • Lichtensztajn D.Y.
      • Keegan T.H.
      • Nelson D.O.
      • Clarke C.A.
      • Gomez S.L.
      Use of and mortality after bilateral mastectomy compared with other surgical treatments for breast cancer in California, 1998-2011.
      The definition of a clear surgical margin was controversial for years, but the current consensus, since 2012, is “no ink on tumor.”
      • Morrow M.
      • Harris J.R.
      • Schnitt S.J.
      Surgical margins in lumpectomy for breast cancer–bigger is not better.
      Intraoperative frozen section is increasingly available and improves surgical outcomes.
      • Gray R.J.
      • Pockaj B.A.
      • Garvey E.
      • Blair S.
      Intraoperative margin management in breast-conserving surgery: a systematic review of the literature.
      Since the late 1990s, sentinel lymph node surgery has replaced traditional axillary lymph node dissection and spares node-negative patients from the unnecessary morbidity associated with extensive axillary surgery.
      • Krag D.N.
      • Julian T.B.
      • Harlow S.P.
      • et al.
      NSABP-32: phase III, randomized trial comparing axillary resection with sentinal lymph node dissection: a description of the trial.
      Patients with a clinically negative axilla (by examination and axillary imaging) at the time of presentation can undergo sentinel lymph node surgery after completion of systemic therapy with similar sentinel node identification and false-negative rates as observed when performed before systemic therapy.
      • Hunt K.K.
      • Yi M.
      • Mittendorf E.A.
      • et al.
      Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients.
      The optimal surgical management of patients with a clinically positive axilla at diagnosis who complete a course of neoadjuvant systemic therapy remains under active investigation. Another vexing question is whether completion of axillary lymph node dissection can be avoided in selected patients who were clinically node-negative preoperatively but found to have a limited number of positive sentinel lymph nodes at surgery. The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial tested this and found no difference in OS in clinically node-negative patients who underwent lumpectomy and whole breast irradiation with no further axillary surgery compared with lymph node dissection.
      • Giuliano A.E.
      • Hunt K.K.
      • Ballman K.V.
      • et al.
      Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.
      In the AMAROS (European Organization for Research and Treatment of Cancer [EORTC] 10981-22023) trial, patients with primary breast tumor 3 cm or less in diameter and no palpable lymphadenopathy were randomized to axillary lymph node dissection or radiotherapy if a positive sentinel lymph node was detected. Both modalities provided excellent and comparable control for this patient population, although axillary radiotherapy was associated with considerably less morbidity.
      • Donker M.
      • van Tienhoven G.
      • Straver M.E.
      • 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.

      Reconstructive Surgery

      Breast reconstruction can greatly improve quality of life for patients with breast cancer. Decision making with regard to the type of reconstruction pursued (prosthetic/implant, autologous tissue, or oncoplastic) depends on the type of surgery (lumpectomy vs radical, skin-sparing, or nipple-areola–sparing mastectomy) and the requirement for adjuvant chemotherapy or radiotherapy.
      • Nahabedian M.Y.
      Factors to consider in breast reconstruction.
      Other relevant factors include the size and location of the tumor, lymph node status, physical characteristics, as well as patient comorbidities and expectations. As always, a multidisciplinary approach can facilitate optimal cosmetic and oncologic outcomes.

      Radiation Therapy

      Patients who undergo lumpectomy (also known as wide local excision) and those with high-risk disease postmastectomy (eg, tumor size >5 cm and positive lymph nodes) usually receive adjuvant radiation therapy.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Antiemesis, Version 2.2017.
      Adjuvant radiotherapy for breast cancer often includes the axilla, and in high-risk patients, comprehensive nodal irradiation of the supraclavicular and parasternal regions may be included.
      • Poortmans P.
      • Struikmans S.
      • Collette S.
      Lymph node radiotherapy improves survival in breast cancer: 10 year results of the EORTC Radiation Oncology and Breast Cancer Groups phase III trial 22922/10925.
      Currently, numerous strategies to de-escalate treatment are being explored; these aim to reduce toxicity and duration of treatment without compromising oncologic outcomes. Examples include hypofractionated radiotherapy, partial breast irradiation, and intraoperative radiotherapy.
      • Castaneda S.A.
      • Strasser J.
      Updates in the treatment of breast cancer with radiotherapy.
      Radiation therapy may be avoided in older patients with low-risk tumors. In the PRIME II (Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial) study, women 65 years and older with HR-positive, node-negative tumors 3 cm or less in size, status post lumpectomy, and receiving endocrine therapy were allocated to no further treatment or whole breast irradiation. Adjuvant radiation therapy was associated with a small but statistically significant reduction in local recurrence; however, there were no differences in rates of distant metastasis or OS.
      • Kunkler I.H.
      • Williams L.J.
      • Jack W.J.
      • Cameron D.A.
      • Dixon J.M.
      PRIME II investigators
      Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.
      The Cancer and Leukemia Group B (CALGB) 9343 trial involved women 70 years and older with stage I, ER-positive disease who were scheduled to receive adjuvant endocrine therapy; after lumpectomy, they were randomized to receive radiation therapy or not.
      • Nichol A.M.
      • Chan E.K.
      • Lucas S.
      • et al.
      The use of hormone therapy alone versus hormone therapy and radiation therapy for breast cancer in elderly women: a population-based study.
      Again, local recurrence rates at 10-year follow-up were slightly lower in the radiation therapy group, but breast cancer–specific or OS rates were comparable. Taken together, these findings support that radiation therapy may be avoided in selected older patients with low-risk tumors.

      Systemic Therapy Considerations

      Chemotherapy is a class of cytotoxic drugs that kills sensitive cancer cells. Its efficacy is correlated with the tumor proliferation rate. It can also kill normal rapidly dividing cells, which results in various adverse effects. Endocrine therapy stops or slows the growth of breast cancer by blocking the interaction of hormones, estrogen and progesterone, with tumor HRs. Biological therapies specifically target molecular components of tumor cell biology
      Biologic therapy definition.
      (eg, the monoclonal antibody trastuzumab targets HER2), and they are either naturally occurring in the body or may be made in the laboratory. Some biological therapies harness the body's immune system to kill breast cancer cells. Targeted therapy is a newer cancer treatment classification that describes drugs that target specific molecules within oncogenic pathways or genetic aberrations. Because these therapies tend to be more selective for cancer cells, they usually result in fewer adverse effects.
      The overarching goal of systemic therapy is to eliminate microscopic metastatic disease. Advances in systemic therapies have been associated with the continued improvements in breast cancer mortality over the past several decades. It may be administered preoperatively (neoadjuvant) or postoperatively (adjuvant). Neoadjuvant chemotherapy provides equivalent clinical outcomes as compared to the administration of the same regimen in the adjuvant setting. Neoadjuvant therapy can potentially downstage disease, facilitate breast conservation therapy, and reduce surgical morbidity. Furthermore, patients with TNBC or HER2-positive disease who achieve a pathological complete response (defined as no residual breast cancer in the breast or axilla) have improved long-term clinical outcomes relative to those with residual disease after neoadjuvant therapy.
      • Cortazar P.
      • Zhang L.
      • Untch M.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
      Although the prognosis of patients with operable stage I to III breast cancer is favorable, the patterns of recurrence do vary by molecular subtype. In general, those with HR-negative disease are at higher risk of relapse than are patients with HR-positive disease. In addition, recurrence typically occurs within the first 5 years of treatment for patients with HR-negative disease, whereas recurrence can occur at any time, even decades after treatment, for patients with HR-positive disease.

      Hormone Receptor-Positive, HER2-Negative

      For patients with operable HR-positive, HER2-negative breast cancer, decisions about adjuvant systemic therapy (which can be given before surgery and/or after surgery) are made on the basis of the estimated risk of recurrence and the sensitivity to the proposed treatment, as well as patient comorbidities and preferences. Endocrine therapy, which targets the estradiol-ERα axis, is typically recommended for most individuals, unless they have an excellent prognosis and/or relevant contraindications; however, not all patients benefit from adjuvant chemotherapy. Traditionally, clinicopathologic features (eg, tumor size, grade, lymph node status, and presence of lymphovascular space invasion)
      • Leong A.S.
      • Zhuang Z.
      The changing role of pathology in breast cancer diagnosis and treatment.
      have been used to estimate the likelihood of recurrence and decide whether chemotherapy is warranted. Information to estimate benefits of adjuvant endocrine therapy and chemotherapy are currently available on www.predict.nhs.uk/predict_v2.0.html. Presently, gene expression analyses of tumor specimens (eg, Oncotype DX and MammaPrint tests) can further personalize prognostic information and predict the benefit of adjuvant chemotherapy on the basis of the results of validation studies of these molecular tools from retrospectively analyzed cohorts.
      • Harris L.N.
      • Ismaila N.
      • McShane L.M.
      • et al.
      American Society of Clinical Oncology
      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.
      • Krop I.
      • Ismaila N.
      • Andre F.
      • 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.
      Early results of prospective validation studies also support their prognostic and predictive value.
      • Sparano J.A.
      A 21-gene expression assay in breast cancer.
      • Cardoso F.
      • van't Veer L.J.
      • Bogaerts J.
      • et al.
      for the MINDACT Investigators
      70-gene signature as an aid to treatment decisions in early-stage breast cancer.
      Per the National Cancer Center Network and American Society of Clinical Oncology (ASCO) guidelines, Oncotype DX can be used for ER-positive, node-negative tumors; its use in patients with 1 to 3 positive axillary lymph nodes is controversial, though commonly used.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2017.
      • Denduluri N.
      • Somerfield M.R.
      • Eisen A.
      • et al.
      Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)—negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.
      When choosing an adjuvant chemotherapy regimen, one must consider the baseline recurrence risk, toxicity profiles, likelihood of benefit, and patient comorbidities.
      • Denduluri N.
      • Somerfield M.R.
      • Eisen A.
      • et al.
      Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)—negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.
      Standard chemotherapy regimens for HER2-negative breast cancer include anthracycline- and/or taxane-based regimens (eg, doxorubicin/cyclophosphamide followed or preceded by paclitaxel)
      • Sparano J.A.
      • Wang M.
      • Martino S.
      • et al.
      Weekly paclitaxel in the adjuvant treatment of breast cancer.
      • Citron M.L.
      • Berry D.A.
      • 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.
      or 4 cycles of docetaxel/cyclophosphamide).
      • Jones S.E.
      • Savin M.A.
      • Holmes F.A.
      • et al.
      Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer.
      In patients with high-risk HER2-negative disease with an excellent performance status, anthracycline- and taxane-based regimens are preferred. Given concerns about the rare, irreversible long-term toxicities of anthracyclines (cardiac failure, myelodysplastic syndromes, and acute myeloid leukemia), carefully selecting patients who do not require these agents is important. A recent joint analysis confirmed the benefit of anthracycline combined with taxane-based chemotherapy in patients with high-risk node-positive disease.
      • Blum J.L.
      • Flynn P.J.
      • Yothers G.
      • 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).
      However, in patients with node-negative breast cancer, adjuvant anthracyclines did not confer additional benefit beyond taxane-based chemotherapy.
      Recommendations for adjuvant endocrine therapy in premenopausal patients with HR-positive, HER2-negative breast cancer include 5 years of tamoxifen for patients with low-risk disease and 10 years of tamoxifen for higher-risk patients.
      • Davies C.
      • Pan H.
      • Godwin J.
      • et al.
      Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group
      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.
      Based on the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) studies, tamoxifen or an AI combined with ovarian function suppression for 5 years is an option in women 35 years and younger and/or with high-risk disease.
      • Pagani O.
      • Regan M.M.
      • Walley B.A.
      • et al.
      TEXT and SOFT InvestigatorsInternational Breast Cancer Study Group
      Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.
      In postmenopausal women, options for adjuvant endocrine therapy include 5 to 10 years of tamoxifen (eg, a shorter duration for women with lower-risk, node-negative disease) or 5 to 10 years of an AI. Extended endocrine therapy beyond the initial 5 years is an approach that can be considered for high-risk patients who have tolerated endocrine therapy well for the first 5 years.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2017.
      Given that AIs are superior to tamoxifen in terms of DFS outcomes,
      • Thürlimann B.
      • Keshaviah A.
      • Coates A.S.
      • et al.
      Breast International Group (BIG) 1-98 Collaborative Group
      A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.
      • Wheler J.
      • Johnson M.
      • Seidman A.
      Adjuvant therapy with aromatase inhibitors for postmenopausal women with early breast cancer: evidence and ongoing controversy.
      switching approaches may also be used,
      • Kwan M.L.
      • Roh J.M.
      • Laurent C.A.
      • et al.
      Patterns and reasons for switching classes of hormonal therapy among women with early-stage breast cancer.
      for example, tamoxifen or AI for 2 to 5 years, followed by a switch to the other for 2 to 5 years to complete a total of 5 to 10 years. For patients with stage II or III disease, trials investigating endocrine therapy combined with novel therapies that target mechanisms of endocrine resistance are ongoing. The adverse effect profiles of tamoxifen and AIs differ, as illustrated in the Arimidex, Tamoxifen Alone or in Combination trial. In this study, compared with tamoxifen, anastrozole was associated with a significantly reduced incidence of endometrial cancer, vaginal bleeding and discharge, hot flashes, venous thromboembolic events, and cerebrovascular events. Conversely, tamoxifen was associated with a lower incidence of musculoskeletal issues and fractures as compared with anastrozole.
      • Baum M.
      • Budzar A.U.
      • Cuzick J.
      • et al.
      ATAC Trialists' Group
      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.

      HER2-Positive

      Standard adjuvant treatment of HER2-positive breast cancer involves chemotherapy and 1 year of trastuzumab. Endocrine therapy is recommended after completion of chemotherapy for patients who are also HR-positive. For patients with high-risk disease, 4 cycles of anthracycline-based chemotherapy followed or preceded by 12 weeks of concurrent administration of trastuzumab and taxane, or the combination of docetaxel, carboplatin, and trastuzumab for 6 cycles, are commonly used options.
      • Denduluri N.
      • Somerfield M.R.
      • Eisen A.
      • et al.
      Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)—negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.
      In a meta-analysis of 8 prospective randomized controlled trials (n=11,991), adjuvant chemotherapy with trastuzumab significantly improved DFS and OS (P<.00001), with relative risk reductions of 50% and 40%, respectively.
      • Moja L.
      • Tagliabue L.
      • Balduzzi S.
      • et al.
      Trastuzumab containing regimens for early breast cancer.
      The optimal use of adjuvant anthracyclines in HER2-positive disease is an ongoing topic of debate. Most of the adjuvant trastuzumab trials did not include patients with tumors 1 cm or less in size and negative lymph nodes; therefore, the management of small node-negative HER2-positive breast cancers is also controversial. The general recommendation is that patients with tumors greater than 0.5 cm in size, especially with adverse biological features such as lymphovascular space invasion, HR-negative status, and/or grade III histology, should be considered for treatment with adjuvant chemotherapy and trastuzumab.
      • O'Sullivan C.C.
      • Bradbury I.
      • Campbell C.
      • et al.
      Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors ≤2 cm: a meta-analysis of the randomized trastuzumab trials.
      Data from the adjuvant trastuzumab trials suggest that the incidence of asymptomatic left ventricular ejection fraction decline ranges from 4.1% to 30.1% during or after trastuzumab therapy, but the rates of symptomatic congestive heart failure are much lower, ranging from 0.6% to 3.8%.
      • Dang C.
      • Guo H.
      • Najita J.
      • et al.
      Cardiac outcomes of patients receiving adjuvant weekly paclitaxel and trastuzumab for node-negative, ERBB2-positive breast cancer.
      • Advani P.P.
      • Ballman K.V.
      • Dockter T.J.
      • Colon-Otero G.
      • Perez E.A.
      Long-term cardiac safety analysis of NCCTG N9831 (Alliance) adjuvant trastuzumab trial.
      • Cameron D.
      • Piccart-Gebhart M.J.
      • Gelber R.D.
      • et al.
      Herceptin Adjuvant (HERA) Trial Study Team
      11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.

      Slamon DJ, Eiermann W, Robert NJ, et al, on behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. Paper presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract S5-04.

      • Romond E.H.
      • Jeong J.H.
      • Rastogi P.
      • et al.
      Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer.
      Unlike anthracycline-associated cardiac toxicity, trastuzumab-associated cardiomyopathy is usually reversible with discontinuation of treatment. Given concerns about chemotherapy-related toxicities, attempts at cautious therapy de-escalation are ongoing. The results of the Adjuvant Paclitaxel and Trastuzumab trial strongly support that 12 weekly doses of paclitaxel and trastuzumab, followed by trastuzumab monotherapy to complete 1 year of treatment, are highly effective for patients with node-negative tumors less than 3 cm in size.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2017.
      • Tolaney S.M.
      • Barry W.T.
      • Dang C.T.
      • et al.
      Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.
      Given the development of novel agents targeting HER2, trials evaluating dual HER2-directed therapy for adjuvant treatment were conducted. In the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation Study (ALTTO), the combination of trastuzumab with the oral epidermal growth factor receptor/HER2 tyrosine kinase inhibitor lapatinib was not found to be better than trastuzumab monotherapy.
      • Piccart-Gebhart M.
      • Holmes E.
      • Baselga J.
      • et al.
      Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial.
      In the APHINITY (A Study of Pertuzumab in Addition to Chemotherapy and Trastuzumab as Adjuvant Therapy in Participants With Human Epidermal Growth Receptor 2 (HER2)-Positive Primary Breast Cancer) trial, 4805 patients were randomized to adjuvant chemotherapy and trastuzumab with placebo or the HER2 monoclonal antibody pertuzumab that inhibits receptor dimerization. Although the study found a significant improvement in 3-year invasive DFS (93.1% with placebo vs 94.2% with pertuzumab; P=.045), the relatively small absolute benefit of adding pertuzumab to trastuzumab needs to be weighed against the additional toxicity (increased diarrhea, rash, etc), longer treatment sessions, and increased costs when making adjuvant treatment decisions.

      Hormone Receptor-Negative, HER2-Negative

      There are no Food and Drug Administration (FDA)–approved targeted therapies for TNBC; therefore, chemotherapy is the mainstay of treatment. Adjuvant therapy is not generally recommended for node-negative tumors 0.5 cm or less in size, but 4 cycles of docetaxel/cyclophosphamide can be considered for tumors 0.6 to 1.0 cm in size if adverse pathological factors are present. Anthracycline combined with taxane-based therapy is often used in patients with tumors greater than 2 cm in size and/or positive lymph nodes.
      • Blum J.L.
      • Flynn P.J.
      • Yothers G.
      • 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).
      In the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial, 24-week adjuvant therapy with the oral antimetabolite capecitabine was compared with no additional therapy in women with HER2-negative breast cancer who had residual disease in the breast and/or axilla after neoadjuvant chemotherapy. Capecitabine was associated with a statistically significant survival advantage, notably in patients with HR-negative disease, and it is an option for selected patients.
      • Masuda N.
      • Lee S.J.
      • Ohtani S.
      • et al.
      Adjuvant capecitabine for breast cancer after preoperative chemotherapy.
      Furthermore, clinical trials are ongoing to assess the role of immunotherapy and/or targeted therapies in the adjuvant setting.

      Bone-Modifying Agents

      Adjuvant bisphosphonate therapy should be considered for postmenopausal patients with HR-positive, HER2-negative breast cancer if they are candidates for systemic therapy and there are no relevant patient comorbidities.
      • Dhesy-Thind S.
      • Fletcher G.G.
      • Blanchette P.S.
      • et al.
      Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline.
      This recommendation is based on bone preservation reasons as AIs can reduce bone mineral density, as can ovarian function suppression or therapeutic salpingo-oophorectomy in premenopausal women. Furthermore, a large meta-analysis has revealed that specific bisphosphonates (intravenous zoledronic acid and oral clodronate) decrease recurrent breast cancer risk (primarily risk of bone metastasis) and improve OS.
      • Hadji P.
      • Coleman R.E.
      • Wilson C.
      • et al.
      Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European panel.
      • Gnant M.
      • Mlineritsch B.
      • Stoeger H.
      • et al.
      Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
      Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial.
      Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
      Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
      The ASCO guidelines recommend adjuvant bisphosphonates as standard of care for postmenopausal patients (by natural menopause or ovarian function suppression or ovarian ablation) who are candidates for adjuvant endocrine therapy, regardless of bone mineral density.
      • Dhesy-Thind S.
      • Fletcher G.G.
      • Blanchette P.S.
      • et al.
      Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: a Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline.
      • Gnant M.
      • Mlineritsch B.
      • Stoeger H.
      • et al.
      Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
      Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial.
      Based on the results of the ABCSG-18 trial,
      • Gnant M.
      • Pfeiler G.
      • Dubsky P.C.
      • et al.
      Austrian Breast and Colorectal Cancer Study Group
      Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.
      denosumab may also be considered as an alternative, though it is not endorsed by ASCO guidelines, as its effect on clinical outcomes remains to be defined.

      Metastatic Breast Cancer

      With rare exception, patients with metastatic breast cancer cannot be cured of their disease. The goals of care are 4-fold, and they should be focused on patients having (1) the fewest symptoms or complications of their cancer, (2) the fewest adverse effects of cancer treatment, (3) the longest possible life, and (4) the best quality of life. Given that metastatic breast cancer is a systemic disease, locoregional therapy with surgery and/or radiation is used only for palliative intent. Systemic therapy is the mainstay of treatment, and an overview of treatment options based on molecular subtype is presented in the Table.
      TableSystemic Treatment Options for Stage IV Breast Cancer
      CDK4/6 = cyclin-dependent kinase 4/6; GnRH = gonadotropin-releasing hormone; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; mTOR = mechanistic target or rapamycin; PARP = poly(ADP ribose) polymerase.
      HR statusHER2 statusOther characteristicsSystemic treatment options
      Clinical trials should be considered for all lines of therapy, regardless of tumor molecular subtype.
      PositiveNegative• Ovarian ablation or ovarian suppression (GnRH analog and goserelin)
      For premenopausal patients, ovarian ablation or suppression may be combined with tamoxifen, but it is required when combined with an aromatase inhibitor, fulvestrant, and/or targeted agents (CDK4/6 or mTOR inhibitors).


      • Aromatase inhibitor (letrozole, anastrozole, and exemestane)

      • Tamoxifen

      • Fulvestrant

      • CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib) plus endocrine therapy

      • Abemaciclib (monotherapy)

      • mTOR inhibitor (everolimus) plus endocrine therapy

      • Sequential single-agent chemotherapy (eg, doxorubicin/epirubicin, pegylated liposomal doxorubicin, paclitaxel, nab-paclitaxel, docetaxel, eribulin, capecitabine, gemcitabine, vinorelbine, carboplatin, cisplatin, cyclophosphamide, and ixabepilone)
      Visceral crisis• Combination chemotherapy
      AnyPositive• Trastuzumab plus pertuzumab plus taxane-based chemotherapy

      • Ado-trastuzumab emtansine

      • Trastuzumab plus lapatinib

      • Lapatinib plus capecitabine

      • Trastuzumab plus chemotherapy
      PositivePositive• Trastuzumab plus endocrine therapy
      NegativeNegative• Sequential single-agent chemotherapy
      Visceral crisis• Combination chemotherapy
      AnyNegativeGermline sequence variation in BRCA1 or BRCA2• PARP inhibitors
      Several Food and Drug Administration–registered clinical trials with PARP inhibitors are completed or in progress for treatment of metastatic breast cancer in patients with a germline sequence variation in BRCA1 or BRCA2.
      AnyAnyBone metastases; supportive care• Bisphosphonates (zoledronic acid and pamidronate)

      • Denosumab
      a CDK4/6 = cyclin-dependent kinase 4/6; GnRH = gonadotropin-releasing hormone; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; mTOR = mechanistic target or rapamycin; PARP = poly(ADP ribose) polymerase.
      b Clinical trials should be considered for all lines of therapy, regardless of tumor molecular subtype.
      c For premenopausal patients, ovarian ablation or suppression may be combined with tamoxifen, but it is required when combined with an aromatase inhibitor, fulvestrant, and/or targeted agents (CDK4/6 or mTOR inhibitors).
      d Several Food and Drug Administration–registered clinical trials with PARP inhibitors are completed or in progress for treatment of metastatic breast cancer in patients with a germline sequence variation in BRCA1 or BRCA2.

      Hormone Receptor-Positive, HER2-Negative

      An increasing number of therapeutic options are available for patients with HR-positive, HER2-negative metastatic breast cancer. In the absence of a visceral crisis, endocrine-based regimens are preferred as first-line therapy over chemotherapy, given the efficacy of this approach and the more favorable toxicity profile.
      • Bonotto M.
      • Gerratana L.
      • Di Maio M.
      • et al.
      Chemotherapy versus endocrine therapy as first-line treatment in patients with luminal-like HER2-negative metastatic breast cancer: a propensity score analysis.
      As for all patients with breast cancer who relapse after adjuvant therapy, reassessing tumor ER, PR, and HER2 status is important to guide further treatment. Traditionally, AI monotherapy was the standard approach for most patients with postmenopausal HR-positive, HER2-negative metastatic breast cancer. However, the advent of the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (eg, palbociclib, ribociclib, and abemaciclib) has been practice changing on the basis of the results of phase III trials showing a near doubling of progression-free survival (PFS) and a 10-month absolute PFS benefit when letrozole was combined with palbociclib (PALOMA-2 [A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer])
      • Finn R.S.
      • Martin M.
      • Rugo H.S.
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      or ribociclib (MONALEESA-2 [Study of Efficacy and Safety of Ribociclib (LEE011) in Postmenopausal Women With Advanced Breast Cancer]) as first-line therapy.
      • Hortobagyi G.N.
      • Stemmer S.M.
      • Burris H.A.
      • et al.
      Ribociclib as first-line therapy for HR-positive, advanced breast cancer.
      Furthermore, adding abemaciclib to letrozole or anastrozole improved PFS as compared with letrozole or anastrozole alone in women with HR-positive, HER2-negative metastatic breast cancer enrolled in the phase III MONARCH 3 (A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer) study; however, at the time of writing, FDA approval has not been granted for this indication. To date, the addition of a CDK4/6 inhibitor to endocrine therapy has not shown an improvement in OS. This is important, as CDK4/6 inhibitors are expensive and their use can result in significant patient inconvenience (ie, extra clinical visits and blood draws to monitor hematologic toxicities). Because many patients can do well for years when treated with endocrine therapy alone, not all patients need a CDK4/6 inhibitor as a part of first-line endocrine therapy, and the decision should be individualized for each patient. Notably, because premenopausal women were not included in PALOMA-2 and MONALEESA-2 trials, the use of CDK4/6 inhibitors in this setting is undefined; studies to assess their additional benefit in these patients are in progress. For the small number of postmenopausal women who have not received prior endocrine therapy or have de novo metastatic breast cancer, the FALCON (A Global Study to Compare the Effects of Fulvestrant and Arimidex in a Subset of Patients With Breast Cancer) trial reported that the selective estrogen receptor downregulator fulvestrant improved PFS in comparison to patients who received anastrozole.
      • Robertson J.F.R.
      • Bondarenko I.M.
      • Trishkina E.
      • et al.
      Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.
      It may be considered for first-line therapy in this specific patient population.
      After disease progression, there are a number of other endocrine therapy–based options that can be used in the second-line setting and beyond. Commonly used agents include nonsteroidal AIs (anastrozole or letrozole), the steroidal AI, exemestane, tamoxifen, and fulvestrant. If a CDK4/6 inhibitor had not been previously administered, it may be used with one of these other endocrine agents. Alternatively, the mechanistic target or rapamycin inhibitor everolimus that targets a common pathway of endocrine resistance can be combined with one of these endocrine agents on the basis of trials showing an improvement in PFS over endocrine monotherapy.
      • Baselga J.
      • Campone M.
      • Piccart M.
      • et al.
      Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
      • Bachelot T.
      • Bourgier C.
      • Cropet C.
      • et al.
      Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.
      After the aforementioned options have been used, the following additional hormonal treatment options can be considered: megestrol acetate, fluoxymesterone, and high dose of estradiol.
      • Bines J.
      • Dienstmann R.
      • Obadia R.M.
      • et al.
      Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial.
      • Schifeling D.J.
      • Jackson D.V.
      • Zekan P.J.
      • Muss H.B.
      Fluoxymesterone as third line endocrine therapy for advanced breast cancer: a phase II trial of the Piedmont Oncology Association.
      • Iwase H.
      • Yamamoto Y.
      Clinical benefit of sequential use of endocrine therapies for metastatic breast cancer.
      Patients with HR-positive metastatic breast cancer can often be treated for years (or sometimes decades) with these therapeutic options while maintaining a good quality of life. If patients have been receiving various hormonal therapy agents for a long period of time, sometimes previously used drugs can be reused with beneficial results. In addition, hormone withdrawal treatment maneuvers can lead to tumor regression.
      • Boyer M.J.
      • Tattersall M.H.
      Diethylstilbestrol revisited in advanced breast cancer management.
      • Gockerman J.P.
      • Spremulli E.N.
      • Raney M.
      • Logan T.
      Randomized comparison of tamoxifen versus diethylstilbestrol in estrogen receptor-positive or -unknown metastatic breast cancer: a Southeastern Cancer Study Group trial.
      Commonly, chemotherapy is recommended after options for endocrine therapy have been exhausted; however, for patients with severe symptoms and/or an impending visceral crisis, systemic chemotherapy may be preferred. Sequential single-agent chemotherapy is often sufficient and preferred on the basis of meta-analyses showing similar OS outcomes when this approach is compared with combination chemotherapy; however, response rates are higher with combination chemotherapy and this approach may be warranted in patients with severe symptoms and/or an impending visceral crisis. Because there is no clear information as to the best sequence of chemotherapy agents, selecting treatment regimens according to patient preferences in terms of schedule, toxicities, and route of administration is advised.

      HER2-Positive

      Trastuzumab has dramatically improved patient outcomes since its FDA approval for use in HER2-positive metastatic breast cancer.
      • O'Sullivan C.C.
      • Smith K.L.
      Therapeutic considerations in treating HER2-positive metastatic breast cancer.
      However, approximately 35% of patients do not respond to trastuzumab (primary resistance) and approximately 70% become resistant within 1 year (secondary resistance).
      • Santa-Maria C.A.
      • Nye L.
      • Mutonga M.B.
      • Jain S.
      • Gradishar W.J.
      Management of metastatic HER2-positive breast cancer: where are we and where do we go from here?.
      Trastuzumab combined with taxane-based chemotherapy (docetaxel or paclitaxel) had been standard first-line therapy for patients with HER2-positive metastatic breast cancer for many years.
      • Slamon D.J.
      • Leyland-Jones B.
      • Shak S.
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      In the past decade, 3 additional HER2-directed therapies have been approved for use in HER2-positive metastatic breast cancer: lapatinib, pertuzumab, and the antibody-drug conjugate ado-trastuzumab emtansine.
      The discovery that continuing trastuzumab beyond disease progression could still confer clinical benefit was an important clinical advance.
      • von Minckwitz G.
      • du Bois A.
      • Schmidt M.
      • 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.
      A subsequent pioneering trial randomized women previously treated with anthracycline, taxane, and trastuzumab to capecitabine alone or combined with lapatinib. The combination resulted in an improved median time to progression.
      • Geyer C.E.
      • Forster J.
      • Lindquist D.
      • et al.
      Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
      Another trial compared lapatinib alone or combined with trastuzumab in patients with HER2-positive trastuzumab-refractory metastatic breast cancer.
      • Blackwell K.L.
      • Burstein H.J.
      • Storniolo A.M.
      • 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.
      In this heavily pretreated population, dual HER2-targeted therapy was associated with a 4.5-month survival advantage. All these trials support that it is beneficial to continue some form of HER2-directed therapy after disease progression. This is often done in combination with sequential chemotherapy agents or endocrine therapy for those patients with HR-positive disease.
      In the CLEOPATRA (A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer) trial, patients were randomized to first-line treatment with docetaxel, trastuzumab, and placebo/pertuzumab.
      • Swain S.M.
      • Baselga J.
      • Kim S.B.
      • et al.
      CLEOPATRA Study Group
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      The median OS in the pertuzumab arm was 56.5 months as compared with 40 months in the placebo arm. Despite an increase in diarrhea, mucositis, and rash, no additional cardiotoxicity was noted for those receiving dual HER2-targeted therapy compared with trastuzumab monotherapy. This trial has defined this regimen as ASCO guideline–recommended first-line therapy for HER2-positive metastatic breast cancer.
      • Swain S.M.
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      • Cortés J.
      • et al.
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      Ado-trastuzumab emtansine was shown to be superior to the combination of capecitabine and lapatinib in patients previously treated with trastuzumab plus taxane-based chemotherapy.
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      • Miles D.
      • Gianni L.
      • et al.
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      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      It is therefore commonly recommended as a second-line treatment.
      • National Comprehensive Cancer Network
      NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2.2017.
      Overall, treatment options for patients with HER2-positive metastatic breast cancer have continued to improve with further advances in HER2-directed therapy, and the median OS is approaching 5 years.
      • Loibl S.
      • Gianni L.
      HER2-positive breast cancer.
      Despite these advances, the identification and investigation of newer and more effective therapies, notably those used to reverse resistance to HER2-directed therapies, remain a critical need. One vexing problem that is in need of improved therapies is the high incidence of HER2-positive central nervous system metastases. With the improved management of systemic disease, up to half of patients will develop brain metastases and/or leptomeningeal carcinomatosis.
      • Lim E.
      • Lin N.U.
      Updates on the management of breast cancer brain metastases.

      Hormone Receptor-Negative, HER2-Negative

      The median OS for patients diagnosed with metastatic TNBC is approximately 11 months; therefore, better treatments are urgently needed.
      • Székely B.
      • Silber A.L.
      • Pusztai L.
      New therapeutic strategies for triple-negative breast cancer.
      Currently, the only FDA-approved option for management is systemic chemotherapy. The use of sequential single agents is generally preferred, as opposed to using combined chemotherapy. Options include taxanes, platinum-based compounds, vinca alkaloids, antimetabolites, and other antitubulins (eg, eribulin). There is no “best” agent, although response rates to platinum-based chemotherapy are higher than seen when platinum-based chemotherapy is used in patients with HR-positive breast cancer.
      • Gerratana L.
      • Fanotto V.
      • Pelizzari G.
      • Agostinetto E.
      • Puglisi F.
      Do platinum salts fit all triple negative breast cancers?.
      Participation in a clinical trial should be considered for all patients with metastatic TNBC who have a good performance status. Targeted therapies under study include the poly(ADP-ribose) polymerase inhibitors, androgen receptor antagonists, and immunotherapies, either as monotherapy or in combination with other standard or investigational agents.
      • Székely B.
      • Silber A.L.
      • Pusztai L.
      New therapeutic strategies for triple-negative breast cancer.
      • Robson M.
      • Im S.A.
      • Senkus E.
      • et al.
      Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.

      Supportive Care

      Patients with breast cancer experience many challenges during their treatment journey that spans diagnosis, treatment, recovery, and surveillance.
      • Ng Z.X.
      • Ong M.S.
      • Jegadeesan T.
      • Deng S.
      • Yap C.T.
      Breast cancer: exploring the facts and holistic needs during and beyond treatment.
      A holistic approach to patient care is important, given that overall well-being is related to how well the physical, social, financial, emotional, psychological, and spiritual needs of the patient are addressed. Each patient has unique needs, which should continually be reassessed throughout the course of the disease trajectory; the use of a multidisciplinary team is ideal.
      • Taylor C.
      • Shewbridge A.
      • Harris J.
      • Green J.S.
      Benefits of multidisciplinary teamwork in the management of breast cancer.
      Health care professionals must effectively address the vast array of potential physical adverse effects due to surgery (lymphedema, reduced arm/shoulder mobility, and body image concerns), chemotherapy (nausea, alopecia, infections, neuropathy, and mucositis), endocrine therapy (arthralgias, hot flashes, and vaginal dryness), and radiotherapy (fatigue and skin toxicity). Furthermore, attention to potential late and/or long-term toxicities such as osteopenia/osteoporosis, infertility, premature menopause, cardiac dysfunction, and cognitive impairment is essential.
      • O'Sullivan C.C.
      • Ruddy K.J.
      Management of potential long-term toxicities in breast cancer patients.
      Patients can greatly benefit from targeted exercise programs, lifestyle modifications, integrative approaches, and psychological and social support.
      • Campbell-Enns H.J.
      • Woodgate R.L.
      The psychosocial experiences of women with breast cancer across the lifespan: a systematic review.
      Given that patients with metastatic breast cancer often have unique issues and concerns,
      • Cardoso F.
      • Harbeck N.
      • Mertz S.
      • Fenech D.
      Evolving psychosocial, emotional, functional, and support needs of women with advanced breast cancer: results from the Count Us, Know Us, Join Us and Here & Now surveys.
      there are dedicated support groups for these patients.
      • Di Lascio S.
      • Pagani O.
      Is it time to address survivorship in advanced breast cancer? A review article.

      Conclusion

      The evaluation and management of DCIS and invasive breast cancer is complex, and numerous diagnostic and treatment options are available. Effective communication between the oncologist, the patient, his or her caregivers, and the multidisciplinary team is essential to provide quality patient care. Minimizing treatment-related toxicities and improving treatment efficacy are key to maintain—and improve—quality of life for patients with breast cancer. Participation in clinical trials, when appropriate, can allow patients to gain access to promising therapies and contribute to the advancement of our knowledge of the field.

      Supplemental Online Material

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