Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer

INTRODUCTION — In the United States, breast cancer is the most commonly diagnosed non-skin cancer and the second most common cause of cancer death in women [1].

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology, which has been associated with a reduction in breast cancer mortality [2,3].

This topic will provide an overview of the initial treatment of breast cancer and post-treatment surveillance. The epidemiology, clinical manifestations, diagnosis, staging of breast cancer, and specific discussions of the multimodality treatments for early breast cancer and the approach to metastatic disease are discussed elsewhere. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer" and "Overview of the approach to metastatic breast cancer" and "The role of local therapies in metastatic breast cancer".)

Because ductal carcinoma in situ (DCIS) and invasive breast cancer are managed differently, we will restrict discussion in this topic to invasive breast cancer. A discussion on DCIS is covered separately. (See "Breast ductal carcinoma in situ: Epidemiology, clinical manifestations, and diagnosis" and "Ductal carcinoma in situ: Treatment and prognosis".)

PATIENT STRATIFICATION — The vast majority of patients with newly diagnosed breast cancer in the United States and developed countries have no evidence of metastatic disease. For these patients, the treatment approach depends on the stage at presentation. For treatment purposes, breast cancer is characterized using the Tumor, Node, Metastasis system (TNM). Where clinical guidance is provided in this topic, the anatomic staging system set forth in the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual is used (table 1). Moreover, the AJCC recommends use of the prognostic staging system for breast cancer that incorporates biomarkers, if resources are available (table 2 and table 3). This staging system is discussed in detail elsewhere. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

Nonmetastatic breast cancer is broadly considered in two categories:

●Early stage – This includes patients with stage I, IIA, or a subset of stage IIB disease (T2N1).

●Locally advanced – This includes a subset of patients with stage IIB disease (T3N0) and patients with stage IIIA to IIIC disease.

Approximately 5 percent of patients will have simultaneous metastatic disease identified at the initial presentation (de novo stage IV breast cancer). The treatment approach to these patients is discussed separately. (See "Overview of the approach to metastatic breast cancer" and "The role of local therapies in metastatic breast cancer".)

EARLY-STAGE BREAST CANCER — In general, patients with early-stage breast cancer undergo primary surgery (lumpectomy or mastectomy) to the breast and regional nodes with or without radiation therapy (RT) (table 4 and algorithm 1).

Following definitive local treatment, adjuvant systemic therapy may be offered, based on primary tumor characteristics such as tumor size, grade, number of involved lymph nodes, the status of estrogen (ER) and progesterone (PR) receptors, and expression of the human epidermal growth factor 2 (HER2) receptor.

However, some patients with early-stage invasive breast cancer (particularly those with HER2-positive or triple-negative disease) may be treated with neoadjuvant therapy first, followed by surgery. Neoadjuvant therapy is discussed below. (See 'Surgical approach after neoadjuvant treatment' below.)

Breast-conserving therapy — Breast-conserving therapy (BCT) is comprised of breast-conserving surgery (BCS; ie, lumpectomy) plus RT. The goals of BCT are to provide the survival equivalent of mastectomy, a cosmetically acceptable breast, and a low rate of recurrence in the treated breast. BCT allows patients with invasive breast cancer to preserve their breast without sacrificing oncologic outcome. Successful BCT requires complete surgical removal of the tumor (with negative surgical margins) followed by moderate-dose RT to eradicate any residual disease. (See "Breast-conserving therapy".)

Among women with operable breast cancer, randomized trials have demonstrated equivalent disease-free and overall survival between mastectomy and breast-conserving therapy [4-7]. However, since the time that these trials were conducted, progress has been made in adjuvant therapy, and more recent observational studies suggest that breast-conserving therapy is associated with at least comparable survival to mastectomy and even with improved survival in some studies [8-11].

Criteria that preclude BCT are as follows (see "Breast-conserving therapy", section on 'Patient selection for BCT'):

●Multicentric disease

●Large tumor size in relation to breast

●Presence of diffuse malignant-appearing calcifications on imaging (ie, mammogram or magnetic resonance imaging [MRI])

●Prior history of chest RT (eg, mantle radiation for Hodgkin disease)

●Pregnancy

●Persistently positive margins despite attempts at re-excision

For patients who desire BCT but are not candidates at the time of presentation, an alternative approach is the use of neoadjuvant therapy, which may allow for BCS without compromising survival outcomes. (See 'Neoadjuvant systemic therapy' below.)

Mastectomy — A mastectomy is indicated for patients who are not candidates for BCT and those who prefer mastectomy. (See "Mastectomy", section on 'Indications for mastectomy'.)

Role of RT — Postmastectomy radiation therapy (RT) is indicated for patients at high risk for local recurrence, such as those with cancer involving the deep margins and pathologically involved axillary lymph nodes.

If the likelihood of postmastectomy RT is high preoperatively, this may affect the choice of mastectomy type, the choice of the reconstructive approach, and optimal timing of the breast reconstruction (immediate versus delayed).

Thus, preoperative coordination of care assures the best outcome. In many centers, this is accomplished by multi-disciplinary breast clinics.

Evaluation of the axillary nodes — The risk for metastases to the axillary nodes is related to tumor size and location, histologic grade, and the presence of lymphatic invasion within the primary tumor. Although internal mammary or supraclavicular nodes may be involved at the initial presentation, they rarely occur in the absence of axillary node involvement. (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Internal mammary lymph nodes' and "Overview of management of the regional lymph nodes in breast cancer", section on 'Supraclavicular lymph nodes'.)

The evaluation of the regional nodes depends on whether axillary involvement is suspected prior to surgery:

●For patients presenting with clinically suspicious axillary lymph nodes, a preoperative work-up including ultrasound plus fine needle aspiration or core biopsy can help to determine the best surgical approach and whether neoadjuvant therapy should be considered. (See 'Neoadjuvant systemic therapy' below.)

•For patients with a positive biopsy who proceed directly to surgery (rather than neoadjuvant therapy), an axillary node dissection should be performed at the time of breast surgery. (See "Technique of axillary lymph node dissection".)

-The management of the axilla for those treated with neoadjuvant treatment is discussed below. (See 'Surgical approach after neoadjuvant treatment' below.)

•For patients presenting with a negative biopsy, no further work-up is required prior to surgery. These patients should undergo a sentinel lymph node biopsy (SLNB) at the time of surgery. (See "Overview of sentinel lymph node biopsy in breast cancer" and "Sentinel lymph node biopsy in breast cancer: Techniques".)

●Patients with a clinically negative axillary examination should undergo an SLNB at the time of surgery. Further evaluation of the regional nodes depends on the findings at SLNB. Patients who have one or two pathologically involved sentinel nodes may not require a complete axillary node dissection [12]. Patients with three or more pathologically involved sentinel nodes typically undergo axillary node dissection, although the patient's performance status and comorbidities are also considered. (See "Overview of sentinel lymph node biopsy in breast cancer".)

Adjuvant systemic therapy

Systemic therapy refers to the medical treatment of breast cancer using endocrine therapy, chemotherapy, and/or biologic therapy. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)

Tumor characteristics predict which patients are likely to benefit from specific types of therapy (table 4 and algorithm 1). For example, hormone receptor-positive patients benefit from the use of endocrine therapy. In addition, patients with HER2-positive cancers benefit from treatment using HER2-directed treatment. (See "Prognostic and predictive factors in early, non-metastatic breast cancer".)

For patients with early-stage breast cancer, treatment is based on tumor characteristics, patient status, and patient preferences:

●In general, patients with hormone receptor-positive breast cancer should receive endocrine therapy. Whether they also should receive adjuvant chemotherapy depends on patient and tumor characteristics. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Indications for treatment'.)

•We offer chemotherapy to patients with early-stage hormone receptor-positive, HER2-negative cancers that have high-risk characteristics. (See "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer".)

•In the absence of high-risk features, we do not administer chemotherapy.

•Select patients with high-risk, node-positive, ER-positive, HER2-negative breast cancer are candidates for adjuvant treatment with the cyclin-dependent kinase 4/6 inhibitor abemaciclib. Patient selection is discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Incorporation of targeted therapies for select patients'.)

●For patients with ER/PR and HER2-negative disease (triple-negative breast cancer), we typically administer adjuvant chemotherapy if the tumor size is ≥0.5 cm. Because these patients are not candidates for endocrine therapy or treatment with HER2-directed agents, chemotherapy is their only option for adjuvant treatment, following or before radiotherapy. Patients with a triple-negative breast cancer <0.5 cm in size may forego adjuvant chemotherapy in most cases, due to minimal, if any, survival advantage. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

●Patients with HER2-positive breast cancer with a tumor size >1 cm typically receive a combination of chemotherapy plus HER2-directed therapy. The management of small (≤1 cm) HER2-positive breast cancers is controversial. Following chemotherapy, patients with hormone receptor-positive disease should also receive adjuvant endocrine therapy. (See "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Additional considerations for HER2-positive disease'.)

●Special considerations for those with rare-histology tumors are discussed elsewhere. (See "Breast cancers with rare histologies".)

LOCALLY ADVANCED BREAST CANCER — Locally advanced breast cancer is best managed with multimodality therapy employing systemic and locoregional therapy (table 4 and algorithm 1). (See 'Patient stratification' above.)

Neoadjuvant systemic therapy — Most patients with locally advanced breast cancer, and some with earlier-stage disease (particularly if triple negative or human epidermal growth factor receptor 2 [HER2] positive), are treated with neoadjuvant systemic therapy. The goal of treatment is to induce a tumor response before surgery and enable breast conservation. Neoadjuvant chemotherapy also provides information about response to therapy that may be useful at a future time, if the cancer recurs.

Neoadjuvant therapy results in long-term distant disease-free survival (DFS) and overall survival (OS) comparable to that achieved with primary surgery followed by adjuvant systemic therapy. (See "General principles of neoadjuvant management of breast cancer", section on 'Patient selection'.)

Our approach to the selection of treatment in the neoadjuvant setting is outlined below:

●For most patients with hormone receptor-positive disease receiving neoadjuvant therapy, we offer chemotherapy rather than neoadjuvant endocrine therapy. Chemotherapy is associated with higher response rates in a shorter time period. For select patients with hormone-positive disease, neoadjuvant endocrine therapy may be an appropriate option if there are serious comorbidities or other factors (eg, patient preference) that necessitate that strategy. Patient selection for neoadjuvant chemotherapy versus endocrine therapy among those with hormone receptor-positive disease is discussed elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Selection of treatment'.)

●For patients with HER2-positive breast cancer, a HER2-directed agent (eg, trastuzumab with or without pertuzumab) should be added to the chemotherapy regimen. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer".)

●For patients with hormone receptor-negative, HER2-negative disease, neoadjuvant therapy consists of chemotherapy, with the addition of immunotherapy for some patients with high-risk disease. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Choice of regimen'.)

Surgical approach after neoadjuvant treatment — All patients should undergo surgery following neoadjuvant systemic therapy, even if they have a complete clinical and/or radiological response. In addition, patients who experience locoregional progression (but not distant spread) while on neoadjuvant systemic therapy should proceed with surgery, rather than switching the chemotherapy regimen. (See "General principles of neoadjuvant management of breast cancer", section on 'Post-treatment evaluation and management'.)

Primary tumor — The choice between breast conservation and mastectomy after neoadjuvant treatment is dependent on the treatment response and patient characteristics (eg, breast size in relation to residual tumor size). Similar criteria used in the treatment of early-stage breast cancer are applied. However, patients who present with a large (ie, T4) breast lesion should undergo a mastectomy following neoadjuvant treatment. (See 'Breast-conserving therapy' above and 'Mastectomy' above.)

Regional nodes — Most patients require a surgical evaluation of the regional nodes following neoadjuvant treatment. (See 'Evaluation of the axillary nodes' above and "General principles of neoadjuvant management of breast cancer", section on 'Management of the axilla'.)

Primary surgery — Although some patients may be candidates for primary surgery at presentation, patients with locally advanced disease have an extremely high risk of local recurrence and distant metastases [13]. As a result, we prefer to treat patients with locally advanced breast cancer with neoadjuvant systemic therapy first.

For patients who proceed with primary surgery, based on pathologic results, postoperative radiation therapy and adjuvant treatment should be administered. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer" and 'Adjuvant therapy' below.)

Adjuvant therapy — The use of postoperative (adjuvant) systemic therapy is guided by the patient's clinical status and tumor characteristics (table 4 and algorithm 1):

●Patients who did not receive neoadjuvant systemic therapy should receive adjuvant treatment. The use of chemotherapy, biologic therapy, and/or endocrine therapy is guided by the same principles used to determine treatment for early-stage breast cancer. (See 'Adjuvant systemic therapy' above.)

●For patients who received the full course of planned neoadjuvant chemotherapy, we take the following approach:

•Hormone receptor-positive breast cancer – Patients with hormone receptor-positive breast cancer should receive endocrine therapy to reduce the risk of breast cancer recurrence and breast cancer-related mortality. Further chemotherapy in the form of adjuvant treatment is unlikely to improve OS in this subset. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

The selection of endocrine therapy is made according to menopausal status. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Indications'.)

Patients treated with neoadjuvant endocrine therapy who undergo surgery should continue endocrine therapy in the adjuvant setting. Whether or not to administer adjuvant chemotherapy should be individualized. (See "General principles of neoadjuvant management of breast cancer".)

•Triple-negative breast cancer – Patients with hormone receptor-negative, HER2-negative (triple-negative) breast cancer who have a complete response to neoadjuvant therapy would typically not receive further chemotherapy in the adjuvant setting as there is no evidence that the addition of adjuvant chemotherapy improves OS. These patients should begin post-treatment surveillance. (See "Approach to the patient following treatment for breast cancer", section on 'Guidelines for post-treatment follow-up'.)

In cases where a triple-negative tumor has not had a complete response to neoadjuvant therapy, adjuvant capecitabine may be administered. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

For patients who initiated pembrolizumab in the neoadjuvant setting, this is typically continued in the adjuvant setting. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer", section on 'Incorporation of immunotherapy with NACT in TNBC'.)

•HER2-positive breast cancer – Patients with HER2-positive breast cancer who have a pathologic complete response at the time of surgical resection should receive trastuzumab, with or without pertuzumab, following completion of surgery to complete a year of treatment, without the addition of further chemotherapy. This recommendation is based on studies of adjuvant chemotherapy with or without trastuzumab that demonstrated that the addition of one year of trastuzumab significantly improves DFS and OS. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)

In cases where the tumor has not had a complete response to neoadjuvant therapy, adjuvant ado-trastuzumab emtansine for 14 cycles, rather than trastuzumab, is recommended. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Residual disease'.)

GERMLINE GENETIC TESTING

Whom to test — Although most breast cancers are sporadic, germline pathogenic variants in breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2 [BRCA]) and other genes account for a small percentage of breast cancers. Criteria for hereditary cancer risk evaluation and possible testing are discussed elsewhere. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes", section on 'Concerning personal or family history'.)

Those found to have BRCA mutations — Breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2 [BRCA]) mutation carriers have increased risks of developing a second breast cancer. Pathogenic variants in other genes, including tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and others, also increase the risk of a second breast cancer. Therefore, even though breast-conserving therapy is effective in these patients, they may opt to undergo bilateral mastectomy to reduce their risk of a second breast cancer. For BRCA1/2 carriers with breast cancer who do not undergo bilateral mastectomy, screening should be performed with annual mammography and breast MRI (age 30 to 75) [14]. (See "Overview of hereditary breast and ovarian cancer syndromes" and "Contralateral prophylactic mastectomy".)

Adjuvant PARP inhibition in high-risk, HER2-negative disease — For select patients with BRCA1/2 mutations and high-risk early, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, adjuvant treatment with olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), has been shown to improve disease-free survival outcomes. This is discussed in detail elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'BRCA carriers with high-risk disease'.)

Other radiation and systemic therapy considerations for BRCA1/2 mutation carriers with early breast cancer are the same as for those who are BRCA wildtype (ie, without a pathologic BRCA variant). (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)

SPECIAL CONSIDERATIONS

Rare histologies — Certain very rare subtypes of metaplastic carcinoma (eg, low-grade adenosquamous and low-grade fibromatosis-like carcinoma) have a favorable prognosis without adjuvant systemic therapies [15]. Patients with tumors of such histologies may be offered observation rather than adjuvant systemic therapies, provided that the favorable histologic type is pure (>90 percent as classified on the surgical excision, not core biopsy alone). The critical step in evaluation of such tumors, because of their rarity, is pathologic review by a highly experienced pathology service to corroborate the diagnosis. This is particularly true when omission of adjuvant therapy is being contemplated. (See "Breast cancers with rare histologies".)

Fertility preservation — Clinicians should discuss with patients the risk of infertility and possible interventions to preserve fertility prior to initiating potentially gonadotoxic therapy (eg, cryopreservation of embryos or oocytes). This discussion should occur soon after diagnosis, since some interventions to preserve fertility take time and could delay the start of treatment. This is consistent with guidance from the American Society of Clinical Oncology [16]. The topic of fertility preservation is covered in detail separately. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Older women — For some patients with estrogen receptor-positive breast cancer, in whom surgery is not an option or life expectancy is limited, primary hormonal treatment with either tamoxifen or an aromatase inhibitor without surgery or radiation therapy can be used [17]. We prefer to individualize treatment based on the presence of medical comorbidities and patient and clinician preference. (See "Overview of the approach to early breast cancer in older women", section on 'Surgery versus endocrine therapy alone for hormone receptor-positive disease'.)

Osteoclast inhibitors — The topic of osteoclast inhibitors as a potential adjuvant anticancer therapy in postmenopausal women is discussed separately. (See "Use of osteoclast inhibitors in early breast cancer", section on 'Adjuvant bone-modifying treatment for higher-risk breast cancers'.)

Male breast cancer — The topic of male breast cancer is discussed separately. (See "Breast cancer in men".)

Breast cancer in pregnancy — The treatment of breast cancer in pregnancy is discussed separately. (See "Gestational breast cancer: Treatment".)

PROGNOSIS — The majority of breast cancer recurrences occur within the first five years of diagnosis [18], particularly with hormone receptor-negative disease [19]. A discussion of the influence of hormone receptor status on short- and long-term outcomes is found elsewhere. (See "Prognostic and predictive factors in early, non-metastatic breast cancer".)

In a study of over 4000 women with operable breast cancer treated on International Breast Cancer Study Group clinical trials I to V, the annual risk of recurrence was highest during the first five years (10.4 percent) with a peak between years 1 and 2 (15.2 percent) [19]. While the highest rate of relapse is within the first few years of treatment, some recurrences occur much later. In one study of patients with stage I, II, or III breast cancer who were without evidence of disease five years out from the original diagnosis, the recurrence risks in the subsequent 5 and 10 years were still 11 and 19 percent, respectively [20]. While these results reflect outcomes among patients with all biologic subtypes of disease, the long-term risk of recurrence differs according to hormone receptor status, with late recurrences occurring more frequently among hormone receptor-positive cancers rather than hormone receptor-negative ones. A discussion of prognostic factors including hormone receptor status and other factors is found elsewhere. (See "Prognostic and predictive factors in early, non-metastatic breast cancer".)

POST-TREATMENT SURVEILLANCE — Cancer survivors who have completed treatment for breast cancer should undergo regular follow-up. Annual mammography should also be performed in patients who underwent breast-conserving therapy. The routine use of breast magnetic resonance imaging or whole-breast ultrasound is not recommended for breast cancer survivors because of a lack of evidence to inform their role in this population. In addition, laboratory tests and whole-body imaging in asymptomatic cancer survivors is not recommended. (See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse", section on 'Long-term adverse effects of primary therapy' and "Approach to the patient following treatment for breast cancer", section on 'Guidelines for post-treatment follow-up'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Breast cancer (The Basics)" and "Patient education: Choosing surgical treatment for early-stage breast cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Breast cancer guide to diagnosis and treatment (Beyond the Basics)" and "Patient education: Factors that affect breast cancer risk in women (Beyond the Basics)" and "Patient education: Treatment of early-stage, hormone-responsive breast cancer in postmenopausal women (Beyond the Basics)" and "Patient education: Treatment of early-stage, hormone-responsive breast cancer in premenopausal women (Beyond the Basics)" and "Patient education: Surgical procedures for breast cancer — Mastectomy and breast-conserving therapy (Beyond the Basics)" and "Patient education: Treatment of early HER2-positive breast cancer (Beyond the Basics)" and "Patient education: Locally advanced and inflammatory breast cancer (Beyond the Basics)")

SUMMARY

●Patient stratification – Patients with a new diagnosis of breast cancer can be stratified as having early or locally advanced disease (see 'Patient stratification' above). Treatment depends on multiple factors, as summarized (table 4 and algorithm 1).

●Early-stage breast cancer: Surgery

•The surgical approach to the primary tumor depends on the size of the tumor and the breast, and whether multifocal disease is present. Options include breast-conserving therapy (breast-conserving surgery plus radiation therapy [RT]) or mastectomy. Both approaches result in equivalent cancer-specific outcomes. (See 'Early-stage breast cancer' above and "Breast-conserving therapy" and "Mastectomy".)

•The surgical approach to the regional nodes depends on whether there is clinical evidence of lymph node involvement. (See 'Evaluation of the axillary nodes' above.)

●Early-stage breast cancer: Adjuvant systemic treatment

•Hormone receptor-positive breast cancer – Patients with hormone receptor-positive breast cancer should receive adjuvant endocrine therapy. The role of adjuvant chemotherapy in these patients requires a risk-stratified approach that takes into account patient and tumor characteristics. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Indications for treatment'.)

•Triple-negative breast cancer – Most patients with estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2)-negative disease (triple-negative breast cancer) receive chemotherapy, with an exception for very small tumors (≤0.5 cm). (See "ER/PR negative, HER2-negative (triple-negative) breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

•HER2-positive breast cancer – Patients with HER2-positive breast cancer >1 cm in size should receive a combination of chemotherapy plus HER2-directed therapy. Following chemotherapy, patients with ER-positive disease should also receive adjuvant endocrine therapy. (See "Adjuvant systemic therapy for HER2-positive breast cancer" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Additional considerations for HER2-positive disease'.)

●Locally advanced breast cancer – Most patients with locally advanced breast cancer and some with earlier-stage breast cancer (particularly if HER2 positive or triple negative) are treated with neoadjuvant systemic therapy prior to surgery. Neoadjuvant treatment improves the rate of breast conservation without compromising survival outcomes. (See 'Neoadjuvant systemic therapy' above.)

•For most patients receiving neoadjuvant treatment, we offer chemotherapy rather than endocrine therapy. A HER2-directed agent should be added to the chemotherapy regimen for tumors that are HER2 positive. For select patients with high-risk triple-negative breast cancer, we incorporate immunotherapy with neoadjuvant chemotherapy. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer" and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Selection of treatment' and "General principles of neoadjuvant management of breast cancer".)

•For patients who received neoadjuvant chemotherapy:

-Patients with hormone receptor-positive breast cancer should receive adjuvant endocrine therapy. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Indications'.)

-For patients with hormone receptor-negative breast cancer with residual disease after neoadjuvant treatment, adjuvant capecitabine is offered. (See "Approach to the patient following treatment for breast cancer", section on 'Guidelines for post-treatment follow-up' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

-Patients with triple-negative disease who initiated pembrolizumab in the neoadjuvant setting should continue it in the adjuvant setting. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

-Patients with HER2-positive breast cancer and a complete response to neoadjuvant treatment receive one year of trastuzumab, with or without pertuzumab, following completion of surgery. If residual disease is present, ado-trastuzumab emtansine is offered, rather than trastuzumab. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)

●Role of radiation therapy in early and locally advanced disease

•Following surgery (with or without neoadjuvant systemic therapy), all patients who undergo breast-conserving surgery should undergo adjuvant RT. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer".)

•Some patients treated with a mastectomy receive postmastectomy RT. The administration of adjuvant RT is typically based upon the original pretreatment stage, though pathologic response to neoadjuvant therapy may play a role as well. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer".)

●BRCA carriers – For select patients with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations and high-risk early, HER2-negative breast cancer, adjuvant treatment an inhibitor of poly(ADP-ribose) polymerase (PARP), improves disease-free survival outcomes. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Moataz N El-Ghamry, MD, who contributed to an earlier version of this topic review.