Breast Cancer Treatment & Management

Updated: May 10, 2023
  • Author: Pavani Chalasani, MD, MPH; Chief Editor: John V Kiluk, MD, FACS  more...
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Approach Considerations

Surgery is considered primary treatment for early-stage breast cancer; many patients are cured with surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and axillary lymph nodes to provide necessary prognostic information.

Preoperative (neoadjuvant) chemotherapy is used in patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. It may allow less extensive surgery (eg, permit breast-conserving surgery in patients who are not candidates for that on initial presentation, or obviate axillary lymph node dissection in patients who present with node-positive breast cancer). In patients with triple-negative (estrogen receptor, progesterone receptor, and HER2) or HER2-positive disease, response to neoadjuvant therapy can guide the selection of adjuvant therapy. [1] The American Society of Clinical Oncology has published a guideline on the optimal use of neoadjuvant therapy for women with invasive nonmetastatic breast cancer. [117]

Race may affect response to neoadjuvant therapy. In a review of Black and White women treated with neoadjuvant endocrine therapy, Black women were more likely to benefit than White women if treated at an earlier disease stage, but were less likely to benefit than White women if treated at a later disease stage. The study included 3521 white women and 365 Black women with stage I-III hormone receptor–positive breast cancer. [118]

Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Adjuvant treatment for breast cancer involves radiation therapy and systemic therapy (including a variety of chemotherapeutic, hormonal, and biologic agents).

 In early-stage breast cancer, tumor gene-expression assays can be used to determine the likelihood of recurrence and thus the potential benefit of adjuvant chemotherapy. For example, with a commercially available 21-gene assay, a recurrence score of 0 to 10 is prognostic for a 2% rate of distant recurrence at 10 years that is unlikely to be improved by adjuvant chemotherapy. A high score, which has variably been defined as 26 or 31 or higher, is predictive of chemotherapy benefit. [119]

The prospective Trial Assigning Individualized Options for Treatment (TAILORx) studied the outcome in 6711 women with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer who had a midrange recurrence score of 11 to 25. At 9 years, patients treated with chemoendocrine therapy or endocrine therapy alone had similar rates of invasive disease–free survival, freedom from disease recurrence, and overall survival. Chemotherapy offered some benefit only in women 50 years of age or younger with a recurrence score of 16 to 25, who represented 46% of this age group. [119]

A secondary analysis of the TAILORx data confirmed that there is a cohort of these women who benefit from chemotherapy. In 1389 women with a recurrence score of 26 to 100, who received adjuvant chemotherapy in addition to endocrine therapy, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93% at 5 years; in comparison, the expected rate in this population of women, if treated with endocrine therapy alone, is 79% at 5 years. [120]

In the prospective RxPONDER trial, which included 5018 women with HR-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower, premenopausal women who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy. In contrast, postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. [121, 122]

See Breast Cancer Treatment Protocols for summarized information. See Oncology Decision Point for expert commentary on breast cancer treatment decisions and related guidelines. To view multidisciplinary tumor board case discussions, see the Memorial Sloan Kettering e-Tumor Boards HR+/HER2- Metastatic Breast Cancer and Recurrent Metaplastic Triple Negative Breast Cancer.


Treatment of Invasive Breast Cancer

Surgical treatment of invasive breast cancer may consist of lumpectomy or total mastectomy. In breast cancer patients who have clinically negative nodes, surgery typically includes sentinel lymph node (SLN) dissection for staging the axilla. (See Surgical Treatment of Breast Cancer.)

In the AMAROS trial, which involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axillae who were undergoing either breast conservation or mastectomy with SLN mapping, axillary radiotherapy was found to be a better treatment option than ALN dissection (ALND) in women with a positive SLN. [123]

In this study, 744 of the patients with a positive SLN went on to receive ALND, and 681 received axillary radiotherapy. [123] After 5 years of follow-up, the axillary recurrence rate was 0.54% in the ALND group and 1.03% in the radiotherapy group, and there were no significant differences between the groups with respect to either disease-free survival (86.9% vs 82.7%) or overall survival (93.3% vs 92.5%). The rate of lymphedema in the ALND group after 5 years, however, was twice the rate seen in the radiotherapy group (28% vs 14%).

Ten-year follow-up results from the multicenter UK Standardization of Breast Radiotherapy (START) trials confirm that 3-week hypofractionated adjuvant radiotherapy—in which lower total doses of radiotherapy are delivered in fewer, larger doses (fractions)—is as effective and safe as the international standard 5-week regimen for women with early-stage breast cancer following primary surgery. Additionally, the hypofractionated regimen may cause less damage to surrounding normal breast tissue. [124]

Lumpectomy margins

The following consensus guideline, released by the Society of Surgical Oncology and the American Society for Radiation Oncology, addresses margins for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer [125] :

  • Positive margins are associated with at least a 2-fold increase in ipsilateral breast tumor recurrence (IBTR)

  • Negative margins optimize IBTR; this risk is not significantly lowered by wider margin widths

  • IBTR rates are reduced with the use of systemic therapy; in patients who do not receive adjuvant systemic therapy, margins wider than no ink on tumor are not needed

  • Biologic subtypes do not indicate the need for margins wider than no ink on tumor

  • Margin width should not determine the choice of WBI delivery technique, fractionation, and boost dose.

  • Wider negative margins than no ink on tumor are not indicated for patients with invasive lobular cancer; classic lobular carcinoma in situ (LCIS) at the margin is not an indication for reexcision; the significance of pleomorphic LCIS at the margin is not clear

  • Young age is associated with an increased risk for IBTR after breast-conserving therapy, an increased risk for local relapse on the chest wall after mastectomy, and adverse biologic and pathologic features; an increased margin width does not nullify the increased risk for IBTR in young patients

  • An extensive intraductal component (EIC) identifies patients who may have a large residual ductal carcinoma in situ (DCIS) burden after lumpectomy; when margins are negative, there is no evidence of an association between an increased risk for IBTR and EIC

Postlumpectomy radiation therapy

The purpose of radiation therapy after breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%. On the basis of results from several randomized controlled studies, irradiation of the intact breast is considered standard of care, even in the lowest-risk disease with the most favorable prognostic features. [72]

There are 2 general approaches used to deliver radiation therapy: conventional external-beam radiotherapy (EBRT) and partial-breast irradiation (PBI). Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a boost dose specifically directed to the area in the breast where the tumor was removed.

Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting ≥6 months after treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma (0.5%).

PBI is employed in early-stage breast cancer after breast-conserving surgery as a way of delivering larger fraction sizes while maintaining a low risk of late effects. Techniques that can deliver this therapy include interstitial brachytherapy (multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]).

Treatment is typically administered twice daily for 5 days. In several nonrandomized studies, these techniques have shown low local recurrence rates comparable to those of EBRT.

The American Society of Breast Surgeons (ASBrS) recommends the following selection criteria when patients are being considered for treatment with accelerated PBI [126] :

  • Age ≥45 years for all tumor types
  • All invasive subtypes or DCIS
  • Total tumor size (invasive and DCIS) ≤ 3 cm
  • T stage Tis, T1, T2 (≤ 3 cm) 
  • Margins; No tumor on ink for invasive tumors or tumors involved with DCIS;  ≥2 mm for DCIS 
  • Node negative 
  • Multifocal acceptable if total span of tumors is ≤3 cm
  • Estrogen receptor positive or negative
  • Focal lymphovascular invasion
  • No genetic mutations

Potential complications of PBI are catheter placement followed by removal secondary to any of the following:

  • Inadequate skin spacing
  • Infection
  • Seroma
  • Fibrosis
  • Chronic pain
  • Disease recurrence

An observational study using data from the SEER–Medicare linked database on 35,947 women aged 66 years and older who had invasive breast cancer (79.9%) or DCIS (20.1%) determined that standard EBRT was associated with a higher 5-year breast preservation rate than either lumpectomy alone or brachytherapy was. [127, 128] However, the study data did not reflect use of the newest forms of brachytherapy, a limitation that may reduce the real-world applicability of these findings.

Single-dose radiotherapy

According to 2 major studies, single-dose radiotherapy delivered during or soon after surgery for breast cancer is a viable alternative to conventional EBRT in selected patients who are at low risk for local recurrence. [129, 130]

In the TARGIT-A trial, more than 3400 patients with early breast cancer were randomized to either 1 intraoperative dose of 20 Gy using a spherical applicator or EBRT delivered according to standard schedules over several weeks. Breast cancer mortality overall was similar in the TARGIT and EBRT groups (2.6% vs 1.9%), but there were significantly fewer non-breast-cancer deaths with TARGIT than with EBRT (1.4% vs 3.5%). Overall mortality rates were 3.9% with TARGIT and 5.3% with EBRT. [129]

In the ELIOT study, 1305 patients were randomized after lumpectomy to receive either intraoperative radiotherapy or EBRT. The 5-year event rate for ipsilateral breast tumor recurrence was 4.4% with ELIOT and 0.4% with EBRT. Overall survival at 5 years was similar in the 2 groups (34 vs 31 deaths), and there was no significant difference between groups in the rate of breast-cancer-related deaths. [129, 130]

Postmastectomy radiation therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), along with several prospective, randomized clinical trials, recommend that postmastectomy radiation therapy be performed according to the following criteria [131] :

  • Positive postmastectomy margins
  • Primary tumors >5 cm
  • Involvement of ≥4 lymph nodes

Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 45-50 Gy to the axillary and supraclavicular regions. For patients in whom ALND shows no node involvement, axillary radiation therapy is not recommended.

Meta-analyses have shown that postmastectomy radiation therapy combined with regional nodal radiation therapy significantly decreases the rate of local relapse and breast cancer mortality.

The benefit of radiation therapy for women with 1-3 positive ALNs has been uncertain. Nonetheless, a meta-analysis of 22 clinical studies found that among women with 1-3 positive nodes (1314 patients) following mastectomy and axillary dissection for early breast cancer, postmastectomy radiotherapy reduced the breast cancer mortality rate by 20% and reduced the recurrence rate by 32%. These benefits were similar among women with 1, 2, or 3 positive nodes. Mean follow-up was 11 years. Radiotherapy also benefited patients with 4 or more positive nodes, while no benefit was seen for those with node-negative disease. Among women with 4 or more positive nodes, radiotherapy reduced breast cancer mortality by 13% and overall recurrence by 21%. [132]


Systemic Adjuvant Therapy for Breast Cancer

Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in mortality. (See Adjuvant Therapy for Breast Cancer.)

Emerging data suggest that adjuvant therapy with bisphosphonates may prevent disease recurrence and prolong survival. The Early Breast Cancer Trialists' Collaborative Group found that in postmenopausal women with early breast cancer, adjuvant bisphosphonate therapy produced highly significant reductions in recurrence (rate ratio [RR] 0.86, P=0.002), distant recurrence (RR 0.82, P=0.0003), bone recurrence (RR 0.72, P=0.0002), and breast cancer mortality (RR 0.82, P=0.002). In premenopausal women, bisphosphonate treatment had no apparent effect on any outcome. [133]


Treatment of Carcinoma in Situ

Ductal carcinoma in situ

Currently, the standard treatment of DCIS is surgical resection with or without radiation. Adjuvant radiation and hormonal therapies are often reserved for younger women, patients undergoing lumpectomy, or those with the comedo subtype.

In the United States, approximately 30% of women with DCIS are treated with mastectomy with or without reconstruction, 30% with conservative surgery alone, and 40% with conservative surgery followed by WBRT. ALND or SLND is not routinely recommended for patients with DCIS. Studies have identified metastasis to the ALNs in 10% of patients.

However, an observational study of 108,196 women with DCIS found that although lumpectomy with radiotherapy or mastectomy reduced the risk for invasive recurrence at 10 years, that approach did not reduce breast cancer-specific mortality. [134] The low mortality from DCIS—by 20 years after diagnosis, 3.3% of the study patients had died from breast cancer—has prompted calls for reconsideration of the treatment approach to DCIS. Instead, the current aggressive approach could be reserved for patients with risk factors for death from breast cancer (eg, age younger than 35 years at diagnosis, African-American ethnicity). These patients constitute approximately 20% of DCIS cases. [135]

For the majority of patients with DCIS, other approaches might be considered, such as endocrine therapy with tamoxifen/raloxifene or aromatase inhibitors. Women at lowest risk might simply be followed with observation and prevention strategies such as diet, exercise, alcohol moderation, and avoidance of postmenopausal hormone therapy with progesterone-containing regimens. [135]

In DCIS, WBRT is delivered over 5-6 weeks after surgery, reducing the local recurrence rate by approximately 60%. Roughly 50% of local recurrences are invasive breast cancer. Meta-analyses of randomized controlled trials have demonstrated slightly higher rates of contralateral breast cancer with radiation therapy than with observation (3.85% vs 2.5%) after surgery for DCIS. Studies comparing accelerated PBI given over 5 days to standard WBRT are currently under way.

Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients treated with breast-conserving surgery and radiation for DCIS. A retrospective study found that patients with ER-positive DCIS who were treated with tamoxifen showed significant decreases in subsequent breast cancer at 10 years. [136]

Adjuvant tamoxifen also reduces the risk of contralateral breast cancer. [137] In a study by Phillips et al, tamoxifen reduced the risk for contralateral breast cancer recurrences in women who carry the BRCA1 and BRCA2 mutations. The analysis used pooled observational cohort data from 3 studies and included 1583 BRCA1 and 881 BRCA2 mutation carriers. Of these, 383 (24%) and 454 (52%), respectively, took tamoxifen after being diagnosed with breast cancer. [137]

Overall, there were a total of 520 contralateral breast cancer cases during 20,104 person-years of observation. Contralateral breast cancer developed in 520 women (24% of BRCA1 and 17% of BRCA2 mutation carriers), and 100 of these cases occurred after the patients' entry into the cohort. An analysis that included both retrospective and prospective data found a hazard ratio (HR) of 0.38 (P< 0.001) for BRCA1 carriers and an HR of 0.33 (P< 0.001) for BRCA2 carriers. When the analysis was limited to prospective data, the effect was reduced, with an HR for BRCA1 carriers of 0.58 (P = 0.1) and an HR for BRCA2 mutation carriers of 0.48 (P =0.07). [137]

A clinical trial comparing anastrozole with tamoxifen as adjuvant therapy in postmenopausal women with DCIS, given for 5 years, found that on median follow-up of 9 years, anastrozole provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. [138]

Lobular carcinoma in situ

Overall, treatment options for lobular carcinoma in situ (LCIS) include observation and close follow-up care with or without tamoxifen and bilateral mastectomy with or without reconstruction. There is no evidence of therapeutic benefit from local excision, axillary dissection, radiotherapy, or chemotherapy. LCIS in the breast of a woman with ductal or lobular cancer does not require further immediate surgery on the opposite breast. Mirror biopsy of the contralateral breast, once advocated for treatment of LCIS, is now mainly of historic interest.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial prospectively studied the efficacy of tamoxifen in the prevention of breast cancer and included patients with LCIS. [21] The researchers found a 55% risk reduction in women treated with tamoxifen.


Treatment of Locally Advanced and Inflammatory Breast Cancer

Originally, the reason for grouping locally advanced breast cancer (LABC) with inflammatory breast cancer (IBC) was the recognition that both diseases had little or no chance of cure from local therapy alone and were therefore considered inoperable. The definition of locally advanced disease has now broadened to include patients who are technically operable but who have large primary tumors (> 5 cm).

It is important to recognize, however, that the reasons for using neoadjuvant therapy in women with large primary tumors, in whom the goal is to increase the possibility of breast-conserving surgery, are different from the reasons in women with disease that meets the original criteria of LABC or IBC, for whom the administration of systemic treatment is essential to make definitive local treatment possible with the intent of cure.

In 2013, the FDA approved pertuzumab for neoadjuvant treatment in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (either greater than 2 cm in diameter or node positive). Approval was based on results in NeoSphere, a randomized trial that compared a number of neoadjuvant regimens with and without pertuzumab in women with HER2-positive breast cancer. In the trial, 39.3% of patients treated with pertuzumab, trastuzumab, and docetaxel (n = 107) achieved a pathologic complete response (pCR) compared with 21.5% of patients treated with trastuzumab and docetaxel (n = 107) at the time of surgery. [139] The 5-year follow-up results of NeoSphere continued to demonstrate the benefit of this regimen. [140]

In March 2022, the FDA approved adjuvant olaparib (Lynparza) for BRCA-mutated HER2-negative high-risk early breast cancer in adults who have undergone treatment with chemotherapy before or following surgery. Approval was based on the phase 3 OlympiA trial (n=1836), which patients treated with olaparib 300 mg BID showed improvement in invasive disease-free survival (DFS), reducing the risk of breast cancer recurrence by 42% compared with the placebo group (hazard ratio [HR], 0.58; 99.5% CI, 0.41-0.82; P < 0.0001). The 3-year distant DFS was 87.5% in the olaparib group and 80.4% in the placebo group (HR for distant disease or death, 0.57; P < 0.001). [141]

Evidence-based guidelines from the American Society of Clinical Oncology (ASCO) recommend HER2-targeted therapy for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. The ASCO guidelines recommend trastuzumab, pertuzumab, and a taxane for first-line treatment and trastuzumab emtansine for second-line treatment. For third-line treatment, the guidelines recommend offering other HER2-targeted therapy combinations or trastuzumab emtansine (if not previously administered) and pertuzumab if the patient has not previously received it. [142]

Overall, the prognosis is better for women with T3N0 (stage IIB) and T3N1 (stage IIIA) breast cancer than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB, T4d). Disease-free survival (DFS) and overall survival are typically better for stage IIB and IIIA patients; however, the likelihood of achieving a pathologic complete response (pCR) from neoadjuvant treatment, a well-recognized surrogate for long-term outcome, is inversely related to tumor size. Thus, the relative proportions of patients in each category are important.

It is also important to recognize that staging criteria in the seventh edition of the AJCC Cancer Staging Handbook differ from those in its predecessors in ways that are relevant to the patient groups discussed here: women with T3 tumors were previously considered to have stage III disease and are so reported in the older literature; women with resectable tumors who are found to have 4 or more involved axillary lymph nodes after initial surgery, formerly called stage II, are currently grouped as IIIA.

The revised staging system is better for defining prognostic subgroups. However, the practical relevance of grouping together all patients who typically receive “upfront” chemotherapy remains, in that their treatment outcomes are usually reported as a function of the particular neoadjuvant program employed.

Inflammatory breast cancer

IBC is a clinical diagnosis that implies presentation with the cardinal signs of inflammation (calor [warmth], rubor [redness], tumor [mass]) involving the breast, although the warmth may be subtle and the mass may not be appreciated as something discrete. Indeed, even when a localized mass is apparent in IBC, the true extent of the disease (as shown by performing skin biopsies from the surrounding normal-appearing skin) is usually greater than is apparent on physical examination.

IBC was originally described as having an erysipeloid border. However, only a minority of cases have this component of a raised edge.

In Western countries, the frequency of IBC is low—1-2% of all breast cancers—but in some parts of the world, such as northern Africa, it is much higher, for reasons that are not known. IBC tends to occur at a younger age than LABC does. Pathologically, IBC was originally associated with the classic finding of involvement of subdermal lymphatic vessels, though this finding is not in itself diagnostic of IBC (it may occur with LABC as a secondary phenomenon).

These tumors are more likely to stain negatively by IHC for ER and PR and somewhat more likely to be positive for HER2 overexpression. In addition, both angiogenesis and lymphangiogenesis appear to be increased by microvessel density or RNA-based gene expression arrays.

Locally advanced breast cancer

LABC is more common in the US than IBC is; by the definition used here, it may account for 10-15% of patients (this drops to about 5% if one uses the older, stricter definition that includes inoperability). Epidemiologically, LABC is associated with lower socioeconomic class and, probably for that reason, with black race in the United States.

LABC encompasses both relatively indolent neglected tumors and those that have grown rapidly as a result of their inherent biology. In most case series, LABC has a better long-term outcome than IBC does, even when only inoperable cases are considered.

Evaluation of lymph nodes and response

Patients with LABC or IBC with clinically positive nodes should undergo a core biopsy before initiating chemotherapy. Those with clinically negative nodes may undergo sentinel lymph node biopsy before they start treatment, or else sentinel node determination may be delayed until after treatment is completed.

Theoretically, it should be preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel lymph node and result in a false-negative result, or altered lymphatic drainage in large tumors might affect accuracy of the procedure. However, data from the NSABP B-27 trial suggest that the false-negative rate for sentinel lymph node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection. [143]

In general, the best single test for evaluating the status of measurable tumor is ultrasonography (preferably done by the same operator). The mass often appears larger on physical examination than on ultrasonography, which can more effectively discriminate hypoechoic masses from surrounding stroma or hematoma. In IBC, magnetic resonance imaging (MRI) may be an important adjunct to response assessment. The role of positron emission tomography (PET) in routine assessment of response must be determined on a case-by-case basis.

No current imaging technique appears to be highly accurate for the prediction of pCR. Thus, the purposes of regular size assessment are as follows:

  • To exclude continuation of therapy in a patient with a growing tumor (seen in < 5% with the initial treatment)
  • To suggest when maximal response of grossly evident disease has been achieved (this may be the optimal time to proceed to resection

Systemic Treatment of Metastatic Breast Cancer

Despite marked advances in the treatment of early-stage breast cancer, many women still develop recurrence and metastasis. In addition, 5-10% of breast cancer patients have metastatic disease at presentation. Although treatments for metastatic breast cancer continue to improve, there remains no cure once distant metastases develop.

Furthermore, although occasional patients with metastatic breast cancer benefit from surgical resection for an isolated recurrence and many require radiation therapy for palliation at a specific site (or definitive treatment of brain metastasis), in general, recurrent or metastatic breast cancer must be approached systemically so that the therapeutic effect reaches all sites of disease. There are two main interventions: hormone therapy and chemotherapy.

Hormone therapy

For patients who have hormone receptor (ER and/or PR)–positive disease without a life-threatening component (eg, massive liver metastases) or systemic symptoms requiring immediate palliation for comfort, in general, hormone manipulation is the initial treatment of choice. Response rates are higher with chemotherapy, but so is the incidence of potentially dangerous toxicity, and there is no evidence that patients live longer as a result of receiving initial chemotherapy.

For ER–positive metastatic breast cancer, the American Society of Clinical Oncology (ASCO) recommends using endocrine therapy rather than chemotherapy as first-line treatment, except in patients with immediately life-threatening disease or if there are concerns about endocrine resistance. The recommendation is part of an ASCO clinical practice guideline on the use of chemotherapy and targeted therapy for women with human epidermal growth factor 2 (HER2)-negative (or unknown) advanced breast cancer, with recommendations based on a systematic review of 79 studies. [144]

A trial of hormone manipulation alone can assess whether hormone therapy is effective, which is impossible to determine if it is given together with cytotoxic chemotherapy. This is especially important when the patient has relapsed disease, because the benefit of second-line hormone manipulation is nearly 50%, and failure to benefit from an initial trial with endocrine therapy correlates with second-line failure. Common hormone therapies and dosages are listed in Table 9, below.

Table 9. Hormone Agents Used in Breast Cancer (Open Table in a new window)


Dose and Schedule



20 mg PO every day

Elacestrant 345 mg PO every day


Aromatase inhibitor


1 mg PO every day


2.5 mg PO every day


25 mg PO every day



500 mg IM on days 1, 15, 29, and once monthly thereafter



40 mg PO 4 times a day



20 mg PO every day


Aromatase inhibitor + LHRH*


7.5 mg IM depot q28d

22.5 mg IM q3mo

30 mg IM q4mo


3.6 mg SC depot q28d

10.8 mg SC q3mo


40 mg PO 4 times a day

*LHRH = luteinizing hormone–releasing hormone.

In a randomized study, Mehta et al found that combination treatment with anastrozole and fulvestrant was superior to either anastrozole alone or sequential anastrozole and fulvestrant treatment in patients with hormone-receptor-positive metastatic breast cancer. [145]

Fulvestrant (Faslodex) was approved by the FDA for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy. Approval was based on results from the phase III FALCON trial (n = 462), in which fulvestrant extended median progression-free survival (PFS) by 2.8 months compared with the aromatase inhibitor anastrozole, and fulvestrant resulted in a median duration of response of 20 months as compared with 13.2 months with anastrozole. Median duration of clinical benefit was 22.1 months with fulvestrant and 19.1 months with anastrozole. Overall response rate and clinical benefit rate did not differ significantly between the drugs. [146]  

In 2023, elacestrant (Orserdu), the first oral selective ER degrader, was approved for men or postmenopausal women with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. Approval was based on the phase III EMERALD trial, which compared elacestrant (n = 239) with standard of care (n = 238) and in which PFS was prolonged in all patients who received elacestrant (P = 0.002), including those with ESR1 mutation (P = 0.0005). [147]   

Alpelisib (Piqray) is a phosphatidylinositol-3-kinase (PI3K) inhibitor approved by the FDA in 2019. It is indicated in combination with fulvestrant for treatment of men and postmenopausal women with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. Approval for alpelisib was supported by the SOLAR-1 trial (n=572), in which adding alpelisib to fulvestrant significantly prolonged median PFS (11 months) compared with fulvestrant alone (5.7 months) in patients whose tumors had a PIK3CA mutation. [148]

Palbociclib and ribociclib are cyclin-dependent kinases (CDK) 4, 6 inhibitors indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Approval of palbociclib for initial endocrine-based therapy in postmenopausal women was based on the phase II PALOMA-1 trial, in which mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group. [149]

Approval of palbociclib for ER+/HER2- advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) with disease progression following endocrine therapy was based on the PALOMA-3 trial (n=521), in which PFS was prolonged with palbociclib plus fulvestrant compared with fulvestrant alone (9.2 mo. vs 3.8 mo.). [150]

Approval of ribociclib was based on interim analysis results from the pivotal phase III MONALEESA-2 trial in postmenopausal women who had received no prior systemic therapy for their advanced breast cancer, which demonstrated that ribociclib plus letrozole reduced the risk for progression or death compared with letrozole alone. After 18 months, the PFS was 63% with a duration of 19.3 months in the ribociclib group and 42.2% with a duration of 14.7 months in the letrozole-alone group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively. [151]  Since those data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination vs 16 months with letrozole alone, according to a company statement.

A third CDK inhibitor, abemaciclib, was approved in 2017 for use in combination with fulvestrant for adults with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. Approval was based on results from the MONARCH 1 and 2 trials. The Monarch 1 trial demonstrated the safety and efficacy of abemaciclib as a stand-alone treatment [152] In MONARCH 2, which included women whose cancer had progressed after endocrine therapy, median PFS was 16.4 months with fulvestrant plus abemaciclib versus 9.3 months with fulvestrant alone. The overall response rates in patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively. [153]

In  2018, the FDA also approved abemaciclib for use in combination with an aromatase inhibitor for first-line treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Approval for use in this setting was based on data from the MONARCH 3 trial, in which the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46%. Median PFS was 28.2 months in the abemaciclib arm versus 14.8 months with the aromatase inhibitor alone. The median duration of response was 27.4 months for the abemaciclib arm compared with 17.5 months in the control arm. [154]


Cytotoxic chemotherapy for metastatic breast cancer initially consisted of single-agent regimens. Combination therapy is currently considered up front, depending on the patient's performance status, because of higher response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen should be to prolong survival while maintaining a good quality of life.

When the patient has life-threatening disease and/or severe symptoms that require quick relief, combinations of cytotoxic agents may be preferable because of their high response rate and early onset of clinical benefit. Randomized trials have shown a survival advantage for the use of a two-drug combination versus a single agent, but this practice has not been widely adopted, because the combination is more toxic and the study designs were flawed in that patients randomized to receive a single agent initially were not crossed over to the other drug component of the initial therapy at the time of relapse.

A second situation, which is becoming increasingly common, is when a cytotoxic chemotherapeutic agent is combined with a targeted agent other than hormone therapy. These targeted agents often have very low response rates when given as monotherapy, but they provide added benefit when given in combination with cytotoxic chemotherapy. A list of targeted chemotherapeutic agents is provided in Table 10, below, followed by Table 11, showing combination regimens for breast cancer.

Table 10. Targeted Chemotherapy for Metastatic Breast Cancer (Open Table in a new window)




Overall Response Rate (ORR)


Abemaciclib CDK inhibitor

200 mg PO BID continue until disease progression

19.7% Diarrhea, fatigue, neutropenia and nausea


Oral fluoro-pyrimidine

1250 mg/m²/d PO for 2 weeks with 1 wk off


Rash, hand-foot syndrome,

diarrhea, mucositis



75-100 mg/m² IV q3wk


40 mg/m²/wk X IV for 6 wk with 2 wk off


Myelosuppression, alopecia,

skin reaction, mucositis,

and fluid retention



(antitumor antibiotic)

45-60 mg/m² IV q3wk


20 mg/m² IV qwk (not to

exceed a cumulative dose

of 450-500 mg/m²)


Myelosuppression, nausea/

vomiting, mucositis, diarrhea

cardiotoxicity, alopecia

Doxil (liposomal




20 mg/m² IV q2wk


35-40 mg/m² IV q4wk


Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot




90 mg/m² IV q3wk (not

to exceed cumulative dose

of 900 mg/m²)


Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity



725 mg/m²/wk IV for 3 wk

then 1 wk off


1 g/m²/wk

IV X 2 then 1 wk off


Myelosuppression, nausea/

vomiting, flulike syndrome,

elevated LFTs



80-100 mg/m²/wk IV X 3 then 1 wk off


260 mg/m² IV q3wk



Less neuropathy, and allergic reaction

Olaparib PARP inhibitor 300 mg PO BID 59.9% Anemia, fatigue, nausea, and vomiting



80 mg/m²/wk IV


175 mg/m² IV over 3 hours q3wk


Myelosuppression, alopecia,

neuropathy, allergic reaction


Monoclonal antibody

840 mg IV loading dose,

then 420 mg q3wk

Give with trastuzumab and docetaxel

80.2% (objective response rate)

Fever, allergic reaction,

cardiotoxicity/congestive heart failure


CDK inhibitor

125 mg/day PO for 3 weeks with 1 wk off

Give with letrozole

Data are not available for ORR

Mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group

Neutropenia, leukopenia, thrombocytopenia, anemia, stomatitis

Ribociclib CDK inhibitor

600 mg/day PO for 3 weeks with 1 wk off

Give with letrozole

Mean PFS was 16 months in the letrozole group and 25.3 months for ribociclib QT prolongation, hepatobiliary toxicity, neutropenia, alopecia, diarrhea, vomiting, constipation, fatigue, anorexia
Sacituzumab  govitecan Monoclonal antibody 10 mg/kg IV on Days 1 and 8 with 2 wk off 33.3% Nausea, neutropenia, diarrhea, fatigue, anemia, vomiting
Talazoparib PARP inhibitor 1 mg PO qDay 62.6% Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite


or biosimilars of trastuzumab
Monoclonal antibody

Combination therapy: 4 mg/kg IV once, then 2 mg/kg weekly for 12-18 weeks, then 6 mg/kg q3weeks to total 52 weeks

Single agent: 8 mg/kg IV once, then 6 mg/kg q3weeks to total 52 weeks
10-15% Fever, allergic reaction, cardiotoxicity/congestive heart failure
Trastuzumab deruxtecan [155] Monoclonal antibody conjugate 5.4 mg/kg IV q3weeks 60.3% Interstitial lung disease and pneumonitis; neutropenia; left ventricular dysfunction
Tucatinib [156] Tyrosine kinase inhibitor of HER2 300 mg PO BID 40.6% Diarrhea, hand-foot syndrome, nausea, fatigue, hepatotoxicity


Vinca alkaloid

20 mg/m²/wk IV


Myelosuppression, nausea/

vomiting, constipation, fatigue,

stomatitis, anorexia


Table 11. Combination Regimens for Metastatic Breast Cancer (Open Table in a new window)


Dose and Schedule





1250 mg/m² bid days 1-14

75 mg/m² day 1

Repeat cycle every 21 days

May decrease capecitabine dose

to 850-1000 mg/m² to reduce

toxicity risk




825 mg/m² bid days 1-14

175 mg/m² day 1

Repeat cycle every 21 days




1000 mg/m² bid days 1-14

25 mg/m² days 1 and 8

Repeat cycle every 21 days


Gemcitabine [157]


1250 mg/m² days 1 and 8

175 mg/m² day 1

Repeat cycle every 21 days

Carboplatin [158]


AUC of 6 day 1

200 mg/m² day 1

Repeat cycle every 21 days

Carboplatin [159]


AUC of 6 day 1

75 mg/m² day 1

Repeat cycle every 21 days

Palbociclib [149]


125 mg PO once daily days 1-21

2.5 mg PO once daily 

days 1-28

Repeat cycle every 28 days



125 mg PO once daily days 1-21

500 mg IM on days 1, 15, 29 and once monthly thereafter 

Repeat cycle every 28 days

Ribociclib [151]


600 mg PO once daily days 1-21

2.5 mg PO once daily days 1-28

Repeat cycle every 28 days

Paclitaxel [160]

90 mg/m² day 1, 8, and 15

Repeat cycle every 28 days


Fulvestrant [153]

150 mg PO BID

500 mg IM on Days 1, 15 and 29 and once monthly thereafter

Repeat cycle every 28 days

Ribociclib [161]


600 mg PO once daily days 1-21

500 mg IM on Days 1, 15 and 29 and once monthly thereafter
Repeat cycle every 28 days

HER2-positive metastatic breast cancer regimens



4 mg/kg loading dose then

2 mg/kg weekly

80 mg/m² IV weekly




8 mg/kg loading dose then

6 mg/kg day 1

100 mg/m² IV day 1

Repeat cycle every 21 days



Loading dose of 1,200 mg pertuzumab/600 mg trastuzumab SC x 1 dose followed by 600 mg pertuzumab/600 mg trastuzumab SC

Docetaxel is 75 mg/mIV, may escalate to 100 mg/m2

Repeat cycle every 3 week; continue until disease recurrence or unmanageable toxicity, whichever occurs first



4 mg/kg loading dose then

2 mg/kg weekly

25 mg/m² day 1 weekly




Tucatinib [156]

8 mg/kg loading dose then

6 mg/kg weekly

1000 mg/m2 PO BID days 1-14

300 mg PO BID
Repeat cycle every 21 days



1250 mg PO daily

2000 mg/m² daily days 1-14

Repeat cycle every 21 days



175 mg/m2

1500 mg/d

Repeat cycle every 3 weeks

AUC = area under the curve (systemic exposure)

References for chemotherapy regimens: XT, [162] XP, [163] XN, [163] HER2-positive metastatic breast cancer regimens [164, 165, 166, 167]

The initial choice of chemotherapy is highly influenced by the patient's personal history of previous drug exposure. For example, if doxorubicin was a component of previous adjuvant therapy, the tumor cells have a higher risk of developing resistance, and there is a relationship between cumulative lifetime total dose of doxorubicin and the risk of potentially fatal cardiomyopathy.

It is important to realize that if 1 year or more has elapsed since completion of adjuvant therapy, a patient's tumor is likely to respond to a previously given drug or combination as though that drug or combination had never been given. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane (docetaxel or paclitaxel) in the adjuvant setting.

Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may be difficult because of residual toxicity. Although taxanes are not cardiotoxic, they can produce lingering neuropathy (especially paclitaxel) or problems with edema (docetaxel especially), which makes further administration problematic. Substitution of one taxane for another is possible, depending on the nature of the chronic toxicity.

If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then changing the schedule of administration can be effective. At least one third of breast cancer patients with taxane resistance due to administration of every-3-week paclitaxel show a response when the same drug is administered on a weekly schedule at a lower dose.

The Cancer and Leukemia Group B (CALGB) 9840 trial reported an improved overall response rate (ORR) in patients receiving weekly dosing of paclitaxel (40%) compared with every-3-week paclitaxel (28%), as well as improved median time to progression (9 mo vs 5 mo). However, care should be taken in watching for progression of adverse effects, especially neuropathy.

In addition to taxanes and anthracyclines, a variety of other chemotherapeutic agents can be used as single agents or in combination with taxanes. Capecitabine (Xeloda) is an oral agent that essentially represents a sustained-release formulation of the older antimetabolite fluorouracil (5-FU) and provides the convenience of self-administration.

Drugs such as capecitabine have very little associated myelosuppression, and they are often chosen when the patient's bone marrow has been damaged by previous therapy or when there is a desire to coadminister a myelosuppressive agent for more rapid effect. As a single agent, capecitabine has an ORR of 25-30%, with minimal toxicity. When combined with a taxane, an ORR of 40-50% has been observed, along with a median overall survival benefit of 3-15 months.

Another antimetabolite, gemcitabine (Gemzar), is typically given in combination with paclitaxel, based on results from a phase III trial comparing paclitaxel with the combination regimen in locally advanced breast cancer (LABC) and metastatic breast cancer. A total of 529 patients were randomized to receive paclitaxel 175 mg/m2 on day 1 plus gemcitabine 1250 mg/m2 on days 1 and 8, or receive the same dose of paclitaxel alone every 3 weeks. ORR (41% vs 26%) and overall survival (18.6 mo vs 15.8 mo) were significantly higher with the paclitaxel/gemcitabine arm than with paclitaxel alone. [168]

Vinorelbine (Navelbine) is a vinca alkaloid that targets tubulin in the mitotic spindle and is administered intravenously, usually on a weekly basis. Vinorelbine is often used as a single agent following treatment with a taxane or anthracycline, yielding an ORR of 25%. However, when used as a first- or second-line agent, vinorelbine can have ORRs of up to 40%.

Palbociclib (Ibrance) is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 used for first-line treatment for ER-positive, HER2-negative metastatic breast cancer in postmenopausal women, in combination with the aromatase inhibitor letrozole. [169]  A phase II study in which progression-free survival (PFS) for women receiving palbociclib and letrozole was 20.2 months, versus 10.2 months for those on letrozole alone (P = 0.0004). [169, 170]

The CDK 4,6 inhibitor ribociclib (Kisqali) was approved by the FDA in March 2017 for postmenopausal HR+/HER- advanced or metastatic breast cancer in combination with letrozole. Approval was based on interim analysis results from the phase III MONALEESA-2 trial in postmenopausal women who had received no prior systemic therapy for their advanced breast cancer (n=668). Ribociclib plus letrozole yielded a PFS rate of 63% with a duration of 19.3 months, compared with a rate of 42.2% and a duration of 14.7 months with letrozole alone. [151]  

Since those data were published, a subsequent analysis with an additional 11 months of follow-up showed that the median PFS was 25.3 months with the ribociclib combination versus 16 months with letrozole alone. [171]

As with hormone therapy, the likelihood of benefit from chemotherapy is related to the success achieved with the previous regimen. Although there are occasional gratifying responses to a drug used in the third- or fourth-line setting of metastatic breast cancer, they are the exception rather than the rule. Thus, patient characteristics, previous treatments, and the expected toxicity of these regimens must be taken into account.

PARP Inhibitors

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. In January 2018, the FDA expanded approval of olaparib to include treatment of BRCA-mutated, HER2-negative metastatic breast cancer in patients who have been previously treated with chemotherapy. Olaparib (which had previously been approved for treatment of BRCA-mutated ovarian cancer) is the first PARP inhibitor approved to treat breast cancer, and the first drug of any kind approved to treat certain patients with BRCA-mutated metastatic breast cancer. [172]

Approval was based on the OlympiAD clinical trial, which was the first phase III trial to demonstrate that PARP inhibitors are superior to chemotherapy for this class of patients. In this trial, patients with a germline BRCA mutation and HER2-negative metastatic breast cancer were assigned to receive either olaparib 300 mg PO BID (n=205) or standard therapy (n=92). Standard therapy was a choice of single-agent chemotherapy, which consisted of 21-day cycles of capecitabine (2500 mg/m2 PO on days 1-14), vinorelbine (30 mg/m2 IV on days 1 and 8), or eribulin (1.4 mg/m2 IV on days 1 and 8). Median progression-free survival (PFS) was significantly longer in those who received olaparib compared with standard therapy (7.0 months vs 4.2 months; hazard ratio, 0.58; P = 0.0009). [173]

The objective response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group. Overall survival and median time to death did not differ significantly between the 2 treatment arms after a median follow-up of 14 months (45.9% vs 47.4%; 19.3 months vs 19.6 months). [173]

In October 2018, talazoparib, another PARP inhibitor, was approved for patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. Approval was based on the phase III EMBRACA trial (n=431), which talazoparib reduced the risk of disease progression or death by 46% compared with chemotherapy in patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. Patients were randomized in a 2:1 ratio to receive talazoparib or physician’s choice of chemotherapy (PCT), which included eribulin, gemcitabine, vinorelbine, and/or capecitabine.  [174]

The ORR was 62.6% in the talazoparib group and 27.2% in the PCT group (p < 0.001). Clinical benefit rate at 24 weeks was 68.6% in the talazoparib group and 36.1% in the PCT group. OS data are not yet mature; however, an interim OS analysis found a positive trend favoring talazoparib. The median OS was 22.3 months with the PARP inhibitor compared with 19.5 months with chemotherapy. [174]

Treatment of HER2-positive metastatic breast cancer

See HER2 Breast Cancer for more information on this topic.

Treatment of triple-negative metastatic breast cancer

Unresectable metastatic triple-negative breast cancer (TNBC; ie, estrogen receptor–negative, progesterone receptor–negative, and HER2 receptor–negative) is aggressive and carries a poor prognosis. However, combination therapy with the programmed cell death ligand–1 (PDL1) inhibitor atezolizumab plus nanoparticle albumin-bound (nab)–paclitaxel has been shown to prolong PFS in these patients. [175]

 In 2019, the FDA approved atezolizumab in combination with nab-paclitaxel for TNBC. [176] Approval was based on the phase III IMpassion130 trial in patients with untreated metastatic TNBC, in which intention-to-treat analysis showed median PFS of 7.2 months with atezolizumab plus nab-paclitaxel versus 5.5 months with placebo plus nab-paclitaxel (hazard ratio [HR] for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); in patients with PDL1-positive tumors, median PFS was 7.5 months and 5.0 months, respectively (HR, 0.62; 95% CI, 0.49 to 0.78; P< 0.001). [175]

However, subsequent study results have placed the status of this combination in jeopardy. In September 2020 the FDA issued an alert that atezolizumb plus paclitaxel is ineffective in patients with previously untreated, inoperable, locally advanced or metastatic TNBC. The alert was based on findings from the phase III IMpassion131 trial showing that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in PD-L1–positive patients. Interim overall survival results in IMpassion131 also favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1–positive and the total study population. The FDA advised that "continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials." [177]

Since metastatic TNBC is aggressive, it is important to have multiple treatment options. In April 2020, the FDA granted accelerated approval to the first antibody-drug conjugate, sacituzumab govitecan-hziy (Trodelvy), for metastatic TNBC in patients who have received at least two prior therapies for metastatic disease. The FDA granted regular approval to sacituzumab govitecan-hziy in April 2021. Initial approval was based on the IMMU-132-01 trial; regular approval was based on results of the phase III ASCENT trial (n=529), in which median PFS was 4.8 months (95% CI: 4.1, 5.8) in patients receiving sacituzumab govitecan, compared with 1.7 months (95% CI: 1.5, 2.5) in those receiving chemotherapy (HR 0.43; 95% CI: 0.35, 0.54; P < 0.0001). [178]

Antiangiogenic therapy in metastatic breast cancer

Angiogenesis is recognized as a key process in the progression and metastasis of breast cancer. Bevacizumab (Avastin) is a humanized mAb directed against vascular endothelial growth factor (VEGF), which exerts an independent effect on the process of new blood vessel formation in tumors (angiogenesis). Bevacizumab was approved by the FDA as a first-line therapy for HER2-negative metastatic breast cancer patients, based on results from the phase III ECOG 2100 trial.

However, in 2011, the FDA officially rescinded its approval of bevacizumab because the drug had not been shown to be safe and effective for this use. The decision was based on the totality of data, including 3 trials in first-line treatment of metastatic breast cancer (E2100, AVADO, and RIBBON-1), as well as the EVF 2119 trial for second-line treatment in this setting. [72]  

The bevacizumab data review found that patients treated with bevacizumab did not live any longer than patients who were not taking it, but they were at greater risk of adverse effects, including those unique to bevacizumab, such as gastrointestinal perforations, which can be life threatening. Other serious and potentially life-threatening effects include the risk of stroke, wound-healing complications, and organ damage or failure; bevacizumab has also been linked with the neurological condition reversible posterior leukoencephalopathy syndrome (RPLS).

Adjunctive bisphosphonate therapy in metastatic breast cancer

See Bone Health and Breast Cancer Management for more information on this topic


Surgical Treatment of Metastatic Breast Cancer

As modern systemic chemotherapy has become more effective, some patients with intact primary tumors and metastasis can have long-term stable distant disease or even no evidence of residual metastatic disease after treatment. There is increasing interest in the role of surgical intervention for the intact primary tumor of these metastatic breast cancer patients. Several single-institution cohort and retrospective studies have concluded that surgical resection of the intact primary tumor may provide a survival advantage.

It is still unknown whether a selection bias affects the findings of a survival advantage in favor of surgery. However, the dogmatic belief that one should never operate in the setting of metastatic disease has certainly been dispelled in favor of critical evaluation of whether surgically achieved local control can lead to improved survival as a part of multimodal treatment. An ongoing prospective randomized clinical trial, E2108, is addressing the role of surgery for the primary tumor in metastatic setting.


Pharmacologic Reduction of Breast Cancer Risk

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are approved for reduction of breast cancer risk in high-risk women. Two NSABP trials (P1 and P2) showed that tamoxifen reduced the risk of DCIS and invasive breast cancer by 30-50%. In the NSABP P2 prevention trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer but was 30% less effective than tamoxifen in reducing the risk of DCIS.

Tamoxifen use for 5 years reduces risk of breast cancer for at least 10 years in premenopausal women, particularly ER-positive invasive tumors. Women 50 years or younger have few adverse effects with tamoxifen, and vascular/vasomotor adverse effects do not persist after treatment.

As noted earlier, in an analysis that used pooled observational cohort data from 3 studies and included 1583 BRCA1 and 881 BRCA2 mutation carriers, adjuvant tamoxifen reduced the risk for contralateral breast cancer recurrences in women who carry these mutations. [137]

Tamoxifen and raloxifene are equally effective in reducing the risk of ER-positive breast cancer in postmenopausal women. Raloxifene is associated with lower rates of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen is. The evidence does not allow determination of whether either agent decreases mortality from breast cancer.

The aromatase inhibitors exemestane and anastrozole are used off label for breast cancer risk reduction in postmenopausal women. In the Mammary Prevention.3 (MAP.3) trial, conducted in 4560 postmenopausal women with moderately increased breast cancer risk, exemestane decreased the incidence of invasive breast cancer by 65% and that of invasive plus in situ breast cancer by 53%, compared with placebo. [179] In the International Breast Cancer Intervention Study II (IBIS-II), conducted in 3864 postmenopausal women at increased risk of developing breast cancer, after a median follow-up of 131 months, anastrozole was associated with a 54% decrease in ER-positive invasive breast cancer, and a 59% decrease in DCIS. [180]

ASCO guidelines on endocrine therapy to reduce breast cancer risk recommend the following [181] :

  • In premenopausal women who are at least 35 years old and have completed childbearing, tamoxifen (20 mg/day for 5 years) remains the standard of care for risk reduction. Low-dose tamoxifen (5 mg/day) may be an alternative in women with intraepithelial neoplasia.

  • Anastrozole, exemestane, or raloxifene should not be prescribed for breast cancer risk reduction in premenopausal women.

  • In postmenopausal women, the choice of endocrine therapy includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day).

The ASCO guidelines delineate the risk thresholds for use of individual agents, along with the benefits and risks that clinician and patient should discuss when considering endocrine therapy for primary breast cancer prevention. In particular, SERMs carry warnings about risk of thromboembolic events, and aromatase inhibitors carry warnings about bone mineral density (BMD) reduction. Hence, tamoxifen and raloxifene are not recommended for use in women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. [181]

Anastrozole is relatively contraindicated in women with a history of osteoporosis and/or severe bone loss, and should be used only with caution in postmenopausal women with moderate BMD loss. If anastrozole is used, the addition of bone-protective agents such as bisphosphonates and RANKL inhibitors should be considered. Regular exercise and adequate calcium and vitamin D supplementation should be encouraged in all patients receiving aromatase inhibitors. [181]


Prophylactic Mastectomy

Prophylactic mastectomy is an option for women found to be at extremely elevated risk for breast cancer. Either total mastectomy or subcutaneous (nipple-sparing) mastectomy may be performed. [182]

Genetic factors that place a woman at very high risk of developing breast cancer include the following [182] :

  • Strong family history of breast and/or ovarian cancer
  • Pathogenic mutation in BRCA1 or BRCA2
  • High-penetrance mutation in another gene associated with breast cancer risk (eg, TP53, PTEN)

The National Comprehensive Cancer Network (NCCN) recommends that in general, the only women who should consider risk-reduction mastectomy are those with a genetic mutation that confers a high risk for breast cancer, a compelling family history, or possibly a personal history of receiving thoracic radiation therapy before 30 years of age. The NCCN notes that while risk-reduction mastectomy had previously been considered for lobular carcinoma in situ (LCIS), risk-reduction therapy (ie, healthy lifestyle, endocrine therapy) is currently the preferred approach for LCIS. [183]

In retrospective studies with median follow-up periods of 13-14 years, bilateral risk-reduction mastectomy decreased the risk of developing breast cancer by at least 90% in women at moderate to high risk and in those with known BRCA1/2 mutations. In women with deleterious mutations in other genes that are associated with a 2-fold or greater risk for breast cancer but without a compelling family history of breast cancer, the value of risk-reducing mastectomy is unknown. [183]

Woman who are considering prophylactic mastectomy should meet with a range of specialists to discuss the risks and benefits of surgery, including its potential psychosocial effects, as well as the nonsurgical options for reducing risk of breast cancer.These may include a breast health specialist, medical social worker, or cancer clinical psychologist or psychiatrist. Early consultation with a reconstructive surgeon is recommended for those considering either immediate or delayed breast reconstruction. [182, 183]

Contralateral prophylactic mastectomy

A consensus statement from the American Society of Breast Surgeons (ASBrS) recommends that women with unilateral breast cancer who are at average risk should be discouraged from undergoing a contralateral prophylactic mastectomy (CPM), because most of those women, with the possible exception of BRCA carriers, will not obtain a survival benefit, and CPM doubles the risk of surgical complications. [184]

However, the ASBrS advises that the final decision whether or not to proceed with contralateral prophylactic mastectomy   is a result of the balance between benefits and risks of CPM and patient preference.

The ASBrS concluded that CPM should be considered for patients with any of the following significant risk factors for contralateral breast cancer:

  • BRCA1/2 mutations
  • Strong family history (in patient who have not undergone genetic testing)
  • Mantle chest radiation before age 30 years

The ASMBrS suggests that CPM can be considered for women with factors that place them at lower risk. These include women who are carriers of a non-BRCA gene (eg, CHEK-2, PALB2, p53, CDH1) and those with a strong family history of breast cancer but who are themselves BRCA negative and have no family member with known BRCA.

Other reasons for considering CPM, according to the ASMBrS, include the following:

  • To limit contralateral breast surveillance (dense breasts, failed surveillance, recall fatigue)
  • To improve reconstructed breast symmetry
  • To manage risk aversion
  • To manage extreme anxiety (although that may be better managed through psychological support strategies)

The ASMBrS recommends discouraging CPM not only in average-risk women with unilateral breast cancer, but in those with any of the following:

  • Advanced index cancer (eg, inflammatory breast cancer, T4 or N3 disease, stage IV disease)
  • High risk for surgical complications (eg, due to comorbidities such obesity, smoking, diabetes)
  • Negative BRCA test results, despite a family history of BRCA carriage

Finally, the ASMBrS recommends against CPM in men with breast cancer, even if they are BRCA carriers.


Long-Term Monitoring

Follow-up guidelines

There is no consensus among oncologists as to appropriate and optimal follow-up for long-term breast cancer survivors. The majority of relapses, both local and distant, occur within the first 3 years, especially in higher-risk and ER-negative patients. The 2007 ASCO guidelines do not support the use of tumor biomarkers, including CEA, CA15.3, and CA27.29, for monitoring patients for recurrence after primary breast cancer therapy. ASCO and NCCN have both provided recommendations for surveillance in the adjuvant setting (see Table 12 below).

Table 12. Follow-up Recommendations for Breast Cancer Survivors (Open Table in a new window)




History and physical examination

Year 1, every 3-4 mo

Year 2, every 4 mo

Year 3-5, every 6 mo

Year 6+, annually

Year 1-3, every 3-6 mo

Year 4-5, every 6-12 mo

Year 6+, annually

Breast self-examination

No recommendation

Counseled to perform monthly breast self-examination


6 mo after post-BCS radiation therapy

Annually thereafter

6 mo after definitive radiation therapy

Every 6-12 mo for surveillance of abnormalities

Annually if stability of abnormalities is achieved

Pelvic examination

Annually, for women on tamoxifen

Annual exam if uterus present

Regular gynecologic follow-up

Patients on tamoxifen should be advised to report any vaginal bleeding

Routine blood tests

Not recommended

Not recommended

Imaging studies

Not recommended

Not recommended

Tumor marker testing

Not recommended

Not recommended

ASCO guidelines for monitoring bone density

Table 13. (Open Table in a new window)

Women aged ≥65 years

Woman aged 60-64 years with ≥1 of the following:

1. Family history of osteoporosis

2. Low body weight

3. Prior nontraumatic fracture

4. Other risk factors (eg, smoking, sedentary lifestyle)

Postmenopausal women on aromatase inhibitors

Premenopausal women who develop treatment related premature menopause

Postoperative imaging

Women who have had surgery for breast cancer may still require breast cancer screening with mammography. If a woman had a total mastectomy, then the other breast requires yearly follow-up, because there is still a higher risk that cancer will develop in the remaining breast. If the woman had a subcutaneous mastectomy, partial mastectomy, or lumpectomy, then that breast itself requires follow-up mammography.

The first mammogram is best performed 6 months postoperatively to provide a baseline for the new postoperative and postirradiation changes. Thereafter, mammography may be performed every 6-12 months for screening and follow-up. (See Postsurgical Breast Imaging.)

Monitoring of metastatic disease

Recommendations for monitoring disease response in the metastatic setting vary. In general, monthly evaluations consisting of a history and physical examination to evaluate progression of disease and toxicities are reasonable.

Measurement of tumor markers, such as CEA, CA15.3, and CA27.29, can be used in conjunction with diagnostic imaging, history, and physical examination for monitoring patients on active therapy. CA15.3 and CA27.29 levels correlate with the course of disease in 60-70% of patients, whereas CEA levels correlate in 40% of patients.

However, data are insufficient to recommend the use of CEA, CA15.3, or CA27.29 alone for monitoring response to treatment. Caution should be used in the interpretation of rising CEA, CA15.3, or CA27.29 levels during the first 4-6 weeks of a new therapy; spurious early rises may occur.

Standardized guidelines for imaging are not yet established; the choice and timing of imaging procedures should be tailored to each patient’s specific needs. In general, computed tomography (CT) of the chest, abdomen, and pelvis; MRI; bone scanning; or PET-CT is performed when symptoms change or tumor markers rise.

Monitoring of radiation-induced heart disease

According to a consensus statement from the European Association of Cardiovascular Imaging and the American Society of Echocardiography, patients treated with radiotherapy to the chest for Hodgkin's disease, or breast, lung, or esophageal cancer, should have an echocardiogram every 5 to 10 years to detect radiation-induced heart disease (RIHD). The relative risk of RIHD is 2- to 5.9 times higher in patients treated with radiation for breast cancer. [185]

Recommendations of the statement include the following [185] :

  • Before starting radiotherapy to the chest, patients should have a baseline echocardiogram to evaluate cardiac morphology and function, and identify any abnormalities

  • After radiotherapy, patients should have a yearly physical exam

  • Modifiable CVD risk factors should be corrected

  • Patients who have a cardiac abnormality or are asymptomatic but at high risk of CVD should have an initial transthoracic echocardiogram screening test five years after radiation treatment

  • Asymptomatic patients who are not at high risk of CVD should have an initial screening echocardiogram 10 years after radiation treatment

  • After an initial screening electrocardiogram, patients should have an echocardiogram every five years

  • When the findings from an echocardiogram are equivocal, cardiac computed tomography (CT), cardiac magnetic resonance (CMR), and nuclear cardiology can be used to confirm and evaluate the extent of RIHD


Integrative Therapy

The Society for Integrative Oncology has released clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. Recommendations include the following [186] :

  • Meditation, yoga, and relaxation with imagery may be useful for alleviating anxiety and mood disorders (grade A evidence)

  • Stress management, yoga, massage, music therapy, energy conservation, and meditation may reduce stress, improve mood, decrease fatigue, and improve quality of life (grade B evidence)

  • Acetyl-L-carnitine for the prevention of taxane-induced neuropathy may increase neuropathy and should not be used (grade H [likely harmful])

  • Evidence of benefit is weak or lacking for many interventions

Psychedelic therapy

Evidence from early clinical trials of psychedelic-assisted psychotherapy suggests that the use of such drugs (eg, psilocybin) in this setting can benefit carefully screened patients with cancer who have persistent existential suffering. [187, 188] Although these agents remain Schedule I controlled substances, National Cancer Institute–supported clinical trials are in progress, and more studies are planned or recruiting.


A systematic review of 37 systematic reviews of rehabilitation interventions for women after breast cancer treatment found the strongest evidence in support of exercise/physical activity and yoga. Overall, the review identified five rehabilitation areas and reached the following conclusions [189] :

  • Exercise and physical activity improved outcomes such as shoulder mobility, lymphedema, pain, fatigue, and quality of life (QoL).
  • Yoga significantly improved QoL and reduced anxiety, depression, sleep disturbance, fatigue, and gastrointestinal symptoms.
  • Complementary and alternative medicine (CAM; tai chi, acupoint stimulation, massage) had positive effects on nausea, pain, fatigue, anger, and anxiety; however, those results need to be interpreted with caution because of low methodological quality in the studies reviewed.
  • Lymphedema treatment: Resistance training had positive effects on volume reduction and muscle strength.
  • Psychosocial interventions (eg, cognitive-behavioral therapy) had positive effects on QoL, anxiety, depression, and mood disturbance.