Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer

INTRODUCTION — Breast cancer is a global health problem and the most common cancer in both resource-rich and resource-poor settings. The lifetime probability of developing breast cancer is one in six overall (one in eight for invasive disease). It is a heterogeneous, phenotypically diverse disease composed of several biologic subtypes that have distinct behaviors and responses to therapy.

The use of adjuvant systemic therapy is responsible for much of the reduction in cause-specific mortality from breast cancer seen in almost every Western nation [1]. Adjuvant chemotherapy refers to the use of cytotoxic chemotherapy after breast cancer surgery, administered with the goal of eradicating microscopic foci of cancer cells that, if untreated, could grow and recur as metastatic cancer. In general, similar chemotherapy regimens are used as adjuvant chemotherapy regardless as to whether tumors are estrogen (ER) or progesterone (PR) receptor positive or negative. Treatment directed against the human epidermal growth factor receptor 2 (HER2) is incorporated for those patients with HER2 overexpression. (See "Adjuvant systemic therapy for HER2-positive breast cancer".)

This topic will discuss the role of chemotherapy in the adjuvant treatment of early-stage breast cancer, how to estimate the benefit and risk of chemotherapy, the indications for adjuvant chemotherapy, and the dosing and timing of treatment. 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 Staging Manual is used (table 1); however, it is recognized that the studies cited may have used previous editions of the staging system, which is a limitation of existing data. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

Adjuvant medical therapy for patients with early-stage HER2-positive breast cancer, adjuvant endocrine therapy, the treatment of male breast cancer, and breast cancer in older patients are discussed separately:

●(See "Adjuvant systemic therapy for HER2-positive breast cancer".)

●(See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)

●(See "Breast cancer in men".)

●(See "Overview of the approach to early breast cancer in older women".)

●(See "Treatment protocols for breast cancer".)

Other topics on the management of non-metastatic breast cancer are discussed elsewhere. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

INDICATIONS FOR TREATMENT — The decision to use adjuvant chemotherapy takes into account tumor histology, expression of estrogen (ER) and/or progesterone (PR) receptors, tumor stage and grade, patient age, as well as high-risk features such as lymphovascular invasion.

Adjuvant or neoadjuvant chemotherapy is standard for patients with triple-negative breast cancer (TNBC) and either a tumor size >0.5 cm or pathologically involved lymph nodes (regardless of tumor size). Indications for adjuvant chemotherapy in TNBC, as well as choice between adjuvant and neoadjuvant therapy, are discussed in more detail elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Non-metastatic disease' and "General principles of neoadjuvant management of breast cancer", section on 'Patient selection'.)

Genomic analysis and benefit-risk calculators are also employed to help determine appropriate candidates for adjuvant chemotherapy in patients with ER-positive tumors. In many instances, the benefits of adjuvant chemotherapy are rather modest, and patient preferences are relevant to treatment decision-making. (See "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer".)

The approach towards patients who received neoadjuvant treatment is discussed below. (See 'Patients who received neoadjuvant treatment' below.)

EFFICACY AND SAFETY — Overall, adjuvant chemotherapy decreases risk of recurrence and improves survival, but the absolute benefits in patients with a low risk of recurrence may be small. Therefore, the decision to offer chemotherapy must take into account risk factors of the disease as well as patient age and comorbidities. (See 'Indications for treatment' above and 'Older women' below.)

The benefits and risks of chemotherapy, in general, are discussed elsewhere. (See "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer", section on 'Benefits and risks of adjuvant chemotherapy'.)

Management of toxicities related to adjuvant chemotherapy is also discussed elsewhere. (See "Overview of side effects of chemotherapy for early-stage breast cancer".)

Benefit of adjuvant chemotherapy — The data to support adjuvant chemotherapy (versus no treatment) and specifically, the administration of anthracycline and taxane therapy in the adjuvant setting come from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). The EBCTCG performs a meta-analysis every five years to review the data on adjuvant treatment of breast cancer.

In the 2012 EBCTCG meta-analysis, the use of an anthracycline-containing regimen compared with no treatment resulted in the following outcomes [2]:

●Decreased risk of recurrence from 47 to 39 percent (relative risk [RR] 0.73, 95% CI 0.68-0.79)

●Decreased breast cancer mortality from 36 to 29 percent (RR 0.79, 95% CI 0.72-0.85)

●Decreased overall mortality from 40 to 35 percent (RR 0.84, 95% CI 0.78-0.91)

Compared with no treatment, the use of cyclophosphamide, methotrexate, and fluorouracil (CMF) was also associated with comparable improvement in these outcomes at 10 years. A comparison of CMF and anthracycline-containing regimens is described below. (See 'Rationale for anthracycline- and taxane-containing regimen' below.)

The meta-analyses from the Early Breast Cancer Trialists Collaborative Group have been very influential in helping clinicians and patients understand the benefits of adjuvant chemotherapy including the assessment of specific agents and treatment regimens. However, many clinicians will look to outcomes in specific randomized trials that have addressed treatment selection factors, chemotherapy agents, and chemotherapy schedules, when discussing the role of chemotherapy in the management of a specific patient, as these trials often describe the individual patient experience with more specificity. For that reason, guidance for whether or not to recommend chemotherapy, or which chemotherapy regimens, may differ from findings of the overview.

Risks — Risks of chemotherapy include acute toxicities including nausea, vomiting, hair loss, myelosuppression, early (though not sustained) cognitive impairment [3], and amenorrhea. Immunosuppression associated with chemotherapy may also lead to severe infections in some. Taxanes are associated with neuropathy, which generally resolves weeks to months after treatment, but may be incomplete in severe cases. Longer-term toxicities also include the risks of cardiotoxicity associated with anthracyclines and the rare risk of chemotherapy-related leukemia [4]. These issues are discussed in detail elsewhere. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of side effects of chemotherapy for early-stage breast cancer" and "Cognitive function after cancer and cancer treatment", section on 'Breast cancer'.)

REGIMEN SELECTION AND ADMINISTRATION

Choosing a regimen — The choice of an adjuvant chemotherapy regimen depends both on baseline characteristics of the patient as well as the breast cancer. Considerations are discussed below.

General approach — There is no single worldwide standard adjuvant chemotherapy regimen in the treatment of breast cancer, and the preferred regimens vary by prescribing clinician, institution, and/or geographic region. The following outlines our approach:

For most patients in whom chemotherapy is recommended, we prefer doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), otherwise referred to as AC-T, administered on a dose-dense schedule (table 2) [5]. (See 'Rationale for anthracycline- and taxane-containing regimen' below.)

Further details for those with triple-negative breast cancer (TNBC) are found elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Chemotherapy'.)

Although no regimen has proven to be superior to AC-T, non-anthracycline-based regimens may be an appropriate strategy for certain groups of patients:

●Patients with lower-risk disease (eg, those with node-negative, hormone receptor-positive breast cancer or node-negative, hormone receptor-negative breast cancer <1 cm) for whom chemotherapy is indicated. (See 'Acceptable alternatives to anthracycline-based treatment' below.)

●Patients with a history of cardiac disease. Given that anthracyclines can promote cardiotoxicity, patients with a history of heart failure or other heart disease may benefit from a non-anthracycline-containing regimen instead of an anthracycline-based therapy. (See 'Acceptable alternatives to anthracycline-based treatment' below.)

Advanced age and chest wall radiation are additional risk factors for anthracycline-related cardiotoxicity, and patients should be counseled about the risks and benefits of treatment. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

●Patients unwilling to accept the risks of anthracycline-based therapy. The risks of congestive heart failure or leukemia, which occur in approximately 1 percent of patients treated on anthracyclines, may be unacceptable to some patients and may be avoided with certain non-anthracycline-based regimens. (See 'Acceptable alternatives to anthracycline-based treatment' below.)

In such patients for whom anthracyclines are not an appropriate choice, we treat with docetaxel and cyclophosphamide (TC). (See 'Acceptable alternatives to anthracycline-based treatment' below.)

We generally offer taxane-based treatment to patients receiving adjuvant therapy. However, taxane therapy usually requires supportive care with some form of steroid treatment to prevent allergic reactions and other side effects of therapy. For patients in whom steroid treatment or risk of peripheral neuropathy is a particular concern, and where there are concerns about anthracycline exposure, we occasionally recommend cyclophosphamide, methotrexate, and fluorouracil (CMF) rather than an anthracycline- or taxane-containing regimen. (See 'Acceptable alternatives to anthracycline-based treatment' below.)

Rationale for anthracycline- and taxane-containing regimen — The AC-T regimen delivered on a dose-dense schedule is the preferred regimen for most patients (table 2), with anthracyclines and taxanes administered sequentially. For patients with lower-risk disease or a history of cardiac disease, non-anthracycline regimens may be preferable. (See 'Acceptable alternatives to anthracycline-based treatment' below.)

●Benefit of anthracycline- and taxane-containing regimens compared with CMF – The rationale for utilizing this regimen is based on evidence demonstrating that an anthracycline-containing regimen is at least equivalent to the historical standard regimen CMF and that the addition of taxane to an anthracycline-based regimen further improves outcomes. These data come from the 2012 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, which suggested that anthracycline-based regimens had similar or better outcomes relative to CMF, historically a standard treatment [2]. The meta-analysis compared the use of CMF with the use of various doses of anthracyclines, defined as either "standard" doses (eg, for four cycles, to a cumulative dose of 240 mg/m² of doxorubicin) or higher doses (ie, for more than four cycles, to cumulative dose >240 mg/m² of doxorubicin) [2]. In over 5000 women, the use of anthracyclines administered at "standard" doses, when compared with CMF, was associated with similar recurrence risk (41 versus 42 percent), breast cancer mortality (32 versus 33 percent), and overall mortality (33 versus 35 percent) at 10 years. Patients receiving higher cumulative doses of anthracyclines had marginal improvements in these measures compared with CMF.

●Benefit of anthracyclines – In a separate EBCTCG meta-analysis, among 15 trials in over 18,000 women, a taxane regimen with an anthracycline reduced recurrence rates compared with a taxane regimen without an anthracycline (relative risk [RR] 0.86, 95% CI 0.79-0.93) [6]. Non-breast cancer deaths were similar, but there was one additional case of acute myeloid leukemia per 700 patients treated with an anthracycline. The greatest benefits were observed when an anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (12 versus 21 percent; RR 0.58, 95% CI 0.47-0.73), which translated to a 10-year reduction in breast cancer mortality of 4.2 percent (95% CI 0.4-8.1).

●Benefit of taxanes – The addition of taxanes to anthracycline-containing chemotherapy was associated with improved recurrence risk, breast cancer mortality, and overall mortality [6]. In trials where the same number of cycles of anthracyclines was used in the control arm as the experimental (anthracyclines followed by taxane) arm (n = 11,167 women), incorporation of taxanes led to the following improvements in outcomes:

•A reduction in the 10-year risk of recurrence from 39 to 36 percent (RR 0.87, 95% CI 0.82-0.93)

•A reduction in the risk of breast cancer mortality from 28 to 24 percent (RR 0.88, 95% CI 0.82-0.95)

The benefits of taxane incorporation seen were independent of age, nodal status, tumor size, tumor grade, and estrogen receptor status.

In trials where the number of cycles of chemotherapy for patients not receiving taxanes was doubled to mirror the addition of four cycles of taxanes to anthracyclines in the experimental arm, the incorporation of taxanes was associated with similar rates of recurrence between the groups.

Is there a role for the addition of capecitabine? — The role of capecitabine in patients who have received neoadjuvant treatment is discussed below. (See 'Patients who received neoadjuvant treatment' below.)

We do not typically incorporate capecitabine into adjuvant chemotherapy regimens for patients who have not received neoadjuvant treatment, due to added toxicity, with almost one-half of patients experiencing hand-foot syndrome [7], as well as conflicting data regarding survival improvements.

In a randomized trial, addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer [8]. Among 1500 patients with axillary node-positive or high-risk node-negative early breast cancer, those assigned to receive capecitabine in addition to an anthracycline- and taxane-containing regimen experienced a longer overall survival (OS; 15-year survival rate of 78 versus 73 percent, respectively; hazard ratio [HR] 0.81, 95% CI 0.66-0.99).

However, a trial only in patients with TNBC found disease-free survival (DFS) benefits with the addition of capecitabine, but no statistically significant improvements in OS [7]. The most common capecitabine-related adverse event was hand-foot syndrome (45.2 percent), with 7.7 percent of patients experiencing a grade 3 event. Other trials have failed to demonstrate statistically significant OS benefits with adjuvant capecitabine in TNBC, as discussed in more detail elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Choice of regimen'.)

Given the sum of data, we do not use capecitabine in the adjuvant setting for those who did not receive neoadjuvant therapy, as it is unclear that the benefits outweigh the risks for patients at standard risk. However, patients with high-risk disease are typically treated with neoadjuvant therapy, and a randomized trial has shown benefit for capecitabine only when residual disease is present, as discussed below. (See 'Patients who received neoadjuvant treatment' below.)

Acceptable alternatives to anthracycline-based treatment — Given that no regimen has proven to be superior to AC-T, we continue to prefer an anthracycline plus taxane-containing regimen for high-risk patients who are candidates for an anthracycline. However, the non-anthracycline-based regimens of TC given every three weeks for four cycles may be an appropriate alternative for patients who have indications for chemotherapy but have lower-risk disease (eg, those with node-negative, hormone receptor-positive breast cancer or node-negative TNBC <1 cm) (table 3) [9]. TC may be preferable to AC-T in these settings, particularly given the shorter duration of treatment (12 versus 16 weeks) and avoidance of the risks of congestive heart failure and secondary leukemias associated with anthracyclines. Patients with a history of cardiac disease and those unwilling to accept the risks of anthracycline-based therapy are also candidates for TC. Discussion of TC in overweight and obese patients is covered below. (See 'Obese women' below.)

●TC versus an anthracycline- and taxane-based regimen – Although an anthracycline plus taxane-based regimen may be superior to TC in high-risk disease, data suggest comparable outcomes in lower-risk disease. For example, joint analysis of the ABC Trials compared TC chemotherapy versus an anthracycline, cyclophosphamide, and taxane-based regimen in over 4000 women receiving adjuvant therapy for HER2-negative breast cancer [10]. Although overall, TC was inferior to the anthracycline and taxane-based regimen in regards to four-year invasive DFS (88.2 versus 90.7 percent; HR 1.23, 95% CI 1.01-1.50), anthracycline-based therapy did not meaningfully improve outcomes in lower-risk, ER-positive breast cancers (figure 1). In the subsequent West German Study Group PlanB trial, six cycles of TC was non-inferior to four cycles of epirubicin/cyclophosphamide, followed by four cycles of docetaxel (EC-T) [11]. However, five treatment-related deaths were reported for TC and one for EC-T, despite a trend toward more severe adverse events in the latter.

●TC versus AC and CMF – Previous data demonstrate that TC is more effective than AC alone, without subsequent treatment with taxanes [9,12]. In a United States Oncology Trial 9735, over 1016 women with stage I to III HER2-negative breast cancer were randomly assigned to AC or TC. With a median follow-up of seven years, TC resulted in a significantly higher DFS (81 versus 75 percent) and OS (87 versus 82 percent) when compared with AC. Furthermore, according to the 2012 EBCTCG meta-analysis discussed above, AC is at least equivalent to an alternative non-anthracycline-based regimen, CMF (table 4) [2]. Thus, through indirect comparison, existing evidence supports TC over CMF as the preferred non-anthracycline-based regimen.

Considering these data together, in higher-risk, ER-positive cancers and in TNBC, there may be a benefit with anthracyclines, whereas in lower-risk disease, four cycles of TC is an appropriate option.

Order of treatment — Studies in the adjuvant and neoadjuvant setting have not revealed differences in efficacy or toxicity when taxanes versus anthracyclines are administered first for patients being treated with both classes of agent. Although by convention, anthracyclines are more commonly administered first, either order is acceptable, depending on patient and provider preferences.

In a meta-analysis involving 1695 patients in nine neoadjuvant and adjuvant trials, administration of taxanes prior to anthracyclines in neoadjuvant trials did not improve OS, DFS, or pathologic complete response rate relative to the opposite order of administration [13]. Among adjuvant trials, although survival outcomes were not provided, taxanes prior to anthracyclines resulted in similar rates of neurotoxicity and appeared to reduce the risk of ≥grade 3 neutropenia (279 patients; RR 0.62, 95% CI 0.40-0.97). However, given the small number of participants and events, it is not clear that these differences would be replicated in larger trials.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplant — While randomized trials for most chemotherapeutic agents demonstrate a dose-response curve, a meta-analysis of 15 trials conducted in the adjuvant setting has shown that high-dose chemotherapy followed by autologous hematopoietic cell transplantation in breast cancer did not improve OS compared with standard adjuvant chemotherapy [14]. Notably, patients enrolled on the high-dose chemotherapy arms of these trials experienced lower survival after relapse. Given the risks and lack of survival benefit, this approach is not recommended.

Importance of chemotherapy schedule — The schedule of chemotherapy administration may influence outcomes, as described below. Data support the use of dose-dense (more frequent administration of doses) over standard dosing.

Dose-dense schedule preferred — "Dose-dense" adjuvant treatment, in which treatment is given more frequently than the historical every-three-week schedule, is associated with better DFS outcomes and similar tolerability compared with standard dosing. It is typically administered on an every-week or every-two-week schedule.

Results of a meta-analysis of dose-dense versus standard dosing, including data from 26 trials and over 37,000 women, demonstrated the following outcomes associated with dose-dense dosing [15]:

●Reductions in disease recurrence (10-year recurrence risk of 28.0 versus 31.4 percent; rate ratio [RR] 0.86, 95% CI 0.82-0.89), both in ER-positive and in ER-negative disease, irrespective of any other patient or tumor characteristics. Recurrence reductions were similar in the seven trials (including over 10,000 patients) that compared two-weekly chemotherapy with the same chemotherapy given three-weekly (10-year risk 24.0 versus 28.3 percent; RR 0·83, 95% CI 0·76–0·91).

●Improvement in 10-year breast cancer mortality (18.9 versus 21.3 percent; RR 0.87, 95% CI 0.83-0.92) and all-cause mortality (22.1 versus 24.8 percent; RR 0.87, 95% CI 0.83-0.91).

●Lower rates of death without recurrence (10-year risk 4.1 versus 4.6 percent; RR 0.88, 95% CI 0.78-0.99).

The DFS and OS benefits observed in this meta-analysis were also seen in a previously published large meta-analysis [16].

Dose-dense therapy is not associated with an increase in treatment-related adverse events [16]. In one trial, patients treated with dose-dense treatment experienced fewer episodes of fever and neutropenia compared with those treated every three weeks because of the use of growth factors [17]. The shortened cumulative time of treatment (16 versus 24 weeks for dose-dense versus every three weeks) is also a favorable feature of dose-dense delivery of adjuvant chemotherapy.

The meta-analysis above also examined the effect of sequential versus concurrent anthracycline and taxane-based chemotherapy in 11,500 women enrolled in six trials [15]. Sequential versus concurrent anthracycline plus taxane chemotherapy (eg, AC then T) was associated with improvement in disease recurrence rates compared with concurrent regimens (eg, TAC. 10-year risk 28.1 versus 31.3 percent; RR 0.87, 95% CI 0.80-0.94). Based on these data, we recommend dose-dense AC followed by sequential taxane therapy as our standard adjuvant chemotherapy regimen.

It is not known which of the common dose-dense strategies of every-two-week AC x 4 followed by every-two-week paclitaxel x 4 or every-two-week AC x 4 followed by weekly paclitaxel x 12 is superior. Finally, there are several widely used chemotherapy regimens, particularly the non-anthracycline regimen, TC, that cannot be delivered in a dose-dense fashion. Such regimens if used should be administered on their regular every-three-week schedule.

Schedule of taxanes — We administer taxanes sequentially rather than concurrently with anthracyclines. Additionally, schedule of each dose of taxane appears to be important and specific for each taxane.

A randomized controlled trial (RCT) conducted by the Eastern Cooperative Oncology Group (ECOG) in the adjuvant setting demonstrated that paclitaxel is more effective when used in a lower, but dose-dense fashion compared with a higher dosage on a three-week schedule (80 mg/m² every week x 12 versus 175 mg/m² every three weeks x 4). Docetaxel, by contrast, appeared to be more effective when given at higher doses every three weeks (100 mg/m² every three weeks x 4 versus 35 mg/m² weekly x 12) [5]. The comparison of paclitaxel every week versus docetaxel every three weeks did not suggest a difference in DFS or OS.

A subsequent RCT conducted by SWOG failed to demonstrate any differential benefit comparing adjuvant paclitaxel at 175 mg/m² every two weeks x 6 versus 80 mg/m² every week x 12 [18]. However, the every-two-week schedule produced more allergic-type reactions, musculoskeletal pain, and neurologic toxicity than the weekly schedule. However, the increased neuropathy may have been due to application of six cycles of paclitaxel treatment. Since a subsequent study by Cancer and Leukemia Group B (CALGB) failed to detect a benefit of six versus four cycles, the latter has become the standard of care [19].

Duration — The duration of treatment varies by the regimen used. For example, dose-dense AC-T is administered over 16 weeks (total of eight cycles at two-week intervals), whereas CMF is generally administered over six months (six cycles at four-week intervals).

Data are limited in regards to whether longer treatment courses lead to better outcomes. For women deemed to be at a low risk of recurrence (eg, invasive breast cancer with no more than three pathologically involved nodes), the CALGB 40101 trial suggested that six cycles of chemotherapy (with either AC or T) did not improve survival outcomes compared with four [19].

TIMING OF CHEMOTHERAPY AND RADIATION — Adjuvant chemotherapy is typically started within four to six weeks after surgery. Earlier treatment is not necessarily better, but observational data suggest a delay of more than three months is detrimental [20-22]. For patients who are also going to receive adjuvant radiation therapy, standard clinical practice is to proceed with chemotherapy before radiation therapy. Concomitant chemotherapy and radiation treatment is associated with an increase in acute toxicity without a survival advantage and is therefore not recommended.

Data to support sequencing radiation after chemotherapy come from a randomized trial presented at the 2011 European Multidisciplinary Cancer Congress that assigned almost 2400 women with early breast cancer to receive adjuvant chemotherapy and radiation either concomitantly or sequentially (with radiation following chemotherapy) [23]. Concomitant treatment was associated with a significant increase in acute skin toxicity (25 versus 16 percent) and the occurrence of moderate or severe skin telangiectasia (2.5 versus 1.3 percent). Although five-year local recurrence rates were significantly improved with concomitant treatment (2.8 versus 5.1 percent), there was no difference in overall or disease-free survival.

SPECIAL POPULATIONS

Patients who received neoadjuvant treatment — For most patients who receive a "standard" course of neoadjuvant chemotherapy, we do not administer further chemotherapy in the adjuvant setting. However, the survival benefit for use of capecitabine in women with residual disease after standard neoadjuvant chemotherapy, particularly in those with triple-negative breast cancer (TNBC), suggests that such patients may be appropriate candidates for adjuvant capecitabine. For patients who did not complete the full course of neoadjuvant treatment, we continue the planned course of treatment in the adjuvant setting, making dose adjustments as necessary for observed toxicities.

The CREATE-X trial randomly assigned approximately 900 patients with HER2-negative breast cancer (approximately one-third of whom had TNBC) and residual disease after neoadjuvant anthracycline and/or taxane therapy to either eight cycles of adjuvant capecitabine or no further chemotherapy [24]. Patients receiving capecitabine had higher rates of five-year disease-free survival (DFS; 74 versus 68 percent; hazard ratio [HR] 0.70, 95% CI 0.53-0.92) and overall survival (OS; 89 versus 84 percent; HR for death 0.59, 95% CI 0.39-0.90). Subgroup analyses suggested that the improvement in DFS with capecitabine was driven by improved outcomes among patients with TNBC (70 versus 56 percent; HR 0.58, 95% CI 0.39-0.87). Toxicities, however, were also higher among patients receiving capecitabine, with side effects including diarrhea, neutropenia, and hand-foot syndrome. Additional studies are evaluating other agents, including platinum chemotherapy and immunotherapy, in this setting. Other studies in patients with TNBC who received adjuvant or neoadjuvant chemotherapy have failed to demonstrate improvements in DFS with subsequent adjuvant capecitabine treatment, as discussed elsewhere. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Choice of regimen'.)

In preliminary results of a patient-level meta-analysis of 52 studies including 28,000 patients treated with neoadjuvant therapy for breast cancer, achieving pathologic complete response (pCR) was associated with improvements in both event-free survival and OS, irrespective of whether adjuvant chemotherapy was administered [25]. Similarly, the randomized WGT-ADAPT trial failed to show a clinical benefit for adding additional chemotherapy to patients with TNBC who achieve a pCR [26]. In that study, patients were offered taxane-based neoadjuvant chemotherapy. Women who achieved a pCR were randomized to additional therapy with epirubicin/cyclophosphamide or not. The addition of chemotherapy did not appear to improve long-term survival.

Based on these experiences, we recommend that patients should, in general, conclude the standard course of neoadjuvant therapy (eg, doxorubicin and cyclophosphamide followed by paclitaxel [AC/T] or docetaxel and cyclophosphamide [TC], or variants) prior to surgery. Those patients with a pCR are, in general, done with chemotherapy. For women with TNBC, we offer capecitabine if there is residual disease after neoadjuvant chemotherapy. Nearly all women with estrogen receptor-positive, HER2-negative cancers will have residual disease after neoadjuvant chemotherapy; these patients should receive adjuvant endocrine therapy alone.

BRCA carriers with high-risk disease

Patient selection for adjuvant PARP inhibitors — For select breast cancer susceptibility gene (BRCA) carriers with high-risk disease who have been treated with neoadjuvant or adjuvant chemotherapy, we suggest adjuvant treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib orally twice daily for one year [27,28]. Olaparib has regulatory approval by the US Food and Drug Administration for the adjuvant treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative, high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy [29].

Specifically, our approach to the following subgroups is as follows:

●Triple-negative disease

•Treated with neoadjuvant chemotherapy – Most patients with high-risk triple-negative disease will be treated with neoadjuvant therapy, including those with node-positive disease or larger primary tumors (eg, ≥T1c; (algorithm 1)). In such patients who are not BRCA carriers, we suggest adjuvant capecitabine if residual disease is present, as discussed above. (See 'Patients who received neoadjuvant treatment' above.)

However, for BRCA carriers, we typically prefer olaparib, particularly for those who prefer to avoid the toxicities of capecitabine (stomatitis, plantar-palmar erythrodysesthesia, etc). This approach is based on the OlympiA trial, discussed below. (See 'Supporting data' below.)

•Treated with adjuvant chemotherapy – A subset of patients with triple-negative disease thought to have lower-risk disease will proceed directly to surgery, only to be found to have higher-risk features on the surgical biopsy specimen. In BRCA carriers who are treated initially with surgery and are found to have either node-positive disease or a primary tumor ≥2 cm on the surgical specimen, we suggest adjuvant olaparib.

●Hormone receptor-positive disease

•Treated with neoadjuvant chemotherapy – For patients with hormone receptor-positive disease treated with neoadjuvant chemotherapy who did not have a complete pathologic response, the pretreatment clinical stage and post-treatment pathologic stage (CPS score) as well as estrogen receptor status and tumor grade (CPS+EG score) are used to prognosticate. For BRCA carriers with residual disease and a CPS+EG ≥3, we suggest adjuvant olaparib.

•Treated with adjuvant chemotherapy – For patients with hormone receptor-positive disease who were treated with adjuvant chemotherapy and had N2 disease, we suggest adjuvant olaparib.

Supporting data — A randomized, double-blind trial (OlympiA) was conducted in 1836 patients with high-risk, HER2-negative early breast cancer with BRCA1 or BRCA2 variants and high-risk clinicopathologic factors who had received local treatment and neoadjuvant or adjuvant chemotherapy [27].

High risk features, according to the OlympiA eligibility criteria, are included in the table (table 5). Additionally, patients had to complete all local therapy between two and 12 weeks of trial entry. All patients completed at least six cycles of chemotherapy. Adjuvant bisphosphonates and endocrine therapy in patients with hormone receptor-positive disease were permitted, according to institutional guidelines. Adjuvant chemotherapy was not allowed in patients who received neoadjuvant chemotherapy.

In this trial, patients assigned to the olaparib group had an improvement in three-year DFS relative to the placebo group (86 versus 77 percent; difference, 8.8 percentage points; 95% CI 4.5-13.0). Distant DFS at three years was 88 percent in the olaparib group and 80 percent in the placebo group (difference, 7.1 percentage points; 95% CI 3.0-11.1). Fewer deaths were reported in the olaparib group (59 of 921 patients) than in the placebo group (86 of 915 patients). Four-year overall survival was 90 versus 86 percent (HR 0.68, 98.5% CI 0.47-0.97) [30].

The benefit of adjuvant olaparib relative to placebo was observed for invasive DFS irrespective of the germline BRCA mutation (BRCA1 versus BRCA2), hormone receptor status, carboplatin administration, or whether chemotherapy was administered in the neoadjuvant versus adjuvant setting.

Grade ≥3 events occurring in >1 percent of the patients in the olaparib group were anemia (8.7 percent), decreased neutrophil count (4.8 percent), decreased white-cell count (3.0 percent), fatigue (1.8 percent), and lymphopenia (1.2 percent). There were no excess cases of acute myeloid leukemia or myelodysplastic syndrome with olaparib over placebo.

These data justify genetic testing for all patients meeting the OlympiA eligibility criteria. Our approach to germline testing is 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'.)

Older women — Adjuvant chemotherapy is generally recommended for older women (≥65 years) with a good performance status. Prospective studies have shown that older women tolerate cyclophosphamide, methotrexate, and 5-fluorouacil (CMF) and doxorubicin plus cyclophosphamide (AC) chemotherapy reasonably well, and clinical experiences suggest that older women can also tolerate taxane-based chemotherapy [31]. Prior to making a decision regarding chemotherapy, older women should be evaluated using a comprehensive geriatric assessment. Specific issues related to the adjuvant treatment of older women are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Overview of the approach to early breast cancer in older women".)

There are fewer data for use of chemotherapy in women over age 70, and the decision to use adjuvant chemotherapy in these women is complicated due to an increased number of comorbidities, which means that the impact of chemotherapy on daily function may be greater, and the benefits of chemotherapy tend to be lower. Nevertheless, age itself is not a definitive reason for not giving chemotherapy.

Male breast cancer — Breast cancer is a rare diagnosis in men, but decisions regarding adjuvant chemotherapy do not differ by gender. In addition, the prognosis for men and women with breast cancer is similar. Male breast cancer is covered in detail separately. (See "Breast cancer in men".)

Women of childbearing age — The issue of fertility preservation should be discussed with patients of childbearing age undergoing adjuvant chemotherapy for breast cancer. This topic is discussed in detail elsewhere. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Breast cancer in pregnancy — Most chemotherapy agents for breast cancer carry a risk of teratogenicity in humans. Chemotherapy can be administered after the first trimester. Breast cancer during pregnancy is covered in detail elsewhere. (See "Gestational breast cancer: Treatment".)

Obese women — Obesity is associated with worsened survival among patients with hormone receptor-positive, HER2-negative breast cancer (though not for patients with TNBC). However, obesity itself is not an indication for chemotherapy in the absence of other indications (see 'Indications for treatment' above). If chemotherapy is indicated, we suggest that standard, weight-based drug doses be administered to all patients regardless of body mass index (BMI), despite the expected high doses thus required. This is consistent with clinical practice guidelines from the American Society of Clinical Oncology [32]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)

Obese women (typically defined as a BMI >30 kg/m²) with hormone-positive breast cancer have a worse prognosis compared with women with a normal BMI, despite appropriate adjuvant therapy [33-36]. In the largest study to demonstrate this association, the Eastern Cooperative Oncology Group (ECOG) examined the relationship between obesity and survival outcomes using information from three randomized trials evaluating adjuvant therapy regimens in breast cancer patients, ECOG 1199, 1158, and 3189 [35]. After adjustment for prognostic factors (including age, race, menopausal status, tumor stage, and type of surgery), obesity was associated with inferior DFS (HR 1.24, 95% CI 1.06-1.46) and OS (HR 1.37, 95% CI 1.13-1.67) among women with hormone receptor-positive breast cancer, but not among women with TNBC or HER2-positive disease. These results indicate that obesity is associated with a poor prognosis among women with hormone receptor-positive disease. Whether prognosis can be modified by dietary and lifestyle interventions requires further evaluation. (See "Approach to the patient following treatment for breast cancer", section on 'Promoting a healthy lifestyle'.)

A discussion of the morbidity and mortality risks associated with obesity is covered separately. (See "Overweight and obesity in adults: Health consequences".)

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.)

●Beyond the Basics topics (see "Patient education: Treatment of early-stage, hormone-responsive breast cancer in premenopausal women (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Benefit of adjuvant chemotherapy – Overall, adjuvant chemotherapy for breast cancer decreases risk of recurrence and improves survival, but the absolute benefits in patients with a low risk of recurrence may be small. Therefore, the decision to offer chemotherapy must take into account risk factors of the disease as well as patient age and comorbidities. (See 'Introduction' above and 'Benefit of adjuvant chemotherapy' above.)

●Indications for chemotherapy – Indications for adjuvant chemotherapy are discussed elsewhere. (See "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer" and "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Non-metastatic disease'.)

●Regimen options – For high-risk patients who are treated with adjuvant chemotherapy, we suggest a regimen that includes an anthracycline and taxane (administered sequentially) rather than a non-anthracycline-based treatment (Grade 2B) (see 'Rationale for anthracycline- and taxane-containing regimen' above). We prefer the dose-dense regimen of doxorubicin and cyclophosphamide every two weeks for four cycles followed by paclitaxel every two weeks for four cycles (AC-T).

Although no regimen has proved to be superior to AC-T, the non-anthracycline-based regimen docetaxel and cyclophosphamide (TC) given every three weeks for four cycles may be an appropriate strategy for patients who have indications for chemotherapy but have lower-risk disease. TC may also be appropriate for those with a history of cardiac disease and those unwilling to accept the risks of anthracycline-based therapy. A decision on the treatment administered should take into account patient convenience and the side effects of each combination. (See 'Choosing a regimen' above and 'Acceptable alternatives to anthracycline-based treatment' above.)

●Timing of treatment – Adjuvant chemotherapy is typically started within four to six weeks after definitive breast surgery. (See 'Timing of chemotherapy and radiation' above.)

●Adjuvant treatments for patients with residual disease after neoadjuvant treatment

•For BRCA wildtype triple-negative breast cancer (TNBC) who have residual disease after completing a standard course of neoadjuvant chemotherapy, we suggest a course of adjuvant capecitabine (algorithm 1) (Grade 2B). However, given the added toxicities, observation rather than further chemotherapy is also an appropriate option. Nearly all women with hormone receptor-positive, HER2-negative cancers will have residual disease after neoadjuvant chemotherapy; these patients should receive adjuvant endocrine therapy alone. (See 'Patients who received neoadjuvant treatment' above.)

•For BRCA carriers with high-risk disease as defined by criteria from the OlympiA trial (table 5), we suggest adjuvant olaparib rather than observation only (algorithm 1) (Grade 2B). For BRCA carriers with TNBC and residual disease after neoadjuvant treatment, adjuvant capecitabine is a reasonable alternative, although we typically prefer olaparib on the basis of improved tolerability. Other high-risk features are discussed above. (See 'Patient selection for adjuvant PARP inhibitors' above.)

●Special populations

•For older women (>70 years), the decision to utilize chemotherapy is complicated by an increased number of comorbidities, which means that the impact of chemotherapy on daily function may be greater, and the benefits of chemotherapy may be lower. Nevertheless, age itself is not a definitive reason for not giving chemotherapy. (See 'Older women' above.)

•Standard, weight-based drug doses should be administered to obese patients, despite the expected high doses required. (See 'Obese women' above.)