Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
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 . 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. 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 "Breast cancer in men".)
Other topics on the management of nonmetastatic breast cancer are discussed elsewhere. (See "Overview of the treatment of newly diagnosed, 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. 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. The approach towards patients who received neoadjuvant treatment is discussed below. (See 'Patients who received neoadjuvant treatment' below.)
Chemotherapy reduces the risk of recurrence in women with early-stage breast cancer. However, the absolute benefits may be small and not worth the added risk of toxicity among women with a baseline low risk of recurrence. Similarly, there are patients with substantial comorbid conditions or markedly advanced age such that chemotherapy is neither feasible nor likely to change overall survival. The discussion below assumes that the patient has sufficient general health and life expectancy to warrant discussion of adjuvant chemotherapy. Our general approach to treatment of human epidermal growth factor receptor 2 (HER2)-negative, early-stage breast cancer uses a risk-stratified approach based on the presence of factors associated with an increased risk of recurrence. It is summarized below according to biologic subtype:
Among hormone receptor-negative cancers ("triple-negative tumors") — Adjuvant chemotherapy is standard for patients with triple-negative breast cancer and either a tumor size >0.5 cm or pathologically involved lymph nodes (regardless of tumor size). Patients with tumors that do not express hormone receptors (ie, ER- and PR-negative) are not candidates for endocrine therapy, and as the tumor is HER2 negative, they are not candidates for anti-HER2 therapy, either. Therefore, our threshold for the use of chemotherapy in these patients is low because this is the only form of adjuvant treatment available to them, and because studies have suggested a significant risk of recurrence if left untreated. The prognosis of small (<0.5 cm), node-negative, triple-negative tumors is generally favorable. For that reason, the benefits of adjuvant chemotherapy are very small, and must be weighed against the chances of serious side effects of chemotherapy. Patients with microinvasive or very small (1 to 3 mm) tumors generally do not need chemotherapy. (See "Prognostic and predictive factors in early, nonmetastatic breast cancer", section on 'Tumor size'.)
The approach to patients who have received neoadjuvant treatment is discussed below. (See 'Patients who received neoadjuvant treatment' below.)
Among hormone receptor-positive breast cancers — Chemotherapy treatment decision-making for women with ER-positive, HER2-negative breast cancers is more complicated, owing to the variation in prognosis among women with ER-positive, HER2-negative tumors, the effectiveness of adjuvant endocrine therapy at reducing recurrence, and the variable sensitivity of ER-positive tumors to chemotherapy treatments. For such patients, the decision to administer chemotherapy is based on an assessment of the composite risk of recurrence and likely benefit of treatment based upon patient age, tumor lymph node status, size, grade, lymphovascular invasion, or the results of a gene expression profile such as the Recurrence Score (RS) .
Most instances of ER-positive breast cancer <1 cm, and all cancers <0.5 cm, have a good prognosis with endocrine therapy alone, and do not typically require adjuvant chemotherapy. At the other end of the risk spectrum, most women with stage III breast cancers will warrant adjuvant chemotherapy because of their risk of recurrence and the likely benefits of chemotherapy treatment.
The majority of cases of ER-positive breast cancer fall in between these two extremes, and decisions regarding the addition of chemotherapy to adjuvant endocrine therapy should be individualized. In general, ER-positive, HER2-negative breast cancers that are low grade, strongly ER and PR positive, with low measures of proliferation have a good prognosis with endocrine treatment alone. By contrast, tumors that are high grade, with higher measures of proliferation and lower levels of ER/PR expression, tend to be less sensitive to endocrine treatment and more likely to benefit from adjuvant chemotherapy. To guide clinical decision-making, gene expression profiles such as the RS, EndoPredict, the Breast Cancer Index (BCI), and the PAM50 intrinsic subtype assay have been developed to identify patients with such a low chance of recurrence that the absolute benefit of chemotherapy may not justify the risk of toxicities . By contrast, patients with higher scores on these assays have a sufficiently high risk of recurrence despite endocrine therapy that the addition of chemotherapy outweighs the risk of toxicities. Moreover, given that the response to treatment is not uniform among all cancers, these assays may identify those cancers that, based on their biologic profile, are likely to have an excellent outcome with endocrine therapy alone versus those in which the addition of chemotherapy would substantially reduce the risk of recurrence.
Among the gene expression profiles, the 21-gene RS is the most well-validated, providing a prognostic signature for outcome with endocrine therapy alone. In addition, the RS is the only assay shown to predict the benefit from chemotherapy for women with ER-positive breast cancer and either limited or no nodal involvement. Patients with ER-positive cancers that are node negative derive substantial benefit from chemotherapy if the 21-gene RS is high (typically, >24). By contrast, if the score is low (<18), there is no marginal benefit to adding chemotherapy to endocrine treatment . Whether women with intermediate scores should receive adjuvant chemotherapy is unknown and is the subject of an ongoing clinical trial (TAILORx) . A separate prospective study (PlanB) has demonstrated that women with limited nodal involvement (one to three nodes) who have low recurrence scores (<12) also have exceptionally good outcomes without the addition of chemotherapy . The development and validation of the RS is discussed in detail elsewhere. (See "Prognostic and predictive factors in early, nonmetastatic breast cancer", section on 'Recurrence Score (RS)' and "Prognostic and predictive factors in early, nonmetastatic breast cancer", section on 'Limited support for use in node-positive disease'.)
Other gene expression profiles can also provide prognostic information on outcomes with endocrine treatment. For example, tumors that are typed as luminal A in the PAM50 intrinsic subtype assay have a very good prognosis without chemotherapy; those that are luminal B are more likely to recur with endocrine treatment alone, and may warrant chemotherapy. (See "Prognostic and predictive factors in early, nonmetastatic breast cancer", section on 'Gene expression profiles'.)
The approach to patients who have received neoadjuvant treatment is discussed below. (See 'Patients who received neoadjuvant treatment' below.)
Benefit-risk calculators — The selection of patients who are most likely to benefit from treatment requires review of an individual's risk for breast cancer recurrence and death. Risk calculators have been developed to estimate a specific patient's risk of breast cancer recurrence and mortality and the benefit that may be derived from chemotherapy (and where appropriate, endocrine therapy). These calculators should not, however, be considered a substitute for molecular diagnostic assays, as they do not take into account all biomarkers and relationships between tumor biology and treatment effects. Of the available calculators, our preferred tool is Adjuvant! Online, which is the most widely studied and validated [7-13].
Adjuvant! Online is a web-based program that determines both recurrence risk and probability of survival based on population-wide data from the Surveillance, Epidemiology, and End Results (SEER) database and overviews on the benefits of adjuvant therapy by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), individual clinical trial results (if not covered in the overview), and the general published literature [7-10]. The estimates provided by Adjuvant! Online have been validated using a large, population-based dataset and are similar to those derived from other large patient datasets [11-13]. Adjuvant! Online can be helpful in framing the realistic benefits of adjuvant treatment.
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.)
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 :
●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.)
Risks — Risks of chemotherapy include acute toxicities including nausea, vomiting, hair loss, myelosuppression, 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. These issues are discussed in detail elsewhere. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity" and "Overview of neurologic complications of non-platinum cancer chemotherapy" and "Acute side effects of adjuvant chemotherapy for early-stage 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 1) . (See 'Rationale for anthracycline- and taxane-containing regimen' below.)
Although no regimen has proven to be superior to AC-T, nonanthracycline-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 nonanthracycline-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, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management 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 nonanthracycline-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 regimen of doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) delivered on a dose-dense schedule is the preferred regimen for most patients (table 1). For patients with lower-risk disease or a history of cardiac disease, nonanthracycline regimens may be preferable. (See 'Acceptable alternatives to anthracycline-based treatment' below.)
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 . 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) . 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.
However, the addition of taxanes to anthracycline-containing chemotherapy was associated with improved recurrence risk, breast cancer mortality, and overall mortality compared with other cytotoxic regimens . 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 risk of recurrence from 35 to 30 percent (relative risk [RR] 0.84, 95% CI 0.78-0.91)
●A reduction in the risk of breast cancer mortality from 24 to 21 percent (RR 0.86, 95% CI 0.79-0.93)
●A reduction in overall mortality from 27 to 24 percent (RR 0.90, 95% CI 0.79-0.93)
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 the following results at five years:
●A reduction in the risk of recurrence from 22 to 19 percent (RR 0.86, 95% CI 0.82-0.91)
●A reduction in the risk of breast cancer mortality from 12 to 10 percent (RR 0.88, 95% CI 0.81-0.95)
●A reduction in overall mortality from 12 to 11 percent (RR 0.90, 95% CI 0.84-0.97)
The benefits of taxane incorporation seen were independent of age, nodal status, tumor size, tumor grade, and estrogen receptor (ER) status.
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 nonanthracycline-based regimens of docetaxel and cyclophosphamide given every three weeks for four cycles (TC) 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, triple-negative breast cancer <1 cm) (table 2) . 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. While AC-T and TC have not been directly compared, a phase III trial of TC versus docetaxel, doxorubicin, and cyclophosphamide (TAC) is ongoing to address the question of whether anthracyclines provide any additional benefit in the setting of effective taxane/alkylator-based chemotherapy (NCT00493870).
Data in support of TC come from randomized trial data that suggest that TC is more effective than AC [24,25]. In a United States Oncology Trial 9735, over 1016 women with stage I to III human epidermal growth factor receptor 2 (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 disease-free survival (DFS, 81 versus 75 percent) and overall survival (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 nonanthracycline-based regimen, CMF (table 3) . Thus, through indirect comparison, existing evidence supports TC over CMF as the preferred nonanthracycline-based regimen.
Joint Analysis of the Anthracyclines in Early Breast Cancer (ABC) Trials, presented at the American Society of Clinical Oncology (ASCO) 2016 annual meeting, compared TC chemotherapy versus an anthracycline, cyclophosphamide, and taxane-based regimen . Thus, this analysis addressed directly the role of anthracycline chemotherapy in the modern era when taxanes are universally given. Preliminary data from that study suggest that anthracycline-based therapy does not meaningfully improve outcomes in lower-risk, ER-positive breast cancers. In higher-risk, ER-positive cancers and in triple-negative breast cancers, there appears to be a role for anthracyclines.
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 . 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. The improvements in DFS over standard dosing are seen particularly in women with ER-negative disease.
A meta-analysis of dose-dense versus standard dosing, including data from 10 trials and over 11,000 women, reported the following outcomes associated with dose-dense dosing :
●In three trials that evaluated the same dose given as either dose-dense or standard administration, dose-dense treatment improved DFS (hazard ratio [HR] 0.83, 95% CI 0.73-0.94) and OS (HR 0.84, 95% CI 0.72-0.98).
●In seven trials in which modified doses or regimens were evaluated, improvement in DFS (HR 0.81, 95% CI 0.73-0.88) and OS (HR 0.85, 95% CI 0.75-0.96) was also demonstrated with dose-dense treatment.
●The benefit in DFS was seen in women with ER-negative disease (HR 0.71, 95% CI 0.56-0.98), but not in women with ER-positive disease (HR 0.92, 95% CI 0.75-1.12).
Dose-dense therapy is not associated with an increase in treatment-related adverse events . In one of these trials, 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 . 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.
A study that was not included in the meta-analysis lends additional support to dose-dense therapy. In the Eastern Cooperative Oncology Group 1199 (ECOG 1199) trial, women with node-positive (N1 or N2) or high-risk, node-negative (ie, T2 or T3, N0) breast cancer were treated with AC every three weeks for four cycles and randomly assigned to receive either paclitaxel or docetaxel administered on either an every-three-week or weekly schedule . It should be noted that higher cumulative doses of taxane were administered with the weekly schedule compared with the every-three-week schedule. Compared with paclitaxel administered every three weeks, treatment with weekly paclitaxel resulted in:
●A significant improvement in DFS at five years (81.5 versus 76.9 percent, respectively; HR 1.27, 95% CI 1.03-1.57)
●A significant improvement in OS at five years (89.7 versus 86.5 percent; HR 1.32, 95% CI 1.02-1.72)
Longer-term follow-up at a median of 12.1 years showed similar, albeit less pronounced, results, favoring weekly paclitaxel over paclitaxel administered every three weeks. Interestingly, weekly paclitaxel particularly improved DFS and OS more substantially in triple-negative breast cancers (HR 0.69; p = 0.010 and HR 0.69; p = 0.019, respectively) .
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 Cancer and Leukemia Group B 40101 trial (CALGB 40101) suggested that six cycles of chemotherapy (with either AC or T) did not improve survival outcomes compared with four .
SEQUENCING CHEMOTHERAPY AND RADIATION — Adjuvant chemotherapy is typically started within four to six weeks after surgery. Earlier treatment is not necessarily better, but a delay of more than 12 weeks may be detrimental [32,33]. 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) . 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 (OS) or disease-free survival (DFS).
Patients who received neoadjuvant treatment — For patients who receive a "standard" course of neoadjuvant chemotherapy, we do not typically administer further chemotherapy in the adjuvant setting, except in patients who did not receive a full course of neoadjuvant chemotherapy. 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 prognosis of patients who do not achieve a pathologic complete response (pCR) with neoadjuvant chemotherapy is worse compared with those who do, especially in patients with either triple-negative or human epidermal growth factor receptor 2 (HER2)-positive cancers. However, whether routine use of further chemotherapy for women who have received a full course of neoadjuvant treatment improves outcomes sufficiently to justify its toxicity is not known [35-37], and is the study of active investigation .
While preliminary data suggest there may be a survival benefit associated with adjuvant capecitabine for patients with residual disease after neoadjuvant chemotherapy, we await final reporting of safety and efficacy data of this approach prior to altering our practice approach. The Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial randomly assigned approximately 900 patients with HER2-negative breast cancer (approximately one-third of whom had triple-negative disease) and residual disease after neoadjuvant anthracycline and/or taxane therapy to either eight cycles of adjuvant capecitabine or no further chemotherapy . Preliminary data demonstrated that patients receiving capecitabine had higher rates of five-year disease-free (74 versus 68 percent) and overall survival (89 versus 84 percent). Subgroup analyses suggested that the improvement in disease-free survival with capecitabine was driven by improved outcomes among patients with triple-negative disease (hazard ratio [HR] 0.58, 95% CI 0.39-0.87). Toxicities were also higher among patients receiving capecitabine, with side effects including diarrhea, neutropenia, and hand-foot syndrome.
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 . 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 "General principles on the treatment of early-stage and locally advanced 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 preservation in patients undergoing gonadotoxic treatment or gonadal resection".)
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 triple-negative or HER2-positive disease). 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 . (See "Dosing of anticancer agents in adults", section on '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 [41-44]. 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 . After adjustment for prognostic factors (including age, race, menopausal status, tumor stage, and type of surgery), obesity was associated with inferior disease-free survival (hazard ratio [HR] 1.24, 95% CI 1.06-1.46) and overall survival (HR 1.37, 95% CI 1.13-1.67) among women with hormone receptor-positive breast cancer, but not among women with triple-negative 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 "Obesity in adults: Health consequences".)
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 5th to 6th 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 10th to 12th 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: Early stage breast cancer treatment in premenopausal women (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●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.)
●The decision to utilize adjuvant treatment can be framed by risk calculators, which estimate a specific patient's risk of breast cancer recurrence and mortality and the benefit that may be expected from chemotherapy, based on population-wide data. (See 'Benefit-risk calculators' above.)
●Adjuvant chemotherapy is the mainstay of systemic treatment for triple-negative breast cancers. For patients with hormone receptor-negative breast cancer and either a tumor size >0.5 cm or pathologically involved lymph nodes (regardless of tumor size), we recommend adjuvant chemotherapy (Grade 1A). Risk of recurrence increases on a continuum, such that larger tumors are more likely to derive benefit from adjuvant chemotherapy than smaller ones. We do not typically administer adjuvant chemotherapy for node-negative tumors that are <0.5 cm.
●For patients with human epidermal growth factor receptor 2 (HER2)-negative, hormone receptor-positive disease, the decision to administer chemotherapy is based on an assessment of the composite risk of recurrence and likely benefit of treatment based upon patient age, tumor stage (lymph node status, size), grade, lymphovascular invasion, or the results of a gene expression profile such as the Recurrence Score (RS). Adjuvant chemotherapy has a critical role in many estrogen receptor (ER)-positive, HER2-negative breast cancers, for example in stage III breast cancers as well as those with a high recurrence score or luminal B features. By contrast, adjuvant chemotherapy does not have a role in stage 1 or 2 breast cancers with low recurrence scores or luminal A features. (See 'Among hormone receptor-positive breast cancers' above.)
●For patients with HER2-negative, hormone receptor-positive disease, we offer treatment with adjuvant endocrine therapy regardless of whether chemotherapy was administered. (See 'Among hormone receptor-positive breast cancers' above.)
●For high-risk patients who are treated with adjuvant chemotherapy, we suggest an anthracycline- and taxane-based combination rather than a nonanthracycline-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 nonanthracycline-based regimen docetaxel and cyclophosphamide given every three weeks for four cycles (TC) 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.)
●Adjuvant chemotherapy is typically started within four to six weeks after definitive breast surgery. (See 'Sequencing chemotherapy and radiation' above.)
●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.)
- Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005; 353:1784.
- Henry NL, Somerfield MR, Abramson VG, et al. Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer: American Society of Clinical Oncology Endorsement of Cancer Care Ontario Guideline Recommendations. J Clin Oncol 2016; 34:2303.
- Harris LN, Ismaila N, McShane LM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2016; 34:1134.
- Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24:3726.
- Sparano JA, Gray RJ, Makower DF, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373:2005.
- Gluz O, Nitz UA, Christgen M, et al. West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment. J Clin Oncol 2016; 34:2341.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.
- Adjuvant! Breast Cancer Help Files. www.adjuvantonline.com/index.jsp (Accessed on October 14, 2011).
- Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001; 19:980.
- Baum M, Ravdin PM. Decision-making in early breast cancer: guidelines and decision tools. Eur J Cancer 2002; 38:745.
- Fisher B, Dignam J, Tan-Chiu E, et al. Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 2001; 93:112.
- Rosen PP, Groshen S, Saigo PE, et al. Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years. J Clin Oncol 1989; 7:1239.
- Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 2005; 23:2716.
- Michaelson JS, Chen LL, Bush D, et al. Improved web-based calculators for predicting breast carcinoma outcomes. Breast Cancer Res Treat 2011; 128:827.
- http://cancer.lifemath.net/ (Accessed on October 20, 2011).
- Lundin J, Lundin M, Isola J, Joensuu H. A web-based system for individualised survival estimation in breast cancer. BMJ 2003; 326:29.
- www.finprog.org/default.asp (Accessed on October 20, 2011).
- de Glas NA, Bastiaannet E, Engels CC, et al. Validity of the online PREDICT tool in older patients with breast cancer: a population-based study. Br J Cancer 2016; 114:395.
- Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res 2010; 12:R1.
- Wishart GC, Bajdik CD, Azzato EM, et al. A population-based validation of the prognostic model PREDICT for early breast cancer. Eur J Surg Oncol 2011; 37:411.
- Wishart GC, Bajdik CD, Dicks E, et al. PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2. Br J Cancer 2012; 107:800.
- Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012; 379:432.
- Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008; 358:1663.
- Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006; 24:5381.
- Jones S, Holmes FA, O'Shaughnessy J, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 2009; 27:1177.
- Blum JL, Flynn PJ, Yothers G, Asmar L. Joint Analysis of the ABC (Anthracyclines in Early Breast Cancer) Trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) Comparing Docetaxel Plus Cyclophosphamide (TC) to Anthracycline/Taxane-Based Chemotherapy Regimens (TaxAC) in Women with High-Risk, HER2-Negative Breast Cancer. J Clin Oncol 2016; 34S: ASCO #1000.
- Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol 2011; 29:3214.
- Bonilla L, Ben-Aharon I, Vidal L, et al. Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 2010; 102:1845.
- Citron ML. Dose-Dense Chemotherapy: Principles, Clinical Results and Future Perspectives. Breast Care (Basel) 2008; 3:251.
- Sparano JA, Zhao F, Martino S, et al. Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer. J Clin Oncol 2015; 33:2353.
- Shulman LN, Cirrincione CT, Berry DA, et al. Six cycles of doxorubicin and cyclophosphamide or Paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol 2012; 30:4071.
- Shannon C, Ashley S, Smith IE. Does timing of adjuvant chemotherapy for early breast cancer influence survival? J Clin Oncol 2003; 21:3792.
- Lohrisch C, Paltiel C, Gelmon K, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 2006; 24:4888.
- Fernando IN, Bowden SJ, Brookes CL, et al. Synchronous chemo-radiation can reduce local recurrence in early stage breast cancer: results of the SECRAB trial. 2011 European Multi-Disciplinary Cancer Conference; Eur Multidisciplinary Cancer Conference, Stockholm, Sweden, 2011.
- Kimmick GG, Cirrincione C, Duggan DB, et al. Fifteen-year median follow-up results after neoadjuvant doxorubicin, followed by mastectomy, followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) followed by radiation for stage III breast cancer: a phase II trial (CALGB 8944). Breast Cancer Res Treat 2009; 113:479.
- Thomas E, Holmes FA, Smith TL, et al. The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol 2004; 22:2294.
- Alvarez RH, Booser DJ, Cristofanilli M, et al. Phase 2 trial of primary systemic therapy with doxorubicin and docetaxel followed by surgery, radiotherapy, and adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil based on clinical and pathologic response in patients with stage IIB to III breast cancer : long-term results from the University of Texas M. D. Anderson Cancer Center Study ID97-099. Cancer 2010; 116:1210.
- Toi M, Lee S-J, Lee ES, et al. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). SABCS 2015; S1-07.
- Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009; 360:2055.
- Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2012; 30:1553.
- Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol 2010; 28:3411.
- Pfeiler G, Königsberg R, Fesl C, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol 2011; 29:2653.
- Sparano JA, Wang M, Zhao F, et al. Obesity at diagnosis is associated with inferior outcomes in hormone receptor-positive operable breast cancer. Cancer 2012; 118:5937.
- Dignam JJ, Wieand K, Johnson KA, et al. Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer. J Natl Cancer Inst 2003; 95:1467.