Version May 2024
INTRODUCTION — For women with early, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, adjuvant endocrine therapy is the mainstay of systemic treatment. However, some of these cancers may also benefit from adjuvant chemotherapy. The magnitude of benefit from chemotherapy depends on the baseline risk of recurrence, which may be estimated from clinical features including the stage and grade of the tumor, as well as biologic features of the tumor, including gene expression. Key aspects of the decision-making are discussed here.
Other relevant topics, including the choice of chemotherapy for hormone receptor (HR)-positive, HER2-negative breast cancer; endocrine therapy for HR-positive breast cancers; neoadjuvant management of HR-positive breast cancers; and prognostic and predictive factors in early breast cancer, are discussed elsewhere.
●(See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)
●(See "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer".)
●(See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer".)
●(See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer".)
●(See "Prognostic and predictive factors in early, non-metastatic breast cancer".)
BENEFITS AND RISKS OF ADJUVANT CHEMOTHERAPY — 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 "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Indications for treatment' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Older women'.)
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).
In the 2012 EBCTCG meta-analysis, the use of an anthracycline-containing regimen compared with no treatment resulted in the following outcomes [1]:
●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. Outcomes according to tumor receptor status were not available, in this analysis. A comparison of CMF and anthracycline-containing regimens is described elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Rationale for anthracycline- and taxane-containing regimen'.)
Risks — Risks of chemotherapy include acute toxicities including nausea, vomiting, hair loss, myelosuppression, early (though not sustained) cognitive impairment [2], 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 [3]. 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'.)
CLINICAL FEATURES THAT GUIDE THE USE OF CHEMOTHERAPY
●Most instances of estrogen receptor (ER)-positive, HER2-negative, node-negative breast cancer <1 cm (T1b), and all cancers ≤0.5 cm (T1a), 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, if they have not received neoadjuvant therapy, 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 are individualized based on patient and disease factors, and on the results of gene expression profiles (see 'Overview of gene expression profiles' below):
•In general, ER-positive, HER2-negative breast cancers that are low grade, strongly ER and progesterone receptor (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.
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). Such calculators include PREDICT [4-10] and Cancermath.net [11,12].
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. (See 'Overview of gene expression profiles' below.)
OVERVIEW OF GENE EXPRESSION PROFILES — The American Society of Clinical Oncology supports the use of the following biomarker assays to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: Oncotype DX 21-gene Recurrence Score (RS), EndoPredict (EP), Predictor Analysis of Microarray 50 (PAM50), and the Breast Cancer Index, all discussed below [13]. Additionally, the Amsterdam 70-gene profile (MammaPrint) may be useful in select cases [14]. However, the National Comprehensive Cancer Network is more conservative, noting that although several prognostic assays are available to estimate recurrence risk, only the RS has been validated for predicting the benefit of adding adjuvant chemotherapy to further reduce the risk of recurrence [15]. (See 'Recurrence Score' below and 'Other genomic tests' below.)
Further information on prognostic versus predictive factors is found elsewhere. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Definitions of predictive and prognostic factors'.)
When a gene expression profile is indicated, we suggest the RS, as the vast majority of the prospective research experience and clinical experience is based on the RS assay, but also note that other assays (eg, the PAM50) may be acceptable.
Providers should choose one assay for any given patient rather than using these tests in combination, particularly given that these tests may lead to discordant results for an individual patient [16]. The prognostic and predictive value of these assays in regard to response to chemotherapy is discussed in the sections below. A separate discussion regarding their utility in predicting response to extended endocrine therapy is found elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)
NODE-NEGATIVE DISEASE
Approach — Among patients with node-negative, estrogen receptor (ER)-positive, HER2-negative disease, our approach to decisions regarding chemotherapy is as follows:
●For patients with T1aN0 disease, we typically do not administer chemotherapy, as these patients have an excellent prognosis with endocrine therapy alone. As such, we do not obtain a gene expression profile in these patients.
●We use gene expression profiles in women in whom the decision regarding whether or not to use chemotherapy is unclear. For example, we typically use gene expression profiles to guide decisions regarding chemotherapy in patients with T1b to T3, node-negative tumors (algorithm 1). (See 'Node-negative disease' above.)
•For breast cancer susceptibility gene (BRCA) carriers with indications for gene expression profiles, we proceed with testing, although we recognize that data in this subset are limited [17].
●For women who are not candidates for chemotherapy, we proceed with endocrine therapy alone. We do not use gene expression profiles, as the primary role of these assays is to determine which clinical situations warrant chemotherapy, and in these situations, the results would not alter management. This might include patients with absolute contraindications to chemotherapy due to baseline health concerns or frailty, or women who for other reasons will not consider chemotherapy.
Preferred gene expression profile
Recurrence Score — Among the gene expression profiles, the Oncotype DX 21-gene Recurrence Score (RS) is the most well validated, providing a prognostic signature for outcome with endocrine therapy alone and a predictive signature for whether chemotherapy reduces recurrence. The RS was developed by identifying the 250 most promising candidate genes described in the literature [18]. Investigators then used a reverse transcription polymerase chain reaction-based method for generating quantitative expression levels of these genes in fixed tissue from 447 patients collected from three datasets. A mathematic formula that includes 16 genes (plus five reference genes) was then generated to optimize prediction of distant relapse despite tamoxifen therapy. The sum of this calculation is known as the RS.
Validation in node-negative, HR-positive disease — The RS has been validated both as a prognostic as well as a predictive tool, by which to identify those patients with node-negative, hormone receptor (HR)-positive breast cancer whose prognosis is so favorable that the absolute benefit of chemotherapy is likely to be very low. Patients with ER-positive cancers that are node negative derive substantial benefit from chemotherapy if the 21-gene RS is high (typically ≥26). By contrast, if the score is low or midrange (≤25), there is no benefit to adding chemotherapy to endocrine treatment for women >50 years old, although younger women may experience some benefit (algorithm 1) [19-21]. (See 'Special considerations for those with intermediate RS' below and "Approach to the patient following treatment for breast cancer", section on 'Components of follow-up'.)
The RS has been prospectively validated as a prognostic tool [22-24]. For example, the TAILORx study evaluated outcomes in 9719 women with HR-positive, HER2-negative, T1 to T2 axillary node-negative breast cancer [20,22,23]. At nine years:
●Among approximately 1600 women with low RS (≤10), all of whom received endocrine therapy without chemotherapy, the rate of invasive disease-free survival (DFS) at nine years was 84 percent [20].
●Among 6700 women with midrange RS (11 to 25), those randomly assigned to endocrine therapy alone had the same invasive DFS outcomes as those randomized to chemotherapy and endocrine therapy (83 versus 84 percent at nine years; hazard ratio 1.08, 95% CI 0.94-1.24) [20]. Rates of distant recurrence and overall survival (OS) were also similar between both groups (95 and 94 percent, for endocrine versus chemoendocrine therapy, respectively).
●Among almost 1400 women with a high RS (≥26), all of whom received chemotherapy (typically taxane- and/or anthracycline-containing regimens), the invasive DFS was 76 percent at nine years, and the rate of freedom from distant recurrence was 87 percent [20,25]. These results are better than what has been observed in other trials of endocrine therapy alone in similar patients (60 to 70 percent for invasive distant recurrence-free survival rates, in the initial validation studies of the RS assay) [18,26]. Observational data also support an OS benefit for the addition of chemotherapy to endocrine therapy in this subset [27].
Although the TAILORx trial did not include patients with T3 tumors, the RxPonder trial, discussed below, did include this subset. (See 'Node-positive disease' below.)
The overall results from TAILORx are similar to those from the PlanB trial [22], as well as earlier retrospective evaluations of the NSABP B-20 clinical trial specimens ("prospective-retrospective" studies) [19]. In the NSABP B20 trial including 651 patients, the addition of cyclophosphamide, methotrexate, plus fluorouracil (CMF) to tamoxifen resulted in a higher rate of distant DFS at 10 years among patients with a high RS (>30) compared with treatment with tamoxifen alone (88 versus 60 percent, respectively; relative risk 0.26, 95% CI 0.13-0.53) [19]. However, there was no evidence of a benefit with the addition of CMF among those with a low (<18) or an intermediate RS (19 to 30). It should be noted that the cutoff for low, intermediate, and high RS differed between the TAILORx and NSABP B-20 studies.
It has been argued that RS can be supplanted by improvements in pathologic grading and quantitative HR scoring. However, the NSABP B-20 study suggests that this may not be true. Even with central laboratory grading, 19 percent of high-grade tumors had a low RS (<18) and 5 percent of low-grade tumors had a high RS (>30). Further, the reproducibility of estrogen receptor (ER) and progesterone receptor (PR), as well as measures of proliferation such as immunohistochemistry analysis of Ki-67, is poor between different laboratories. A tool, RSClin, has been developed integrating genomic and clinical features and is available on the company's provider portal [28], but prospective validation is necessary.
Special considerations for those with intermediate RS — Intermediate Oncotype DX 21-gene Recurrence Score (RS) is typically thought of as scores of 16 to 25. Our approach to those with intermediate RS is as follows (algorithm 1):
●Women >50 years old with an intermediate RS – For those >50 years with an RS ≤25, we suggest not using chemotherapy. As discussed above, women with an intermediate RS did not experience DFS benefits from the addition of chemotherapy to endocrine therapy, overall. (See 'Validation in node-negative, HR-positive disease' above.)
Moreover, exploratory analyses according to age suggested that chemoendocrine therapy in women >50 years was associated with a similar rate of distant recurrence relative to endocrine therapy alone [20].
●Women ≤50 years with intermediate RS – UpToDate contributors are divided in regards to the approach for patients ≤50 years with RS of 16 to 25. Some note that for most such patients they would not treat with chemotherapy, instead offering endocrine therapy alone and adding ovarian suppression for patients who are premenopausal. Other UpToDate experts, however, offer chemotherapy to select women ≤50 years with RS of 16 to 25, especially those who have either high-intermediate scores (21 to 25) or clinical risk factors, based on subset analyses of TAILORx discussed below [29].
•Rationale for omission of chemotherapy in those ≤50 years with intermediate RS – As discussed above, women with an intermediate RS did not experience benefits with the addition of chemotherapy to endocrine therapy. (See 'Validation in node-negative, HR-positive disease' above.)
Furthermore, among premenopausal women, the benefit from chemotherapy in patients with intermediate RS in TAILORx peaked for those at age 45 years; menopausal women did not have as much of a benefit. This trend raises the hypothesis that the benefit with chemotherapy in premenopausal women with intermediate RS may be due to chemotherapy-induced premature menopause. (Women younger than 45 years are unlikely to go into a permanent menopause because of chemotherapy and women older than 45 years are more likely to be entering menopause irrespective of chemotherapy. At an age of approximately 45 years, women receiving chemotherapy are most likely to experience menopause due to the chemotherapy). Some UpToDate contributors support this hypothesis, and therefore offer ovarian suppression rather than chemotherapy for premenopausal women with intermediate RS scores.
•Rationale for chemotherapy in those ≤50 years with intermediate RS, particularly for RS 21 to 25, or high-risk clinical features – In TAILORx, exploratory analyses suggested that in women ≤50 years with a high intermediate RS, endocrine therapy plus chemotherapy was associated with a lower rate of distant recurrence relative to endocrine therapy alone (at nine years, absolute percentage-point difference was 6.5 for RS of 21 to 25; compared with just 1.6 percent for those with RS of 16 to 20) [20]. This benefit was not observed among women >50 years.
Clinical-risk stratification was also used with the RS, with possible implications for those with low intermediate scores (16 to 20).
-The level of clinical risk was predictive for a benefit from chemotherapy in the subset of patients ≤50 years with an RS of 16 to 20. Among these women, there was a decrease in distant recurrence rates with versus without chemotherapy among those with high clinical risk (5.5 versus 12 percent, respectively), but not with low clinical risk (4.6 versus 4.8 percent, respectively). In this trial, low clinical risk was defined as tumors ≤3 cm and low grade, ≤2 cm and intermediate grade, or ≤1 cm and high grade [20]. Tumors that did not fit any of these categories were high risk.
-However, among women ≤50 years with an RS of 21 to 25, similar benefits with chemotherapy were observed in both the low- and high-clinical-risk subgroups (absolute chemotherapy benefit of 6.4 versus 8.7 percent, respectively).
Moreover, in the EBCTCG analysis described above, there was no effect of age (or size, grade, stage, or ER status) in the relative benefit from chemotherapy [1]. In a subsequent EBCTCG meta-analysis evaluating dose-intense/dose-dense versus standard every-three-weekly chemotherapy with 37,000 randomized patients, a similar relative benefit with chemotherapy was demonstrated, independent of age and clinical risk factors [30]. However, these meta-analyses were conducted in unselected patients, and not in the intermediate-RS group, and pathologic assessment was not performed centrally.
Given different interpretations of available data, we recognize that differences in approach among experts exist.
NODE-POSITIVE DISEASE — There are more limited data for use of gene expression profiles in lymph node-positive disease. Although both the Amsterdam 70-gene profile (MammaPrint) and the Oncotype DX 21-gene Recurrence Score (RS) have been evaluated in node-positive disease, data for both are limited in this setting. Our approach to use of gene expression profiles, according to menopausal status, is discussed below.
Postmenopausal women — Our approach to postmenopausal women with involved lymph nodes is as follows.
●For patients with >3 lymph nodes who have not received neoadjuvant treatment, we recommend chemotherapy, as long as there are no contraindications. Adjuvant chemotherapy in patients who have received neoadjuvant therapy is discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)
●However, for those with one to three involved lymph nodes who are candidates for chemotherapy, the approach is variable among UpToDate experts. Some apply the RS for those with one to three lymph nodes and offer chemotherapy for more involved lymph nodes; others do not utilize gene expression profiles in the setting of lymph node involvement and recommend chemotherapy for any involved lymph nodes. As such, one may opt for either of the following approaches, taking into account the pros and cons of each strategy, as discussed below.
•Apply the RS for those with one to three positive nodes, using cutoffs as for those with node-negative disease, and recommend chemotherapy to those with >3 lymph nodes involved. This approach is included in the American Society of Clinical Oncology guidelines and in the National Comprehensive Cancer Network guidelines [15,31].
Supporting data for using the RS in lymph node-positive, HR-positive, HER2-negative breast cancer are as follows.
-In the RxPonder trial, among 5018 pre- and postmenopausal women with RS ≤25 and one to three involved lymph nodes, the use of adjuvant chemotherapy plus endocrine therapy failed to demonstrate benefit over endocrine therapy alone (hazard ratio for invasive disease free survival [DFS] 0.97, 95% CI 0.77-1.22) [32].
Among postmenopausal women (two-thirds of those enrolled), the five-year invasive DFS was 91.3 versus 91.9 percent, with and without chemotherapy (hazard ratio 1.02, 95% CI 0.82-1.26), indicating no benefit from chemotherapy (table 1).
In regards to the overall study population, approximately 10 percent had grade 3 disease; 9 percent had three involved nodes. Approximately 50 percent of the patients were treated with docetaxel and cyclophosphamide, and 50 percent received an anthracycline-based regimen.
-In the PlanB study, among 348 patients with RS ≤11 (approximately 40 percent of whom had one to three involved lymph nodes and the rest of whom had node-negative disease), the three-year progression-free survival was 98 percent, after a median follow-up of 35 months [22]. Although subset analysis for patients with node-positive, low-RS cancers was not provided, the overall results suggest that patients with limited nodal disease may be able to avoid chemotherapy if the RS is low.
•Administer chemotherapy to all patients with lymph node-positive disease.
If choosing this approach, one does not assess RS, as it does not change management. This approach may represent overtreatment and corresponding toxicity for the majority of patients in this category, in an effort to avoid missing patients who could have benefited if they were treated. Supporting rationale and data are as follows.
Adjuvant chemotherapy appears to provide a relative risk reduction in breast cancer mortality of approximately 20 to 30 percent, irrespective of size, stage, grade, estrogen receptor status, and whether patients were given endocrine therapy, according to the EBCTCG meta-analyses of 100,000 and 37,000 patients [1,30]. This translated to an approximate absolute benefit of approximately 7 percent, among all patients (36 versus 29 percent; relative risk 0.79, 95% CI 0.72-0.85) [1]. However, lymph node-positive cancers have almost a twofold increase in recurrence rates compared with lymph node-negative cancers, in the absence of chemotherapy. Therefore, given the higher absolute likelihood of recurrence in those with lymph node-positive disease, the absolute benefit of chemotherapy is higher in this subset, and therefore chemotherapy is offered.
Premenopausal women — For premenopausal women with node-positive disease, contributors are divided in their approach; although some contributors suggest chemotherapy (TF, JB, SH), others use a gene expression profile to guide treatment decisions (HB), according to the overall trial results of RxPonder, discussed above. In this case, ovarian suppression with AI is administered for RS ≤25; and chemotherapy for RS ≥26, followed by endocrine therapy. (See 'Postmenopausal women' above.)
In subset analysis of the RxPonder trial, among 1665 premenopausal women with RS ≤25 and one to three involved lymph nodes, the use of adjuvant chemotherapy improved outcomes [32]. The five-year invasive DFS, with and without chemotherapy, was 94 versus 89 percent, respectively (hazard ratio 0.60, 95% CI 0.43-0.83) (table 1). Although the event number was small, the hazard ratio for overall survival (OS) was 0.47 in preliminary reporting, favoring the chemotherapy group (five-year OS rates of 98.6 versus 97.3 percent; 95% CI 0.24-0.94) [33]. Approximately 16 percent of patients receiving endocrine therapy only received ovarian suppression, versus 4 percent in the chemotherapy-endocrine-therapy arm.
However, some UpToDate experts (HB) note that much of the benefit from chemotherapy may have been from its ovarian suppressive effect, and therefore use ovarian suppression and AI for those with low RS scores. Ovarian suppression is discussed in detail elsewhere. (See "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer", section on 'Ovarian suppression plus endocrine therapy'.)
OTHER GENOMIC TESTS — 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 Predictor Analysis of Microarray 50 (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 'PAM50 risk of recurrence score' below.)
PAM50 risk of recurrence score — The Predictor Analysis of Microarray 50 (PAM50) is a 50-gene test that characterizes an individual tumor by intrinsic subtype [34]. It was designed to determine the intrinsic subtype of a cancer using only 50 prespecified genes. Results from the PAM50 are used to generate the risk of recurrence (ROR) score, which can stratify patients with estrogen receptor (ER)-positive disease into high-, medium-, and low-risk subsets. The test can be performed on formalin-fixed, paraffin-embedded tissue with a high degree of analytical validity [35].
The PAM50 was developed using microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR) data from a set of almost 190 prototype samples [34]. In the initial testing set that included over 700 samples, a continuous score was composed of the intrinsic subtype (defined by the PAM50) and tumor size, called the ROR score. The ROR was significantly predictive of prognosis among patients with node-negative breast cancer [34].
The prognostic clinical utility of the PAM50 and ROR score has been demonstrated in several studies [35-39]:
●Using data from two separate trials, the ROR score and PAM50 added prognostic information beyond what could be assessed by clinical factors [37,38]. In an analysis of 1017 postmenopausal patients treated with adjuvant tamoxifen or anastrozole (ATAC trial), ROR had a continuous relationship with the risk of distant recurrence at 10 years in both node-negative and node-positive disease and added significant prognostic information in all subgroups of patients [37]. In the same retrospective analysis of the ATAC trial, the ROR was compared with the Oncotype DX 21-gene Recurrence Score (RS) in its ability to stratify patients with HR-positive, node-negative breast cancer [37]. ROR classified more patients with HER2-negative/node-negative tumors to the high-risk group and fewer in the intermediate group compared with RS.
●These findings were confirmed in analyses conducted in postmenopausal patients who participated in the ABCSG-8 trial [40,41]. Among all patients, the estimated 10-year distant relapse-free survival rates were 96.7, 91.3, and 79.9 percent in the low-, intermediate-, and high-risk groups based on the ROR. These results were seen regardless of whether pathologic node involvement was present or not. In a separate multivariate analysis, ROR score was an independent prognostic factor for risk of local recurrence [41].
Amsterdam 70-gene profile (MammaPrint) — The Amsterdam 70-gene prognostic profile was one of the first gene expression arrays approved for commercial use (MammaPrint). Although it was originally approved for use with unfixed, frozen tissue, it has now been adapted for use with formalin-fixed, paraffin-embedded tissue. Based on the randomized trial discussed below (MINDACT), the American Society of Clinical Oncology has suggested MammaPrint is one of several assays that might be used to determine prognosis for those with high clinical risk, HR-positive, HER2-negative breast cancer and no or limited (one to three) involved lymph nodes to inform decisions regarding withholding chemotherapy [14,29]. However, those with low clinical risk are unlikely to benefit from chemotherapy regardless of the results of this assay. For those with lymph node involvement and a low risk by Amsterdam genetic profile, counseling should be provided that a benefit from chemotherapy cannot be excluded, particularly in patients with more than one involved lymph node.
The 70-gene profile was developed using a supervised DNA microarray analysis of gene expression arrays on frozen tissue from 98 primary breast tumors [42]. A mathematic model is used to calculate a score that stratifies patients as having a breast cancer with an associated poor prognosis or good prognosis.
The clinical validity of the 70-gene prognostic profile has been demonstrated in multiple studies [43-47]. Results from an international randomized trial, the MINDACT trial, suggest that this genetic profile may identify subsets of patients who have a low likelihood of distant recurrence despite high-risk clinical features [47-49]. In this trial, 6693 women, approximately 80 percent of whom had lymph node-negative disease (and 20 percent of whom had one to three positive lymph nodes), underwent risk assessment by clinical criteria (using Adjuvant! Online) and by the 70-gene profile. Patients with discordant clinical and genomic predictions were randomly assigned to receive or not receive adjuvant chemotherapy. Among patients in the intention-to-treat population who had a high clinical risk of recurrence but a low risk by Amsterdam genetic profile, the five-year distant metastasis-free survival rates were similar with and without chemotherapy (95.9 versus 94.4 percent, respectively; hazard ratio for distant metastasis or death 0.78, 95% CI 0.50-1.21), suggesting that this profile might identify patients with high clinical risk who may reasonably forego chemotherapy. However, it should be noted that the MINDACT study was not powered to exclude a benefit of chemotherapy.
Data also suggest that the 70-gene profile identifies patients with a low chance of recurrence, independent of nodal status, tumor grade, or hormone or HER2 receptor status [49,50]. In MINDACT, patients with an ultralow-risk 70-gene signature had the best prognosis (even better than the low risk group), with an eight-year breast cancer-specific survival above 99 percent [49].
EndoPredict — Another prognostic assay is RNA based and utilizes RT-PCR of 11 genes (including three reference genes) to calculate a prognostic score. Known as EndoPredict (EP), it was validated using the data from the ABCSG-6 and ABCSG-8 trials, and its prognostic value was found to be independent of conventional prognostic factors [51]. EP appears to be useful in the identification of a subgroup of patients with ER-positive, HER2-negative tumors that have a very low risk of recurrence without adjuvant chemotherapy [52] and appears to identify patients at low risk for a late recurrence [52]. EP can be reliably run in routine molecular pathology laboratories [53] using formalin-fixed, paraffin-embedded samples and can be performed with tissue from either the diagnostic core biopsies or final surgical specimens [54]. Although retrospective comparisons suggest at least comparable prognostic ability of EP relative to other genetic profiles [55,56], head-to-head comparisons with other prognostic tests have not been made prospectively in randomized trials.
Breast Cancer Index — The Breast Cancer Index (BCI) is a combination of two profiles, the antiapoptotic homeobox B13 (HOXB13)-to-interleukin 17B receptor (IL17BR) expression ratio (H:I ratio) and the Molecular Grade Index (MGI). Using genome-wide microarray analysis, three differentially expressed genes that were associated with an increased risk of progression among ER-positive patients treated with tamoxifen were: HOXB13 (overexpressed in tamoxifen-recurrent cases) and both IL17BR and EST AI240933 (both overexpressed in tamoxifen-nonrecurrent cases) [57]. Compared with clinical prognostic factors (eg, age, tumor size, tumor grade, and lymph node status), the H:I ratio was significantly and independently correlated with outcome (odds ratio 7.3, 95% CI 2.1-26).
Subsequent studies have validated the BCI as an accurate predictor of endocrine responsiveness among patients with ER-positive breast cancer [58-60], with observational evidence suggesting it may identify those who would benefit from extended treatment with tamoxifen (although no such studies have been performed evaluating length of aromatase inhibitor therapy) [58,61]. The role of genomic profiles in determining duration of endocrine treatment is discussed elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)
Investigational assays — Several other genomic assays have been studied, though we do not suggest their routine use outside of a clinical trial. These have not been validated to the extent of the RS, PAM50, EP, BCI, or MammaPrint.
●Genomic grade index – The genomic grade index (GGI) is a gene expression signature of 97 genes that were found to best distinguish histologic grade 1 from grade 3 tumors [62]. In the initial report, GGI could reclassify grade 2 tumors into two groups of high versus low risk of recurrence, thus improving the prognostic value of tumor grading [62]. Subsequent validation in various datasets of untreated or tamoxifen-treated ER-positive tumors showed that GGI was prognostic independently from classical markers and performed equally well as the RS [63]. In a subgroup of 204 patients treated in the PACS01 trial, GGI outperformed histologic grade and other proliferation markers (Ki-67 mRNA and protein, mitotic activity index) as a predictor of disease-free survival [64]. Further validation of GGI is required. Interestingly, another independent gene signature has been reported for risk classification of grade 2 tumors [65]. In addition, grade 2 tumors are reported to be effectively separated into risk groups by Ki-67 [66]. Despite these results, further studies are required to inform whether this index has clinical utility.
●IHC4 – In an effort to identify an alternative to gene expression analysis for defining intrinsic breast cancer subtypes, an immunohistochemistry (IHC) assay of four standard markers (estrogen receptor [ER], progesterone receptor [PR], HER2, and Ki-67) was developed, known as the IHC4. Although some studies show it can effectively separate luminal A from luminal B tumors [67] and has a similar prognostic profile as the RS score [68], another study showed it performed worse than PAM50 [35].
Of note, the IHC4 is not a simple combination of these standard assays; instead, it is a highly analytically validated test performed in a single laboratory using strict methodologies for staining and reading, with the results placed into a complex, weighted, multifactorial equation on which the IHC4 score is derived [68].
●Cancer Grade Model – Although grade 3 is considered a high-risk feature and grade 1 is considered low risk, the grade-2 phenotype is a heterogeneous class, with gene expression and RNA-based sequencing suggesting that it is not its own distinct entity [62,65,69]. As such, prognosis and appropriate treatment can be difficult to determine for tumors that have histologically been classified as grade 2, but genetic expression analyses can refine predictive information [62,70]. As an example, a machine-learning platform was developed to classify grade-2 and unknown-grade tumors into high- and low-risk groups, after training the model on genomic data of high- and low-grade cancers and generating a 70-gene signature from microarray data of 5031 untreated breast tumors [70]. Although the resulting Cancer Grade Model was cross referenced with existing genomic tests and demonstrated similar predictive power of tumor risk, prospective validation is necessary prior to clinical use.
APPROACH TO THOSE WHO RECEIVED NEOADJUVANT THERAPY — For most patients with HR-positive, HER2-negative breast cancer who received a standard course of neoadjuvant chemotherapy (eg, four cycles of doxorubicin and cyclophosphamide followed by four cycles of a taxane, or four cycles of docetaxel and cyclophosphamide), we do not administer further chemotherapy in the adjuvant setting. Available data are discussed in detail elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)
Data regarding using the Oncotype DX 21-gene Recurrence Score in the neoadjuvant setting are discussed elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Biomarkers'.)
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".)
SUMMARY AND RECOMMENDATIONS
●General considerations – For women with early, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, adjuvant endocrine therapy is the mainstay of systemic treatment. However, some of these cancers also stand to benefit from adjuvant chemotherapy. The magnitude of benefit from chemotherapy depends on the baseline risk of recurrence, which may be estimated from clinical features including the stage and grade of the tumor, as well as biologic features of the tumor, including gene expression. (See 'Introduction' above.)
•All women with hormone receptor (HR)-positive, HER2-negative, non-metastatic breast cancer should be offered endocrine therapy. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)
•Most instances of ER-positive, HER2-negative, node-negative breast cancer <1 cm, and all cancers ≤0.5 cm, have a sufficiently good prognosis with endocrine therapy alone, that they 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 are individualized based on patient and disease factors. (See 'Clinical features that guide the use of chemotherapy' above.)
●Node-negative disease – For patients who are candidates for chemotherapy and have T1b to T3, node-negative, HR-positive, HER2-negative tumors, we use the Oncotype DX 21-gene Recurrence Score (RS) to guide adjuvant chemotherapy decisions. Although the RS is the most well-validated and widely used assay in the United States, we note that other assays (eg, the Predictor Analysis of Microarray 50 [PAM50]) may also be acceptable. (See 'Overview of gene expression profiles' above and 'Other genomic tests' above.)
•For women with HR-positive, HER2-negative, node-negative breast cancer (algorithm 1):
-Who are of any age and have an RS ≤15, or for those >50 years with an RS ≤25, we typically suggest not using chemotherapy (Grade 2B).
-Who are ≤50 years and whose RS is 16 to 25, some UpToDate experts do not suggest chemotherapy (instead opting for the addition of ovarian suppression to endocrine therapies for premenopausal women in this subset who have high-risk factors for recurrence). Other UpToDate experts suggest chemotherapy to select patients in this subset, particularly those who have either high-intermediate scores (21 to 25) or high clinical risk. Clinical risk is defined above. (See 'Special considerations for those with intermediate RS' above.)
-Whose RS is ≥26, irrespective of age, we typically suggest chemotherapy (Grade 2B), noting that supporting data are strongest for those with RS >30. (See 'Validation in node-negative, HR-positive disease' above.)
However, we recognize that the Oncotype score is not the sole factor, and that other variables may also affect the decision to use chemotherapy such as patient preference and performance status, as well as tumor features including size and grade (with T3, higher grade carcinomas are more likely to achieve benefit from chemotherapy).
●Node-positive disease
•For patients who have more than three involved lymph nodes who have not received neoadjuvant chemotherapy, we recommend adjuvant chemotherapy (Grade 1B), provided that they have no contraindications. (See 'Node-positive disease' above.)
•The approach to incorporating the RS among those with one to three lymph nodes, according to menopausal status, is as follows:
-For postmenopausal women with one to three involved lymph nodes, some UpToDate contributors offer chemotherapy, while others apply the RS, offering chemotherapy to those with RS ≥26 and omitting it for those with RS ≤25.
-For premenopausal women with one to three involved lymph nodes, contributors are divided in their approach. Some contributors suggest chemotherapy, given demonstrated benefit to this approach from a randomized trial, and lack of available data regarding ovarian suppression as an alternative; others use a gene expression profile to guide treatment decisions (offering ovarian suppression with aromatase inhibition for RS ≤25, and chemotherapy for RS ≥26).
●Choice of chemotherapy regimen – Discussion on the selection of chemotherapy regimen and its administration is found elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
