Over the past decade, genomic profiling of the primary breast tumor has become a well-accepted approach for estimating prognosis and predicting benefit from adjuvant chemotherapy in patients with node-negative and estrogen receptor (ER)-positive breast cancer (N Engl J Med 2004;351(27):2817-2826, J Clin Oncol 2006;24(23):3726-3734, Breast Cancer Res 2006;8(3):R25, J Clin Oncol 2010;28(11):1829-1834). In recent years, a growing discussion has taken place around personalizing treatment also for patients with node-positive, ER-positive breast cancer. Traditionally, chemotherapy treatment decisions have been made on the basis of clinicopathologic criteria such as tumor size, grade, and number of positive axillary nodes.
While these clinicopathologic factors continue to play an important role in guiding treatment decisions, there is now mounting clinical evidence demonstrating the benefit of using the biologic characteristics of the tumor to more precisely tailor the use of adjuvant chemotherapy in these patients. This growing body of evidence suggests a genomic signature such as a 21-gene recurrence score (RS) accurately quantifies risk of distant recurrence and also predicts the magnitude of chemotherapy benefit in patients with node-positive, ER-positive breast cancer (J Clin Oncol 2010;28(11):1829-1834, Lancet Oncol 2010;11(1):55-65, J Clin Oncol 2008;26(25):4063-4071). This information can be useful with the decision of whether to add adjuvant chemotherapy to adjuvant endocrine therapy, as it is becoming increasingly evident that patients with 1-3 positive nodes and low 21-gene RS do very well without chemotherapy and likely receive no appreciable benefit from it.
As our understanding of breast cancer biology across the continuum of the disease continues to evolve, genomics can now help physicians deliver on the promise of precision medicine for breast cancer patients.
Review of the Evidence
Tailoring the use of adjuvant chemotherapy in patients with ER-positive breast cancer has been explored in depth in studies focused on both node-negative and node-positive disease.
For patients with node-negative, ER-positive breast cancer, the 21-gene RS has been shown to identify a sizeable subgroup of patients (low recurrence score) who have excellent prognosis with adjuvant endocrine therapy alone (N Engl J Med 2004;351(27):2817-2826, Breast Cancer Res 2006;8(3):R25, J Clin Oncol 2010;28(11):1829-1834, Lancet Oncol 2010;11(1):55-65). We are confident patients with low RS are not likely to benefit from chemotherapy and those with high RS obtain significant benefit from chemotherapy (J Clin Oncol 2006;24(23):3726-3734, Lancet Oncol 2010;11(1):55-65). The TAILORx trial is evaluating the effect of adjuvant chemotherapy in women with mid-range RS (11-25), attempting to garner more clarity on whether that group of patients benefits from adjuvant chemotherapy or not through a large, prospective, randomized clinical trial (J Clin Oncol 2008;26(5):721-728). The outcome results from that trial are eagerly awaited.
For patients with node-positive, ER-positive breast cancer, the 21-gene RS has also been shown to predict risk of distant recurrence and benefit from the addition of adjuvant chemotherapy to adjuvant hormonal therapy (J Clin Oncol 2006;24(23):3726-3734, Lancet Oncol 2010;11(1):55-65).
As a result of the above evidence, use of the 21-gene RS in ER-positive, HER2-negative, node-negative breast cancer was first incorporated into the ASCO guidelines in 2007 and the in the NCCN guidelines in 2008 (J Clin Oncol 2007;25(33):5287-5312, NCCN Clinical Practice Guidelines in Oncology, Breast Cancer (V.2 2008). Furthermore, in 2015, the NCCN updated its recommendation to allow for the use of the assay in patients with 1-3 positive nodes NCCN Clinical Practice Guidelines in Oncology, Breast Cancer (V.1 2015).
However, in 2016, the ASCO Breast Cancer Guidelines Advisory Group and Clinical Practice Guidelines Committee made a moderate-strength recommendation that the clinician should not use the 21-gene RS to guide treatment decisions in patients with node-positive, ER-positive breast cancer and called the quality of evidence intermediate (J Clin Oncol, 2016;34(10):1134-1150). However, this recent ASCO guideline did not include new node-positive evidence published after August 2014 that included three prospective outcome studies showing that node-positive patients with 1-3 positive nodes and low RS have excellent prognosis and can be safely and effectively treated with endocrine therapy alone (Breast Cancer 2016;2:16017, J Clin Oncol 2016;34(20):2341-2349, Ann Oncol 2016;27 (suppl_6):147PD, Breast Cancer Res Treat 2017; doi: 10.1007/s10549-017-4162-3). This recent additional evidence warrants an updated consideration by the ASCO guideline process.
At the 2016 San Antonio Breast Cancer Symposium, a comprehensive review of clinical evidence was presented in order to examine the ability of the 21-gene RS to accurately predict clinical outcomes in node-positive breast cancer patients (Cancer Research 2017; DOI: 10.1158/1538-7445).
The rationale behind the study was to address the discrepancy in the recommendations by presenting the totality of the evidence of the 21-gene RS assay in node-positive breast cancer. The studies included in the review were analyzed according to their design and category of study (validation, supportive, decision impact, cost-effectiveness, and prospective outcomes). A total of seven studies (including over 8,000 patients) employed a prospective-retrospective design or were prospective outcomes studies with clinical utility. These studies consistently demonstrated that patients with low number of positive nodes and low RS results who had good clinical outcomes with or without adjuvant chemotherapy (see Table on page 38).
Additional studies assessed the impact of the RS on chemotherapy decisions or cost-effectiveness. In 11 decision-impact studies, the use of RS in node-positive breast cancer changed treatment recommendations in an average of 39 percent of the patients (the majority of the effect was in reduction of adjuvant chemotherapy use). In nine unique global market studies, use of RS was found to be a cost-effective and/or cost-saving approach worldwide.
The totality of the evidence is concordant with the NCCN guidelines and underscores that patients with estrogen receptor-positive breast cancer, 1-3 positive nodes (N1), and low RS have very good outcomes (with or without adjuvant chemotherapy) and do not seem to derive any appreciable benefit with the addition of adjuvant chemotherapy to adjuvant endocrine therapy.
The question of whether the addition of adjuvant chemotherapy to adjuvant endocrine therapy improves disease-free survival and overall survival in patients with 1-3 positive nodes (N1) and low 21-gene RS (<25) is also being prospectively evaluated in a randomized clinical trial conducted by SWOG (RxPONDER). The trial is ongoing and will hopefully provide a definitive answer to the question in several years. However, until the results of the RxPONDER trial become available, patients with estrogen-receptor positive breast cancer and 1-3 positive nodes should have a discussion with their oncologist regarding the pros and cons of receiving adjuvant chemotherapy and the contribution of the 21-gene RS assay in further refining their risk of distant recurrence and the likelihood that adjuvant chemotherapy will substantially modify that risk.
TERRY MAMOUNAS, MD, MPH, FACS, is Medical Director of the Comprehensive Breast Program at the UF Health Cancer Center-Orlando Health in Florida.