A prospective validation study of a 21-gene expression assay showed that treatment with endocrine therapy alone in women with hormone receptor–positive, HER2-negative breast cancer who had a low recurrence risk score resulted in low risk of recurrence. All patients included in the study were eligible for adjuvant chemotherapy on the basis of current guidelines, as reported in The New England Journal of Medicine by Joseph A. Sparano, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, and colleagues.1
Study Details
Between April 2006 and October 2010, the trial enrolled 10,253 women with hormone receptor–positive, HER2-negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6–1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for receiving adjuvant chemotherapy.
A 21-gene reverse-transcriptase polymerase chain reaction assay was performed on paraffin-embedded tumor tissue, with results being used to calculate a score of 0 to 100, indicating lower to higher risk of recurrence. Patients with a score of 0 to 10, indicating very low risk, were assigned to receive endocrine therapy without chemotherapy.
Patient Characteristics
In total, 1,626 women (15.9%) had a recurrence score of 0 to 10 and were assigned to receive endocrine therapy alone. Totals of 6,897 (67.3%) and 1,730 (16.9%) had midrange-risk (11–25) and high-risk scores (≥ 26). Compared with the subgroup with midrange-risk scores, women with low-risk scores had a similar tumor size (median, 1.5 cm in both), and a similar proportion had intermediate-grade tumors (59% vs 57%).
Significant differences (all P < .001) included proportions with low-grade (34% vs 29%) and high-grade tumors (7% vs 14%), age (median, 58 vs 55 years), menopausal status (70% vs 64% postmenopausal), progesterone receptor expression (positive for 98% vs 92%; > 99% estrogen receptor positive in both), and primary surgery (lumpectomy for 68% vs 72%, mastectomy for 32% and 28%). The age distribution in the low-risk group was ≤ 40 years for 4%, 41 to 50 years for 23%, 51 to 60 years for 35%, 61 to 70 years for 32%, and > 70 years for 7%. Distribution of tumor size was < 1.0 cm in 8%, 1.0 to 1.9 cm in 61%, 2.0 to 2.9 cm in 23%, 3.0 to 3.9 cm in 6%, and ≥ 4.0 cm in 2%.
In the low-risk group, endocrine therapy consisted of an aromatase inhibitor in 59%, tamoxifen in 34%, sequential tamoxifen and aromatase inhibitor in 1%, ovarian-function suppression in 3%, and other therapy in 3%. Six patients received adjuvant chemotherapy against protocol, with one having recurrence despite such treatment.
Recurrence and Survival
Within 5 years, there were 88 events of either invasive cancer or death and 30 deaths in the low-risk group. The initial event was local or regional recurrence in 8 patients, distant recurrence in 10, invasive contralateral breast cancer in 15, other invasive new primary cancer in 43, and death without another event in 12.
Five-year rates were 93.8% (95% confidence interval [CI] = 92.4%–94.9%) for invasive disease–free survival, 99.3% (95% CI = 98.7%–99.6%) for freedom from distant recurrence, 98.7% (95% CI = 97.9%–99.2%) for freedom from any recurrence, and 98.0% (95% CI = 97.1%–98.6%) for overall survival.
Risk Factor Analysis
In a multivariate analysis in the low-risk group that included age, tumor size, histologic grade, and surgery type, no factors were associated with a significantly increased risk of the composite endpoint of recurrence, second primary breast cancer, second primary nonbreast invasive cancer, or death without recurrence of cancer. Borderline associations were noted for age (hazard ratios [HRs] = 0.87 for 51–60 vs ≤ 50 years and 1.53 for 61–75 vs ≤ 50 years; P = .07) and lumpectomy vs mastectomy (HR = 0.63, P = .07). No factors were associated with a significantly increased risk of recurrence at a distant site. Tumor grade was associated with risk of any recurrence (HRs = 8.07 for intermediate- vs low-grade and 4.73 for high- vs low-grade, P = .02).
Five-year rates for invasive disease–free survival, freedom from distant recurrence, freedom from any recurrence, and overall survival were 95.8%, 99.8%, 99.8%, and 98.7% among patients with low-grade tumors, 93.6%, 99.0%, 98.2%, and 97.9% among those with intermediate-grade tumors, and 91.3%, 100%, 98.7%, and 97.3% among those with high-grade tumors.
The investigators concluded: “Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone.” ■
Disclosure: The study was funded by the National Cancer Institute, Canadian Cancer Society Research Institute, National Institutes of Health, Breast Cancer Research Foundation, and Susan G. Komen. For full disclosures of the study authors, visit www.nejm.org.
Reference
1. Sparano JA, Gray RJ, Makower DF, et al: Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. September 28, 2015 (early release online).
