Prospective Validation of a 21-Gene Expression Assay in Breast Cancer

Abstract

Background: Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.

Methods: We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).

Results: Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).

Conclusions: 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. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

Figure 1. Kaplan–Meier Estimates in the Analyses of Invasive Disease–free Survival, Freedom from Recurrence of Breast Cancer at a Distant Site, Freedom from Recurrence at Any Site, and Overall Survival

A total of 1626 patients with a recurrence score of 0 to 10 (on a scale from 0 to 100, with higher scores indicating a greater risk of recurrence) were included in the analyses. In the time-to-event analysis of invasive disease–free survival, Panel A shows the probability of freedom from the first event of recurrence of ipsilateral breast tumor, local recurrence, regional recurrence, distant recurrence, contralateral second primary invasive cancer, second primary nonbreast invasive cancer (excluding nonmelanoma skin cancer), or death without evidence of recurrence (which corresponds to the standardized definitions for efficacy end points [STEEP] definition of invasive disease–free survival). In the time-to-event analysis of freedom from the recurrence of breast cancer at a distant site, Panel B shows the probability of freedom from the first event of distant recurrence of breast cancer or death with distant recurrence, if death was the first manifestation of distant recurrence (which corresponds to the STEEP definition of distant recurrence–free interval). In the time-to-event analysis of freedom from recurrence at any site, Panel C shows the probability of freedom from the first event of recurrence of breast cancer (ipsilateral breast cancer, local or regional recurrence, or distant recurrence) or the date of death with recurrence, if death was the first manifestation of recurrence (which corresponds to the STEEP definition of recurrence-free interval). Panel D shows the probability of overall survival in the time-to-event analysis. In each panel, dashed lines indicate 95% confidence intervals and the insets show the same data on an enlarged y axis.