Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial

Abstract

Background: The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence.

Methods: The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes.

Findings: There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0.97; HR 1.02, 0.54-1.93), but an improvement in disease-free survival for those with a high recurrence score (score > or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival.

Interpretation: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes.

Funding: National Cancer Institute and Genomic Health.

Figure 1

Modified REMARK diagram, showing the specimen acquisition, distribution and processing for the RT-PCR analyses, resulting in the final sample size of 367 patients.

Figure 2

Prognostic disease-free survival and overall survival analyses by Recurrence Score (RS) group in patients treated with tamoxifen alone. Panel A depicts disease-free survival and Panel B, overall survival. The log-rank tests are stratified by number of positive nodes.

Figure 3

Primary disease-free survival endpoint by treatment and Recurrence Score (RS) groups. The log-rank tests are stratified by number of positive nodes. Panel A shows disease-free survival by treatment (CAF followed by tamoxifen versus tamoxifen alone) overall, and Panels B–D depicts the outcomes within each RS risk group of low, intermediate, and high, respectively.

Figure 4

Secondary endpoints of overall survival by Recurrence Score (RS) groups (Panels A, B and C) and the exploratory endpoint of breast cancer specific survival by RS groups (Panels D, E and F), all adjusted for number of positive nodes.

Figure 5

Disease-free survival hazard ratios with 95% confidence intervals for tamoxifen alone versus CAF followed by tamoxifen displayed (from top to bottom) for the overall parent trial, the entire Recurrence Score (RS) sample, and RS groups of low, intermediate, and high. The diamond indicates all years, the circle the first 5 years and the square, after 5 years.

Figure 6

Risks of a disease-free survival (DFS) event by linear Recurrence Score, by treatment (tamoxifen alone and CAF followed by tamoxifen) and number of positive nodes, depicted for 10-year (left panel) and 5-year (right panel) landmarks. In each panel, the top two lines are represent the subset with 4 or more positive axillary nodes and the bottom 2 lines, 1–3 positive nodes.