Elsevier

The Lancet Oncology

Volume 11, Issue 1, January 2010, Pages 55-65
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(09)70314-6Get rights and content

Summary

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 ≥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.

Introduction

Multigene tumour assays report useful prognostic information for women with axillary node-negative breast cancer.1, 2, 3, 4 Of these, the 21-gene recurrence score assay provides a prognosis for patients with oestrogen-receptor-positive disease treated with tamoxifen alone.1 In one study, the recurrence score also predicted chemotherapy benefit from standard chemotherapy.5 Patients with a high recurrence score seemed to benefit greatly from the addition of chemotherapy to tamoxifen, whereas those with a low recurrence score did not.

Recent studies have shown the value of the recurrence score when used with the standard pathology report,6, 7, 8 which improved physician and patient decision making in lymph-node-negative scenarios. Use of the recurrence score as a prognostic and predictive tool in oestrogen-receptor-positive, lymph-node-negative breast cancer was recommended by the American Society of Clinical Oncology.9

There have been no assessments of the value of the recurrence score in patients with oestrogen-receptor-positive disease and involved axillary nodes in studies that contain a tamoxifen-alone control group. These patients are routinely treated with chemotherapy and endocrine adjuvant therapy.10 However, exploratory data suggest that those with higher concentrations of tumour oestrogen receptors might not derive benefit from chemotherapy, even if they are at high risk of recurrence because of positive nodes.11, 12, 13 Some studies have shown less benefit of chemotherapy when the node-positive disease was both oestrogen-receptor positive and HER2 negative (ERBB2 negative).11, 14, 15

Consequently, we analysed the 21-gene recurrence score assay in a phase 3 node-positive trial that contained a tamoxifen-only control group.16 Our two co-primary objectives were to establish whether the assay provides prognostic information for women with node-positive disease treated only with tamoxifen, and whether the assay allows prediction of a node-positive group that does not benefit from anthracycline-based chemotherapy.

Section snippets

Patients and procedures

The Southwest Oncology Group (SWOG)-8814, INT-0100 study was a phase 3, open-label, parallel-group, randomised controlled trial.16 The study design and main results of the trial have been reported elsewhere.16 Briefly, postmenopausal women with axillary node-positive breast cancer were eligible for inclusion if they had oestrogen-receptor-positive or progesterone-receptor-positive tumours, or both, classified by local institutional standards. Enrolled patients were randomly assigned in a 2:3:3

Results

Tumour samples were available for 664 (45%) of the 1477 patients in SWOG-8814 (figure 1), including 413 (45%) of the 927 patients in the CAF-T and tamoxifen groups. RT-PCR analysis was feasible in 367 (40%) specimens from the tamoxifen and CAF-T groups (tamoxifen, 148 [89%] of 166 samples; CAF-T, 219 [89%] of 247), suggesting no bias by group in sample availability. Analyses were not done for the remaining 46 (11%) of samples because of exhaustion of invasive tumour in the block, no submission

Discussion

Our study suggests that patients with involved axillary lymph nodes, but a low recurrence score, do not seem to benefit from anthracycline-based chemotherapy, whereas those with a higher recurrence score have major benefit, independent of the number of positive nodes. TRANSBIG collaborators presented analyses of a non-randomised cohort of 106 patients with one to three positive nodes. In a subset of patients who were identified as low risk by the 70-gene profile,3 patients given chemotherapy

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