Breast Cancer Index (BCI) risk scores prognostic in premenopausal patients with HR+ early stage breast cancer

Among premenopausal women with hormone receptor (HR)-positive, early-stage breast cancer enrolled in the SOFT trial, those with a high score on a genomic assay called Breast Cancer Index (BCI) had increased risk of distant recurrence. Furthermore, the BCI (H/I) was predictive of ovarian suppression benefit. However, contrary to the study hypothesis, the BCI (H/I)-low group consistently derived clinically meaningful benefit while the BCI (H/I)-high group did not.

The SOFT trial showed that adding ovarian function suppression (OFS) to endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) benefited a subset of premenopausal women with HR-positive, early-stage breast cancer. However, OFS increases short and long-term toxicity and is not tolerated by all patients. Therefore, determining which patients truly need OFS is crucial to avoid added toxicities in patients who are unlikely to benefit. Unfortunately however, there are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS and its resultant toxicities. The Breast Cancer Index (BCI) is a genomic assay that incorporates molecular grade index (MGI) and the HOXB13/IL17BR (H/I) index ratio for N0 patients. In N1 patients, the BCIN+ further incorporates tumour size and grade. The BCI stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence and predicts the likelihood of benefit from extended endocrine therapy in early stage HR+ breast cancer. The purpose of this study is to assess BCI’s prognostic and predictive ability in premenopausal women randomly assigned to 5-years treatment with E+OFS or T+OFS vs. T alone in the SOFT trial. Investigators hypothesized that BCI (H/I)-high status would be predictive for OFS benefit, while BCI (H/I) low status would not.

Methods

All available FFPE tumour samples from the SOFT trial (N=1,718 of 3,047) were included in the study. BCI testing was performed blinded to clinical characteristics, treatment and outcome. Median follow-up was 13 years. Primary endpoint was breast cancer-free interval (BCFI). Secondary endpoints were distant recurrence-free interval (DRFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of BCI (H/I) status (High vs. Low), and secondarily H/I as a continuous score. Hypothesis testing for interaction was performed by stratified log-rank tests.

Results

Of the 1,718 patient included in the analysis, 30 had insufficient RNA quantity so the final translational BCI cohort included 1,687 patients. Investigators assessed tumour samples from 573 patients assigned to tamoxifen, 551 assigned to T+OFS and 563 assigned to E+OFS. The cohort was representative of the parent SOFT trial. In total, 30.4% of patients were < 40 years, 64.1% T1, 50.1% G2, 65.8% N0, 85.5% HER2- and 53.3% received prior chemotherapy. Overall, 58% of tumours were BCI (H/I)-low and 42% were BCI (H/I)-high.

After 12 years of follow-up, BCI was prognostic of distant recurrence in premenopausal women with HR+ cancers, with higher risk scores associated with worse outcome. Furthermore, the BCI (H/I) index was predictive of OFS benefit. In the overall HR-positive cohort, patients with BCI (H/I)-high tumours did not derive an absolute benefit for E+OFS vs. tamoxifen (HR[95%CI: 1.03[0.70-1.53]) or T+OFS vs. tamoxifen (HR[95%CI]: 1.05[0.72-1.54]). The absolute benefit was –0.4% for E+OFS and –1.2% for T+OFS. Contrary to the study hypothesis, among patients in the BCI (H/I)-low group, there was an absolute benefit of 11.6% for E+OFS vs. tamoxifen (HR[95%CI[: 0.48[0.33-0.71] and an absolute benefit of 7.3% for T+OFS (HR[95%CI]: 0.69[0.48-0.97]) vs. tamoxifen alone. In patients with HR-positive, HER2-negative tumours, BCI (H/I) was again predictive in the low group. The absolute 12-year benefit was 13.2% for E+OFS vs. tamoxifen (HR[95%CI]: 0.39[0.25-0.60]) and 7.4% for T+OFS vs. tamoxifen (HR[95%CI]: 0.64[0.44-0.93]). The predictive benefit of the H/I ratio was observed regardless of age, lymph node involvement, and receipt of chemotherapy.

Conclusion

The BCI translational cohort was representative of the SOFT parent trial. BCI risk scores were prognostic in premenopausal women with HR+ tumours receiving adjuvant endocrine therapy, with higher risk scores associated with worse outcome. Furthermore, the BCI (H/I) index was predictive of OFS benefit. Contrary to the study hypothesis, BCI (H/I)-low group consistently derived clinically meaningful benefit while BCI (H/I)-high group did not.

Reference

O’Regan R, et al. Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial. Presented at SABCS 2022; Abstract GS1-06.