Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer: data from the randomized SBII:2 trial

Background Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer. Methods RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling ( n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments ( q -values) were applied to account for multiple hypothesis testing. Results In patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR] FOXA1 (high) = 1.04, 95% CI = 0.61–1.76, HR FOXA1 (low) = 0.30, 95% CI = 0.14–0.67, q interaction = 0.0013), and a resembling trend was observed for AR (HR AR (high) = 1.15, 95% CI = 0.60–2.20, HR AR (low) = 0.42, 95% CI = 0.24–0.75, q interaction = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HR RFi ESR1 (high) = 0.76, 95% CI = 0.43–1.35, HR RFi, ESR1 (low) = 0.56, 95% CI = 0.29–1.06, q interaction = 0.37). Irrespective of molecular subtype, higher levels of ESR1 , Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HR ESR1 = 0.80, 95% CI = 0.69–0.92, q = 0.005; HR Mast cells = 0.74, 95% CI = 0.65–0.85, q < 0.0001; and HR PGR = 0.78, 95% CI = 0.68–0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HR BCproliferation = 1.54, 95% CI = 1.33–1.79, q < 0.0001; HR Hypoxia = 1.38, 95% CI = 1.20–1.58, q < 0.0001). The results were similar for OS. Conclusions Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR , ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors. Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687 .