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

Abstract

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 .

Keywords: Gene expression signatures; Predictive; Premenopausal; Prognostic; Tamoxifen.