Association between FGFR1 copy numbers, MAP3K1 mutations, and survival in axillary node-positive, hormone receptor-positive, and HER2-negative early breast cancer in the PACS04 and METABRIC studies

Purpose Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early breast cancer (BC) is the most prevalent BC subtype with substantial biological heterogeneity. Although clinicopathological (CP) characteristics have a clear prognostic value, additional biomarkers could refine survival prediction and guide treatment decision. Methods Copy number aberrations and somatic driver mutations were obtained with OncoScan CGH array and sequencing of 36 genes on HR+/HER2- node-positive early BC patients treated with chemotherapy from the PACS04 trial. We built a two-gene genomic score (GS) associated with distant disease-free survival (DDFS), whose prognostic value was assessed on the external METABRIC data (n = 1413) using overall survival (OS) and breast cancer-specific survival (BCSS). Results In the PACS04 trial (n = 327), the median follow-up for DDFS (65 events) was 9.6 years. FGFR1 amplifications (HRAmplification\documentclass[12pt]= 2.44, 95% CI [1.25; 4.76], p = 0.009) and MAP3K1 mutations (HRMutation = 0.10, [0.01; 0.78], p = 0.03) were associated with DDFS beyond CP characteristics. A prognostic GS combining FGFR1 amplifications and MAP3K1 mutations added more information to CP model (chi DDFS2< 0.001 and chi OS2\ < 0.001). In the METABRIC study (n = 1413), FGFR1 amplifications (HRAmplification= 2.00 [1.40; 2.87], p < 0. 001) and MAP3K1 mutations (HRMutation\documentclass= 0.58 [0.41; 0.83], p = 0.003) were significantly associated with BCSS beyond CP characteristics. The prognostic GS added significant prognostic information to CP model (chi(BCSSS)(2) = 15.39, pBCSS < 0.001 and chi(OS)(2)= 5.62, pOS= 0.02). Conclusion In axillary node-positive, HR+, and HER2- early BC, amplifications of FGFR1 gene were strongly associated with increased risk for distant disease, while mutations of MAP3K1 gene were significantly associated with decreased risk.