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 (HR _{Amplification} = 2.44, 95% CI [1.25; 4.76], p = 0.009) and MAP3K1 mutations (HR _Mutation = 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 (χDDFS2 = 12.97, p_DDFS < 0.001 and χOS2 = 11.52, p_OS < 0.001). In the METABRIC study (n = 1413), FGFR1 amplifications (HR _{Amplification} = 2.00 [1.40; 2.87], p < 0.001) and MAP3K1 mutations (HR _Mutation = 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 (χBCSSS2 = 15.39, p_BCSS < 0.001 and χOS2 = 5.62, p_OS = 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.