Associations between Breast Cancer Index and MSK-IMPACT genomic and transcriptomic profiles in HR+ breast cancer

Background: The Breast Cancer Index (BCI) is a gene expression-based assay that stratifies patients based on their risk of overall (0-10 years) and late (beyond 5 years) distant recurrence. In addition , BCI can also predict the benefit of extended endocrine therapy in early-stage, HR+ breast cancer. In this study, we assessed the relationships between BCI and risk of distant recurrence and explored associations between BCI classification and the tumor genomic and transcriptomic profiles of HR+ patients who experienced metastatic relapse. Methods: Primary tumors from patients with metastatic or recurrent HR+ breast cancer underwent BCI testing, MSK-IMPACT targeted sequencing (up to 505 cancer genes), and mRNA sequencing. Time to DR (TTDR) was defined as the time from surgery to first distant recurrence. A 5-year cutoff was used to distinguish early versus late DR groups. Kaplan-Meier and Cox proportional hazards analyses were used to assess BCI's prognostic value. Wilcoxon tests were applied for pairwise comparisons of BCI scores between early and late DR groups, and Fisher's exact tests were used to identify genomic alterations differing by BCI groups as well as DR groups. Given the limited cohort size, multiple testing correction was not applied. Transcriptomic data (N=91) were analyzed for differentially expressed genes by comparing BCI high-risk vs. low-risk tumors and early vs. late DR groups (|log 2 FC|>1, adjusted p<0.05). Results: The study included 180 HR+ patients (47% post-menopausal, 61% N+, 65.3% grade 3). Most tumors were classified as BCI high risk (86.7%), and patients classified as high risk by BCI had earlier recurrence than those classified as low risk (median TTDR: 3.0 years vs. 4.7 years; HR = 1.89, 95% CI: 1.20-2.96; p = 0.0053). BCI scores differ significantly between early and late DR groups (p = 0.005). The genomic landscape was consistent with high-risk luminal tumors and showed frequent TP53 mutations (38%). PIK3CA and TBX3 mutations were more common in BCI low-risk tumors (71% vs. 41%, p=0.007; 21% vs. 5%, p=0.01). CDKN2A deletions and MCL1 amplifications were enriched in early DR, whereas ERBB2 and SPOP amplifications as well as NOTCH3 , and MAP2K4 mutations were more frequent in late DR (p<0.05). Transcriptomic analysis revealed downregulation of cell cycle, p53 signaling, senescence, and progesterone-mediated oocyte maturation pathways in BCI high-risk tumors. The cell cycle pathway was also downregulated in late recurrences, suggesting reduced proliferative activity associated with delayed relapse. Conclusion: BCI remained a strong prognostic indicator in this HR+ metastatic cohort, with higher scores predicting shorter TTDR. Integrated genomic and transcriptomic profiling highlighted distinct molecular programs associated with BCI classification providing insight into biological mechanisms underlying early versus late relapse in HR+ breast cancer.