Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer.

Even with contemporary treatment strategies, >10% of HER2-positive early-stage breast cancer (BC) patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive BC. 677 HER2-positive stage I-III BC patients from ShortHER trial, CherLOB trial, and two institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site-specific) was evaluated using competing risk-analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. Stage III and high HER2DX risk-score identified patients at the highest risk of distant relapse as first event (10-yr incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared to other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-yr incidence 3.8% vs. 0.6%, p = 0.005), basal-like tumors were associated with an increased risk of lung metastases (10-yr incidence 11.1% vs. 2.6%, p = 0.001), and luminal tumors developed more frequently bone-only metastases (10-yr incidence 5.1% vs. 2.0%, p = 0.042). When added to stage or HER2DX risk-score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. The integration of intrinsic molecular subtypes with stage or HER2DX risk-score predicts site-specific metastatic risk in HER2-positive BC, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

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© The Author(s) 2023. Published by Oxford University Press.