MicroRNA-mediated resistance mechanisms in NAT-treated HER2-positive breast cancer (BC): A single centre retrospective analysis from matched primary and residual tumours.

e12613 Background: HER2+ accounts for 20–25 % of all BC, is aggressive and clinically challenging. Though treatment outcomes have improved with anti-HER2 agents in the past decade, primary and acquired drug resistance limit the benefits of treatment. MicroRNAs(MIRs) regulate gene expression post-transcriptionally and influence drug resistance. This study examined miRNA-mediated resistance to anti-HER2 therapy through analysis of 78 matched primary and residual tumor specimens. Methods: 78 primary FFPE tumour specimens from HER2 + BC, treated uniformly with standard NAT were accepted for analysis after Institutional Ethics approval. Using public datasets, we identified 8 prognostically significant miRs and in our series, analysed them via Taqman RT-qPCR. A predictive regression model incorporating miR-98, 15b, 193A, and 187 was developed using machine learning methods. Results: Patients showed 54% overall pCR rate following NAT, with 65% of pCR under dual anti-HER2 blockade. HR-ve /HER2+ cases demonstrated superior response (61% vs 39% p<0.05). High miRNA expression correlated with poor response (p<0.05). Dual anti-HER2 therapy and early clinical stage significantly predicted pCR (p=0.014, p=0.037). Analysis of subset of residual tumors and comparing with primary, revealed differential increased levels of oncogenic miRs-15b (p=0.021), 193A (p=0.0003), 98 (p=0.03), 129(p=0.0001), and 130b (p=0.7), suggesting increased acquired resistance. This pattern was more evident in ER-ve HER2+ cases (p<0.05). Conclusions: We identified candidate miRNAs which predict response to NAT in HER2+ BC, and this represents understanding the epigenetic mechanisms of treatment resistance in HER2+ BC, potentially leading to more effective, personalized therapeutic strategies. More analysis of primary and matched residual tumours are ongoing with functional validation for selected MIRs underway.