Abstract 34P
Background
Despite the clear benefits of Anti HER2 therapies, many patients demonstrate resistance, primary or adaptive, mechanisms that are not fully understood. Current studies have shown that miRNAs are essential for both expressions of HER2 and the action of trastuzumab/pertuzumab in breast cancer. Heterodimerization of HER2 with other HER family members under the regulation of miRNAs could induce various intracellular signaling pathways and resistance in breast cancer. Based on this, miRNAs not only can be utilized as significant predictors of drug resistance in HER2-positive breast cancer but can also be targeted. In the current study, we aim to demonstrate miRNA mediated resistance to therapy in anti-HER2 treated patients by correlating miRNA levels to response to NACT.
Methods
This study was conducted at Sri Shankara Cancer Hospital and Research Centre, Bangalore after obtaining Institutional Ethical Committee approval. Patients were enrolled fromJune 2022 to Jan 2024. FFPE blocks from 100 confirmed primary HER2 positive BCs, treated with standard NACT were collected. Responders and non-responders were classified based on residual cancer burden (RCB) post-surgery and followed prospectively. The levels of miR were estimated using Taqman q-RT-PCR technique and correlated with RCB. Choice of specific MIRs was guided by meta-analysis from TCGA.
Results
The median age of our cohort was 49 y. Following standard of care NACT, 55% of patients achieved pCR. The highest pCR rates (65%) were seen in the subgroup which received dual anti HER2 therapy. The pCR rates were higher for the HR-ve, HER2 +ve subgroup when compared to HR+ve HER2 +ve BC. (73.1% vs 44.9%, p < 0.05).Top MIRs Mir21, 193a, 15b, 98, and 187 associated with disease-free survival were used to generate a score to correlate with response to NACT. More work to complete q-PCR analysis and analyze specific downstream pathways that contribute to resistance and also functional elucidation in-vitro for mechanism is underway.
Conclusions
Our work demonstrates a possible mechanism for primary resistance to anti HER2 therapy and pave the way for application of microRNA as a tool for predicting and targeting against resistance to trastuzumab in breast cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Sri Shankara Cancer Hospital and Research Center, Bangalore.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.