Abstract P3-06-13: Whole exome sequencing of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (ExdCR) to trastuzumab (T)

Abstract

Abstract Background: Trastuzumab (T) has shown clinical efficacy in early-stage and MBC. However, within 1-year 40-50% develop resistance to T. The exact mechanism of the development of T resistance is not completely understood. Anecdotal observations suggest that a small fraction of patients with HER2+ MBC may be "extraordinary durable complete responders (ExdCR)". Indeed, we previously reported that 9% of MBC achieve dCR following T and chemotherapy. Understanding the genomic mechanisms underlying exceptional dCR to T may improve patient selection and treatment rationale to identify HER2+ MBC pts who are more likely to achieve dCR following T treatment. Methods: Genomic DNA was extracted from paraffin embedded formalin fixed (FFPE) tissue. Whole exome sequencing (WES) on primary tumours from 9 MBC ExdCR > 60 mo (5 matched T:N) and 6 non-responders (NR) or PR < 6 mo (3 matched T:N). Tumours were analysed for single nucleotide variants (SNVs) point mutations, insertions/deletions (indels), copy number alterations (CNA), and tumour mutational burden. Detailed clinicopathologic data was collected for each patient and linked to the genomic information. Results: WES of matched tumour:normal samples revealed differences in SNVs and indels between the ExdCR pts compared to NR. Mutations in TP53 were found in 2/5 ExdCR pts and in 0/3 NR. Initial analysis of CNA revealed that HER2 is significantly more amplified in ExdCR pts compared to NR, and this was also shown by IHC and FISH. Conclusions: We present a genomic landscape of extraordinary durable complete responders compared to non-responders using WES. High variability exists in mutation profile of ExdCR pts with few overlapping genes. Further analysis into clinically relevant genomic and molecular alterations will be performed to potential aid in patient selection and choice of therapy, and novel drug targets. Citation Format: Walsh N, Gullo G, Quinn C, Furney SJ, Crown J. Whole exome sequencing of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (ExdCR) to trastuzumab (T) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-13.