Abstract B51: Tumor genetic shift post standard of care therapy

Abstract

Abstract Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Public sequencing efforts have focused, by design, on diagnostic (pre-treatment) biopsies, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard protocol. Many gold standard algorithms used to call mutations perform poorly in ultra-deep sequencing data necessary for sensitive detection of resistance mutations emerging in circulating tumor DNA. They can also miss a wide range of complex genetic aberrations prevalent in cancer genomes. We have performed whole exome sequencing on post treatment core needle biopsies from 47 DLBCL patients post-relapse following anthracycline-based therapy such as R-CHOP, 8 with matched diagnostic biopsies. Similarly we have profiled 88 post-treatment solid tumor biopsies from triple negative breast and lung adenocarcinoma patients recurrent following platinum or multi-agent chemotherapy, 12 with matched diagnostic biopsies. We compared the somatic variant frequencies and copy number variation between matched pre- and post-treatment samples, and with published data for cohorts of primary (diagnostic) samples matched by patient and tumor characteristics. NGS data from all samples were processed using the same mutation caller, VarDict http://github.com/AstraZeneca-NGS/VarDict, optimized to call large InDels and complex variants in ultra-deep sequencing. For DLBCL, the average mutation rate and founding driver mutation profile were similar, however a number of oncogenic driver mutations were found to have emerged in the post-treatment biopsies. Collectively these data further highlight the value of re-assessing the tumor genetic landscape at the time therapeutic choices are made. Citation Format: Dry R. Jonathan, Danielle Greenawalt, Zhongwu Lai, Carl Barrett. Tumor genetic shift post standard of care therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B51.