Evaluation of clinical outcomes by analysis of mutations in tumor tissue and circulating plasma DNA using next-generation sequencing (NGS) from STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).

Abstract

11510 Background: STEAM (NCT01765582) assessed the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to assess somatic mutations in 77 cancer-related genes by NGS in tissue, and both pre- and post-induction plasma samples (n = 182, 150 and 118 respectively) from STEAM. Four mutation classes including single-nucleotide variants (SNVs), indels, copy number amplifications (CNAs) and fusions were identified. SNVs and indels were called in tissue and plasma at allele frequencies of 5% and 0.25% respectively. Results: Overall concordance of mutations in pre-induction plasma with tissue was 83%. Concordance for the seven most mutated genes ranged from 91.5%-100%. In pts with matched samples (n = 118), RAS WT pts showed significantly longer progression-free survival (PFS) in both cFOLFOXIRI-BEV (A) and sFOLFOXIRI-BEV (B) arms versus FOLFOX-BEV (C), using genotyping of either tissue or plasma. This was not seen in RAS MUT pts. In contrast, TP53 WT showed no significant treatment differences while TP53 MUT showed longer PFS for cFOLFOXIRI-BEV versus FOLFOX-BEV. A list of mutation frequencies for all samples, as well as hierarchical clustering analysis of tissue mutations will be presented. Conclusions: The AVENIO ctDNA Expanded Kit identified mutations in 77 cancer-related genes, in both plasma and tissue, with high overall concordance. Compared to FOLFOX-BEV, longer PFS was observed for c- or s- FOLFOXIRI-BEV in RAS WT pts and for cFOLFOXIRI-BEV in TP53 MUT pts, irrespective of sample type. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582. [Table: see text]