RAS amplified colorectal cancers are enriched in RAS-WT, BRAF-WT, MSS tumors and may predict for anti-EGFR resistance.

Abstract

547 Background: Pre-clinical models implicate RAS amplifications ( RASa) as a mechanism of resistance to anti-Epidermal Growth Factor Receptor (EGFR) therapies. Yet, there is little guidance on the impact of RASa, as identified by next generation sequencing (NGS), on anti-EGFR response. Methods: We investigated the Foundation Medicine (FM) database for RASa in CRC and characterized this population based on patient (pt) characteristics and other concurrent genomic alterations. We subsequently investigated City of Hope (COH) mCRC molecular data set (using FoundationOne) and described the RASa population characteristics and response to anti-EGFR. Results: FM cohort included 21,315 CRC unique pt cases. 365 (1.5%) pts had RASa, of which 123 (0.6%) had ≥ 20 copy number (CN) ( RASa≥20). The incidence of MSI-H, RAS and BRAF short variant mutations in the overall, RASa, and RASa≥20 populations were (MSI-H: 5%, 0%, 0%), ( RAS: 54%, 32%, 2%), and ( BRAF: 6%, 1%, 0%), respectively. RASa≥20 tumors had higher level of genomic amplification than the overall population (29% vs. 5% had ≥ 5 genes amplified). COH cohort included 338 mCRC. 12 pts (3.6%) had RASa. The median RAS CN was 27 (7 - 72); 8/12 pts had RASa≥20. All but 2 COH pts with RASa had a RAS/BRAF-WT tumors. Both pts with concurrent RAS mutations had relatively low RAS CN (7&13). Tumors with RASa were predominantly left-sided (11/12). 7/12 pts were treated with anti-EGFR therapy. All 7 pts were RAS/BRAF wild-type: 6 left-sided; 3 pts 1st/2nd lines (1 pt oxaliplatin-based and 2 pts irinotecan-based) and 4 pts chemo-refractory (all irinotecan-based). All 4 chemo-refractory pts had RASa≥20 and progressed on anti-EGFR on 1st post-treatment CT (PFS in all pts ≤ 3 mo). One 1st line pt had SD (PFS = 4 mo). One 2nd line pt had SD (PFS = 7 mo) and one had PD as best response. Conclusions: NGS identifies RASa and RASa≥20in 1.5% and 0.6% of CRC, respectively. RASa≥20 tumors are MSS and, generally lack RAS/ BRAF mutations, and predict for resistance to anti-EGFR. This supports the potential relevance of 20-CN cut-point for the exclusion of pts from anti-EGFR. These findings would benefit from additional validation from retrospective analyses of completed prospective anti-EGFR clinical trials.