RAS-amplified colorectal cancers: Microsatellite stability status, RAS/BRAF mutations, and prediction of anti-EGFR resistance.

3533 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. Copy number variation inversely correlated with likelihood of RAS mutation. COH cohort included 396 mCRC. 13 pts (3.3%) had RASa. The median RAS CN was 25 (7 - 79); 8/13 pts had RASa≥20. All but 3 COH pts with RASa had a RAS/BRAF-WT tumors. Pts with concurrent RAS mutations had relatively low RAS CN (7, 8, &13). Tumors with RASa were predominantly left-sided (12/13). 7/13 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≥20and 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.

• Publication year

  2019

• Venue

  Journal of Clinical Oncology

• Publication date

  2019-05-20

• Fields of study

  Medicine

• Identifiers
  DOI 10.1200/JCO.2019.37.15_SUPPL.3533
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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