RAS Amplification as a Negative Predictor of Benefit from Anti-EGFR–Containing Therapy Regimens in Metastatic Colorectal Cancer

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Background RAS short variant mutations (SV) in colorectal cancer (CRC) are associated with lack of benefit from EGFR monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti‐EGFR therapy in CRC remain ill‐defined. Methods Genomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling (CGP) database (GDB) of 37,233 CRC cases. Clinical outcomes were assessed using 2 independent cohorts (1) The City of Hope (COH): 338 metastatic CRC (mCRC) patients, (2) Flatiron Health (FH)‐FM real‐world clinico‐GDB (CGDB): 3,904 mCRC patients. Results RASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6‐9 (n=241, 39%), 10‐19 (n=165, 27%) and ≥20 copy (n=209, 34%) subsets had co‐RAS SV/BRAF V600E in 63%/3%, 31%/0.6% and 4.8%/0% of cases, respectively. COH cohort: 6 patients with RASa (13‐54 copies) received EGFRmAb; 4/6 had progressive disease, 2 had stable disease; median time to treatment discontinuation (TTD) was 2.5 months. CGDB EGFRmAb‐treated patients: RASa (n=9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months; RAS SV (n=101) had median TTD and OS of 5.3 and 9.4 months; RAS/BRAF wild‐type (n=608) had median TTD and OS of 7.6 and 13.7 months. Conclusions Patients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies. Implications for Practice Genomic data suggests that RAS amplification occurs as the sole RAS/RAF alteration in in >1% of CRC, and degree of amplification inversely correlates with co‐occuring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti‐EGFR therapies in colorectal cancer. More clinical data is needed, and comprehensive genomic profiling including detection of RAS amplification should be utilized in trial design to inform therapy selection.

This publication has 16 references indexed in Scilit: