Abstract 351P
Background
In colorectal cancer (CRC) resistance to EGFR inhibitors such as cetuximab or panitumumab can involve activating alterations in human epidermal growth factor receptor 2 (ERBB2/HER2). Anti-ERBB2 therapy is indicated in ERBB2-amplified CRC that is RAS and BRAF wild type. ERBB3/4 alterations can also activate HER2 signaling and thus be effective therapy targets. Our study investigates the prevalence of ERBB alterations in patients with CRC, as well as their importance for treatment.
Methods
The tumor-normal pairing based OncomapTM ExTra assay was employed to sequence CRC samples by whole-exome DNA sequencing to detect single base substitutions, indels, copy number alterations, and structural variants, and calculate tumor mutational burden (TMB) and microsatellite instability (MSI). Clinically actionable alterations, defined as associated with FDA-approved drugs or clinical trial enrollment, were identified. BRAF mutations, and RAS (KRAS, NRAS, HRAS) and ERBB (ERBB2/3/4) amplification or gain-of-function missense mutations were summarized.
Results
Of 757 CRC patients assayed, 38 ERBB alterations were found in 37 (4.9%) patients; 32% of the alterations were not in ERBB2 (26 ERBB2, 11 ERBB3, 1 ERBB4). Of the 38 ERBB alterations, 16 (42%) were ERBB2 amplifications and the rest were gain-of-function missense mutations capable of activating the ERBB2 signaling pathway; 1 patient had alterations in two ERBB genes. There were 56 (7.4%) BRAF mutant samples and 375 (49.5%) RAS mutant samples (348 KRAS, 27 NRAS, 0 HRAS), which included 5 (1.3%) KRAS amplifications. Of the 37 patients with an ERBB alteration, 22 (59%) had no RAS or BRAF alteration (17 ERBB2, 3 ERBB3, 1 ERBB4, 1 ERBB2 ERBB3) identifying a subset in which anti-ERBB2 therapy is likely to respond. Further, 15 (39%) had a RAS but no BRAF alteration (8 ERBB2, 7 ERBB3), which may be targeted by a combination of anti-ERBB2 and MEK inhibitors. Presence of both a BRAF and ERBB mutation, which may be targeted by anti-ERBB2 and RAF/MEK inhibitors, was not observed.
Conclusions
The results of whole-exome genomic profiling of CRC samples highlight that combinations of gene alterations are critical in the management of CRC and guidance towards appropriate clinical trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Exact Sciences Corporation.
Funding
Exact Sciences Corporation.
Disclosure
M.N. Kundranda: Financial Interests, Personal, Advisory Role: Bayer, BMS; Financial Interests, Personal, Research Grant: Bayer, Chronix. M. Wang: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. D.W. Hall: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. J. Hoag: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. F. Alyaqoub: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. P. Noel: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. S. Szelinger: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. S.S. Udhane: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. A.A. Ozols: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. J.R. Lobello: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. F.L. Baehner: Financial Interests, Personal, Full or part-time Employment: Exact Sciences. S.G. Thakkar: Financial Interests, Personal, Full or part-time Employment: Exact Sciences.