Molecular landscape of ErbB2/ErbB3 mutated colorectal cancer

Abstract

Background: Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC. Methods: We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided. Results: ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] ¼ 2.4% to 6.4%), 5.8% (95% CI ¼ 4.1% to 8.0%), and 5.1% (95% CI ¼ 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI ¼ 3.7% to 8.4%, 95% CI ¼ 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] ¼ 5.98, 95% CI ¼ 2.47 to 14.49, P < .001; OR ¼ 5.13, 95% CI ¼ 2.38 to 11.05, P < .001) and ERBB3 mutations (OR ¼ 3.48, 95% CI ¼ 1.51 to 8.02, P ¼ .002; OR ¼ 3.40, 95% CI ¼ 1.05 to 10.96, P ¼ .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR ¼ 3.68, 95% CI ¼ 1.83 to 7.41, P ¼ .001; OR ¼ 2.25, 95% CI ¼ 1.11 to 4.58, P ¼ .02; OR ¼ 2.11, 95% CI ¼ 1.25 to 3.58, P ¼ .004) and ERBB3 mutations in the MDACC cohort (OR ¼ 13.26, 95% CI ¼ 5.27 to 33.33, P