ERBB2/ERBB3-Mutant Colorectal Cancer


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A study reported in the Journal of the National Cancer Institute by Loree and colleagues found that ERBB2/ERBB3 mutations in colorectal cancer are associated with microsatellite instability and PIK3CA mutation. Kanwal Raghav, MD, MBBS, of the Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author of the Journal of the National Cancer Institute article.

Kanwal Raghav, MD, MBBS

Kanwal Raghav, MD, MBBS

The study involved retrospective analysis of 419 patients from The University of Texas MD Anderson Cancer Center (MDACC) and 619 patients from the Nurses’ Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with stage I to IV disease, with tissue sequencing, clinicopathologic, mutational, and colorectal cancer consensus molecular subtype (CMS) profiles of patients with ERBB2/ERBB3 mutations. The circulating tumor DNA profile associated with ERBB2 mutation was also investigated in an additional cohort of 1,623 patients with circulating tumor DNA assay results.

Factors Associated With ERBB2/ERBB3 Mutation

ERBB2 mutations were found in 4.1%, 5.8%, and 5.1% of the MDACC cohort, NHS/HPFS cohort, and circulating tumor DNA cohort, respectively. ERBB3 mutations were found in 5.7% of both the MDACC and NHS/HPFS cohorts. No association was seen between either mutation and age, disease stage, or tumor location.

The presence of microsatellite instability was significantly associated with a higher likelihood of ERBB2 mutation in the MDACC (odds ratio [OR] = 5.98, P < .001) and NHS/HPFS cohorts (OR = 5.13, P < .001) and ERBB3 mutation in the MDACC (OR = 3.48, P = .002) and NHS/HPFS cohorts (OR = 3.40, P = .03). Neither mutation was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in the tissue cohorts.

PIK3CA mutations were significantly associated with ERBB2 mutations in the MDACC (OR = 3.68, P = .001), NHS/HPFS (OR = 2.25, P = .02), and circulating tumor DNA cohorts (OR = 2.11, P = .004) and with ERBB3 mutations in the MDACC cohort (OR = 13.26, P < .001). ERBB2 (P = .08) and ERBB3 mutations (P = .008) were associated with the CMS-1 subtype. ERBB2 (hazard ratio [HR] = 1.82, P = .009) but not ERBB3 mutations (HR = 0.88, P = .73) were associated with poorer overall survival.

The investigators concluded, “[Microsatellite instability] and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.” ■

Loree JM, et al: J Natl Cancer Inst. April 27, 2018 (early release online).


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