Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

Cancer. 2018 Apr 1;124(7):1358-1373. doi: 10.1002/cncr.31125. Epub 2018 Jan 16.


Background: In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies.

Methods: In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas.

Results: A total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB-mutated samples, and ERBB3-mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2-amplified samples compared with wild-type CRC samples (51.8%), and ERBB2- or ERBB3-mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways.

Conclusions: Although observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti-HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2-positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti-HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358-73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Keywords: ERBB2, ERBB3; colorectal adenocarcinoma; comprehensive genomic profiling; human epidermal growth factor receptor 2 (HER2); lapatinib; microsatellite instability; pertuzumab; trastuzumab; tumor mutational burden.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Child
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • Humans
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Molecular Targeted Therapy*
  • Mutation*
  • Prognosis
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-3 / genetics*
  • Young Adult


  • Biomarkers, Tumor
  • ERBB2 protein, human
  • ERBB3 protein, human
  • Receptor, ErbB-2
  • Receptor, ErbB-3