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

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

Author information

1
Foundation Medicine Inc, Cambridge, Massachusetts.
2
Department of Pathology, Albany Medical Center, Albany, New York.
3
Department of Medical Oncology and Therapeutics Research City of Hope, Duarte, California.

Abstract

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

PMID:
29338072
PMCID:
PMC5900732
DOI:
10.1002/cncr.31125
[Indexed for MEDLINE]
Free PMC Article

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