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

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.

Figure 1

Genes commonly altered in metastatic colorectal cancer (mCRC) and cooccurrence with mutations in ERBB2 or ERBB3. Statistically significant differences in mutation frequencies (P<.05) by the Fisher exact text are indicated with an asterisk; differences without an asterisk were not statistically significant. (A) The frequency of gene mutations in 8887 colonic (denoted by C) and rectal (denoted by R) adenocarcinomas. (B) Genes coaltered with ERBB2 in colonic and rectal mCRCs. (C) Genes coaltered with ERBB3 in colonic adenocarcinomas. (D) Mutation frequencies for genes in the mismatch repair pathway in all samples, ERBB2‐mutated, and ERBB3‐mutated samples for colonic and rectal mCRC. Statistically significant (P<.05) differences between ERBB2‐mutated or ERBB3‐mutated and nonmutated samples are highlighted with an asterisk. (E) Differences in mutation frequencies among samples with ERBB2 amplification (AMP) only, short variants (SV) only, or cooccurring AMP and SV (the statistical significance of observations illustrated in Figure 1E is reported in Table 3). MLH1 indicates MutL homolog 1; MSH2, mutS homolog 2; MSH6, mutS homolog 6.

Figure 2

(A) Distribution of the ERBB2/3 variants in 569 metastatic colorectal cancer (mCRC) cases. (B) Alterations most commonly observed in (Top) ERBB2 and (Bottom) ERBB3. Shown here are the extracellular (I‐IV), transmembrane (TM), and kinase (KD) domains of human epidermal growth factor receptor 2 (HER2) and HER3. Dark blue dots represent known activating missense alterations, whereas light blue dots are missense mutations suspected to be activating or recurrent in cancer. Green dots represent truncating frameshift alterations that are expected to remove a regulatory phosphorylation site from the C‐terminus of HER2. Amp indicates amplification; SV, short variants.

Figure 3

(A) Moderately differentiated adenocarcinoma of the colon in a 72‐year‐old white man. The tumor invaded through the colon wall and involved numerous pericolonic lymph nodes (pathologic classification T3N2A). The patient rapidly developed stage IV disease. (B) The copy number plot below the histologic images demonstrates extremely high‐level amplification of ERBB2 at 60 copies, associated with lower level coamplification of topoisomerase (DNA) II Alpha (TOP2A) at 7 copies. Using comprehensive genomic profiling, this metastatic colorectal cancer also harbored base substitutions in KRAS (G12D), F‐box/WD repeat‐containing protein 7 (FBXW7) (R479Q), adenomatous polyposis coli (APC) (Q1367*), SRY‐box 9 (SOX9) (D274fs*22), and tumor protein p53 (TP53) (C275W).

Figure 4

Response of an ERBB2‐amplified metastatic colorectal cancer (mCRC) to antihuman epidermal growth factor receptor 2 (HER2)‐targeted therapy. A 39‐year‐old woman with a pT3N0 rectal adenocarcinoma developed widespread metastatic disease and was treated with systemic chemotherapy and metastasectomies. The mCRC was found to be KRAS wild‐type on routine single‐gene testing and anti‐EGFR therapy with cetuximab was used until disease progression. Comprehensive genomic profiling was performed on a metastasis sample at that time and revealed ERBB2 amplification at 21 copies and a tumor protein p53 (TP53) base substitution. Combination therapy with trastuzumab with a backbone of capecitabine and oxaliplatin was initiated. Treatment with trastuzumab continued for 12 months, after which time the patient's symptoms returned with biomarkers and radiology confirming progressive disease. Representative computed tomography scan image of upper lung metastasis is shown (A) at baseline and (B) after 3 months of trastuzumab and chemotherapy. The arrow indicates significantly regressed tumor burden accounting for improved pulmonary symptoms. The targeted therapy using trastuzumab in combination with cytotoxic chemotherapy maintained a strong response in the patient over a 1‐year course of therapy, reducing tumor burden and improving quality of life.

Figure 5

(A) Metastatic colorectal cancer to the liver in a 72‐year‐old woman whose tumor had progressed after 4 separate lines of chemotherapy. (B) Comprehensive genomic profiling revealed both ERBB2 (163 copies) and retinoic acid receptor alpha (RARA) (35 copies) amplification as well as multiple untargetable short variant genetic alterations. This tumor responded clinically for 6 months to a combination of trastuzumab and lapatinib, with a significant decrease in serum carcinoembryonic antigen levels.