Oncogenic alterations in ERBB2/HER2 represent potential therapeutic targets across tumors from diverse anatomic sites of origin

Abstract

Background: Targeted ERBB2/HER2 inhibitors are approved by the U.S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents. Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications.

Materials and methods: We explored the spectrum of activating ERBB2 alterations across a collection of ∼ 7,300 solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes.

Results: Known oncogenic ERBB2 alterations were identified in tumors derived from 27 tissues, and ERBB2 amplification in breast, gastric, and gastroesophageal cancers accounted for only 30% of these alterations. Activating mutations in ERBB2 were identified in 131 samples (32.5%); amplification was observed in 246 samples (61%). Two samples (0.5%) harbored an ERBB2 rearrangement. Ten samples (2.5%) harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases.

Conclusion: Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Compared with current clinical standards, comprehensive genomic profiling of a more diverse set of tumor types may identify ∼ 3.5 times the number of patients who may benefit from ERBB2-targeted therapy.

Keywords: Antibodies; High-throughput nucleotide sequencing; Humanized; Lapatinib; Monoclonal; Mutation; Pertuzumab; Trastuzumab.

Figure 1.

Distribution of ERBB2 alterations across diseases. Mutations, amplifications, and rearrangements involving ERBB2 were identified in 403 tumors across 27 disease types. Data are expressed as a percentage compared with the total number of tumors within that subtype in our data set. Abbreviations: cholangio, cholangiocarcinoma; GE, gastroesophageal.

Figure 2.

Schematic diagram of mutations observed in ERBB2. Mutation frequency at each residue is depicted by vertical red bars. All exon 20 insertions (ex20ins) are graphed in red; however, only the most frequent site is labeled (A775_G776insYVMA). For a complete list of exon 20 alterations and the diseases in which they occur, see supplemental online Table 3. Abbreviation: CRC, colorectal cancer.