Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas

Abstract

Background Activating mutations in the tyrosine kinase domain of HER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in US patients. Experimental Design Lung ADC samples (n=1478) were first screened for mutations in EGFR (exons 19 and 21) and KRAS (exon 2) and negative cases were then assessed for HER2 mutations (exons 19–20) using a sizing assay and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT was performed by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH. Results We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for 96% (24/25) of the cases. Compared to insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12bp insertion causing duplication of amino acids YVMA at codon 775. Morphologically, 92% (23/25) were moderately or poorly differentiated ADC. HER2 mutation was not associated with concurrent HER2 amplification in 11 cases tested for both. HER2 mutations were more frequent among never-smokers (p<0.0001) but there were no associations with sex, race, or stage. Conclusions HER2 mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, routine clinical genotyping of lung ADC should include HER2.

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

“…85 In-frame insertions in exon 20 and substitutions at S310 are the most common mutations seen, and are typically mutually exclusive with other recurrent alterations, including mutations in EGFR, KRAS, and BRAF, as well as rearrangements involving ALK and ROS1. Insertions in exon 20 are variable, with most being a 12ebase pair duplication of codons 775e778 encoding amino acids YVMA, 81 and are more commonly observed in younger patients and patients with no smoking history. De novo ERBB2 amplification may occur with or without ERBB2 mutation, 82,84,86 with highly variable reported rates of cooccurrence from 0% to 87%.…”

“…De novo ERBB2 amplification may occur with or without ERBB2 mutation, 82,84,86 with highly variable reported rates of cooccurrence from 0% to 87%. 81,84,86 Although differences in methods and criteria defining amplification levels may be responsible for these observed discrepancies and require standardization, the higher prevalence of ERBB2 amplification independent of ERBB2 mutation suggests that mutation and amplification could represent distinct markers and therapeutic targets in lung cancer. 89 ERBB2 amplification has also been reported rarely as a secondary event in patients with sensitizing EGFR mutations and as a potential mechanism of resistance following treatment with EGFR inhibitors.…”

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

“…HER‐2 kinase domain mutations can be categorized as: missense point mutations, small in‐frame insertions or duplications which almost occurring in exon 20 and in frame deletions. Among these mutations, the in‐frame insertions or duplications in exon 20 are the most frequently encountered types of mutations 22, 30, 31, 32. In addition, we also take the HER‐2 splice variants into account, including p95HER‐2 and Δ16HER‐2.…”

Implications of Evolving Medical Science for Proof of Lung Cancer Causation

“…A typical tumor contains two to eight driver mutations that can affect as many as 12 key cellular signaling pathways. Reported genetic alterations for lung adenocarcinoma include: EGFR (32,(42)(43)(44)(45)(46)(47), KRAS (42,(48)(49)(50)(51)(52), BRAF (53)(54)(55)(56), and ERBB2 (formerly HER2) (45, 56-60) driver mutations; ROS1 (32,(61)(62)(63), KIF5b-RET (32,64,65), and EML4-ALK rearrangements (20,45,57,61,(66)(67)(68)(69)(70); and other gene amplifications (20). An estimated 50% of lung adenocarcinomas in patients in Western populations have either an EGFR or KRAS driver mutation (42).…”

“…Most studies conducted to date have demonstrated a higher rate of EGFR mutations among Asian patients than Western patients, and these studies are consistent with those findings. Nonetheless, the LI and DOGAN studies, among others (42,45,57,77,85,86), establish that a significant number of smoking patients harbor EGFR mutations in their tumor specimens. These findings stand in contrast to those reported in some of the early EGFR studies (47,(71)(72)(73), which seemed to indicate that an EGFR mutation occurred exclusively in nonsmokers.…”