ERBB2 (also HER2) is a transmembrane receptor that is a member of the ERBB family of receptor tyrosine kinases. ERBB2 is altered by amplification and/or overexpression in various cancers, most frequently in breast, esophagogastric and endometrial cancers. Somatic mutations in ERBB2 have been identified in a series of tumors including lobular breast, lung adenocarcinoma, and gastric cancers, among others, with recurrent hotspot alterations in both the extracellular and kinase domains. Preclinical and clinical studies have demonstrated that many of these mutations are transforming and sensitive to FDA-approved ERBB targeted therapies, including trastuzumab, ado-trastuzumab emtansine, lapatinib, and pertuzumab. The ERBB2 p.G776delinsVC variant is one of the in-frame insertions in exon 20 of ERBB2 that have been described in lung adenocarcinoma. Overall, in-frame ERRB2 insertions in exon 20 have been reported in approximately 6% of cases of lung adenocarcinoma which are negative for EGFR, KRAS, ALK alterations and these variants are more frequent in patients who were never-smokers. In vitro studies have shown that this specific variant is associated with constitutive kinase activation and is associated with sensitivity to some ERBB2 inhibitors and therefore, it may represent a targetable mutation in some clinical settings. Please refer to clinicaltrials.gov for additional information. Recommend correlation with other clinical and laboratory findings.

ERBB2 V842I is a mutation identified in breast cancer patients, located within the kinase domain, which increases kinase activity, in vitro, and increases the number of colonies formed in soft agar. Cells with this mutation display an invasive morphology, but tumor xenografts formed from these cells do not grow more rapidly than those with wild-type HER2. When assessing sensitization to HER2-targeted therapies in vitro, cells with this mutation are highly sensitive to neratinib but less sensitive to lapatinib, in a manner similar to wild-type HER2.

The ERBB2 p.V842I mutation has been previously reported in several cancer types and has been reported to be an activating mutation. The potential for these mutations to be used for selection of patients to targeted therapies continues to be evaluated.

Activating extracellular domain ERBB2 mutations (S310F, S310Y, R157W) have been identified in urothelial carcinoma (enriched in micropapillary variant) and adenocarcinomas of breast and lung. These activating mutations may have therapeutic potential in some clinical settings.

ERBB2 exon 20 insertions occur within exon 20, which encodes part of the kinase domain. These mutations occur with a frequency of approximately 2--4% of all NSCLC. Overall, in-frame ERRB2 insertions in exon 20 have been reported in approximately 6% of cases of lung adenocarcinoma which are negative for EGFR, KRAS, ALK alterations and these variants are more frequent in patients who were never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro studies have shown that this specific variant is associated with constitutive kinase activation and is associated with sensitivity to some ERBB2 inhibitors and therefore, it may represent a targetable mutation in some clinical settings. Please refer to clinicaltrials.gov for additional information. Recommend correlation with other clinical and laboratory findings.

ERBB2 kinase domain mutations are seen in up to 4.3% of breast cancers. In vitro analyses demonstrated that L755S confer resistance to lapatinib and could potentially emerge as an acquired mutation during therapy. Another preclinical study has shown that L755S is sensitive to irreversible TKIs neratinib and canertinib. The predictive and prognostic as well as therapeutic implications of ERBB2 mutations need further elucidation.

In breast cancer, ERBB2 (HER2) amplification and over-expression are associated with sensitivity to anti-HER2 agents, such as Trastuzumab. Drug : Lapatinib + Trastuzumab, Pertuzumab + Trastuzumab, Ado-trastuzumab emtansine, Lapatinib, Trastuzumab,

ERBB2 encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. ERBB2 mutations have been reported in ~2-3% of lung adenocarcinomas. The majority of ERBB2 mutations are in-frame insertions in exon 20, which encodes part of the kinase domain; however, point mutations (L755S and G776C) have also been identified. Lung adenocarcinomas with ERBB2 mutations are mutually exclusive with EGFR, KRAS, ALK alterations and these variants are more frequent in patients who are never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro analyses have shown that ERBB2 L755P and L755S mutations are associated with constitutive kinase activation and resistance to lapatinib treatment. The predictive significance of ERBB2 mutations in lung adenocarcinomas needs further elucidation. Recommend correlation with other clinical and laboratory findings.

This mutation is located at extracellular domain. Patients with mutation of ERBB2 S310F, which is very close to S295 and also an extracellular domain, have been treated successfully with anti-HER agents (Jia et al, 2014; Vornicova et al, 2014). Although mutation at extracellular domain does not elevate HER2 protein level (negative for IHC), it might still activate HER2 protein or it’s downstream signaling.

This mutation is recognized as gain of function mutation. Tumor with this mutation responds to neratinib, a type of TKI which is against HER2 and EGFR.

An acquired HER2 gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer

This gene is a known cancer gene.

This gene is a known cancer gene.

ERBB2 encodes HER2, an EGFR receptor tyrosine kinase, which activates PI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathways. ERBB2 (HER2) amplification has been implicated in several tumor types. ERBB2 (HER2) G776V lies within the protein kinase domain of the ERBB2 protein. G776V has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on ERBB2 protein function is unknown. ERBB2 kinase domain mutations are seen in up to 4.3% of breast cancers. In a preclinical study, AP32788 (EGFR and ERBB2 TKI) inhibited growth of transformed cell lines over expressing ERBB2 G776V in culture. The clinicopathologic significance of this variant remains to be further elucidated.

ERBB2 encodes HER2, a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. ERBB2 mutations have been reported in ~12% of urothelial carcinomas. This particular variant I767M lies within the protein kinase domain of HER2 and has been shown to result in increased kinase activity in vitro. This variant has been identified in rare cases of urothelial carcinomas, among other cancer types, and is considered to be oncogenic. Further studies are needed to elucidate the role of anti-HER2 therapy in this setting. Clinical correlation is recommended.