HER2 Transmembrane Domain (TMD) Mutations (V659/G660) That Stabilize Homo- and Heterodimerization Are Rare Oncogenic Drivers in Lung Adenocarcinoma That Respond to Afatinib

Abstract Introduction Erb-b2 receptor tyrosine kinase (HER2) transmembrane domain (TMD) mutations (HER2 V659E , HER2 G660D ) have previously been identified in lung adenocarcinomas, but their frequency and clinical significance is unknown. Methods We prospectively analyzed 8551 consecutive lung adenocarcinomas using hybrid capture–based comprehensive genomic profiling (CGP) at the request of the individual treating physicians for the purpose of making therapy decisions. Results We identified 15 cases (0.18%) of HER2 TMD mutations (HER2 V659E/D , HER2 G660D ) through CGP of 8551 lung adenocarcinomas. HER2 TMD mutations were mutually exclusive from HER2 kinase domain mutations and other oncogenic drivers in lung adenocarcinoma. Only two cases with HER2 TMD mutations (13%) had concurrent Erb-b2 receptor tyrosine kinase 2 gene ( HER2 ) amplification. Structural analysis of HER2 TMD association revealed that mutations at positions V659 and G660 to the highly polar residues glutamic acid, aspartic acid, or arginine should stabilize homodimerization and heterodimerization of HER2 in the active conformation. Treatment with afatinib, a pan-HER inhibitor, resulted in durable clinical response in three of four patients with lung adenocarcinoma, with two harboring HER2 V659E and one with double HER2 V659E/G660R mutations. HER2 TMD mutations (V659 and G660) are found in other non-NSCLC malignancies, and analogous TMD mutations are also found in EGFR, HER3, and HER4. Conclusion HER2 TMD mutations represent rare but distinct targetable driver mutations in lung adenocarcinoma. CGP capable of detecting diverse HER2 alterations, including HER2 TMD mutations, should be broadly adopted to identify all patients who may benefit from HER2-targeted therapies.