TERT Promoter Mutations Are Preferentially Associated With the ERBB2 G776-Altered Subtype of HER2-Mutant NSCLC.

HER2-mutant non-small cell lung cancer (NSCLC) comprises molecularly heterogeneous tumors with diverse ERBB2 mutation subtypes, and HER2-directed therapies have increased the need for refined molecular stratification. However, subtype-specific co-occurring genomic alterations remain incompletely characterized. We performed a two-stage clinicogenomic analysis to identify and validate recurrent co-mutations in HER2-mutant NSCLC. A public MSK-IMPACT lung adenocarcinoma cohort was used for discovery, and a nationwide Japanese real-world cohort from the Center for Cancer Genomics and Advanced Therapeutics was used for validation. In the MSK-IMPACT cohort of 2201 lung adenocarcinomas, TERT mutations were significantly enriched in ERBB2-mutant tumors compared with ERBB2-wild-type tumors (odds ratio, 2.40; 95% confidence interval, 1.12-4.70; p = 0.017). This association was reproduced in the independent validation cohort, where 16 of 174 HER2-mutant NSCLC cases harbored concurrent TERT mutations, all of which were promoter-region variants. Among the evaluated clinicogenomic variables, the ERBB2 mutation subtype was the only factor significantly associated with TERT mutation status. The ERBB2 G776-altered subtype remained independently associated with TERT mutation after multivariable adjustment (adjusted odds ratio, 7.49; 95% confidence interval, 1.81-31.0; p = 0.006). In a small exploratory subset of trastuzumab deruxtecan-treated patients (n = 52; TERT-mutated, n = 5), no statistically robust differences in treatment outcomes were observed according to TERT mutation status. TERT promoter mutations are recurrent co-mutations in HER2-mutant NSCLC and are preferentially associated with the ERBB2 G776-altered subgroup. These findings support ERBB2 subtype-aware molecular stratification and highlight previously underappreciated genomic heterogeneity within HER2-mutant NSCLC.