TERT Promoter Mutations Are Preferentially Associated With the ERBB2 G776 ‐Altered Subtype of HER2 ‐Mutant

ABSTRACT

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.