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Lung Cancer Research Studies / Lung Cancer Treatments and Mutations · Journal article
Cancer Science · August 13, 2026
Encouraging direction, but not yet definitive.
This two-stage clinicogenomic study identified TERT promoter mutations as recurrent co-mutations preferentially associated with the ERBB2 G776-altered subtype of HER2-mutant NSCLC, with the association validated in an independent cohort and independent of other clinical variables. The finding supports refined genomic stratification within HER2-mutant NSCLC but lacks evidence of clinical prognostic or predictive utility, as the exploratory treatment outcome analysis in trastuzumab deruxtecan-treated patients was underpowered.
Two-stage retrospective clinicogenomic discovery and validation study. Discovery cohort: 2201 lung adenocarcinomas from MSK-IMPACT database. Validation cohort: 174 HER2-mutant NSCLC cases from nationwide Japanese real-world registry. Exploratory subset: 52 trastuzumab deruxtecan-treated patients.. Intervention: Genomic sequencing and mutation analysis via MSK-IMPACT and sequencing; trastuzumab deruxtecan treatment in exploratory subset.. Compared with: ERBB2-mutant versus ERBB2 wild-type tumors; ERBB2 G776-altered subtype versus other ERBB2 subtypes; TERT-mutated versus TERT wild-type cases.. Discovery cohort from MSK-IMPACT (United States); validation cohort from Japanese nationwide registry..
TERT mutations enriched in ERBB2-mutant tumors vs. ERBB2 wild-type tumors (odds ratio 2.40; 95% CI 1.12–4.70; p = 0.017) in MSK-IMPACT discovery cohort of 2201 lung adenocarcinomas In validation cohort, 16 of 174 HER2-mutant NSCLC cases harbored concurrent TERT mutations, all promoter-region variants ERBB2 G776-altered subtype independently associated with TERT mutation after multivariable adjustment (adjusted odds ratio 7.49; 95% CI 1.81–31.0; p = 0.006)
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Clinicians evaluating HER2-mutant NSCLC should recognize that TERT promoter mutations are preferentially associated with the ERBB2 G776-altered subtype, supporting molecular stratification. However, the lack of established prognostic or predictive value in the treatment outcome analysis means TERT mutation status should not yet guide clinical decisions; further prospective study is needed.
A validated two-stage clinicogenomic discovery study identifying a recurrent co-mutation association in a molecularly defined NSCLC subtype, but limited by small sample sizes in functional or treatment-outcome validation and lack of prospective clinical utility data.
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Quoted from the source exactly as published.
Clinicians evaluating HER2-mutant NSCLC should recognize that TERT promoter mutations are preferentially associated with the ERBB2 G776-altered subtype, supporting molecular stratification. However, the lack of established prognostic or predictive value in the treatment outcome analysis means TERT mutation status should not yet guide clinical decisions; further prospective study is needed.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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.
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