In:
The Oncologist, Oxford University Press (OUP), Vol. 25, No. 3 ( 2020-03-01), p. e545-e554
Abstract:
Human epidermal growth factor receptor 2 (HER2)-mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of HER2 variants and co-mutations on responses to anti-HER2 treatments in lung cancer. Patients and Methods Patients with stage IV/recurrent HER2-mutant lung cancers identified through next-generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co-mutations in lung cancer and a cohort B to assess associations between HER2 variants, co-mutations, and clinical outcomes. Results The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty-one HER2 variants and 35 co-mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co-mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%–26.8%), 40% (4/10, 14.7%–72.6%), and 13% (1/8, 0.7%–53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression-free survival in group 1 (1.2 months; 95% CI, 0–2.4) was shorter than those in group 2 (7.6 months, 4.9–10.4; hazard ratio [HR] , 0.009; 95% CI, 0.001–0.079; p & lt; .001) and group 3 (3.6 months, 2.6–4.5; HR, 0.184; 95% CI, 0.062–0.552; p = .003). TP53 co-mutations (6.317; 95% CI, 2.180–18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098–92.039; p & lt; .001) conferred additional resistance to afatinib. Conclusion G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co-mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co-mutations may help improve the efficacy of anti-HER2 treatment in lung cancer.
Type of Medium:
Online Resource
ISSN:
1083-7159
,
1549-490X
DOI:
10.1634/theoncologist.2019-0547
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2020
detail.hit.zdb_id:
2023829-0
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