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Published on: June 26, 2019
Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2-Mutant Lung Adenocarcinoma
Wenfeng Fang1,2, Shen Zhao1,2, Ying Liang1,2
1Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
Background:
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 < .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 < .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.
Implications For Practice:
Human epidermal growth factor receptor 2 (HER2)-mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti-HER2 treatments. TP53 is the most common co-mutation in HER2-mutant lung cancers. Co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti-HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.
Insights
HER2-mutant lung cancer treatment varies by specific HER2 variants and co-mutations. Certain HER2 variants like G778_P780dup and G776delinsVC benefit from afatinib, while others like A775_G776insYVMA show resistance. Co-mutations such as TP53 also impact treatment efficacy.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- HER2-mutant lung cancer lacks specific targeted therapies, leading to variable patient responses.
- Understanding the impact of HER2 variants and co-mutations is crucial for optimizing anti-HER2 treatment strategies.
Purpose of the Study:
- To investigate the diverse patterns of HER2 variants and co-mutations in lung cancer.
- To assess the association between specific HER2 variants, co-mutations, and clinical outcomes in patients receiving anti-HER2 therapy.
Main Methods:
- Retrospective analysis of stage IV/recurrent HER2-mutant lung cancers from seven hospitals.
- Utilized next-generation sequencing to identify HER2 variants and co-mutations.
- Assessed treatment response (objective response rate, progression-free survival) to afatinib in relation to genetic profiles.
Main Results:
- Identified 31 HER2 variants and 35 co-mutations in 118 patients.
- A775_G776insYVMA was the predominant variant (42%), showing 0% response to afatinib.
- G778_P780dup and G776delinsVC variants showed higher response rates (40%) and longer progression-free survival.
- TP53 co-mutations and PI3K/AKT/mTOR pathway activation were associated with resistance to afatinib.
Conclusions:
- HER2 variants exhibit differential sensitivity to anti-HER2 therapies like afatinib.
- G778_P780dup and G776delinsVC variants benefit most from afatinib.
- Co-mutations, particularly TP53, significantly modify treatment response, necessitating personalized therapeutic approaches.
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