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Poster Session (ID 8)
- Event: ACLC 2018
- Type: Poster Session
- Presentations: 1
- Coordinates: 11/07/2018, 00:00 - 00:00, Poster Hall
P088 - Distribution of Different HER2 Mutations (ID 219)
00:00 - 00:00 | Author(s): W Wang
Human epidermal growth factor receptor 2 (HER2)-targeted therapies in lung cancer exhibit limited and variable efficacies, suggesting the heterogeneity of HER2-mutant lung cancers. Here, we explored the genetic characteristics in different HER2 mutations and co-mutations and their impact on responses to afatinib in NSCLC patients.
Eighty-six HER2-mutant lung cancer patients who were referred to OrigiMed (Shanghai, China) for NGS-based genomic testing were identified (OrigiMed cohort). The frequency and distribution of genomic alterations were analyzed with a 37 or 450 gene panel with a mean coverage depth of >800X. Another 32 HER2-mutant adenocarcinoma patients who treated with afatinib were identified (Afatinib cohort). Clinical outcomes on afatinib were retrospectively evaluated according to types of HER2 mutations. The most common mutation A775_G776insYVMA were classified into Group 1; Group 2 contained other exon 20 insertions; Group 3 contained missense mutations.
The frequency of HER2 mutation was 4.23% (86/2035), which was higher than those observed in TCGA (15/546, 2.75%) and MSK-IMPACT (45/1275, 3.53%). Thirty-one different HER2 mutations were detected in OrigiMed cohort. The most frequent HER2 mutations in two cohort were A775_G776insYVMA (35/86; 14/32), G778_P780dup (6/86; 5/32), G776delinsVC (4/86; 5/32) and S310F/Y (7/86; 1/32). A775_G776insYVMA and G776delinsVC/G778_P780dup respectively correlated with the worst and the best clinical outcomes on afatinib in overall response rate (P=0.018), disease control rate (P=0.001) and progression-free survival (PFS) (Figure 1). In multivariable analysis, A775_G776insYVMA (HR[95%CI]: G2/G1, 0.009 [0.001-0.079], P<0.001; G3/G1, 0.184 [0.062-0.552], P=0.003), TP53 co-mutations (6.317 [2.180-18.302], P=0.001) and PI3K/AKT/mTOR pathway co-mutations (19.422 [4.098-92.039], P<0.001) correlated with significantly shorter PFS, while G776delinsVC and G778_P780dup correlated with the longest PFS (G2/G3, 0.050 [0.008-0.307], P=0.001).
Different HER2 genotypes exhibit divergent drug sensitivities. G776delinsVC and G778_P780dup derive the greatest benefit from afatinib, while A775_G776insYVMA, co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer primary resistance to afatinib.