NSCLC is characterized by genome alterations that promote cancer cell growth. TO what extent co-mutations cooperate with the EGFR driver and explain the variable response to EGFR TKI is not well understood. Here, we screened additional co-mutations (ACMs) and evaluate their clinical impact in patients (pts) with advanced NSCLC.
We identified 204 pts with EGFR mutated tumors from the IFCT Biomarkers France study cohort with available tumor DNA who received first or second line first-generation EGFR-TKIs. Samples were assessed by NGS using the AmpliSeq Cancer Hotspot Panel v2. Among the 204 samples, 167 were fully contributive.
EGFR mutations were: classical with del 19 (74; 44%) and L858R (59; 35%), complex (17; 10%) including T790M (9; 5%) or uncommon (17; 10%). EGFR was amplified in 27 (17%) samples. ACMs were identified in 120 (72%) samples with an average of mutations at 2.9 (2-8). Recurrent ACMs (more than 6 samples) were in TP53 (84; 50.3%), CTNNB1 (16; 10%), PI3KCA (15; 9%), RB (12; 7%), APC (10; 6%), PTEN (8; 5%) and ATM (7; 4.5%). EGFR complex mutations were more frequent in smokers (p = 0.01) whereas RB1 mutations were more frequent in non-smokers (p = 0.03). CTNNB1 mutations were mutually exclusive with TP53 (p = 0.01) or PI3KCA (p = 0.05) mutations. High EGFR variant allelic fraction was associated to EGFR amplification (p < 0.001) suggesting mutant allele amplification and to TP53 mutations (p = 0.003). Non-classical or complex EGFR mutations were linked to rapid (< 3 months) versus normal (3-20 months)/slow (> 20 months) progression (p = 0.07 and p = 0.05 respectively). In the non-T790M group, ATM and PTEN mutations were negative predictors of first-line TKI efficacy (mPFS 3.7 versus 8.9 months, HR 2.85, 95CI% 1.14-7.15 and mPFS 5.6 versus 9.0 months, HR 2.46, 95CI% 1.16-5.9, respectively).
EGFR mutated NSCLC have heterogeneous molecular profiles. This work suggests that PTEN and ATM mutations could limit EGFR inhibitor efficacy. However, large series of EGFR mutated NSCLC will be needed to validated links between clinical outcomes and specific EGFR altered pathways.
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AstraZeneca: INCa (French NCI); IFCT (Alain Depierre Research Award 2015).
D. Debieuvre: Consulting: Roche; Honoraria: AstraZeneca, Chugaï, Lilly, Roche, Novartis, Pfizer, MSD, BMS; Grants: Roche, AstraZeneca, Lilly, BMS, Boehringer Ingelheim, Chiesi, Chugaï, Janssen, Pfizer, MSD, Novartis, GSK, Sandoz; Board: Roche, Boehringer Ingelheim, Pfizer, MSD, BMS, Novartis; Conferences: Roche, Boehringer Ingelheim, Novartis, Pierre Fabre, Pfizer, MundiPharma, BMS. C. Audigier Valette: Clinical trials (PI): AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche; Consulting: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; Conferences: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche. S. Moreau Fraboulet: Personal fees and non-financial support: Novartis; Non-financial support: Lilly. D. Moro-Sibilot: Personal fees: Roche, Eli Lilly, Pfizer, Novartis, AstraZeneca, BMS, MSD, Boehringer Ingelheim. A. Lemoine: AstraZeneca, Boehringer, Roche. F. Barlesi: Personal fees: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer. J. Cadranel: Clinical research (PI): AbbVie, AstraZeneca, Bayer, Boehringer–Ingelheim, BMS, MSD, Novartis, Roche, Takeda; Consulting: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche; Conferences: AstraZeneca, BMS, MSD, Pfizer. M. Beau-Faller: Board: BMS, Boehringer-Ingelheim, AstraZeneca; Non-financial support: AstraZeneca, Roche. All other authors have declared no conflicts of interest.