Li-Li Deng1, Ge Gao1, Hong-Bin Deng2, Feng Wang1, Zhi-Hui Wang1, Yu Yang3. 1. Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China. 2. Dental Hospital, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Road, Nangang District, Harbin, 150001, Heilongjiang, People's Republic of China. 3. Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China. yangyuyyyy@126.com.
Abstract
PURPOSE: To determine the frequency of co-occurring genes in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and the predictive effect of co-mutations on the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). METHODS: 54 patients with advanced NSCLC were tested for 422 clinically relevant genes by next-generation sequencing (NGS) before treatment. Among them, patients with EGFR mutation received first-line treatment of EGFR-TKIs. Progression-free survival (PFS) and objective response rate (ORR) were evaluated using Kaplan-Meier methods and compared between two groups using log-rank test. RESULTS: Among 24 EGFR mutant and 30 EGFR wild-type patients, co-mutation rate was lower in patients with EGFR mutation (62.5% [15/24] vs 93.3% [28/30], p = 0.005). There was lower frequency for co-alterations in BRAF (0% [0/24] vs 20% [7/30], p = 0.033), NF1 (4.2% [1/24] vs 30% [9/30], p = 0.038) and RAS-RAF-MAPK pathway genes (16.6% [4/24] vs 56.7% [17/30], p = 0.003) in EGFR mutation group. 24 patients with EGFR mutation received first-line treatment of gefitinib or erlotinib, with an ORR of 83.3% and a median PFS of 12.3 months (95% CI 10.00-14.60). Co-mutation was associated with shorter median PFS (10.2 months [95% CI 5.20-15.20] vs 15.3 months [95% CI 12.09-15.81]; HR 0.29 [95% CI 0.10-0.82]; p = 0.014) in EGFR mutation cohort. Among patients with EGFR mutation and distant metastasis, median PFS was decreased in those with co-mutations (6.3 months [95% CI 3.25-9.35] vs 22.0 months[95% CI 12.10-31.90]; HR 0.12 [95% CI 0.00-5.87]; p = 0.007) and frequency of PIK3CA (0% [0/12] vs 41.7% [5/12], p = 0.037) and PI3K/AKT/mTOR pathway genes (0% [0/12] vs 50% [6/12], p = 0.014) was lower. CONCLUSION: The presence of co-mutations was lower in the EGFR mutation patients and reduces the efficacy of EGFR-TKI, especially in patients with distant metastases. Lower frequency of co-mutation in PIK3CA and PI3K/AKT/mTOR pathway genes may be responsible for promoting metastasis and limiting the efficacy of EGFR-TKIs.
PURPOSE: To determine the frequency of co-occurring genes in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and the predictive effect of co-mutations on the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). METHODS: 54 patients with advanced NSCLC were tested for 422 clinically relevant genes by next-generation sequencing (NGS) before treatment. Among them, patients with EGFR mutation received first-line treatment of EGFR-TKIs. Progression-free survival (PFS) and objective response rate (ORR) were evaluated using Kaplan-Meier methods and compared between two groups using log-rank test. RESULTS: Among 24 EGFR mutant and 30 EGFR wild-type patients, co-mutation rate was lower in patients with EGFR mutation (62.5% [15/24] vs 93.3% [28/30], p = 0.005). There was lower frequency for co-alterations in BRAF (0% [0/24] vs 20% [7/30], p = 0.033), NF1 (4.2% [1/24] vs 30% [9/30], p = 0.038) and RAS-RAF-MAPK pathway genes (16.6% [4/24] vs 56.7% [17/30], p = 0.003) in EGFR mutation group. 24 patients with EGFR mutation received first-line treatment of gefitinib or erlotinib, with an ORR of 83.3% and a median PFS of 12.3 months (95% CI 10.00-14.60). Co-mutation was associated with shorter median PFS (10.2 months [95% CI 5.20-15.20] vs 15.3 months [95% CI 12.09-15.81]; HR 0.29 [95% CI 0.10-0.82]; p = 0.014) in EGFR mutation cohort. Among patients with EGFR mutation and distant metastasis, median PFS was decreased in those with co-mutations (6.3 months [95% CI 3.25-9.35] vs 22.0 months[95% CI 12.10-31.90]; HR 0.12 [95% CI 0.00-5.87]; p = 0.007) and frequency of PIK3CA (0% [0/12] vs 41.7% [5/12], p = 0.037) and PI3K/AKT/mTOR pathway genes (0% [0/12] vs 50% [6/12], p = 0.014) was lower. CONCLUSION: The presence of co-mutations was lower in the EGFR mutation patients and reduces the efficacy of EGFR-TKI, especially in patients with distant metastases. Lower frequency of co-mutation in PIK3CA and PI3K/AKT/mTOR pathway genes may be responsible for promoting metastasis and limiting the efficacy of EGFR-TKIs.
Authors: M Cecilia Caino; Jagadish C Ghosh; Young Chan Chae; Valentina Vaira; Dayana B Rivadeneira; Alice Faversani; Paolo Rampini; Andrew V Kossenkov; Katherine M Aird; Rugang Zhang; Marie R Webster; Ashani T Weeraratna; Silvano Bosari; Lucia R Languino; Dario C Altieri Journal: Proc Natl Acad Sci U S A Date: 2015-06-29 Impact factor: 11.205
Authors: Mark A DePristo; Eric Banks; Ryan Poplin; Kiran V Garimella; Jared R Maguire; Christopher Hartl; Anthony A Philippakis; Guillermo del Angel; Manuel A Rivas; Matt Hanna; Aaron McKenna; Tim J Fennell; Andrew M Kernytsky; Andrey Y Sivachenko; Kristian Cibulskis; Stacey B Gabriel; David Altshuler; Mark J Daly Journal: Nat Genet Date: 2011-04-10 Impact factor: 38.330
Authors: Elza C de Bruin; Catherine Cowell; Patricia H Warne; Ming Jiang; Rebecca E Saunders; Mary Ann Melnick; Scott Gettinger; Zenta Walther; Anna Wurtz; Guus J Heynen; Daniëlle A M Heideman; Javier Gómez-Román; Almudena García-Castaño; Yixuan Gong; Marc Ladanyi; Harold Varmus; René Bernards; Egbert F Smit; Katerina Politi; Julian Downward Journal: Cancer Discov Date: 2014-02-17 Impact factor: 39.397
Authors: Collin M Blakely; Thomas B K Watkins; Wei Wu; Beatrice Gini; Jacob J Chabon; Caroline E McCoach; Nicholas McGranahan; Gareth A Wilson; Nicolai J Birkbak; Victor R Olivas; Julia Rotow; Ashley Maynard; Victoria Wang; Matthew A Gubens; Kimberly C Banks; Richard B Lanman; Aleah F Caulin; John St John; Anibal R Cordero; Petros Giannikopoulos; Andrew D Simmons; Philip C Mack; David R Gandara; Hatim Husain; Robert C Doebele; Jonathan W Riess; Maximilian Diehn; Charles Swanton; Trever G Bivona Journal: Nat Genet Date: 2017-11-06 Impact factor: 38.330