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Comprehensive Genomic Profiling Identifies Novel Genetic Predictors of Response to Anti-PD-(L)1 Therapies in Non-Small Cell Lung Cancer.
Fang, Wenfeng; Ma, Yuxiang; Yin, Jiani C; Hong, Shaodong; Zhou, Huaqiang; Wang, Ao; Wang, Fufeng; Bao, Hua; Wu, Xue; Yang, Yunpeng; Huang, Yan; Zhao, Hongyun; Shao, Yang W; Zhang, Li.
Afiliação
  • Fang W; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China. zhangli6@mail.sysu.edu.cn fangwf@sysucc.org.cn yang.shao@geneseeq.com.
  • Ma Y; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • Yin JC; Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
  • Hong S; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • Zhou H; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • Wang A; Geneseeq Technology Inc., Toronto, Ontario, Canada.
  • Wang F; Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
  • Bao H; Geneseeq Technology Inc., Toronto, Ontario, Canada.
  • Wu X; Geneseeq Technology Inc., Toronto, Ontario, Canada.
  • Yang Y; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • Huang Y; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • Zhao H; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • Shao YW; Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. zhangli6@mail.sysu.edu.cn fangwf@sysucc.org.cn yang.shao@geneseeq.com.
  • Zhang L; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Clin Cancer Res ; 25(16): 5015-5026, 2019 08 15.
Article em En | MEDLINE | ID: mdl-31085721
PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood. EXPERIMENTAL DESIGN: We performed genomic profiling of 78 patients with non-small cell lung cancer (NSCLC) who underwent anti-PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response. RESULTS: We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32-4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09-4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types. CONCLUSIONS: We identified novel genomic biomarkers that were predictive of response to anti-PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biomarcadores Tumorais / Carcinoma Pulmonar de Células não Pequenas / Genômica / Neoplasias Pulmonares Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biomarcadores Tumorais / Carcinoma Pulmonar de Células não Pequenas / Genômica / Neoplasias Pulmonares Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article