Zhen Zhang1,2, Hao-Xiang Wu1,2, Wu-Hao Lin1,2, Zi-Xian Wang1,2, Lu-Ping Yang1,2, Zhao-Lei Zeng1,2, Hui-Yan Luo3,4. 1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. 2. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China. 3. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. luohy@sysucc.org.cn. 4. Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People's Republic of China. luohy@sysucc.org.cn.
Abstract
BACKGROUND: A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. METHODS: Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. RESULTS: Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor. CONCLUSIONS: EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.
BACKGROUND: A critical and challenging process in immunotherapy is to identify cancerpatients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. METHODS: Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. RESULTS: Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor. CONCLUSIONS:EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.
Authors: A Ari Hakimi; Martin H Voss; Fengshen Kuo; Alejandro Sanchez; Ming Liu; Briana G Nixon; Lynda Vuong; Irina Ostrovnaya; Ying-Bei Chen; Victor Reuter; Nadeem Riaz; Yuan Cheng; Parul Patel; Mahtab Marker; Albert Reising; Ming O Li; Timothy A Chan; Robert J Motzer Journal: Cancer Discov Date: 2019-01-08 Impact factor: 39.397
Authors: Diana Miao; Claire A Margolis; Wenhua Gao; Martin H Voss; Wei Li; Dylan J Martini; Craig Norton; Dominick Bossé; Stephanie M Wankowicz; Dana Cullen; Christine Horak; Megan Wind-Rotolo; Adam Tracy; Marios Giannakis; Frank Stephen Hodi; Charles G Drake; Mark W Ball; Mohamad E Allaf; Alexandra Snyder; Matthew D Hellmann; Thai Ho; Robert J Motzer; Sabina Signoretti; William G Kaelin; Toni K Choueiri; Eliezer M Van Allen Journal: Science Date: 2018-01-04 Impact factor: 47.728
Authors: Alexandra Snyder; Vladimir Makarov; Taha Merghoub; Jianda Yuan; Jedd D Wolchok; Timothy A Chan; Jesse M Zaretsky; Alexis Desrichard; Logan A Walsh; Michael A Postow; Phillip Wong; Teresa S Ho; Travis J Hollmann; Cameron Bruggeman; Kasthuri Kannan; Yanyun Li; Ceyhan Elipenahli; Cailian Liu; Christopher T Harbison; Lisu Wang; Antoni Ribas Journal: N Engl J Med Date: 2014-11-19 Impact factor: 91.245
Authors: Mary J Goldman; Brian Craft; Mim Hastie; Kristupas Repečka; Fran McDade; Akhil Kamath; Ayan Banerjee; Yunhai Luo; Dave Rogers; Angela N Brooks; Jingchun Zhu; David Haussler Journal: Nat Biotechnol Date: 2020-06 Impact factor: 54.908
Authors: Willy Hugo; Jesse M Zaretsky; Lu Sun; Chunying Song; Blanca Homet Moreno; Siwen Hu-Lieskovan; Beata Berent-Maoz; Jia Pang; Bartosz Chmielowski; Grace Cherry; Elizabeth Seja; Shirley Lomeli; Xiangju Kong; Mark C Kelley; Jeffrey A Sosman; Douglas B Johnson; Antoni Ribas; Roger S Lo Journal: Cell Date: 2016-03-17 Impact factor: 41.582
Authors: Vésteinn Thorsson; David L Gibbs; Scott D Brown; Denise Wolf; Dante S Bortone; Tai-Hsien Ou Yang; Eduard Porta-Pardo; Galen F Gao; Christopher L Plaisier; James A Eddy; Elad Ziv; Aedin C Culhane; Evan O Paull; I K Ashok Sivakumar; Andrew J Gentles; Raunaq Malhotra; Farshad Farshidfar; Antonio Colaprico; Joel S Parker; Lisle E Mose; Nam Sy Vo; Jianfang Liu; Yuexin Liu; Janet Rader; Varsha Dhankani; Sheila M Reynolds; Reanne Bowlby; Andrea Califano; Andrew D Cherniack; Dimitris Anastassiou; Davide Bedognetti; Younes Mokrab; Aaron M Newman; Arvind Rao; Ken Chen; Alexander Krasnitz; Hai Hu; Tathiane M Malta; Houtan Noushmehr; Chandra Sekhar Pedamallu; Susan Bullman; Akinyemi I Ojesina; Andrew Lamb; Wanding Zhou; Hui Shen; Toni K Choueiri; John N Weinstein; Justin Guinney; Joel Saltz; Robert A Holt; Charles S Rabkin; Alexander J Lazar; Jonathan S Serody; Elizabeth G Demicco; Mary L Disis; Benjamin G Vincent; Ilya Shmulevich Journal: Immunity Date: 2018-04-05 Impact factor: 43.474
Authors: Aaron M Newman; Chih Long Liu; Michael R Green; Andrew J Gentles; Weiguo Feng; Yue Xu; Chuong D Hoang; Maximilian Diehn; Ash A Alizadeh Journal: Nat Methods Date: 2015-03-30 Impact factor: 28.547
Authors: Jianfang Liu; Tara Lichtenberg; Katherine A Hoadley; Laila M Poisson; Alexander J Lazar; Andrew D Cherniack; Albert J Kovatich; Christopher C Benz; Douglas A Levine; Adrian V Lee; Larsson Omberg; Denise M Wolf; Craig D Shriver; Vesteinn Thorsson; Hai Hu Journal: Cell Date: 2018-04-05 Impact factor: 41.582
Authors: Neal Ready; Matthew D Hellmann; Mark M Awad; Gregory A Otterson; Martin Gutierrez; Justin F Gainor; Hossein Borghaei; Jacques Jolivet; Leora Horn; Mihaela Mates; Julie Brahmer; Ian Rabinowitz; Pavan S Reddy; Jason Chesney; James Orcutt; David R Spigel; Martin Reck; Kenneth John O'Byrne; Luis Paz-Ares; Wenhua Hu; Kim Zerba; Xuemei Li; Brian Lestini; William J Geese; Joseph D Szustakowski; George Green; Han Chang; Suresh S Ramalingam Journal: J Clin Oncol Date: 2019-02-20 Impact factor: 44.544