Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer
Background Despite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.Methods This study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patient...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000374.full |
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| author | Lin Shen Huan Chen Ming Lu Shuang Li Henghui Zhang Jifang Gong Zhihao Lu Zhi Peng Xi Jiao Lihong Wu Wenbo Han Jianling Zou Jianing Yu Huaibo Sun |
| author_facet | Lin Shen Huan Chen Ming Lu Shuang Li Henghui Zhang Jifang Gong Zhihao Lu Zhi Peng Xi Jiao Lihong Wu Wenbo Han Jianling Zou Jianing Yu Huaibo Sun |
| author_sort | Lin Shen |
| collection | DOAJ |
| description | Background Despite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.Methods This study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.Results In the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.Conclusions Our results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs. |
| format | Article |
| id | doaj-art-d766e6f16abe4c22a03534e640902608 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d766e6f16abe4c22a03534e6409026082025-08-20T02:13:19ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2019-000374Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancerLin Shen0Huan Chen1Ming Lu2Shuang Li3Henghui Zhang4Jifang Gong5Zhihao Lu6Zhi Peng7Xi Jiao8Lihong Wu9Wenbo Han10Jianling Zou11Jianing Yu12Huaibo Sun13State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital, Beijing, China2 Genecast Precision Medicine Technology Institute, Beijing, ChinaClinical Epidemiology Unit, Shandong University Qilu Hospital, Jinan, China1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, People`s Republic of China4 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, ChinaDepartment of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China1 Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China1 Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, ChinaDepartment of General Practice, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China2 Genecast Precision Medicine Technology Institute, Beijing, China1 Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China2 Genecast Precision Medicine Technology Institute, Beijing, China2 Genecast Precision Medicine Technology Institute, Beijing, ChinaBackground Despite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.Methods This study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.Results In the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.Conclusions Our results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.https://jitc.bmj.com/content/8/2/e000374.full |
| spellingShingle | Lin Shen Huan Chen Ming Lu Shuang Li Henghui Zhang Jifang Gong Zhihao Lu Zhi Peng Xi Jiao Lihong Wu Wenbo Han Jianling Zou Jianing Yu Huaibo Sun Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer Journal for ImmunoTherapy of Cancer |
| title | Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer |
| title_full | Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer |
| title_fullStr | Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer |
| title_full_unstemmed | Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer |
| title_short | Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer |
| title_sort | tumor copy number alterations predict response to immune checkpoint blockade in gastrointestinal cancer |
| url | https://jitc.bmj.com/content/8/2/e000374.full |
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