Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden
Background Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007440.full |
| _version_ | 1827854657694728192 |
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| author | Ignacio Garrido-Laguna Asaf Maoz Wungki Park Abdul Rafeh Naqash Vaia Florou Breelyn Wilky Jonathan Trent Umang Swami Garrett Frampton Heloisa P Soares Sonam Puri Aik Choon Tan Charalampos S Floudas Carter Norton Ethan S Sokol Peter Hosein Gilberto de Lima Lopes |
| author_facet | Ignacio Garrido-Laguna Asaf Maoz Wungki Park Abdul Rafeh Naqash Vaia Florou Breelyn Wilky Jonathan Trent Umang Swami Garrett Frampton Heloisa P Soares Sonam Puri Aik Choon Tan Charalampos S Floudas Carter Norton Ethan S Sokol Peter Hosein Gilberto de Lima Lopes |
| author_sort | Ignacio Garrido-Laguna |
| collection | DOAJ |
| description | Background Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients.Methods Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups.Results We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A.Conclusions FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB. |
| first_indexed | 2024-03-12T11:25:53Z |
| format | Article |
| id | doaj.art-206cd2d9903d405d9e63f577bd3f9aea |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T11:25:53Z |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-206cd2d9903d405d9e63f577bd3f9aea2023-09-01T08:40:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007440Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burdenIgnacio Garrido-Laguna0Asaf Maoz1Wungki Park2Abdul Rafeh Naqash3Vaia Florou4Breelyn Wilky5Jonathan Trent6Umang Swami7Garrett Frampton8Heloisa P Soares9Sonam Puri10Aik Choon Tan11Charalampos S Floudas12Carter Norton13Ethan S Sokol14Peter Hosein15Gilberto de Lima Lopes16Medicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USAMedical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAMedicine, Memorial Sloan Kettering Cancer Center, New York, New York, USAMedical Oncology/TSET Phase 1 Program, The University of Oklahoma Stephenson Cancer Center, Oklahoma City, Oklahoma, USAMedicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USAMedicine, University of Colorado Denver Health Sciences Center, Aurora, Colorado, USAMedicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USAMedicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAMedicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USAMedicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USAOncological Sciences and Biomedical Informatics, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USACenter for Immuno-Oncology, National Cancer Institute, Bethesda, Maryland, USAMedicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USAFoundation Medicine Inc, Cambridge, Massachusetts, USAMedicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USAMedicine, Sylvester Comprehensive Cancer Center, Miami, Florida, USABackground Pembrolizumab is FDA approved for tumors with tumor mutational burden (TMB) of ≥10 mutations/megabase (mut/Mb). However, the response to immune checkpoint inhibitors (ICI) varies significantly among cancer histologies. We describe the landscape of frameshift mutations (FSs) and evaluated their role as a predictive biomarker to ICI in a clinical cohort of patients.Methods Comprehensive genomic profiling was performed on a cohort of solid tumor samples examining at least 324 genes. The clinical cohort included patients with metastatic solid malignancies who received ICI monotherapy and had tumor sequencing. Progression-free survival (PFS), overall survival, and objective response rates (ORR) were compared between the groups.Results We analyzed 246,252 microsatellite stable (MSS) and 4561 samples with microsatellite instability across solid tumors. Histologies were divided into groups according to TMB and FS. MSS distribution: TMB-L (<10 mut/Mb)/FS-A (absent FS) (N=111,065, 45%), TMB-H (≥10 mut/Mb)/FS-A (N=15,313, 6%), TMB-L/FS-P (present ≥1 FS) (N=98,389, 40%) and TMB-H/FS-P (N=21,485, 9%). FSs were predominantly identified in the p53 pathway. In the clinical cohort, 212 patients were included. Groups: TMB-L/FS-A (N=80, 38%), TMB-H/FS-A (N=36, 17%), TMB-L/FS-P (N=57, 27%), TMB-H/FS-P (N=39, 18%). FSs were associated with a higher ORR to ICI, 23.8% vs 12.8% (p=0.02). TMB-L/FS-P had superior median PFS (5.1 months) vs TMB-L/FS-A (3.6 months, p<0.01). The 12-month PFS probability was 34% for TMB-L/FS-P vs 17.1% for TMB-L/FS-A.Conclusions FSs are found in 47% of patients with MSS/TMB-L solid tumors in a pan-cancer cohort. FS may complement TMB in predicting immunotherapy responses, particularly for tumors with low TMB.https://jitc.bmj.com/content/11/8/e007440.full |
| spellingShingle | Ignacio Garrido-Laguna Asaf Maoz Wungki Park Abdul Rafeh Naqash Vaia Florou Breelyn Wilky Jonathan Trent Umang Swami Garrett Frampton Heloisa P Soares Sonam Puri Aik Choon Tan Charalampos S Floudas Carter Norton Ethan S Sokol Peter Hosein Gilberto de Lima Lopes Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden Journal for ImmunoTherapy of Cancer |
| title | Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden |
| title_full | Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden |
| title_fullStr | Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden |
| title_full_unstemmed | Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden |
| title_short | Real-world pan-cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden |
| title_sort | real world pan cancer landscape of frameshift mutations and their role in predicting responses to immune checkpoint inhibitors in cancers with low tumor mutational burden |
| url | https://jitc.bmj.com/content/11/8/e007440.full |
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