{"doi":"10.1136/jitc-2023-007440","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","abstract":"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.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":343143,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":683609,"name":"Charalampos S. Floudas","orcid":"0000-0002-0020-237X","position":1,"is_corresponding":false},{"id":463110,"name":"Asaf Maoz","orcid":"0000-0002-7502-3923","position":2,"is_corresponding":false},{"id":564663,"name":"Abdul Rafeh Naqash","orcid":"0000-0001-7622-720X","position":3,"is_corresponding":false},{"id":1080644,"name":"Carter Norton","orcid":"0009-0001-4991-6998","position":4,"is_corresponding":false},{"id":261753,"name":"Aik Choon Tan","orcid":"0000-0003-2955-8369","position":5,"is_corresponding":false},{"id":564674,"name":"Ethan Sokol","orcid":"0000-0002-5480-8473","position":6,"is_corresponding":false},{"id":16660,"name":"Garrett M. Frampton","orcid":"0000-0002-2361-2750","position":7,"is_corresponding":false},{"id":984543,"name":"Heloisa P. Soares","orcid":"0000-0002-5185-2583","position":8,"is_corresponding":false},{"id":734906,"name":"Sonam Puri","orcid":"0000-0001-8068-5051","position":9,"is_corresponding":false},{"id":298929,"name":"Umang Swami","orcid":"0000-0003-3518-0411","position":10,"is_corresponding":false},{"id":621799,"name":"Breelyn A. Wilky","orcid":"0000-0001-5080-497X","position":11,"is_corresponding":false},{"id":814032,"name":"Peter J. Hosein","orcid":"0000-0001-8537-6397","position":12,"is_corresponding":false},{"id":260070,"name":"Jonathan C. Trent","orcid":"0000-0001-6169-5238","position":13,"is_corresponding":false},{"id":105135,"name":"Gilberto Lopes","orcid":"0000-0002-1151-9903","position":14,"is_corresponding":false},{"id":242186,"name":"Wungki Park","orcid":"0000-0002-8006-3102","position":15,"is_corresponding":false},{"id":337606,"name":"Ignacio Garrido‐Laguna","orcid":"0000-0003-2273-9028","position":16,"is_corresponding":false},{"id":901609,"name":"Vaia Florou","orcid":"0000-0001-5558-753X","position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:11:21.758449Z","pmid":"37586768","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}