{"doi":"10.1016/j.esmoop.2025.105768","title":"Impact of DNA damage repair alterations on real-world response to therapy in metastatic colorectal cancer","abstract":"BACKGROUND: Alterations in DNA damage repair (DDR) pathway genes can be exploited by cytotoxic chemotherapy regimens that induce DNA damage. Platinum chemotherapy has been shown to be particularly effective in DDR-mutated populations. However, the clinical impact of DDR mutations in metastatic colorectal cancer is still unknown. PATIENTS AND METHODS: In this retrospective cohort study, we utilized a de-identified nationwide (USA-based) colorectal cancer clinicogenomic database. We included 5607 patients with metastatic colorectal cancer who received a standard fluorouracil-based, first-line chemotherapy regimen. Time to next treatment (TTNT) and overall survival (OS) were summarized with Kaplan-Meier curves and compared between groups with Cox proportional hazards models. Multivariable analysis controlled for age, sex, race, Eastern Cooperative Oncology Group performance status at diagnosis, category of first-line treatment, stage at diagnosis, KRAS status, BRAF status, mismatch repair status, carcinoembryonic antigen and albumin level. RESULTS: DDR alterations were identified in 31.8% (n = 1785) of patients. The most frequent were in ATM (12.4%) and BRCA2 (6.7%). There was no difference in TTNT based on DDR mutational status. Median OS was greater in patients with a DDR mutation [34.3 months versus 31.9 months, hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.86-0.99]. Within DDR-altered patients, there was no difference in OS based on first-line treatment received. TTNT was significantly improved with an irinotecan doublet (12.7 months versus 10.3 months, HR 0.78, 95% CI 0.69-0.87) or triplet (12.4 months versus 10.3 months, HR 0.70, 95% CI 0.54-0.91) compared with an oxaliplatin doublet. CONCLUSIONS: In this real-world population, OS was improved in DDR-altered patients with metastatic colorectal cancer compared with DDR-wildtype patients. There was no difference in OS in DDR-mutated patients based on first-line treatment received.","journal":"ESMO Open","year":2025,"id":546795,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1438866,"name":"Christine Norton","orcid":"0000-0003-2259-0948","position":1,"is_corresponding":false},{"id":1364242,"name":"Zachary Rubnitz","orcid":null,"position":2,"is_corresponding":false},{"id":901609,"name":"Vaia Florou","orcid":"0000-0001-5558-753X","position":3,"is_corresponding":false},{"id":579537,"name":"Chris Nevala-Plagemann","orcid":"0000-0003-4048-2692","position":4,"is_corresponding":false},{"id":337606,"name":"Ignacio Garrido‐Laguna","orcid":"0000-0003-2273-9028","position":5,"is_corresponding":false},{"id":578103,"name":"Laura Miotke","orcid":null,"position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-19T02:53:36.567932Z","pmid":"40930024","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":[]}