8fb60b03c09a1561097d3d9a4d57ed5b ijms-26-04245-v3_2_.pdf a6dfb7fb1a898d4c1f18e0d3a39f010227cb6bbc ijms-26-04245-v3_2_.pdf 298eec4571803efc44f4afc0fb5592d4515377ceb5515320a0ca49ac07ef5528 ijms-26-04245-v3_2_.pdf Title: CD274 (PD-L1) Polymorphisms as Predictors of Efficacy in First-Line Platinum-Based Chemotherapy for Extensive-Stage Small Cell Lung Cancer Subject: The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29–0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09–0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23–0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14–0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02–0.70; p = 0.02, and OR 0.08, 95% CI 0.01–0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC. Keywords: extensive-stage small cell lung cancer; platinum-based chemotherapy; pharmacogenetics; biomarker; CD274 gene; PD-L1 Author: Andrés Barba, Laura López-Vilaró, Malena Ferre, Sergio Martinez-Recio, Margarita Majem, Ivana Sullivan and Juliana Salazar Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sun May 4 02:46:47 2025 CEST ModDate: Sun May 4 02:51:44 2025 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2607004 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MIKRSI+VnURWPalladioL Type 1 Custom yes yes yes 10 0 CJQMTX+URWPalladioL-Roma Type 1 Custom yes yes yes 16 0 NFJUFD+URWPalladioL-Bold Type 1 Custom yes yes yes 22 0 ZLJGDB+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 QQJGNQ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 GVNITL+CMSY10 Type 1 Builtin yes yes yes 58 0 FNTSBS+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 77 0 PalatinoLinotype-Italic TrueType WinAnsi no no no 83 0 PalatinoLinotype-Bold TrueType WinAnsi no no no 86 0 PalatinoLinotype-Roman TrueType WinAnsi no no no 89 0 YSCNED+EURM10 Type 1 Builtin yes yes yes 124 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-05-22 02:42:44 CEST RepresentationInformation: ijms-26-04245-v3_2_.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-05-21 19:42:06 CEST Size: 2607004 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 368 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Patients’ Characteristics and Clinical Variants Analyses Destination: subsection.2.1 Item: Title: Polymorphisms of Immune Checkpoint Genes and Progression-Free Survival Analyses Destination: subsection.2.2 Item: Title: Polymorphisms of Immune Checkpoint Genes and Overall Survival Analyses Destination: subsection.2.3 Item: Title: Haplotype Analyses for CD274 Variants and Survival Destination: subsection.2.4 Item: Title: Polymorphisms of Immune Checkpoint Genes and Platinum Sensitivity Analyses Destination: subsection.2.5 Item: Title: Analyses of PD-L1 Protein Expression and CD274 Polymorphisms Destination: subsection.2.6 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Study Population Destination: subsection.4.1 Item: Title: Definitions of Clinical Endpoints Destination: subsection.4.2 Item: Title: Selection of Polymorphisms Destination: subsection.4.3 Item: Title: Genotyping Destination: subsection.4.4 Item: Title: Immunohistochemistry Analysis Destination: subsection.4.5 Item: Title: Statistical Analysis Destination: subsection.4.6 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: CD274 (PD-L1) Polymorphisms as Predictors of Efficacy in First-Line Platinum-Based Chemotherapy for Extensive-Stage Small Cell Lung Cancer Author: Andrés Barba, Laura López-Vilaró, Malena Ferre, Sergio Martinez-Recio, Margarita Majem, Ivana Sullivan and Juliana Salazar Subject: The cornerstone of first-line treatment in extensive-stage small cell lung cancer (ES-SCLC) is platinum- and etoposide-based chemotherapy. Platinum compounds could immunomodulate the tumor microenvironment in addition to their cytotoxic effect. Genetic variation in immune checkpoint (IC) pathways may predict chemotherapy efficacy. Polymorphisms in the IC genes were determined, and their association with survival was analyzed in 78 patients with ES-SCLC treated with chemotherapy. PD-L1 protein expression in tumor tissue was determined. Three variants in CD274 were associated with better median progression-free survival (mPFS): rs2297136 (hazard ratio [HR] 0.52, 95% CI 0.29 0.93; p = 0.03), rs2282055 (HR 0.23, 95% CI 0.09 0.64; p = 0.005), and rs822336 (HR 0.41, 95% CI 0.23 0.73; p = 0.002). CTLA4 rs231775 was also associated with mPFS (HR 0.30, 95% CI 0.14 0.63; p = 0.002). The variants CD274 rs2297136 and CD274 rs822336 were associated with platinum sensitivity (odds ratio [OR] 0.13, 95% CI 0.02 0.70; p = 0.02, and OR 0.08, 95% CI 0.01 0.46; p = 0.005, respectively). CD274 rs2297136 was also associated with better overall survival (p = 0.02), but not after adjustment for covariates. No association was found between CD274 germline variants and PD-L1 tumor expression. Our results suggest that CD274 and CTLA4 variants may be predictive biomarkers for platinum plus etoposide treatment in ES-SCLC. 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