e41617995f252628b3a86eeea8bfde45 308585.pdf befb93d9dbd83f8b49b17e050f209f75ddcccb82 308585.pdf 8a729575f7556ad9a744fa91774d99b5c9fb57f7acbc0d54a76c7bb3127796fc 308585.pdf Title: ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer Subject: Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38–7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09–17.55] months versus negative expression 13.3 [95% CI 7.32–19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08–9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed. Keywords: ERCC1; ERCC2; platinum-based chemotherapy; small cell lung cancer; pharmacogenomics Author: Andrés Barba, Laura López-Vilaró, Malena Ferre, Margarita Majem, Sergio Martinez-Recio, Olga Bell, María J. Arranz, Juliana Salazar and Ivana Sullivan Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sun Aug 25 13:47:09 2024 CEST ModDate: Sun Aug 25 13:50:11 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2680057 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- XWOCXD+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 TBHVUG+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 WPFBKA+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 IOATCD+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 IBQLYZ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 GMVGFY+CMSY10 Type 1 Builtin yes yes yes 37 0 QWUCUL+VnURWPalladioL Type 1 Custom yes yes yes 42 0 IAFAOG+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 59 0 ZXDKIP+EURM10 Type 1 Builtin yes yes yes 88 0 PHIOID+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 106 0 PHIOIE+PalatinoLinotype CID TrueType Identity-H yes yes yes 109 0 PHIOIF+PalatinoLinotype TrueType WinAnsi yes yes no 115 0 PHIOIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 118 0 PHIPCG+PalatinoLinotype TrueType MacRoman yes yes no 121 0 PHIOID+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 139 0 PHIOIE+PalatinoLinotype CID TrueType Identity-H yes yes yes 142 0 PHIOIF+PalatinoLinotype TrueType WinAnsi yes yes no 148 0 PHIOIH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 151 0 PHIPCG+PalatinoLinotype TrueType MacRoman yes yes no 154 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-02-28 02:42:39 CET RepresentationInformation: 308585.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-02-27 13:52:15 CET Size: 2680057 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 402 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Study Sample Destination: subsection.2.1 Item: Title: Clinical Assessment Destination: subsection.2.2 Item: Title: SNPs Selection and Genotyping Destination: subsection.2.3 Item: Title: Immunohistochemical Studies Destination: subsection.2.4 Item: Title: Proximity Ligation Assay (PLA) Destination: subsection.2.5 Item: Title: Statistics Destination: subsection.2.6 Item: Title: Results Destination: section.3 Children: Item: Title: Clinical Results Destination: subsection.3.1 Item: Title: Survival and Objective Response Rate Analyses Destination: subsection.3.2 Children: Item: Title: Analyses of Genetic Variants Destination: subsubsection.3.2.1 Item: Title: Analyses of ERCC1 and ERCC1-XPF Complex Expression Destination: subsubsection.3.2.2 Item: Title: Safety Analyses Destination: subsection.3.3 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer Author: Andrés Barba, Laura López-Vilaró, Malena Ferre, Margarita Majem, Sergio Martinez-Recio, Olga Bell, María J. Arranz, Juliana Salazar and Ivana Sullivan Subject: Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38 7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09 17.55] months versus negative expression 13.3 [95% CI 7.32 19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08 9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed. 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