ebf416de0580bb10b95baa8b90bbab70 308684.pdf 02200a9a10b316350ef30f0baa0ccd4d95967846 308684.pdf cf71775f9da80b988366ff5cd706f8fdd22e9ec3dfe64eaff06b73437870a918 308684.pdf Title: Pharmacogenetics of Neoadjuvant MAP Chemotherapy in Localized Osteosarcoma: A Study Based on Data from the GEIS-33 Protocol Subject: Background: Osteosarcoma is a rare disease, but it is the most frequent malignant bone tumor. Primary treatment consists of preoperative MAP (methotrexate (MTX), doxorubicin and cisplatin) chemotherapy followed by surgery and adjuvant chemotherapy. Pathological response to preoperative chemotherapy is one of the most important prognostic factors, but molecular biomarkers are lacking. Additionally, chemotherapy-induced toxicity might jeopardize treatment completion. We evaluated variants in genes involved in DNA repair and drug metabolism pathways as predictors of response to MAP-based treatment. Material and Methods: Germline polymorphisms in MTHFR, SLC19A1, ABCB1, ABCC2, ABCC3, ERCC1, ERCC2 and GSTP1 genes were determined for association studies in 69 patients diagnosed with localized osteosarcoma who enrolled in the prospective GEIS-33 trial. P-glycoprotein expression in tumor tissue was also analyzed. Results: In the multivariate analysis, the ABCC2 rs2273697 (odds ratio [OR] 12.3, 95% CI 2.3–66.2; p = 0.003) and ERCC2 rs1799793 (OR 9.6, 95% CI 2.1–43.2; p = 0.003) variants were associated with poor pathological response. P-glycoprotein expression did not correlate with pathological response. The ABCB1 rs1128503 (OR 11.4, 95% CI 2.2–58.0; p = 0.003) and ABCC3 rs4793665 (OR 12.0, 95% CI 2.1–70.2; p = 0.006) variants were associated with MTX grade 3–4 hepatotoxicity. Conclusions: Our findings add to the evidence that genetic variants in the ABC transporters and DNA-repair genes may serve as predictive biomarkers for MAP chemotherapy and contribute to treatment personalization. Keywords: osteosarcoma; neoadjuvant chemotherapy; pharmacogenomics; personalized medicine Author: Juliana Salazar, María J. Arranz, Javier Martin-Broto, Francisco Bautista, Jerónimo Martínez-García, Javier Martínez-Trufero, Yolanda Vidal-Insua, Aizpea Echebarria-Barona, Roberto Díaz-Beveridge, Claudia Valverde, Pablo Luna, María A. Vaz-Salgado, Pilar Blay, Rosa Álvarez and Ana Sebio Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Thu Dec 12 12:39:54 2024 CET ModDate: Thu Dec 12 12:43:39 2024 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 450949 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- QGYAWM+SFRM0800 Type 1 Custom yes yes yes 10 0 OPETZR+VnURWPalladioL-Bold Type 1 Custom yes yes yes 16 0 ZNCICL+URWPalladioL-Bold Type 1 Custom yes yes yes 22 0 DBZLJZ+URWPalladioL-Roma Type 1 Custom yes yes yes 28 0 EAOZPM+URWPalladioL-Ital Type 1 Custom yes yes yes 33 0 YQOTQA+VnURWPalladioL Type 1 Custom yes yes yes 38 0 IKKWKP+CMSY10 Type 1 Builtin yes yes yes 68 0 OVNEXW+EURM10 Type 1 Builtin yes yes yes 82 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 90 0 PNKDLI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 108 0 PNKDLK+PalatinoLinotype TrueType WinAnsi yes yes no 111 0 PNKDLM+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 114 0 PNKFCE+PalatinoLinotype TrueType MacRoman yes yes no 117 0 PNKIFD+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 120 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-03-07 02:43:17 CET RepresentationInformation: 308684.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-03-06 19:17:54 CET Size: 450949 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 308 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 Design Destination: subsection.2.1 Item: Title: Patients’ Characteristics Destination: subsection.2.2 Item: Title: Outcome Measures Destination: subsection.2.3 Item: Title: SNPs Selection and Genotyping Destination: subsection.2.4 Item: Title: Immunohistochemical Studies Destination: subsection.2.5 Item: Title: Statistical Analysis Destination: subsection.2.6 Item: Title: Results Destination: section.3 Children: Item: Title: Clinical Results Destination: subsection.3.1 Item: Title: P-Glycoprotein Expression and ABCB1 Genetic Variants Destination: subsection.3.2 Item: Title: Association Analyses and Pathological Response Destination: subsection.3.3 Item: Title: Association Analyses and Toxicity Destination: subsection.3.4 Item: Title: Survival Analyses Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: Pharmacogenetics of Neoadjuvant MAP Chemotherapy in Localized Osteosarcoma: A Study Based on Data from the GEIS-33 Protocol Author: Juliana Salazar, María J. Arranz, Javier Martin-Broto, Francisco Bautista, Jerónimo Martínez-García, Javier Martínez-Trufero, Yolanda Vidal-Insua, Aizpea Echebarria-Barona, Roberto Díaz-Beveridge, Claudia Valverde, Pablo Luna, María A. Vaz-Salgado, Pilar Blay, Rosa Álvarez and Ana Sebio Subject: Background: Osteosarcoma is a rare disease, but it is the most frequent malignant bone tumor. Primary treatment consists of preoperative MAP (methotrexate (MTX), doxorubicin and cisplatin) chemotherapy followed by surgery and adjuvant chemotherapy. Pathological response to preoperative chemotherapy is one of the most important prognostic factors, but molecular biomarkers are lacking. Additionally, chemotherapy-induced toxicity might jeopardize treatment completion. We evaluated variants in genes involved in DNA repair and drug metabolism pathways as predictors of response to MAP-based treatment. Material and Methods: Germline polymorphisms in MTHFR, SLC19A1, ABCB1, ABCC2, ABCC3, ERCC1, ERCC2 and GSTP1 genes were determined for association studies in 69 patients diagnosed with localized osteosarcoma who enrolled in the prospective GEIS-33 trial. P-glycoprotein expression in tumor tissue was also analyzed. Results: In the multivariate analysis, the ABCC2 rs2273697 (odds ratio [OR] 12.3, 95% CI 2.3 66.2; p = 0.003) and ERCC2 rs1799793 (OR 9.6, 95% CI 2.1 43.2; p = 0.003) variants were associated with poor pathological response. P-glycoprotein expression did not correlate with pathological response. The ABCB1 rs1128503 (OR 11.4, 95% CI 2.2 58.0; p = 0.003) and ABCC3 rs4793665 (OR 12.0, 95% CI 2.1 70.2; p = 0.006) variants were associated with MTX grade 3 4 hepatotoxicity. Conclusions: Our findings add to the evidence that genetic variants in the ABC transporters and DNA-repair genes may serve as predictive biomarkers for MAP chemotherapy and contribute to treatment personalization. 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