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ABCB1 Variation Affects Myelosuppression, Progression-free Survival and Overall Survival in Paclitaxel/Carboplatin-treated Ovarian Cancer Patients
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-4450-0333
Leuven Canc Inst, Belgium.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
2018 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 3, p. 277-287Article in journal (Refereed) Published
Abstract [en]

The standard chemotherapy for ovarian cancer is paclitaxel/carboplatin. Patients often exhibit myelosuppressive toxicity, and the treatment response varies considerably. In this study, we investigated the previously reported SNPs 1199Gamp;gt;A (rs2229109), 1236Camp;gt;T (rs1128503), 2677Gamp;gt;T/A (rs2032582), 3435Camp;gt;T (rs1045642) in ABCB1, and 1196Aamp;gt;G (rs10509681) in CYP2C8 and their association with treatment-induced myelosuppression, progression-free survival (PFS) and overall survival (OS). From the phase III study, OAS-07OVA, 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n=260) or Taxol((R)) (Arm B, n=265) were included and genotyped using pyrosequencing. Genotype associations with myelosuppression, PFS and OS were investigated using anova, Kaplan-Meier analysis and Cox proportional hazard models. The most prominent finding was for the ABCB1 variant 3435TT, which was significantly associated with increased PFS in All (hazard ratio (HR) = 0.623), in Arm A (HR=0.590) and in Arm B (HR=0.627), as well as increased OS in All (HR=0.443) and in Arm A (HR=0.372) compared to the wild-type, 3435CC. For toxicity, the most interesting finding concerned the haplotype, including 1236TT, 2677TT and 3435TT, which was associated with higher neutrophil values in Arm B (p=0.039) and less neutrophil decrease in All (p=0.048) and in Arm B (p=0.021). It is noteworthy that the results varied depending on the treatment arm which indicates that the effects of ABCB1 variants vary with the treatment regimen. Our results reflect the contradictory results of previous studies, confirming that small variations in the composition of treatment regimens and patient populations may influence the interpretation of SNPs effects on treatment outcome.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 123, no 3, p. 277-287
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:liu:diva-150852DOI: 10.1111/bcpt.12997ISI: 000441237300009PubMedID: 29504705OAI: oai:DiVA.org:liu-150852DiVA, id: diva2:1245913
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; ALF grants Region Ostergotland; Oasmia Pharmaceuticals AB, Uppsala, Sweden

Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-26

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