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ABCB 1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients
Author(s) -
Björn Niclas,
Jakobsen Falk Ingrid,
Vergote Ignace,
Gréen Henrik
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12997
Subject(s) - paclitaxel , carboplatin , medicine , ovarian cancer , hazard ratio , oncology , progression free survival , proportional hazards model , chemotherapy , pharmacology , cancer , cisplatin , confidence interval
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 SNP s 1199G>A (rs2229109), 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642) in ABCB 1 , and 1196A>G (rs10509681) in CYP 2C8 and their association with treatment‐induced myelosuppression, progression‐free survival ( PFS ) and overall survival ( OS ). From the phase III study, OAS ‐07 OVA , 525 patients (All) treated with carboplatin and paclitaxel administered as Paclical (Arm A, n = 260) or Taxol ® (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 ABCB 1 variant 3435 TT , 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, 3435 CC . For toxicity, the most interesting finding concerned the haplotype, including 1236 TT , 2677 TT and 3435 TT , 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 ABCB 1 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 SNP s effects on treatment outcome.