ABCB1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients

Abstract

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 1199G>A (rs2229109), 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642) in ABCB1, and 1196A>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 (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.

Predictive value of two polymorphisms in ABCB1, rs1045642 and rs1128503, in prognosis following taxane-containing chemotherapy: A meta-analysis

“…Our study demonstrated the predictive value of ABCB1 C1236T for the PFS and OS in patients who were administered taxane-contained chemotherapy, which is consistent with the results reported by Bjorn et al [1] and Zhou et al [44]. The effect of genetic variation on prognosis may be related to mutations that cause changes in the encoded amino acids, affecting the normal function of certain drug transporters, such as decreased expression of P-gp.…”

“…Significant heterogeneities were found in the overall meta-analysis of the homozygote model (I 2 = 56%, P = 0.03) and dominant model (I 2 = 53%, P = 0.03). Sensitivity analyses showed that heterogeneity was decreased in the heterozygous model (I 2 = 30%, P = 0.21) after excluding the study by Li et al and in the dominant model (I 2 = 7%, P = 0.0.37) after excluding the study by Bjorn et al (Arm A) [1].…”

“…Clinical studies have shown that the toxicity and efficacy of taxane vary widely and exhibit inter-individual differences, leading to large variations in individual prognosis. An increasing number of studies have indicated that genetic factors such as single-nucleotide polymorphisms (SNPs) play an important role in individual differences in the prognosis of patients administered taxane-containing chemotherapy [1][2][3][4].…”

CHD1L contributes to cisplatin resistance by upregulating the ABCB1–NF-κB axis in human non-small-cell lung cancer

“…In recent years, numerous studies have shown that ABCB1 is widely expressed in human tumor cells at different stages 22 . The patients who suffer from tumors with high levels of ABCB1, including patients with colorectal cancer 23 , pancreatic cancer 24 , liver cancer 25 , adrenal cortex carcinoma 26 , acute leukemia 27 , and ovarian cancer 28 , are usually found to also have a poorer prognosis. It is also reported that ABCB1 has an important effect on absorption, distribution, metabolism, and excretion of its substrate drugs 29 .…”

GSTP1andABCB1Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel‐Based Chemotherapy in Ovarian Cancer

“…18,25,26 Similar to studies of GST polymorphisms, the associations of ABCB1 genetic variation with treatment outcomes is inconsistent across studies. 27,28 Patients developing severe toxicities often require dose reduction, dose delay, or treatment interruption that require clinical interventions and may affect the disease prognosis. 4 However, no study has been found so far focus on regarding the utility of polymorphisms in the management of chemotherapy and toxicities for ovarian cancer.…”