GSTP1 rs1695 is associated with both hematological toxicity and prognosis of ovarian cancer treated with paclitaxel plus carboplatin combination chemotherapy: a comprehensive analysis using targeted resequencing of 100 pharmacogenes.

Tomoko Yoshihama,Wataru Yamagami,Daisuke Aoki,Akira Hirasawa,Koya Fukunaga,Tomoko Akahane,Taisei Mushiroda,Hiroyuki Nomura,Fumio Kataoka

doi:10.18632/oncotarget.25712

Tomoko Yoshihama, Wataru Yamagami + Show 7 more

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https://doi.org/10.18632/oncotarget.25712

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Abstract

PurposeTo find genetic variants that predicted toxicity and/or efficacy of paclitaxel plus carboplatin combination therapy (TC therapy).Patients and methodsIn a retrospective case-control study, we analyzed 320 patients who had received TC therapy for gynecological cancers (ovarian, fallopian tube, peritoneal, uterine, and cervical cancers) and collected their germline DNA. We performed a comprehensive pharmacogenomic analysis using a targeted resequencing panel of 100 pharmacogenes. For 1,013 variants passing QC, case-control association studies and survival analyses were conducted.ResultsGSTP1 rs1695 showed the smallest p value for hematotoxicity association, and the 105Ile wild type allele had a significantly higher risk of severe hematotoxicity (neutropenia G4, thrombocytopenia ≥ G3 and anemia ≥ G3) than the 105Val allele (p=0.00034, odds ratio=5.71 (95% confidence interval:1.77-18.44)). Next, we assessed 5-year progression-free survival (PFS) and overall survival (OS) in 56 advanced ovarian cancer patients who received tri-weekly TC as a first-line chemotherapy. Patients with the 105Ile/105Ile genotype showed significantly better PFS (p=0.00070) and OS (p=0.0012) than those with the 105Ile/105Val or 105Val/105Val genotype.ConclusionOur study indicates that the GSTP1 rs1695 105Ile/105Ile genotype is associated with both severe hematotoxicity and high efficacy of TC therapy, identifying a possible prognostic indicator for patients with TC therapy.

Highlights

Paclitaxel plus carboplatin combination chemotherapy (TC therapy) is an important treatment for gynecological malignancies, including ovarian, peritoneal, fallopian tube, uterine, and cervical cancers
Our study indicates that the GSTP1 rs1695 105Ile/105Ile genotype is associated with both severe hematotoxicity and high efficacy of TC therapy, identifying a possible prognostic indicator for patients with TC therapy
Several candidate genes have been reported, such as efflux transporters of the ATP binding cassette (ABC) family, including ABCB1, ABCC2, and ABCG2 [6,7,8,9,10]; influx transporters of the solute carrier (SLC) family, including SLCO1B3 [8, 11]; members of the cytochrome p450 (CYP) family, including CYP3A4, CYP3A5, and CYP2C8 [12,13,14,15]; genes involved in detoxification, including GSTP1, GSTT1, and GSTM1 [16,17,18,19]; and genes involved in base-excision DNA repair, including ERCC1 and XRCC1 [19,20,21]

Summary

Introduction

Paclitaxel plus carboplatin combination chemotherapy (TC therapy) is an important treatment for gynecological malignancies, including ovarian, peritoneal, fallopian tube, uterine, and cervical cancers. Conventional antitumor drugs have a narrow therapeutic window, with a high frequency of www.oncotarget.com adverse drug reactions (ADRs). TC therapy is often associated with serious hematological toxicities, such as neutropenia, thrombocytopenia, and anemia [1, 2]. These toxicities can be a dose-limiting factor, potentially affecting patient quality of life. It is known that the severity or frequency of these adverse events varies between individuals clinically [5]. To date, no genetic factors have been established as useful biomarkers of toxicity or efficacy of TC therapy

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