Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

Y J He; S J Winham; J M Hoskins; S Glass; J Paul; R Brown; A Motsinger-Reif; H L McLeod

doi:10.1038/tpj.2015.52

Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

Pharmacogenomics J. 2016 Jun;16(3):243-8. doi: 10.1038/tpj.2015.52. Epub 2015 Jul 21.

Authors

Y J He^{1

2

3

4}, S J Winham^{5

6}, J M Hoskins³, S Glass³, J Paul⁷, R Brown⁸, A Motsinger-Reif⁵, H L McLeod^{1

2

3

4}

Affiliations

¹ Department of Clinical Pharmacology, Xiang-Ya Hospital, Central South University, Changsha, China.
² Pharmacogenetics Research institute, Central South University, Changsha, China.
³ Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA.
⁴ Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
⁵ Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
⁶ Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁷ Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
⁸ Department of Surgery and Cancer, Imperial College London, London, UK.

PMID: 26194361
DOI: 10.1038/tpj.2015.52

Abstract

Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics
Antineoplastic Combined Chemotherapy Protocols / adverse effects*
Carboplatin / adverse effects*
Cation Transport Proteins / genetics
Copper-Transporting ATPases
Docetaxel
Female
Gastrointestinal Diseases / chemically induced*
Gastrointestinal Diseases / diagnosis
Gastrointestinal Diseases / genetics*
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Kaplan-Meier Estimate
NAV1.8 Voltage-Gated Sodium Channel / genetics
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / mortality
Pharmacogenetics*
Pharmacogenomic Variants / genetics*
Phenotype
Polymorphism, Single Nucleotide*
Proportional Hazards Models
Risk Factors
Scotland
Severity of Illness Index
Taxoids / adverse effects*
Time Factors
Treatment Outcome
Vascular Endothelial Growth Factor A / genetics

Substances

Cation Transport Proteins
NAV1.8 Voltage-Gated Sodium Channel
SCN10A protein, human
Taxoids
VEGFA protein, human
Vascular Endothelial Growth Factor A
Docetaxel
Carboplatin
Adenosine Triphosphatases
ATP7B protein, human
Copper-Transporting ATPases

Abstract

Publication types

MeSH terms

Substances

Grants and funding