1. Genetic variability in drug transport, metabolism or DNA repair affecting toxicity of chemotherapy in ovarian cancer.
- Author
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Lambrechts S, Lambrechts D, Despierre E, Van Nieuwenhuysen E, Smeets D, Debruyne PR, Renard V, Vroman P, Luyten D, Neven P, Amant F, Leunen K, and Vergote I
- Subjects
- Adult, Aged, Aged, 80 and over, Anemia chemically induced, Anemia genetics, Carboplatin administration & dosage, Colony-Stimulating Factors adverse effects, Female, Genotype, Hematinics adverse effects, Humans, Middle Aged, Multidrug Resistance-Associated Protein 2, Neurotoxicity Syndromes genetics, Ovarian Neoplasms metabolism, Paclitaxel administration & dosage, Polymorphism, Single Nucleotide genetics, Thrombocytopenia chemically induced, Thrombocytopenia genetics, Young Adult, Carboplatin adverse effects, Carrier Proteins genetics, DNA Repair genetics, Inactivation, Metabolic genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Paclitaxel adverse effects
- Abstract
Background: This study aimed to determine whether single nucleotide polymorphisms (SNPs) in genes involved in DNA repair or metabolism of taxanes or platinum could predict toxicity or response to first-line chemotherapy in ovarian cancer., Methods: Twenty-six selected SNPs in 18 genes were genotyped in 322 patients treated with first-line paclitaxel-carboplatin or carboplatin mono-therapy. Genotypes were correlated with toxicity events (anemia, neutropenia, thrombocytopenia, febrile neutropenia, neurotoxicity), use of growth factors and survival., Results: The risk of anemia was increased for variant alleles of rs1128503 (ABCB1, C > T; p = 0.023, OR = 1.71, 95% CI = 1.07-2.71), rs363717 (ABCA1, A > G; p = 0.002, OR = 2.08, 95% CI = 1.32-3.27) and rs11615 (ERCC1, T > C; p = 0.031, OR = 1.61, 95% CI = 1.04-2.50), while it was decreased for variant alleles of rs12762549 (ABCC2, C > G; p = 0.004, OR = 0.51, 95% CI = 0.33-0.81). Likewise, increased risk of thrombocytopenia was associated with rs4986910 (CYP3A4, T > C; p = 0.025, OR = 4.99, 95% CI = 1.22-20.31). No significant correlations were found for neurotoxicity. Variant alleles of rs2073337 (ABCC2, A > G; p = 0.039, OR = 0.60, 95% CI = 0.37-0.98), rs1695 (ABCC1, A > G; p = 0.017, OR = 0.55, 95% CI 0.33-0.90) and rs1799793 (ERCC2, G > A; p = 0.042, OR = 0.63, 95% CI 0.41-0.98) associated with the use of colony stimulating factors (CSF), while rs2074087 (ABCC1, G > C; p = 0.011, OR = 2.09, 95% CI 1.18-3.68) correlated with use of erythropoiesis stimulating agents (ESAs). Homozygous carriers of the rs1799793 (ERCC2, G > A) G-allele had a prolonged platinum-free interval (p = 0.016)., Conclusions: Our data reveal significant correlations between genetic variants of transport, hepatic metabolism, platinum related detoxification or DNA damage repair and toxicity or outcome in ovarian cancer.
- Published
- 2015
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