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Genetic variability in drug transport, metabolism or DNA repair affecting toxicity of chemotherapy in ovarian cancer.

ABSTRACT: 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.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.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).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.

SUBMITTER: Lambrechts S

PROVIDER: S-EPMC4359565 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic variability in drug transport, metabolism or DNA repair affecting toxicity of chemotherapy in ovarian cancer.

Lambrechts Sandrina S Lambrechts Diether D Despierre Evelyn E Van Nieuwenhuysen Els E Smeets Dominiek D Debruyne Philip R PR Renard Vincent V Vroman Philippe P Luyten Daisy D Neven Patrick P Amant Frédéric F Leunen Karin K Vergote Ignace I

BMC pharmacology & toxicology 20150227

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 25881102

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Project description:ObjectiveOur objective is to document progress in developing personalized therapy with fluoropyrimidine drugs (FPs) to improve outcomes for cancer patients and to identify areas requiring further investigation.BackgroundFPs including 5-fluorouracil (5-FU), are among the most widely used drugs for treating colorectal cancer (CRC) and other gastrointestinal (GI) malignancies. While FPs confer a survival benefit for CRC patients, serious systemic toxicities, including neutropenia, occur in ~30% of patients with lethality in 0.5-1% of patients. While serious systemic toxicities may occur in any patient, patients with polymorphisms in DPYD, which encodes the rate-limiting enzyme for pyrimidine degradation are at very high risk. Other genetic factors affecting risk for 5-FU toxicity, including miR-27a, are under investigation.MethodsLiterature used to inform the text of this article was selected from PubMed.gov from the National Library of Medicine while regulatory documents were identified via Google search.ConclusionsClinical studies to date have validated four DPYD polymorphisms (DPYD*2A, DPYD*13, c.2846A>T, HapB3) associated with serious toxicities in patients treated with 5-FU. Genetic screening for these is being implemented in the Netherlands and the UK and has been shown to be a cost-effective way to improve outcomes. Factors other than DPYD polymorphisms (e.g., miR-27a, TYMS, ENOSF1, p53) also affect 5-FU toxicity. Functional testing for deficient pyrimidine catabolism {defined as [U] >16 ng/mL or [UH2]:[U] <10} is being implemented in France and has demonstrated utility in identifying patients with elevated risk for 5-FU toxicity. Therapeutic drug monitoring (TDM) from plasma levels of 5-FU during first cycle treatment also is being used to improve outcomes and pharmacokinetic-based dosing is being used to increase the percent of patients within optimal area under the curve (AUC) (18-28 mg*h/L) values. Patients maintained in the optimal AUC range experienced significantly reduced systemic toxicities. As understanding the genetic basis for increased risk of 5-FU toxicity becomes more refined, the development of functional-based methods to optimize treatment is likely to become more widespread.

Project description:Compared with conventional intravenous platinum and taxane-based chemotherapy for ovarian cancer, both intraperitoneal chemotherapy and more frequent dose-dense intravenous chemotherapy have been associated with improved survival in some studies. We examined the utilization and toxicity of these three methods of chemotherapy delivery in women with ovarian cancer.We performed a population-based study and analyzed data on women with ovarian cancer who underwent primary surgery followed by platinum and taxane-based chemotherapy from 2009 to 2013 who were recorded in the MarketScan database. Adjuvant chemotherapy was classified as: intraperitoneal chemotherapy, dose-dense chemotherapy (weekly administration of chemotherapy), or standard chemotherapy (every 3 weeks). Hospitalizations and emergency department visits for chemotherapy-associated complications and costs were recorded and compared using ? tests.A total of 5,892 patients, including 4,135 (70.2%) who received standard chemotherapy, 859 (14.6%) who received intraperitoneal chemotherapy, and 898 (15.2%) treated with dose-dense chemotherapy, were identified. From 2009 to 2013, use of intraperitoneal chemotherapy remained constant (16.3-16.3%), whereas use of dose-dense therapy increased (8.7-18.1%) (P<.001). Hospitalizations for chemotherapy-associated complications occurred in 21.3% of women receiving standard chemotherapy, 34.7% of patients treated with intraperitoneal therapy, and in 25.2% of those receiving dose-dense treatment (P<.001); emergency department visits occurred in 18.3%, 26.3%, and 20.3%, respectively (P<.001). The largest differences in hospitalizations and emergency department visits were seen for gastrointestinal toxicities and electrolyte disorders. The per-patient costs of hospitalization were higher for intraperitoneal chemotherapy than other treatment modalities.Intraperitoneal chemotherapy was used in less than 15% of women with ovarian cancer, whereas use of dose-dense chemotherapy is increasing. Although we did not examine survival, intraperitoneal chemotherapy is significantly more toxic than the other methods of treatment.

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Genetic variability in drug transport, metabolism or DNA repair affecting toxicity of chemotherapy in ovarian cancer.

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Genetic variability in drug transport, metabolism or DNA repair affecting toxicity of chemotherapy in ovarian cancer.

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