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

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, Vergote I, Belgian and Luxembourg Gynaecological Oncology Group (BGO - BMC Pharmacol Toxicol (2015)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. sandrina.lambrechts@uzleuven.be.

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.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier curve for platinum-free interval correlated with polymorphisms of rs1799793 in ERCC2. Kaplan-Meier survival analysis reveales a significant advantage in PFI for GG cariers of rs1799793 compared to AA or GA carriers (p = 0.016).
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Fig1: Kaplan-Meier curve for platinum-free interval correlated with polymorphisms of rs1799793 in ERCC2. Kaplan-Meier survival analysis reveales a significant advantage in PFI for GG cariers of rs1799793 compared to AA or GA carriers (p = 0.016).

Mentions: The median follow-up of all patients participating to the study was 2.5 years (95% CI = 2.2-2.8 years) with 157 events for progression (59%) and 84 events for OS (31.6%). Uncorrected P-values were calculated using Cox regression analysis either adjusted for age at diagnosis only or fully adjusted for age at diagnosis, FIGO stage, tumor grade, tumor histology and residual disease after debulking surgery. Only one variant, rs1799793 (ERCC2 G > A), was significantly correlated with PFI in both cases (p = 0.003, HR = 0.71, 95% CI = 0.57-0.89, p = 0.016, HR = 0.75, 95% CI = 0.60-0.95). In particular, Kaplan-Meier survival analysis revealed a significant advantage in PFI for GG carriers of rs1799793 compared to AA or GA carriers (p = 0.016; Figure 1). Variants rs12762549 (ABCC2 A > G) and rs6104 (SERPINB2 C > G) were significantly associated with PFI in the fully-adjusted model (p = 0.037 and p = 0.040, respectively), but these associations were not statistically significant in model adjusted for age only (p = 0.402 and p = 0.219, respectively). No significant correlations were found for OS.Figure 1


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

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, Vergote I, Belgian and Luxembourg Gynaecological Oncology Group (BGO - BMC Pharmacol Toxicol (2015)

Kaplan-Meier curve for platinum-free interval correlated with polymorphisms of rs1799793 in ERCC2. Kaplan-Meier survival analysis reveales a significant advantage in PFI for GG cariers of rs1799793 compared to AA or GA carriers (p = 0.016).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359565&req=5

Fig1: Kaplan-Meier curve for platinum-free interval correlated with polymorphisms of rs1799793 in ERCC2. Kaplan-Meier survival analysis reveales a significant advantage in PFI for GG cariers of rs1799793 compared to AA or GA carriers (p = 0.016).
Mentions: The median follow-up of all patients participating to the study was 2.5 years (95% CI = 2.2-2.8 years) with 157 events for progression (59%) and 84 events for OS (31.6%). Uncorrected P-values were calculated using Cox regression analysis either adjusted for age at diagnosis only or fully adjusted for age at diagnosis, FIGO stage, tumor grade, tumor histology and residual disease after debulking surgery. Only one variant, rs1799793 (ERCC2 G > A), was significantly correlated with PFI in both cases (p = 0.003, HR = 0.71, 95% CI = 0.57-0.89, p = 0.016, HR = 0.75, 95% CI = 0.60-0.95). In particular, Kaplan-Meier survival analysis revealed a significant advantage in PFI for GG carriers of rs1799793 compared to AA or GA carriers (p = 0.016; Figure 1). Variants rs12762549 (ABCC2 A > G) and rs6104 (SERPINB2 C > G) were significantly associated with PFI in the fully-adjusted model (p = 0.037 and p = 0.040, respectively), but these associations were not statistically significant in model adjusted for age only (p = 0.402 and p = 0.219, respectively). No significant correlations were found for OS.Figure 1

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Division of Gynaecologic Oncology and Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Leuven, Belgium. sandrina.lambrechts@uzleuven.be.

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.

No MeSH data available.


Related in: MedlinePlus