Snps and Taxane Toxicity in Breast Cancer Patients

Bosó, Virginia; Herrero, Marí­a José; Santaballa, Ana; Palomar, Laura; Megías, Juan Eduardo; Cueva, Helena de la; Rojas, Luis; Marqués, María Remedios; Poveda, José Luís; Montalar, Joaquín; Aliño, Salvador F.

doi:10.2217/pgs.14.127

Cited by 42 publications

(53 citation statements)

References 47 publications

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“…26 Pharmacogenomic variations between these groups of patients with respect to treatment response and toxic effects may partially explain these differences in outcome. 27,28 …”

Section: Discussionmentioning

confidence: 99%

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

et al. 2016

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BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P = 0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P = 0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P = 0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P = 0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.)

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“…26 Pharmacogenomic variations between these groups of patients with respect to treatment response and toxic effects may partially explain these differences in outcome. 27,28 …”

Section: Discussionmentioning

confidence: 99%

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

et al. 2016

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“…To suppress the growth of tumour, docetaxel inhibits cell division by disrupting the physiological assembly and disassembly of microtubules . However, the usage of docetaxel in cancer therapy often induces adverse drug reactions (ADRs), such as peripheral neuropathy, gastrointestinal toxicity and myelosuppression . Myelosuppression is one major reason of patients' early withdrawal from docetaxel‐based cancer treatment .…”

Section: What Is Known and Objectivementioning

confidence: 99%

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

et al. 2019

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What is known and objective Myelosuppression, an adverse drug reaction (ADR), often causes medical treatment termination in cancer patients. It has been known that genetic components, such as single‐nucleotide polymorphisms (SNPs), influence the risk of myelosuppression at the individual‐patient level. However, due to ethnic variation in frequency of genetic polymorphisms, results reported in Caucasian patients may not be generalizable to the Chinese Han population. Until now, few researches on myelosuppression included Chinese Han patients. In this study, we conducted a systematic study of potential biomarkers for docetaxel‐induced myelosuppression in Han Chinese patients. Methods We examined 61 SNPs in 36 genes that code for drug transporters, metabolism enzymes, nuclear receptors and DNA repair pathway in 110 Chinese Han patients receiving docetaxel‐based chemotherapy. Genotyping was conducted using the Sequenom MassARRAY system. Significant SNPs were identified by logistic regression, and gene‐gene interactions were investigated by generalized multifactor dimensionality reduction (GMDR) analysis. Results and discussion Our results revealed that 11 SNPs in nine genes (SLC15A1, SLCO1A2, CYP2D6, FMO3, UGT1A1, NAT2, SULT2A1, PXR and HNF4α) were associated with docetaxel‐induced myelosuppression. GMDR analyses suggested that a 3‐locus model: SLC15A1 rs2297322—PXR rs3732359—FMO3 rs2266782 was an appropriate predictive model of docetaxel‐induced myelosuppression (P = .017, Testing Bal.Acc = 0.653, CV Consistency = 10/10). What is new and conclusion Our findings suggest multiple novel predictive biomarkers of docetaxel‐induced myelosuppression: SLC15A1 rs2297322, PXR rs3732359 and FMO3 rs2266782. These discoveries should help in advancing future personalized therapy of docetaxel‐based chemotherapy specific to Chinese Han patients.

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“…These studies have varied widely in size, disease setting, phenotype definition, and genotype methodology. (4-12) Here we investigated genetic biomarkers of TIPN in two large, adjuvant breast cancer trials that incorporated taxanes; ECOG-5103(13) and ECOG-1199. (14)…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199

Schneider

Radovich

et al. 2015

Clinical Cancer Research

122

130

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Purpose Taxane induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design We performed a genome wide association study (GWAS) in 3431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results When evaluating for Grade 3-4 TIPN, 120 SNPs had a p-value <10−4 from patients of European descent (EA) in ECOG-5103. 30 candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with Grade 3-4 TIPN (p=1.7×10−3; OR=1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of Grade 2-4 TIPN (HR=2.1; p=5.6×10−16) and Grade 3-4 TIPN (HR=2.6; p=1.1×10−11) compared with others. A SNP in FCAMR, rs1856746, had a trend toward an association with Grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR=5.5; p=1.6×10−7). Conclusion rs3125923 represents a validated SNP to predict Grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

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Snps and Taxane Toxicity in Breast Cancer Patients

Abstract: Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients.

Cited by 42 publications

References 47 publications

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

Genetic associations of docetaxel‐based chemotherapy‐induced myelosuppression in Chinese Han population

Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199

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