Pharmacogenetics of Capecitabine in Advanced Breast Cancer Patients

Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism.Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS.Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR ¼ 2.02, 95% CI ¼ 1.02-3.99, P ¼ 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D 0 ¼ 0.92), which was more clearly associated with HFS (OR ¼ 0.51, 95% CI ¼ 0.27-0.95, P ¼ 0.028) in patients and with total CDD gene expression (P ¼ 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. Conclusions:The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS.

“…This SNP was not included in the analyses. Lethal outcome or high toxicity has been reported after treatment with 5-FU or capecitabine (8,16,18).…”

Section: Resultsmentioning

confidence: 99%

Section: -Fu Is Ts (Thymidylate Synthase) Finally 5-fu Is Catabolimentioning

confidence: 99%

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

Caronia

Martín

Sastre

et al. 2011

“…The presence of a G!C mutation in the E-box of the second repeat of the 3R allele was investigated (PCR-RFLP; ref. 16). This G!C mutation allows samples to be classified as a function of the number of functional E-box binding sites likely to bind USF proteins (class 2 = 2R2R or 2R3RC or 3RC3RC; class 3 = 2R3RG or 3RC3RG; class 4 = 3RG3RG).…”

Section: Methodsmentioning

confidence: 99%

K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy

Étienne-Grimaldi

Formento

Francoual

et al. 2008

Self Cite

137

Purpose: K-Ras mutations predict resistance to anti^epidermal growth factor receptor (EGFR) monoclonal antibodies. Because combinations of anti-EGFR with 5-fluorouracil (5-FU)-based chemotherapy are promising treatments, we analyzed the effect of K-Ras mutations in patients having received exclusive 5-FU therapy. Experimental Design:This study was conducted on 93 stage IV colorectal cancer patients with unresectable measurable liver metastasis receiving 5-FU-leucovorin (56 men and 37 women; 77 cancer deaths). Liver metastases (n = 93) along with primary tumors (n = 48) were analyzed for K-Ras mutations (codons 12 and 13), p53 mutations (exons 4-9), p53 polymorphism (codon 72), thymidylate synthase (TS) polymorphism (28-bp repeats including G>C mutation), methylenetetrahydrofolate reductase polymorphism (677C>T, 1298A>C), thymidylate synthase (TS) activity, dihydropyrimidine dehydrogenase activity, folylpolyglutamate synthase activity, and p53 protein expression. Results: Thirty-six of 93 (38.7%) metastases were K-Ras mutated (30 at codon 12 and 6 at codon 13). Mutated primary tumors (16 of 48) matched perfectly with mutated metastases. The additional analyzed tumor markers were not different between K-Ras mutated and wild-type tumors.The objective response rate was 37%: 44.4% in K-Ras mutated versus 32.1% in wild-type K-Ras metastasis (P = 0.27). Low TS activity in metastasis was the only significant predictor of tumor response (P = 0.047). K-Ras status did not influence specific survival. Conclusions: The present data indicate a perfect concordance of K-Ras mutations between primary and liver metastasis and suggest that any predictive and/or prognostic value of K-Ras mutations in treatments combining anti-EGFR monoclonal antibodies with 5-FU should be exclusively linked to the anti-EGFR agent.

“…In the TS enhancer region, varying copies of 28-bp tandem repeated sequences (TSER*2, TSER*3, TSER*4, and TSER*9) have been described that increase TS expression and portend a worse response (86). MTHFR polymorphisms, 677C>T and 1298A>C, are associated with low enzyme activity but did not correlate with capecitabine toxicities (87). Complete or partial DPD deficiency resulting in severe 5-FU toxicities occurs in approximately 0.1% and 3% to 5% of individuals, and at least 20 functional DYPD variants have been described, with the DYPD*2A splice site variant being the most common.…”

Section: Other Chemotherapy Agentsmentioning

confidence: 99%

Pharmacogenetics in Breast Cancer Therapy

Tan

Lee

Goh

et al. 2008

Interindividual and interethnic variability of drug pharmacokinetics and pharmacodynamics may be contributed by commonly occurring genetic polymorphisms of drug-metabolizing enzymes and transporters. Polymorphisms of CYP2D6 in particular have been associated with effects on tamoxifen disposition and clinical efficacy, with interethnic differences in distribution of functional alleles that affect metabolizer phenotype. Other tamoxifen-related genetic variants of CYP3A4, CYP3A5, and sulfotransferase1A1 (SULT1A1) are also briefly reviewed here. Polymorphisms of CYP19A1 (aromatase gene) have been reported to correlate with clinical outcomes from aromatase inhibitors in small studies but require further confirmation. Many studies on chemotherapy are based on hypothesis-generating association studies and need to be validated through larger-scale cooperative group studies. For anthracyclines, polymorphisms in genes such as carbonyl reductase 3 (CBR3), ATP-binding cassette subfamily B, member 1 (ABCB1), glutathione-related transporter genes, and oxidative stress^related genes have been reported to correlate with clinical outcomes. The pharmacogenetics of taxanes has been extensively investigated, but associations of genetic polymorphisms in drug-metabolizing enzymes and transporters reported in earlier small studies have not been validated in a recent large clinical trial. Allelic variants associated with gemcitabine, capecitabine/5-fluorouracil, vinorelbine, and platinum disposition are reviewed. No pharmacogenetic studies have been published for targeted agents thus far, although several potential candidate genes warrant investigation. Future pharmacogenetic studies will need to focus on integration of multiple drug pathways to allow a more comprehensive analysis of genetic factors influencing drug efficacy and toxicity.