Variants inCDAandABCB1are predictors of capecitabine-related adverse reactions in colorectal cancer

Abstract

Adverse reactions to capecitabine-based chemotherapy limit full administration of cytotoxic agents. Likewise, genetic variations associated with capecitabine-related adverse reactions are associated with controversial results and a low predictive value. Thus, more evidence on the role of these variations is needed. We evaluated the association between nine polymorphisms in MTHFR, CDA, TYMS, ABCB1, and ENOSF1 and adverse reactions, dose reductions, treatment delays, and overall toxicity in 239 colorectal cancer patients treated with capecitabine-based regimens. The ABCB1*1 haplotype was associated with a high risk of delay in administration or reduction in the dose of capecitabine, diarrhea, and overall toxicity. CDA rs2072671 A was associated with a high risk of overall toxicity. TYMS rs45445694 was associated with a high risk of delay in administration or reduction in the dose of capecitabine, HFS >1 and HFS >2. Finally, ENOSF1 rs2612091 was associated with HFS >1, but was a poorer predictor than TYMS rs45445694. A score based on ABCB1-CDA polymorphisms efficiently predicts patients at high risk of severe overall toxicity (PPV, 54%; sensitivity, 43%) in colorectal cancer patients treated with regimens containing capecitabine. Polymorphisms in ABCB1, CDA, ENOSF1,and TYMS could help to predict specific and overall severe adverse reactions to capecitabine.

A phase II study of preoperative chemoradiation with tegafur-uracil plus leucovorin for locally advanced rectal cancer with pharmacogenetic analysis

“…Although fluoropyrimidines are not a known substrate of ABCB1, ABCB1 expression is induced along with 5-FU resistance in some cell lines [28], which suggests polymorphisms concerning ABCB1 activity might be related to efficacy of fluoropyrimidines. Otherwise, ABCB1 haplotype*1 was reportedly associated with capecitabine toxicity compared to variant haplotypes [29]. However, a significant relationship between ABCB1 polymorphisms and clinical outcome was not observed in this study.…”

What Do We Learn from Spheroid Culture Systems? Insights from Tumorspheres Derived from Primary Colon Cancer Tissue

“…Recently, CDA was identified as a regulator of cell proliferation and chemoresistance in breast and pancreatic cancer [ 52 , 53 ]. In CRC genomic variations of CDA are associated with adverse drug response [ 63 ]. Most importantly, high expression of CDA was found in blood from CRC patients [ 64 ], hinting to a potential use of CDA as a diagnostic marker.…”

Single Nucleotide Polymorphisms as Biomarkers for Drug Response and Toxicity in the Management of Colorectal Cancer

“…A study by Caronia et al genotyped 130 breast and colorectal cancer patients and found that two variants in the promoter of CDA gene rs532545 (-451 C>T) & rs3215400 (-31 del C) are in linkage disequilibrium are strongly associated with the development capecitabine induced HFS [16]. In another study conducted by Gracia [17].…”