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.
Highlights
Capecitabine is an oral fluoropyrimidine that delivers 5-fluorouracil (5-FU) to the tumor [1]. Both alone and in combination with other chemotherapeutic and biological agents, capecitabine is increasingly used in adjuvant and metastatic settings because it is easier to administer and has a more favorable toxicity profile than 5-FU [1]. Since their discovery in 1957, fluoropyrimidines have been the mainstay of treatment of colorectal cancer (CRC), a major cause of morbidity in developed countries [2]. 5-FU acts by inhibiting thymidylate synthase (TYMS)
We demonstrated that functional genetic variants in TYMS, ENOSF1, and ABCB1 were associated with severe toxicity
The genetic polymorphisms rs34489327 and rs45445694 in TYMS have been studied extensively to determine the patient’s response to fluoropyrimidinebased chemotherapy, fewer studies have focused on their association with toxicity. In this cohort of capecitabine treated CRC patients we found a correlation between the TYMS polymorphism rs45445694 and hand-foot syndrome (HFS)
Summary
Capecitabine is an oral fluoropyrimidine that delivers 5-fluorouracil (5-FU) to the tumor [1] Both alone and in combination with other chemotherapeutic and biological agents, capecitabine is increasingly used in adjuvant and metastatic settings because it is easier to administer and has a more favorable toxicity profile than 5-FU [1]. Capecitabine-treated patients commonly experience severe, even fatal, adverse drug reactions (ADRs) at some point during their treatment. These reactions often lead to dose reductions, delays in administration, and discontinuation of treatment [4, 5]. We performed a prospective/retrospective study of a cohort of CRC patients treated with capecitabinecontaining regimens in order to evaluate possible associations between severe ADRs to capecitabine and genomic variations in CDA, ABCB1, ENOSF1, TYMS, and MTHFR
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