Variants in<i>CDA</i>and<i>ABCB1</i>are predictors of capecitabine-related adverse reactions in colorectal cancer

Abstract

// Xandra Garc&iacute;a-Gonz&aacute;lez 1,* , Luc&iacute;a Cortejoso 1,* , Mar&iacute;a I. Garc&iacute;a 1 , Pilar Garc&iacute;a-Alfonso 2 , Luis Robles 3 , Cristina Gr&aacute;valos 3 , Eva Gonz&aacute;lez-Haba 1 , Pellicer Marta 1 , Mar&iacute;a Sanjurjo 1 and Luis A. L&oacute;pez-Fern&aacute;ndez 1 1 Department of Pharmacy, Hospital General Universitario Gregorio Mara&ntilde;&oacute;n, Instituto de Investigaci&oacute;n Sanitaria Gregorio Mara&ntilde;&oacute;n, Madrid, Spain 2 Department of Medical Oncology, Hospital General Universitario Gregorio Mara&ntilde;&oacute;n, Instituto de Investigaci&oacute;n Sanitaria Gregorio Mara&ntilde;&oacute;n, Madrid, Spain 3 Department of Medical Oncology, Hospital Universitario Doce de Octubre, Instituto de Investigaci&oacute;n Sanitaria Doce de Octubre, Madrid, Spain * These authors contributed equally to the manuscript Correspondence: Luis A. L&oacute;pez-Fern&aacute;ndez, email: // Keywords : Flouropyrimidine, toxicity, chemotherapy, genetics Received : October 14, 2014 Accepted : January 02, 2015 Published : January 21, 2015 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 &gt;1 and HFS &gt;2. Finally, ENOSF1 rs2612091 was associated with HFS &gt;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.