An evaluation of the clinical utility of a panel of variants in DPYD and ENOSF1 for predicting common capecitabine related toxicities
Authors: C. Palles, S. Fotheringham, L. Chegwidden, M. Lucas, G. Mozolowski, I. Tomlinson, D. Kerr
Journal: Annals of Oncology (2018)

Introduction: 5-Flurouracil (5-FU) based adjuvant chemotherapy, including the 5-FU oral prodrug capecitabine, is commonly used as it is extremely effective in increasing survival of stage III colorectal cancer patients and patients with resectable gastric or breast cancer. Its use is however limited by the concomitant toxicities that arise in some patients. ∼ 50% of patients experience dose limiting toxicity when treated with capecitabine as a single agent and this percentage increases when given in combination e.g. with oxaliplatin. We have tested the diagnostic accuracy of a panel of toxicity associated/DPYD deficiency alleles at predicting patients risk of Capecitabine-related toxicity. Methods: Genetic markers were included if they met one of the following criteria: Minor allele frequency (MAF)< 1%, identified in patients with DPYD deficiency. 3 of these markers were also associated with toxicity at P < 0.05. MAF >1% and associated with global Capecitabine-related toxicity with an odds ratio > 1.5 at pathway level significance and associated with an individual toxicity at genome wide significance. DPYD genotype based dosing guidelines have been published. These were incorporated in a simple genotype guided risk classification system with the following grades: critical risk, high risk, standard risk and standard risk with high risk of hand foot syndrome (HFS). Dose reductions based on DPYD haplotype B3 have been recommended. Whilst this variant didn't meet inclusion criteria for the panel we have evaluated the clinical utility of including the variant. In order to test the clinical utility of the panel the markers selected were genotyped in 888 participants of the QUASAR2 trial for whom DNA and CTCAE graded toxicity data on gastrointestinal toxicities (Diarrhoea, Mucositis/Stomatitis, Vomiting), haematological toxicities (Neutropenia/Thrombocytopenia) and HFS were available. Results: 17 DPYD low function/no function alleles, 1 common (MAF>1%) polymorphism mapping to DPYD and one common polymorphism mapping to ENOSF1 were selected for inclusion in the panel. The test has high sensitivity and specificity when toxicity induced death or grade 4 haematological toxicities are the outcome of interest (100% sensitivity, 98% specificity, negative predictive value (NPV) 1.0, positive predictive value (PPV) 0.1 (death); 75% sensitivity, 98% specificity, NPV 1, PPV 0.14 (haematological toxicities). Two deaths occurred during QUASAR2 which were attributable to Capecitabine administration. Both patients would have been highlighted by the test as high risk and a 50% reduction in starting dose would have been recommended. Whilst the sensitivity and specificity of the common markers included to provide a measure of risk of HFS are only moderate (83% sensitivity, 31% specificity, NPV 0.87, PPV 0.25), explanation by an oncologist of ways to mitigate the impact of this side effect on quality of life may enable participants to continue with treatment for longer. Inclusion of HapB3 in the panel was not supported as evidenced by reduced area under the curve and reduced sensitivity/specificity. Conclusion: A panel of no function/low function DPYD alleles has clinical utility for the prediction of the most serious capecitabine related adverse events. Inclusion of two HFS associated markers may assist clinicians and patients in the management of this side effect.