Abstract P3-15-04: A French prospective pilot study to identify dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients receiving capecitabine

Abstract

Abstract Background: Health Authorities point out that DPD deficiency confers a significant risk of major toxicity for patients receiving capecitabine. Identification of at-risk patients is thus of major concern. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping to predict severe cap-related toxixity in metastatic breast cancer patients. Methods: 303 patients were included between February 2009 and February 2011 (15 institutions). Eighty-eight% received capecitabine as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment uracil (U, physiological DPD substrate) plasma concentration was measured in 286 patients (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was performed on 281 patients. Severe toxicity (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 toxicity (diarrhea, vomiting, hematoxicity, hand-foot syndrome) has been observed in 19.6% of patients (one toxic death). A marked trend for higher U concentrations has been noted in patients developing severe toxicity vs those who didn't (median 12.7 ng/ml (Q1-Q3 9-17) vs median 10.2 ng/ml (range 8-13), respectively, p = 0.014). However, ROC curve has showed that this difference was too small for use as a reliable toxicity predictor. The patient with toxic death had an elevated U concentration at 17 ng/ml. Among the 7 patients with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe toxicity (including the toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe toxicity was 4.60 in mutated patients vs wild-type patients (95%CI 2.95-7.16, p = 0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: Breast cancer patients harbouring a DPD variant allele are at risk to develop severe, up to lethal, capecitabine-related toxicity. Pre-treatment U measurement remains to be more firmly established as a reliable predictor of capecitabine toxicity. These observations are of major interest for breast cancer patients candidate for capecitabine therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-04.