DPD status and fluoropyrimidines-based treatment: high activity matters too
Open Access
- 18 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 20 (1), 1-9
- https://doi.org/10.1186/s12885-020-06907-0
Abstract
Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution. Lymphocytic DPD activity was assessed in a group of 136 patients receiving FP-based chemotherapy from 2004 to 2016. There were 105 digestive (77.2%), 24 breast (17.6%) and 7 head and neck cancers (5.2%). Cox or logistic regression models were applied with adjustment on all confounding factors that could modify OS, PFS or response. All models were stratified on the three cancer locations. A cut-off for DPD activity was assessed graphically and analytically. An optimal cut-off for DPD activity at 0.30 nmol/min/mg protein was identified as the best value for discriminating survivals and response. In multivariate analysis, individual lymphocytic DPD activity was significantly related to overall survival (p = 0.013; HR: 3.35 CI95%[1.27–8.86]), progression-free survival (p < 0.001; HR: 3.15 CI95%[1.75–5.66]) and response rate (p = 0.033; HR: 0.33 CI95%[0.12–0.92]) with a marked detrimental effect associated with high DPD activity. DPD status screening should result in a two-pronged approach with FP dose reduction in case of low intrinsic DPD and, inversely, an increased FP dose for high intrinsic DPD. In a context of personalized FP-based treatment, this innovative strategy needs to be prospectively validated.Keywords
This publication has 30 references indexed in Scilit:
- Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic studyBritish Journal of Cancer, 2014
- Comparative Functional Analysis of DPYD Variants of Potential Clinical Relevance to Dihydropyrimidine Dehydrogenase ActivityCancer Research, 2014
- microRNAs miR-27a and miR-27b Directly Regulate Liver Dihydropyrimidine Dehydrogenase Expression through Two Conserved Binding SitesMolecular Cancer Therapeutics, 2014
- Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5‐fluorouracil–based chemotherapyCancer, 2011
- DNA Mismatch Repair Status and Colon Cancer Recurrence and Survival in Clinical Trials of 5-Fluorouracil-Based Adjuvant TherapyJNCI Journal of the National Cancer Institute, 2011
- Individual Fluorouracil Dose Adjustment Based on Pharmacokinetic Follow-Up Compared With Conventional Dosage: Results of a Multicenter Randomized Trial of Patients With Metastatic Colorectal CancerJournal of Clinical Oncology, 2008
- Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracilEuropean Journal of Cancer, 2004
- Can dihydropyrimidine dehydrogenase impact 5-fluorouracil-based treatment?European Journal of Cancer, 2000
- A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracilEuropean Journal of Cancer, 1994
- Circadian rhythm of rat liver dihydropyrimidine dehydrogenase: Possible relevance to fluoropyrimidine chemotherapyBiochemical Pharmacology, 1988