Dataset Information

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

ABSTRACT: Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.

SUBMITTER: Guijarro-Eguinoa J

PROVIDER: S-EPMC10298094 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Guijarro-Eguinoa Javier J Arjona-Hernandez Sara S Stewart Stefan S Pernia Olga O Arias Pedro P Losantos-García Itsaso I Rubio Tania T Burdiel Miranda M Rodriguez-Antolin Carlos C Cruz-Castellanos Patricia P Higuera Oliver O Borobia Alberto M AM Rodriguez-Novoa Sonia S de Castro-Carpeño Javier J Ibanez de Caceres Inmaculada I Rosas-Alonso Rocio R

International journal of molecular sciences 20230607 12

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that <i>DPYD</i> variant carriers had significantly shorter progression-free survival and overall survival compared to <i>DPYD</i> w ...[more]

PMID: 37372990

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and biomarkers to guide treatment decisions in PDAC are generally lacking. Intratumoural expression of dihydropyrimidine dehydrogenase (DPD) is a potential prognostic parameter in patients with PDAC undergoing surgical resection and postoperative chemotherapy. In the present study, DPD was analysed by immunohistochemistry of a tissue microarray platform including a real-world cohort of 495 patients with PDAC who had undergone resection with curative intent at any of three tertiary centres, including Northern, Western and Southeastern regions of Sweden, between 1993 and 2019. DPD level (high/low) was analysed and overall survival associations were assessed in treatment subgroups using a multivariate Cox regression model accounting for potential confounders. In patients who had not received adjuvant chemotherapy (n=182), the median overall survival time was 11.6 months (95% CI 9.6-13.5), compared with 28.8 months (25.0-32.6) among those who had (n=313; log-rank P<0.001). The most common type of chemotherapy was gemcitabine single agent (Gem, n=239) followed by gemcitabine plus capecitabine (GemCape, n=39). Tumour-Node-Metastasis (TNM) stage and DPD expression were statistically significant prognostic parameters in the Gem group (HR 1.19, 95% CI 1.01-1.41, P=0.036), with high expression of DPD linked with worse survival. In addition, tumour grade and TNM stage were statistically significant prognostic factors in the group that did not receive any chemotherapy (P≤0.001). No statistically significant parameters were identified in the GemCape group. Taken together, intratumoural expression of DPD may be considered a prognostic marker for patients with PDAC treated with adjuvant gemcitabine following surgical resection, with low expression levels predicting better survival. Further studies in larger cohorts of patients receiving multi-drug or non-gemcitabine based regimens are warranted.

Project description:Background and objectiveWhile standard doses of adjuvant fluoropyrimidine-based chemotherapies are generally safe for most patients, the risk of severe adverse drug reactions (ADRs) is increased for those with dihydropyrimidine dehydrogenase deficiency (DPYD), a genetic variation that affects drug metabolism. The objective of this study was to examine the cost effectiveness of offering DPYD pharmacogenetic-guided care, where genetic testing informs personalized dosing versus the current standard of care (SoC), which involves administering fluoropyrimidine-based therapies without prior genetic screening, for local or metastatic breast cancer patients in Qatar.MethodsWe developed a two-stage decision analysis, with an analytic tree model over a 6-month period, followed by a life-table Markov model over a lifetime horizon. We compared the current SoC with the alternate strategy of DPYD genetic screening in patients living in Qatar with local or metastatic breast cancer who were eligible for adjuvant fluoropyrimidine therapy. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were estimated from Hamad Medical Corporation, Qatar. The short-term outcome included the incremental cost-effectiveness ratio (ICER), defined as cost per success (survival without grade III/IV ADRs) at 6 months. The long-term outcome was the ICER, defined as cost per quality-adjusted life year (QALY) gained, with a 3% annual discount rate. The study adopted a public healthcare perspective in Qatar. Sensitivity analyses were conducted to explore the impact of key input parameters on the robustness of the model.ResultsIn the short-term model, at its base case, DPYD genomic screening was dominant over SoC with a mean cost-saving of QAR84,585 (95% confidence interval [CI], 45,270-151,657). This cost saving reflects the overall economic benefits associated with the implementation of DPYD genomic screening. In the long-term model, compared to the current SoC, DPYD genetic screening would result in an ICER of QAR21,107 (95% CI -59,382-145,664) per QALY gained.ConclusionBased on our model, implementing DPYD genetic screening to detect DPYD mutations in breast cancer patients before therapy initiation seems to be a cost-saving and cost-effective strategy in Qatar.

Dataset Information

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Publications

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

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