453P Routine DPYD mutation testing for patients receiving fluoropyrimidines for gastrointestinal (GI) cancers: Real world experience in a tertiary UK oncology centre

Abstract

Methods: 76 consecutive mCRC patients treated with first-line bevacizumab were retrospectively selected. Immunohistochemistry analysis of tissue microarrays assessed NICD, JAG1, CD44, CD3, CD4, CD8, CD20, DLL3 and DLL4 expression. Abdominal CT scans were imported into a dedicated software for tumor segmentation and extraction of 852 radiomic features (RFs), which were included into machine learning-based predictive models. Pre-processing of RFs included redundant features elimination and standardization; L2 penalized logistic regression with Monte-Carlo cross-validation were implemented for wrapper-based feature selection and model training/test. Three models were developed: clinical/genomic (C/G), radiomic (R) and the comprehensive integrated model (I), which were compared based on ROC-AUC and accuracy metrics.Results: NICD and JAG1 expression was associated with response to bevacizumab (p<0.05). Using likelihood-ratio test as inclusion criteria, the selected variables were 5 for both C/G and R models, then aggregated into the I model. C/G features included NICD expression, number of involved sites, primitive location, resection of metastases and performance status, while selected RFs belonged to both firstand higher-orders classes. ROC-AUC and accuracy were 0.724 (95%CI:0.722-0.727) and 0.669 (95%

Implementation of upfront DPYD genotyping with a low-cost and high-throughput assay to guide fluoropyrimidine treatment in cancer patients

“…This is in accordance with previous studies in which the combined frequency of the four variants explained about 12–30% of fluoropyrimidine toxicity [4,20,34]. Regarding the pretreatment group, 2.5% of the patients presented DPYD gene variants, a value somewhat inferior to that described in other European populations, in which the four variants combined were detected in about 5–10% of the patients in a pretherapeutic screening setting [20,29,31,32]. The frequency of DPYD variants can differ among populations, as previously described for the c.1905 + 1G>A variant, for which the incidence among European populations ranges from 0.7–3.5% [4,10,17,20,26,29,31–33,35–37].…”

“…Regarding the pretreatment group, 2.5% of the patients presented DPYD gene variants, a value somewhat inferior to that described in other European populations, in which the four variants combined were detected in about 5–10% of the patients in a pretherapeutic screening setting [20,29,31,32]. The frequency of DPYD variants can differ among populations, as previously described for the c.1905 + 1G>A variant, for which the incidence among European populations ranges from 0.7–3.5% [4,10,17,20,26,29,31–33,35–37]. Likewise, the frequency of the c.2846A>T and c.1129-5923C>G variants also varies between populations, ranging from 0.4–3% to 2.4–6.2% in European populations, respectively [4,10,17,20,29,31–33].…”

“…The frequency of DPYD variants can differ among populations, as previously described for the c.1905 + 1G>A variant, for which the incidence among European populations ranges from 0.7–3.5% [4,10,17,20,26,29,31–33,35–37]. Likewise, the frequency of the c.2846A>T and c.1129-5923C>G variants also varies between populations, ranging from 0.4–3% to 2.4–6.2% in European populations, respectively [4,10,17,20,29,31–33]. The c.1679T>G variant is rarer, being reported in frequencies of 0.1 to less than 1% [4,10,17,20,29,31–33].…”

“…DPYD gene variants can be predictors of fluoropyrimidine-associated toxicity, and dose adaptation based on DPYD variants genotyping is currently recommended by the EMA’s Pharmacovigilance Risk Assessment Committee and by the Portuguese national authority of medicines and health products (INFARMED). Several studies demonstrated the clinical validity of genotyping the four most common and well-established variants associated with fluoropyrimidine toxicity, namely the c.1129-5923C>G, the c.1679T>G, the c.1905 + 1G>A, and the c.2846A>T DPYD variants [4,16,20,29,31–33]. However, these four DPYD variants correlate differently with DPD enzyme activity; for instance, the c.1129-5923C>G variant appears to present a milder impact on DPD activity, and the available data are unclear regarding the appropriate dose reduction for carriers [15,17,18,20].…”

“…Several authors suggested that upfront genotyping of DPYD variants followed by individualized dose adjustment would improve the safety of fluoropyrimidine therapy for patients and reduce overall treatment costs [17,20,24–29]. On 13 March 2020, the European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment Committee has recommended that patients receiving fluorouracil given by injection or infusion and the related medicines capecitabine and tegafur should be tested for the lack of DPD enzyme, either by measuring the level of uracil in the blood or DPYD gene variant analysis, before starting treatment.…”