Background Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. Methods Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25–50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. Results Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5–75%) for DPYD heterozygous carriers and 93.2% (42.9–100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). Conclusions Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.

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%

No abstract