Page 297 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

cycle. Upon this increased dose, the patient developed thrombocytopenia CTC-AE grade 3 and complaints of anorexia, nausea and fatigue CTC-AE grade 1─2. In the third cycle, 57% dose was applied, resulting in a new thrombocytopenia CTC-AE grade 2. After these three cycles disease progression was noted and treatment was discontinued. For the purpose of this study, additional material was collected for the PacBio analysis and this patient carried both DPYD variants on different alleles (in trans). (Also described by Henricks et al.).1
Patient 4
A 38 year old patient was diagnosed with breast cancer. After surgery (pT2N0) and hormonal therapy (tamoxifen for three years) disease progression was established, and other hormonal therapies (anastrozole for two years, exemestane for two years andfulvestrant) followed. Due to liver metastases treatment was continued with capecitabine (1,500 mg twice daily). Severe side effects (CTC-AE grade 3 oral mucositis) occurred after seven days of treatment for which chemotherapy was discontinued immediately and the patient was admitted to the hospital. During two weeks of hospital admission severe thrombocytopenia (CTC-AE grade 3), neutropenia and leukopenia (both CTC-AE grade 4) occurred. The patient deteriorated (respiratory problems, multiple organ failure), treatment against side effects was stopped and the patient died. During hospital admission, DPD enzyme activity was measured, which was extremely low (0.11 nmol/(mg*h)). Also, the DPYD genotype was determined and two variants (DPYD*2A and c.2846A>T) were found. No additional analyses for this study were performed for this patient.
Patient 5
Supplement
A 57 year old patient was diagnosed with colorectal adenocarcinoma (T4N0) for which a right hemicolectomy and trans anal endoscopic microsurgery of the rectum were performed. Approximately one year later, recurrence of rectal carcinoma was discovered (T4N2). The patient was also diagnosed with prostate cancer around the same time. Chemo radiotherapy was planned, consisting of radiotherapy on the rectum (25x2Gy) and prostate (total of 78Gy) combined with capecitabine. The patient participated in a clinical trial (NCT00838370) for which prospective genotyping (DPYD*2A) was performed.2 The patient tested positive and treatment was adjusted on the second day to 50% of capecitabine dose (800 mg twice daily). No severe side effects occurred. During treatment, DPD enzyme activity was measured, and was within normal range (7.2 nmol/(mg*h)). After treatment the patient was genotyped retrospectively for additional DPYD variants and was also a carrier of the c.2846A>T variant. For the purpose of this study, extra material was collected for the PacBio analysis and this patient carried both DPYD variants on a single allele (in cis).
Patient 6
A 67 year old patient was diagnosed with metastasized colorectal adenocarcinoma and treated with capecitabine (1,000 mg/m2 twice daily) and oxaliplatin. The patient experienced CTC-AE grade 4 neutropenia, thrombocytopenia and leukopenia, CTC-AE grade 3 nausea, vomiting, diarrhea, stomatitis and anorexia. Toxicity resolved after continuing with an unknown dose reduction. The DPD enzyme activity and DPYD genotype were determined
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