Page 296 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 11
Patient cases
Patient 1
A 50 year old patient was diagnosed with breast cancer (cT3N3M0, triple negative), for which neo-adjuvant chemotherapy was started, followed by a breast saving surgery and axillary lymph node dissection (ypT1N1), and thereafter radiotherapy. Approximately a year later, lymph node metastases were found, for which capecitabine (1,000 mg/m2 bid) was started. The patient experienced severe toxicity in the first cycle of capecitabine and was hospitalized for one week (allergic reaction ─red swollen face─, complaints in the mouth, neutropenic fever, nausea, diarrhea, leukopenia CTC-AE grade 4). The patient was genotyped hereafter and turned out to be a carrier of DPYD*2A and c.1236G>A. DPD enzyme activity was determined and was reported to be as low as 0.9 nmol/(mg*h) (normal range 5.9─14 nmol/(mg*h)). Internal evaluation using plasmids showed that these variants were both located at a different chromosome (in trans). Digital droplet PCR showed inconclusive results.
Patient 2
A 44 year old patient was diagnosed with breast cancer (cT1N1M0), for which the patient underwent surgery followed by radiotherapy and adjuvant chemotherapy (cyclophosphamide/methotrexate/5-FU dosed 600 mg/m2 iv). Approximately seven years later, a relapse was discovered and one breast was removed followed by hormonal therapy (tamoxifen for three years, anastrozol for three years). Three years hereafter, palpable axillary lymph nodes were found, which turned out to be metastases of the tumor. TAC (docetaxel, doxorubicin, cyclophosphamide) cycles were started, however poorly tolerated and therefore cycles 2─6 were continued on 75% of the dose. Axillary radiotherapy was given hereafter. All was followed by letrozole. Then, metastases in the liver, bones and adrenal glands were found. Palliative chemotherapy with capecitabine (1,000 mg/m2 bid) was started, for which DPYD genotyping was performed. She turned out to carry both DPYD*2A and c.2846A>T. Taking this result into account and previous 5-FU combination therapy without any problems, capecitabine was started at 50% dose (800 mg twice daily). The therapy was discontinued due to side effects (hand-foot syndrome CTC-AE grade 1, diarrhea CTC-AE grade 1─2 and abdominal cramps CTC-AE grade 1─2). Internal evaluation using plasmids showed that the SNPs were both located at a different chromosome (in trans). For the purpose of this study, additional material was collected for DPD enzyme activity, which was low, but within normal range 6.0 nmol/(mg*h) (normal range 5.9─14 nmol/(mg*h).
Patient 3
A 61 year old patient was diagnosed with metastatic colorectal cancer (pT4N2M1). After a laparoscopic hemicolectomy was performed, chemotherapy with capecitabine and oxaliplatin was scheduled. The DPYD genotype was determined and two variants (c.2846A>T and c.1236G>A) were found. In addition to this, the DPD enzyme activity was measured, which was 4.5 nmol/(mg*h). The capecitabine dose was adjusted to ~50% (1,800 mg per day). Because of good tolerance, the capecitabine dose was increased to ~70% in the second
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