Christof Vulsteke

Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC)

BACKGROUND To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy. PATIENTS AND METHODS Twenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points). RESULTS Carriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38). CONCLUSION Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

Rituximab-induced fatal interstitial pneumonitis: case report

Rituximab is a mouse/human chimeric immunoglobulin G1 (IgG1)-k monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appear to involve complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitizes tumor cells to the effects of conventional chemotherapeutic drugs. There is antitumoral activity in nearly all subtypes of B-cell lymphomas. The association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an exceptional revolution in the prognosis of DLBCL, and is the current standard of therapy. The association of rituximab with chemotherapy deeply modifies prognostic factors defined before the rituximab era [1]. We report an 87-year-old male diagnosed in October 2007 with stage IV DLBCL involving the mediastinal nodes, lung parenchyma, and peritoneal fat (International Prognostic Index score 3/5, high intermediate risk). Rituximab with CHOP chemotherapy was started. Pegfilgrastim was given 24 h after chemotherapy to avoid deep neutropenia. His past medical history included arterial hypertension with secondary ventricular hypertrophy, deep venous thrombosis with lung embolism, transient ischemic attack, and idiopathic lung fibrosis. Medication included pravastatin, allopurinol, an oral antivitamin K antagonist, and an angiotensin II receptor antagonist. Lung function prior to chemotherapy revealed a diffusion capacity of 71% and a normal forced expiratory volume for his age. Echocardiography showed normal systolic function with impaired relaxation. On staging computed tomography of the thorax, relatively mild reticular opacities and areas of honeycombing were seen peripherally in the bases of both lungs, indicating interstitial lung disease consistent with his medical history of idiopathic pulmonary fibrosis (IPF). Following the first course of rituximab–CHOP, methylprednisolone was continued and tapered (0.125 mg/kg a day for 1 week and 0.06 mg/kg a day for another week). During tapering he developed dyspnea. Radiography of the lungs showed tumor regression and signs of interstitial lung disease. A new pulmonary function test revealed a decreased diffusion capacity to 20%. The second course of rituximab–CHOP was given after careful risk assessment by a pneumologist, and the patient was sent home with methylprednisolone 0.25 mg/kg a day. Seven days later he was admitted in an external hospital with complaints of severe dyspnea. Computed tomography of the thorax was performed, showing a significant tumor reduction, but also an increase of the interstitial lung disease pattern. Methylprednisolone was increased and the patient could be discharged. When he returned for the third course of rituximab–CHOP he had a significantly impaired performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2). At that moment, weakness and fatigue were his main complaints. The diffusion capacity remained consistently low (19%) and the

First evidence of treatment efficacy in metastatic carcinoma of the parotid gland with BRD4/NUT translocation

Background: Nuclear protein in testis (NUT) midline carcinomas (NMC) are characterized by rearrangements of the gene NUT. In the majority of NMCs, a translocation t(15;19), resulting in a BRD4/NUT fusion gene, is present. Nuclear protein in testis midline carcinomas is a rare, but probably underdiagnosed entity due to misdiagnosis. Most cases have been reported in the mediastinum and upper aero-digestive tract. The clinical course of a NMC is extremely aggressive, in spite of intensive chemotherapy and radiotherapy, with an average survival < 1 year. Methods and results: A 32-year-old man presented with a pre-auricular swelling on the left side. After partial parotidectomy, the diagnosis of a NMC was made based on the presence of t(15;19)(q14;p13.1) and BRD4/NUT fusion gene demonstrated by fluorescence in situ hybridization (FISH). During postoperative radiotherapy, the patient developed bone metastases for which chemotherapy consisting of cisplatine, doxorubicine and ifosfamide (PAI) was initiated with remarkable clinical and radiological improvement. Nevertheless, the response was not durable. Conclusion: This case illustrates that responses to chemotherapy in the palliative treatment of a t(15;19)-translocated salivary gland carcinoma are possible but not durable.