Karel Eechoute

Genetic Polymorphisms Associated with a Prolonged Progression-Free Survival in Patients with Metastatic Renal Cell Cancer Treated with Sunitinib

Purpose: The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib. Experimental design: A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model. Results: Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001). Conclusions: This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy. Clin Cancer Res; 17(3); 620–9. ©2010 AACR.

Drug transporters of platinum-based anticancer agents and their clinical significance

Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, acquired and/or intrinsic resistance still represent a major limitation. Lately, in particular mechanisms leading to impaired uptake and/or decreased cellular accumulation of platinum compounds have attracted attention. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics (PK) and pharmacodynamics (PD). First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters--with special emphasis on organic cation transporters (OCTs)--and discuss their role on clinical outcome (i.e. efficacy and adverse events) of platinum-based chemotherapy. In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed.

A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Purpose: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. Experimental Design: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging. Results: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. Conclusions: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future trough level – clinical benefit analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance. Clin Cancer Res; 18(20); 5780–7. ©2012 AACR.

Sunitinib-Induced Hypothyroidism Is due to Induction of Type 3 Deiodinase Activity and Thyroidal Capillary Regression

CONTEXTnAnticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction.nnnOBJECTIVEnOur objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction.nnnDESIGNnThyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7).nnnSETTINGnPatients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study.nnnINTERVENTIONnSunitinib was taken according to a 4 wk on, 2 wk off treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology.nnnMAIN OUTCOME MEASURESnTSH and free T(4) levels, deiodinase activity, and thyroid histology were assessed.nnnRESULTSnForty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T(3)/rT(3) ratio. In rats, serum T(4) and T(3) decreased, hepatic type 3 deiodinase activity increased, and thyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal.nnnCONCLUSIONnSunitinib induces hypothyroidism due to alterations in T(4)/T(3) metabolism as well as thyroid capillary regression.

Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: the ClearSun study.

Background and ObjectiveThe wide inter-patient variability in drug exposure partly explains the toxicity and efficacy profile of sunitinib treatment. In this prospective study cytochrome P450 (CYP) 3A and adenosine triphosphate binding cassette (ABC) B1 phenotypes were correlated to the pharmacokinetics of sunitinib and its active metabolite N-desethylsunitinib.MethodsA correlation analysis was performed between sunitinib pharmacokinetics and 1′OH-midazolam/midazolam ratio and parameters derived from technetium-99m-2-methoxy isobutyl isonitrile (99mTc-MIBI) scans, respectively. A population pharmacokinetic model using non-linear mixed-effects modeling software NONMEM was built, which included the phenotype tests as covariate.ResultsIn 52 patients, the mean trough concentration of sunitinib plus metabolite increased from 21.4xa0ng/mL at dayxa01 of a cycle to 88.1xa0ng/mL in the fourth week of treatment. A trend for a correlation was observed between 99mTc-MIBI elimination constant and trough concentrations of N-desethylsunitinib; however, this was not significant. Correlations were found between 1′OH-midazolam/midazolam ratio and sunitinib clearance (Pxa0=xa00.008) and dayxa01 N-desethylsunitinib trough concentrations (Pxa0=xa00.005), respectively. Moreover, patients suffering from grade 3 toxicities had significant lower clearance of sunitinib than patients without grade 3 toxicities (34.4 vs. 41.4xa0L/h; Pxa0=xa00.025).ConclusionsPhenotype tests for ABCB1 and CYP3A4 did not explain inter-individual variability of sunitinib exposure sufficiently. However, the correlation between sunitinib clearance and the occurrence of severe toxicity suggests a direct exposure–toxicity relationship.

Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment.

AIM OF THE STUDYnAs a rise in mean corpuscular volume (MCV) of the erythrocyte is frequently seen during treatment with imatinib and sunitinib, we investigated whether macrocytosis (MCVxa0>xa0100 fl) also occurs as a class effect in other tyrosine kinase inhibitors (TKIs) and whether occurrence of macrocytosis is associated with outcome.nnnMATERIALS AND METHODSnIn 533 patients, using 5 TKIs, we investigated if macrocytosis and an increase in MCV were associated with progression-free survivalxa0and overall survival (OS) in specific tumour-treatment combinations.nnnRESULTSnMacrocytosisxa0as well as an increase in MCV from baseline of >10 fl (ΔMCV +10 fl), when included as a time-dependent covariate, were associated with improved OS in patients with renal cell cancer (RCC) treated with sunitinib (macrocytosis, hazard ratio [HR]xa0=xa00.61, pxa0=xa00.031, and ΔMCV +10 fl, HRxa0=xa00.58, pxa0=xa00.016).nnnCONCLUSIONnIn sunitinib-treated patients with RCC, the occurrence of macrocytosis, or a substantial increase in MCV levels after start of treatment, could potentially serve as a positive prognostic factor for survival, if validated prospectively.

Prospective Analysis in GIST Patients on the Role of Alpha-1 Acid Glycoprotein in Imatinib Exposure

BackgroundFor imatinib, a relationship between systemic exposure and clinical outcome has been suggested. Importantly, imatinib concentrations are not stable and decrease over time, for which several mechanisms have been suggested. In this study, we investigated if a decrease in alpha-1 acid glycoprotein (AGP) is the main cause of the lowering in imatinib exposure over time.MethodsWe prospectively measured imatinib trough concentration (Cmin) values in 28 patients with gastrointestinal stromal tumours, at 1, 3 and 12xa0months after the start of imatinib treatment. At the same time points, AGP levels were measured.ResultsOverall, imatinib Cmin and AGP levels were correlated (r2xa0=xa00.656; Pxa0<xa00.001). However, AGP levels did not fluctuate significantly over time, nor did the change in AGP levels correlate with the change in the imatinib Cmin.ConclusionWe showed that systemic AGP levels are not likely to be a key player in the decrease in systemic imatinib exposure over time. As long as intra-individual changes in imatinib exposure remain unexplained, researchers should standardize the sampling times for imatinib in order to be able to assess the clinical applicability of therapeutic drug monitoring.

Suppressing effects of sunitinib on allergic rhinitis: previously undefined side effects with therapeutic potential.

W observed 2 female patients (51 and 59 years old, respectively) who had had serious pollen allergy (hay fever) since childhood, expressed by rhinoconjunctivitis and asthma. For many years, these conditions were treated with antihistamines, β2 agonists, and pulmonary corticosteroids. In 2007, both patients were diagnosed with metastatic renal cell cancer for which they had been treated with sunitinib monotherapy since October and November 2007, respectively. Since the start of anticancer treatment, allergic rhinitis–related comedication was not allowed, to prevent unwanted drug-drug interactions. To their surprise and despite this prohibition, during the pollen season of 2008, both patients experienced no allergic rhinitis complaints at all. In this study, we tried to elucidate the underlying mechanism for this remarkable observation. Sunitinib malate is an anticancer drug currently used in the palliative treatment of metastatic renal cell carcinoma and gastrointestinal stromal cell tumors. Treatment regimens exist of once-daily dosing of 50 mg for 4 consecutive weeks, followed by 2 weeks of rest. Sunitinib acts as a multitargeted tyrosine kinase inhibitor, known to inhibit the intrinsic tyrosine kinase activity of several specific proteins, including KIT, vascular endothelial growth factor receptor (VEGF-R), and the platelet-derived growth factor receptor (PDGF-R), resulting in reduced tumor vessel growth or carcinogenesis. Sunitinib-induced toxicities may be serious and quite diverse. They include hypertension, diarrhea, hand-foot syndrome, mucositis, vomiting, leukopenia, cardiotoxicity, and hypothyroidism. Of all these molecular targets inhibited by sunitinib, KIT is most likely to be involved in the pathogenesis of allergic rhinitis. KIT is encoded by the c-kit gene. It is a trans-membrane protein, expressed on a variety of cells, including mast cells, hematopoietic progenitor cells, melanocytes, germ cells, and gastrointestinal pacemaker cells. Heterozygous loss of function of KIT in mice results in macrocytic anemia, hair depigmentation, sterility, and reduced numbers of gastrointestinal pacemaker cells. Moreover, in mast cells, KIT acts as a receptor for the stem cell factor. Binding of stem cell factor on KIT is essential for the survival and differentiation, chemotaxis, and functional activity of mast cells. Mast cells on their part play a vital role in the symptomatology of allergic rhinitis. Allergic reactions usually occur when an individual who has been sensitized to an allergen (eg, grass pollen) produces allergen-specific immunoglobulin isotype E antibodies (IgE) and subsequently encounters this particular allergen again.

Tamoxifen-induced fatty liver disease in a Caucasian patient

__Background__ nTamoxifen is a well-established hormonal treatment modality for hormone receptor-positive breast cancer. Though generally well tolerated, typical side effects resulting from its selective hormonal receptor modulation, such as hot flushes, are frequently reported. nAlthough preclinical data indicate that tamoxifen also induces lipid accumulation in the liver, up until now hepatic steatosis has not been reported in Caucasian patients. This is in contrast with patients of Asian ethnicity, in whom tamoxifen-induced hepatic steatosis has been described in more than 40% of the cases.

Single-nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) and vascular endothelial growth factor (VEGF) and its relationship to sunitinib-induced hypertension

4611 Background: Hypertension is a common side-effect in patients treated with sunitinib and is likely associated with inhibition of the VEGF/VEGF receptor(R)-2 pathway. SNPs in VEGF-A, VEGFR-2, but also in NOS3and endothelin-1 (EDN1) have been mentioned as possible candidates associated with a higher risk on development of hypertension.nnnMETHODSnA retrospective multicenter study was performed in 255 patients with advanced renal cell cancer and gastrointestinal stromal tumor treated with sunitinib 50 mg/day in a 4 weeks on 2 weeks off or 37.5 mg/day continuous schedule. Office systolic (SBP) and diastolic blood pressure (DBP) were measured at baseline and on days 14 and 28 of the first treatment cycle. Hypertension was graded according to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE). Seven SNPs in genes encoding for VEGF-A (rs2010963, rs833061, rs3025039, rs699947), VEGFR-2 (rs1870377), EDN1 (rs5370) and NOS3 (rs2070744) were selected. SNPs were univariately tested against hypertension grades according to CTCAE.nnnRESULTSnDuring the first treatment cycle, sunitinib induced a mean increase of 13 ± 23 mmHg and 10 ± 12 mmHg in SBP and DBP (t-test, P < 0.001), respectively. According to CTCAE, 36.5 % of patients developed hypertension. Among these patients, 10.6%, 12.9% and 12.9% had hypertension grade 1, 2, and 3, respectively. Development of grade 3 hypertension was associated with two copies of the C-allele in VEGF-A (rs833061; Chi-square, P = 0.048), two copies of the A-allele in VEGF-A(rs699947; P = 0.053) and a C-allele in NOS3 (rs2070744; P = 0.051).nnnCONCLUSIONSnSNPs in genes of NOS3 and VEGF-A are associated with the development of severe hypertension in patients treated with sunitinib. In particular, the association between the NOS3 pathway and hypertension induced by an inhibitor of the VEGF/VEGFR-2 pathway is a new finding. Hence, SNPs in VEGF-A and NOS3 genes may identify patients predisposed to develop hypertension on sunitinib treatment.