Papers by Patricia Soetekouw
Journal of Clinical Oncology
Journal of Clinical Oncology
ABSTRACT Background: The oral PARP inhibitor olaparib is well tolerated at doses ≤400 mg bid (cap... more ABSTRACT Background: The oral PARP inhibitor olaparib is well tolerated at doses ≤400 mg bid (capsule formulation) and has shown efficacy in patients (pts) with BRCA-mutated ovarian cancer (Ledermann et al ASCO 2013). This is the first study to evaluate the effect of food on olaparib PK. Methods: InPart A of this open-label, randomized, crossover Phase I trial (NCT01851265), adult pts with refractory/resistant advanced solid tumors received a single oral dose of olaparib 400 mg (8 x 50 mg capsules) in each of 3 prandial states, after (1) an overnight fast (2) a high-fat meal and (3) a standard meal (5–14 days’ washout between doses). Blood samples were taken pre-dose and regularly up to 72 h post-dose. Part B was an extension phase to further evaluate safety, where pts completing Part A could receive continuous dosing with olaparib 400 mg bid (capsules) whilst deriving clinical benefit. AE data were collected in both phases. Results: 32 pts (ECOG PS 0/1: n=30; PS 2: n=2) entered the study (female, 84%; median age, 59.5 y; most common tumor types, ovarian [44%], breast [19%], rectal [13%]). 30 pts contributed to statistical analysis (2 pts were excluded: n=1, previous gastric surgery; n=1, withdrawal after first dose [grade 1 vomiting]). The effect of food was similar for both meals. The rate of absorption was slower in the presence of food (tmax delayed by ~2 h) resulting in little impact on Cmax whilst the extent of absorption (AUC) was increased by ~20% in the fed state. AE data from Part A were consistent with the known safety profile of olaparib. Part B is ongoing. Conclusions: The PK of olaparib following oral dosing of the capsule formulation is affected by food. Olaparib capsule doses should be taken on an empty stomach. Clinical trial information: NCT01851265
The Journal of Pathology
Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formati... more Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types.
World Journal of Urology
with PN in cT1a and laparoscopic RN in cT1b were evaluated with logistic regression analyses. Res... more with PN in cT1a and laparoscopic RN in cT1b were evaluated with logistic regression analyses. Results An increase in nephron-sparing treatment strategies (NSS) of cT1a patients (N total = 2436) was observed; in 2014, 67 % underwent NSS (62 % PN and 5 % thermal ablation). Age, a non-central tumor localization and being treated in a high-volume hospital were associated with PN. Although NSS were applied more frequently over time, the majority (70 %) of cT1b patients (N total = 2205) underwent RN in 2014, mainly performed laparoscopically. Increasing tumor size, tumor localization in the right kidney and being treated in a university hospital were associated with a lower probability of a laparoscopic RN versus open. Treatment in a high-volume hospital was associated with a higher probability of laparoscopic RN. Conclusions Dutch patients with cT1 renal cancer are predominantly treated according to current guidelines. Data of this pre-specified quality indicator analysis of a urological national guideline may serve as a model for international comparison of treatment of cT1 renal cancers.
International Journal of Epidemiology
Background: Sodium intake, but not potassium or fluid intake, has been associated with higher ren... more Background: Sodium intake, but not potassium or fluid intake, has been associated with higher renal cell cancer (RCC) risk. However, risk factors may differ by molecular subtypes of the tumour. In renal physiology, electrolyte and water homeostasis is facilitated by ion transport mechanisms (ITM). Aberrant regulation of ITM genes, for example by promoter CpG island methylation, may modify associations between sodium, potassium and fluid intake and RCC risk. Methods: We identified ARHGDIG, ATP1A1, SCNN1B and SLC8A3 as ITM genes exhibiting RCC-specific promoter methylation and down-regulation. Methylation-specific polymerase chain reaction (PCR) was used to analyse promoter CpG island methylation in tumour DNA of 453 RCC cases from the Netherlands Cohort Study (n ¼ 120 852) after 20.3 years of follow-up. Diet was measured at baseline using food-frequency questionnaires. Cox regression analyses were restricted to clear-cell (cc)RCC (n ¼ 306) and stratified by tumours with no, low (1 gene) and high (2 genes) methylation. Results: Sodium intake (high vs low) increased ccRCC risk particularly in tumours with a high methylation index: hazard ratio (HR) [95% confidence interval (CI)]: 2.04 (1.16-3.58), whereas heterogeneity across the methylation index was not significant (P-heterogeneity ¼ 0.26). Potassium intake was differentially associated with ccRCC risk (P-heterogeneity ¼ 0.008); the risk for high (vs low) potassium intake was low for unmethylated tumours [HR (95%
Journal of Clinical Oncology
257 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic cas... more 257 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59–0.83; P < 0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. Methods: This prospective, multinational, open-label study ( NCT01087021 ) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula QTcF). Results: A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts fol...
Clinical therapeutics, Jan 10, 2016
The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonst... more The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios...
Psychol Med, 2001
Background. Dutch (ex-)servicemen were deployed in the 1992–3-peace operation UNTAC in Cambodia. ... more Background. Dutch (ex-)servicemen were deployed in the 1992–3-peace operation UNTAC in Cambodia. Since their return, they have voiced concerns about the health consequences of their service and they have reported symptoms such as fatigue and cognitive problems. The natural course of symptoms in Dutch Cambodia veterans was evaluated in a prospective study.Methods. At 18-months follow-up, a questionnaire was sent to 354 veterans who met a set case definition for symptoms in Cambodia veterans or who had sub-threshold scores. Initial measurement of fatigue severity, psychological well-being, depression, post-traumatic stress disorder, trait-anxiety, self-efficacy and causal attributions, was used to evaluate predictors for self-reported improvement and low levels of fatigue at follow-up.Results. At follow-up, 19% of the respondents reported complete recovery, 20% felt much better, 57% had the same complaints and 4% had become worse compared with their initial assessment. Self-reported improvement and less severe fatigue at follow-up were predicted by less severe fatigue at initial assessment and more perceived control over symptoms.Conclusions. Self-reported improvement was reported in a considerable percentage of Cambodia veterans, whereas another substantial percentage of Cambodia veterans continued to suffer with severe levels of fatigue and related symptoms. Predictors of improvement in Cambodia veterans and patients with chronic fatigue syndrome show similarities and also seem to bear importance for Gulf War veterans.
Http Dx Doi Org 10 3200 Aeoh 58 12 740 745, Aug 7, 2010
Following their participation in a United Nations peacekeeping operation in Cambodia (1992-1993),... more Following their participation in a United Nations peacekeeping operation in Cambodia (1992-1993), Dutch veterans complained of symptoms similar to those reported by Gulf War veterans. The authors conducted a matched case-control study to evaluate 76 symptomatic and 32 matched asymptomatic Cambodia veterans on the basis of data collected by postal questionnaire. The number of symptomatic veterans who reported having used insect repellants that contained N,N,-diethyl-meta-toluamide (DEET) during the mission in Cambodia was significantly higher, compared with asymptomatic veterans. The percentage of veterans who reported feeling ill following brief exposures to chemicals such as paint or pesticides was equal in both groups, but the percentage was low compared with the results of other studies of Multiple Chemical Sensitivity Syndrome. The current study was limited by self-report and time delay (potential recall bias) between deployment to Cambodia and the time of survey. Nevertheless, the study results did not support the hypothesis that symptoms in the total group of Cambodia veterans could be related to Multiple Chemical Sensitivity Syndrome.
Nederlands tijdschrift voor geneeskunde, Jan 24, 2007
Two women, aged 57 and 55 years, with metastatic breast cancer were admitted for uncontrolled pai... more Two women, aged 57 and 55 years, with metastatic breast cancer were admitted for uncontrolled pain due to bone metastases. Despite the fact that progressive disease was evident, a change in antitumour therapy had not been recommended. The pain control was optimised in both patients. In one patient, palliative chemotherapy was installed, combined with trastuzumab because of HER2/neu overexpression. She was still alive after one and a half year of treatment. The other patient could not adjust mentally to the fact that her palliative therapy was changed to antitumour therapy; she died one month later. It is important to be aware of the various kinds of therapy in metastatic breast cancer because palliative treatment is more than just symptomatic treatment. Systemic antitumour therapy includes hormone therapy, chemotherapy and targeted therapy. Furthermore, in patients with bone metastases, radiotherapy combined with bisphosphonates results in pain relief and can reduce skeletal complic...
Oncotarget, Jan 14, 2015
Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial f... more Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic ...
Cancer Chemotherapy and Pharmacology, 2015
The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Ph... more The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.
Advances in Therapy, 2015
The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at dos... more The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer. This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5-14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID. 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19 [1.08-1.31] for high-fat meal). The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib. AstraZeneca.
Current Angiogenesis, 2012
Clinical Cancer Research, 2015
Purpose: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC)... more Purpose: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival. Experimental Design: We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests. Results: Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P ¼ 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12-2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25-2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihoodratio P ¼ 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P < 0.001). Conclusions: CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis. Clin Cancer Res; 21(15); 3492-500. Ó2015 AACR.
Biochimica et biophysica acta, 2015
The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial grow... more The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on futu...
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Papers by Patricia Soetekouw