Ignace Vergote

Universitair Ziekenhuis Leuven, Louvain, Flemish, Belgium

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Publications (353)2275.83 Total impact

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    ABSTRACT: MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.
    Breast Cancer Research 12/2015; 17(1). DOI:10.1186/s13058-015-0526-y · 5.33 Impact Factor
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    ABSTRACT: The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. Patients were randomized 1:1 to ixabepilone (40 mg/m(2)), or either paclitaxel (175 mg/m(2)) or doxorubicin (60 mg/m(2)), every 21 days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. At the time of database lock, 496 patients were randomized to receive ixabepilone (n = 248) or control (n = 248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio = 1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P = 0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control. Copyright © 2015. Published by Elsevier Inc.
    Gynecologic Oncology 04/2015; DOI:10.1016/j.ygyno.2015.04.026 · 3.69 Impact Factor
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    ABSTRACT: Well-characterized, low-passage, primary cell cultures established directly from patient tumors are an important tool for drug screening because these cultures faithfully recapitulate the genomic features of primary tumors. Here, we aimed to establish these cell cultures from primary endometrial carcinomas (ECs) and to develop subcutaneous and orthotopic xenograft models as a model to validate promising treatment options for EC in the in vivo setting. Primary cell cultures of EC tumors were established and validated by analysing histologic and genetic characteristics, telomerase activity, and in vitro and in vivo growth characteristics. Using these primary cell cultures, subcutaneous and orthotopic mouse models were subsequently established. We established and characterized 7 primary EC cell cultures and corresponding xenograft models of different types of endometrioid tumors. Interestingly, we observed that the chance to successfully establish a primary cell culture seems higher for microsatellite instable than microsatellite stable tumors. For the first time, we also established an orthotopic murine model for EC derived from a primary cell culture. In contrast to EC cell lines, grafted tumor cultures preserved the original tumor structure and mimicked all histologic features. They also established abdominal and distant metastases, reflecting the tumorigenic behavior in the clinical setting. Remarkably, the established cell cultures and xenograft tumors also preserved the genetic characteristics of the primary tumor. The established EC cultures reflect the epithelial genetic characteristics of the primary tumor. Therefore, they provide an appropriate model to investigate EC biology and apply high-throughput drug screening experiments. In addition, the established murine xenograft models, in particular the orthotopic model, will be useful to validate promising therapeutic strategies in vivo, as the grafted tumors closely resemble the primary tumors from which they were derived. Microsatellite instable status seems to determine the success rate of establishing primary cell cultures.
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    ABSTRACT: This study aimed to determine whether single nucleotide polymorphisms (SNPs) in genes involved in DNA repair or metabolism of taxanes or platinum could predict toxicity or response to first-line chemotherapy in ovarian cancer. Twenty-six selected SNPs in 18 genes were genotyped in 322 patients treated with first-line paclitaxel-carboplatin or carboplatin mono-therapy. Genotypes were correlated with toxicity events (anemia, neutropenia, thrombocytopenia, febrile neutropenia, neurotoxicity), use of growth factors and survival. The risk of anemia was increased for variant alleles of rs1128503 (ABCB1, C > T; p = 0.023, OR = 1.71, 95% CI = 1.07-2.71), rs363717 (ABCA1, A > G; p = 0.002, OR = 2.08, 95% CI = 1.32-3.27) and rs11615 (ERCC1, T > C; p = 0.031, OR = 1.61, 95% CI = 1.04-2.50), while it was decreased for variant alleles of rs12762549 (ABCC2, C > G; p = 0.004, OR = 0.51, 95% CI = 0.33-0.81). Likewise, increased risk of thrombocytopenia was associated with rs4986910 (CYP3A4, T > C; p = 0.025, OR = 4.99, 95% CI = 1.22-20.31). No significant correlations were found for neurotoxicity. Variant alleles of rs2073337 (ABCC2, A > G; p = 0.039, OR = 0.60, 95% CI = 0.37-0.98), rs1695 (ABCC1, A > G; p = 0.017, OR = 0.55, 95% CI 0.33-0.90) and rs1799793 (ERCC2, G > A; p = 0.042, OR = 0.63, 95% CI 0.41-0.98) associated with the use of colony stimulating factors (CSF), while rs2074087 (ABCC1, G > C; p = 0.011, OR = 2.09, 95% CI 1.18-3.68) correlated with use of erythropoiesis stimulating agents (ESAs). Homozygous carriers of the rs1799793 (ERCC2, G > A) G-allele had a prolonged platinum-free interval (p = 0.016). Our data reveal significant correlations between genetic variants of transport, hepatic metabolism, platinum related detoxification or DNA damage repair and toxicity or outcome in ovarian cancer.
    02/2015; 16(1). DOI:10.1186/s40360-015-0001-5
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    ABSTRACT: The aim of this study was to evaluate perioperative outcomes of robotic-assisted laparoscopic para-aortic lymphadenectomy (PAL) in patients with gynecologic cancers during the learning phases of robotic surgery programs and to compare results of extraperitoneal versus transperitoneal approaches of PAL. This study is a retrospective multicentric study of patients who underwent robotically assisted laparoscopic PAL (N = 487). Eleven European centers and 1 US center participated in the study. Abstracted data included age, body mass index, indication, type of surgical approach (transperitoneal or extraperitoneal), associated surgical procedures, operative time, estimated blood loss, lymph node count, hospital length of stay (LOS), and complications. Para-aortic lymphadenectomy was performed by an extraperitoneal approach in 58 cases (12%) and transperitoneal in 429 cases (88%). The mean (SD) para-aortic lymph node count was 12.6 (8.1), operative time was 217 (85) minutes, estimated blood loss was 105 (110) mL, and LOS was 2.8 (3.2) days. Four (0.8%) conversions to open and 2 (0.4%) conversions to laparoscopy were described. There were 32 lymphocysts (6.6%), 3 deep venous thromboses (0.6%), and 10 transfusions (2.1%). For transperitoneal approach, the average number of lymph nodes removed was higher in isolated PAL group than the hysterectomy combined group (report node counts 95% confidence interval, -7.29 to -3.52, P = 1.5 × 10). For isolated PAL, the LOS was shorter in the extraperitoneal group than in the transperitoneal group (report data 95% CI, -1.35 to -0.35, P = 0.001). Robotic-assisted PAL seems safe and feasible. More lymph nodes were removed during an isolated transperitoneal PAL dissection compared with a combined procedure with hysterectomy. Extraperitoneal approach seems attractive relative to transperitoneal dissection, but the superiority of one or the other way is not demonstrated by our study.
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
  • Ignace B Vergote, Christian Marth, Robert L Coleman
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    ABSTRACT: Folate can be transported into the cell by the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), or the folate receptor (FR), of which various isoforms exist. While the RFC and PCFT are expressed by many normal cells, the FR is present only in a small proportion of normal tissues. In these tissues, the FR expression level is often low and restricted to the apical surface of polarized epithelial cells. In contrast, FR is expressed on the blood-accessible basal and lateral membranes of many types of epithelial cancer. Considering that FR is expressed in few nonmalignant cell types on luminal membranes generally not accessible for molecules transported in the blood, FR is considered a promising antitumor target. As FR expression seems associated with tumor progression and prognosis, anticancer therapies targeting FR are currently being developed, such as farletuzumab (Morphotek, Exton, PA, USA), IMGN853 (ImmunoGen, Waltham, MA, USA), vintafolide, and EC1456 (both Endocyte Inc., West Lafayette, IN, USA). FR expression could be used as a response-predictive biomarker for these treatments. The ability to identify patients and treat them with an effective therapy based on the known expression of the tumor marker would, indeed, be the next step in predictive medicine for these patients. This review summarizes the role of FR in ovarian cancer and the value of FR as a prognostic biomarker for ovarian cancer and a response-predictive biomarker for folate-targeted therapeutics.
    Cancer and metastasis reviews 01/2015; 34(1). DOI:10.1007/s10555-014-9539-8 · 6.45 Impact Factor
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    ABSTRACT: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2,185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. Copyright © 2014. Published by Elsevier Inc.
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    ABSTRACT: Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma.
    Gynecologic Oncology 12/2014; 136(2). DOI:10.1016/j.ygyno.2014.12.019 · 3.69 Impact Factor
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    ABSTRACT: To perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial.
    European Journal of Cancer 12/2014; 51(3). DOI:10.1016/j.ejca.2014.11.017 · 4.82 Impact Factor
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    ABSTRACT: Malignant ascites is a common phenomenon in cancer patients. It poses a great challenge to the clinician, because of limited treatment options and strong impairment of the quality of life of the often palliative patients. The SECIMAS study investigated the feasibility of a re-challenge with four catumaxomab intraperitoneal infusions in patients who had already received a first cycle of four infusions in the phase III CASIMAS study, which compared catumaxomab with and without prednisolone premedication. The primary endpoint was the proportion of patients who received at least three catumaxomab infusions. Secondary endpoints included a composite safety score (CSS) summarising the worst grades for the main catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain), safety, efficacy and the occurrence of anti-drug antibodies (ADAs). Eight of nine screened patients received a second catumaxomab cycle. Compliance with a catumaxomab re-challenge was high: all eight patients (100 %) received all four infusions. The median CSS was 3.0 versus 3.4 in CASIMAS. The tolerability profile of the second catumaxomab cycle was comparable to that of the first cycle. Median puncture-free survival (48 days) and overall survival (407 days) were longer than in CASIMAS (35 and 103 days, respectively), although median time to next puncture was shorter (60 vs. 97 days). Of six patients sampled, all were ADA positive at screening and remained ADA positive until the end of the study. The presence of ADAs did not affect catumaxomab's safety or efficacy. The CSS and tolerability profile for catumaxomab in SECIMAS were comparable to those in CASIMAS. The majority of patients benefitted from a second cycle of catumaxomab. A re-challenge seems to be feasible and safe for selected patients with recurrent malignant ascites due to carcinoma after a first cycle of catumaxomab.
    Medical Oncology 12/2014; 31(12):308. DOI:10.1007/s12032-014-0308-x · 2.06 Impact Factor
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    ABSTRACT: Analysis of progression-free survival (PFS) as the primary endpoint in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer (AEOC) trials may be confounded by the difficulty of radiologic evaluation of disease progression and the potential for discrepancy between investigator and blinded independent central assessments. PFS as assessed by local investigator (INV) was the primary endpoint of AGO-OVAR16, a randomized, double-blind trial of pazopanib maintenance therapy in AEOC. To confirm the robustness of the primary analysis, PFS was also evaluated by blinded independent central review (BICR). Patients with histologically confirmed AEOC (N=940) were randomized 1:1 to receive pazopanib 800mg/day or placebo for up to 24months. Tumor response in the intent-to-treat population was evaluated by CT/MRI every 6months and analyzed per RECIST 1.0. Pazopanib prolonged PFS versus placebo by INV (median 17.9 vs 12.3months; hazard ratio [HR]=0.766, 95% confidence interval [CI]: 0.643-0.911; P=0.0021). Results for PFS by BICR were similar (median 15.4 vs 11.8months; HR=0.802, 95% CI: 0.678-0.949; P=0.0084). Progression events were recorded later by INV in 23% of pazopanib-treated patients and 17% of placebo-treated patients. The overall concordance between INV and BICR assessments was 84% and 86% in the pazopanib and placebo arms, respectively. By INV and BICR assessments, maintenance therapy with pazopanib in AEOC provided a significantly longer PFS than placebo. The good overall concordance between INV and BICR assessments, as well as HR and P value consistency, supports the reliability of investigator-assessed PFS as the primary endpoint in AGO-OVAR16. Copyright © 2014. Published by Elsevier Inc.
    Gynecologic Oncology 11/2014; 136(1). DOI:10.1016/j.ygyno.2014.11.074 · 3.69 Impact Factor
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    ABSTRACT: Endometrial cancer (EC) can affect sexual functioning based on anatomical, physiological, psychological, and relational mechanisms.
    Journal of Sexual Medicine 11/2014; 12(1). DOI:10.1111/jsm.12764 · 3.15 Impact Factor
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    ABSTRACT: Aims: We assessed the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of Pazopanib with weekly Carboplatin/Paclitaxel in patients with platinum- refractory/resistant ovarian, fallopian tube or peritoneal carcinoma after at least one line of platinum-based treatment. Methods: Patients received Paclitaxel followed by Carboplatin intravenously weekly concurrently with daily Pazopanib orally (except during the first course and on day 1 of each subsequent course) for a maximum of 18 weeks and, in absence of progression, continued Pazapanib 800 mg/d until progression. Six dose levels were established at C (AUC)/P (mg/m2) q 1 week/P (mg daily): 1.5/30/400; 2.0/30/400; 2.0/30/800; 2.0/45/800; 2.7/45/800; 2.7/60/800. Results: A total of 28 patients were enrolled of which 23 were evaluable for DLT; 5 patients were excluded due to lack of Pazopanib exposure. Three out of six patients experienced DLTs at the dose level 3 Carboplatin AUC 2.0/Paclitaxel 30/Pazopanib 800). An intermediate dose level (2.0/30/600) yielded two DLTs out of 6. No DLTs were observed on dose level 2 (2.0/30/400). Notable toxicities up to week 6 included neutropenia, fatigue, hypertension, vomiting and liver enzyme elevations. Out of the 23 evaluable patients, 8 (35%) achieved a RECIST response (6 partial and 2 complete responses ). Conclusion: Pazopanib 400 mg per day can be combined with Carboplatinin AUC 2.0 and Paclitaxel 30 mg/m2 weekly. The activity of the regimen will be assessed in a phase II trial of the EORTC-GCG trial randomized against Carboplatin AUC 2.7 and Paclitaxel 60mg/m2 weekly.
    15th Biennial Meeting of the International Gynecologic Cancer Society, Melbourne, Australia; 11/2014
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    ABSTRACT: Purpose To ascertain the spectrum of clinical management of endometrial carcinoma (EC) the largest international survey was conducted to evaluate and identify differences worldwide. Methods After validation of a 15-item questionnaire regarding surgical and adjuvant treatment of EC in Germany, an English-adapted questionnaire was put online and posted to all the major gynecological cancer Societies worldwide for further distribution commencing in 2010 and continued for 26 months. Results A total of 618 Institutions around the world participated: Central Europe (CE), Southern Europe (SE), Northern Europe (NE), Asia and USA/Canada/UK. Both a therapeutic and staging value was attributed to systematic pelvic and paraaortic lymph node dissection (LND) in CE (74.6 %) and in Asia (67.2 %), as opposed to USA/UK where LND was mainly for staging purposes (53.5 %; p p p p Conclusions There is broad range in both the surgical and adjuvant treatment of EC across different countries. Large-scale multicenter prospective trials are warranted to establish consistent, evidence-based guidelines to optimize treatment worldwide.
    Archives of Gynecology and Obstetrics 10/2014; 291(4). DOI:10.1007/s00404-014-3510-3 · 1.28 Impact Factor
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    ABSTRACT: Objective To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum − resistant or partially platinum − sensitive ovarian cancer. Methods In this open − label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m2 (cohorts A1 and A3, respectively) or topotecan 4 mg/m2 (cohorts B1 and B3, respectively). Endpoints were dose − limiting toxicity (DLT; primary); treatment − emergent adverse events (AEs), overall response rate, anti − trebananib antibodies, and pharmacokinetics (secondary). Results 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n = 1) and sudden death (n = 1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug − drug interactions were apparent. Conclusions Trebananib 10 mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum − resistant or partially platinum − sensitive ovarian cancer. Antitumor activity was evident across all cohorts.
    Gynecologic Oncology 10/2014; 135(1). DOI:10.1016/j.ygyno.2014.07.003 · 3.69 Impact Factor
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    ABSTRACT: Objective The role of secondary cytoreductive surgery (SCR) in platinum-sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis. Methods Using data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery. Results Of the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001). Conclusion SCR was associated with improved OS in platinum-sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential.
    Gynecologic Oncology 09/2014; 136(1). DOI:10.1016/j.ygyno.2014.09.017 · 3.69 Impact Factor
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    ABSTRACT: Objective Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. Methods SCNAs were assessed in a discovery (n = 86) and validation cohort (n = 115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n = 227). Results We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P < 0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR = 1.670; P = 0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR = 2.69, P = 1.7 × 10− 4; HR = 1.82, P = 1.9 × 10− 2 and HR = 1.80, P = 2.2 × 10− 2 respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P = 2.8 × 10− 11;R2 = 0.26). Conclusions We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy.
    Gynecologic Oncology 09/2014; 135(3). DOI:10.1016/j.ygyno.2014.09.014 · 3.69 Impact Factor
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    ABSTRACT: Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy.
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    ABSTRACT: Purpose Hypoxia is a common phenomenon encountered in solid cancers, leading to chemotherapy resistance and therefore to aggressiveness of the disease. The homeostatic response to hypoxia is mediated by hypoxiainducible factor-1 (HIF-1). The aim of this study was to investigate the impact of HIF1α in patients with primary epithelial ovarian cancer. Methods In this multicentric study, 275 patients with advanced primary epithelial ovarian cancer were included. All patients underwent cytoreductive surgery with maximal surgical effort and adjuvant platinum-based chemotherapy. HIF1α expression was analyzed in tissue lysates, using an enzyme-linked immunosorbent assay. Results HIF1α was detected in 79.3% of the tissue samples. Patients with increased HIF1α expression (cutoff: 80 pg/mg protein) in tumoral tissue lysates were more likely to have less favorable survival. HIF1α (P=0.009, hazard ratio [HR] 2.505, 95% confidence interval [95% CI] 1.252–5.013) together with International Federation of Gynecology and Obstetrics (III versus IV) (P=0.013, HR 0.540, 95% CI 0.332–0.878), histology (P=0.007, HR 2.748, 95% CI 1.315–5.743), presence of peritoneal carcinomatosis (P=0.014, HR 2.176, 95% CI 1.170–4.046), residual tumor mass (P=0.017, HR 1.641, 95% CI 1.091–2.468), and response to platinum-based chemotherapy (P<0.001, HR 8.131, 95% CI 5.13–12.88) were independent prognosis factors for overall survival. The independent prognostic factors for progression-free survival were International Federation of Gynecology and Obstetrics stage (P=0.01), histological subtypes (P=0.016), and presence of peritoneal carcinomatosis (P<0.05). Conclusion HIF1α overexpression in ovarian cancer is associated with poor overall survival, underlining the importance of hypoxia in this angiogenesis driven disease.
    OncoTargets and Therapy 09/2014; 7:1563-9. DOI:10.2147/OTT.S65373 · 1.34 Impact Factor

Publication Stats

8k Citations
2,275.83 Total Impact Points

Institutions

  • 1996–2015
    • Universitair Ziekenhuis Leuven
      • • Department of Gynaecology and obstetrics
      • • Department of Surgical oncology
      Louvain, Flemish, Belgium
  • 2014
    • WWF United Kingdom
      Londinium, England, United Kingdom
    • European Union
      Bruxelles, Brussels Capital, Belgium
    • European Organisation for Research and Treatment of Cancer
      Bruxelles, Brussels Capital, Belgium
    • West Georgia Obstetrics and Gynecology
      Georgetown, Georgia, United States
  • 2007–2014
    • University of Leuven
      • Department of Reproduction, Development and Regeneration
      Louvain, Flanders, Belgium
    • University of Milan
      Milano, Lombardy, Italy
  • 2013
    • University of Amsterdam
      • Department of Clinical Epidemiology and Biostatistics
      Amsterdamo, North Holland, Netherlands
    • University of Southern California
      • Department of Preventive Medicine
      Los Angeles, CA, United States
  • 2012
    • Medical University of Vienna
      • Comprehensive Cancer Center Vienna
      Vienna, Vienna, Austria
    • Catholic University of Louvain
      • Department of Gynaecology, Obstetrics and Pediatrics - GYPE
      Лувен-ла-Нев, Walloon, Belgium
  • 2011
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States
  • 2010
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2009
    • Radboud University Nijmegen
      Nymegen, Gelderland, Netherlands
  • 2006
    • Dr. Horst Schmidt Kliniken Wiesbaden
      Wiesbaden, Hesse, Germany
  • 2003
    • Leiden University
      Leyden, South Holland, Netherlands
    • Erasmus MC
      • Department of Internal Oncology
      Rotterdam, South Holland, Netherlands
  • 2001
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 1993–1995
    • University of Oslo
      • Department of Chemistry
      Oslo, Oslo, Norway
    • Lund University
      Lund, Skåne, Sweden
  • 1992
    • Gynecologic Oncology Group
      Buffalo, New York, United States
  • 1983
    • University of Antwerp
      Antwerpen, Flanders, Belgium