Vegfr1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib – a multicentric retrospective analysis

Acta Oncologica, 2013; Early Online: 1–10 ORIGINAL ARTICLE
VEGFR1 single nucleotide polymorphisms associated with
outcome in patients with metastatic renal cell carcinoma treated
with sunitinib – a multicentric retrospective analysis

BENOIT BEUSELINCK 1,2 , ALEXANDRA KARADIMOU 2 , DIETHER LAMBRECHTS 3,4 , BART CLAES 3,4 , PASCAL WOLTER 1 , GABRIELLE COUCHY 2 , JOOST BERKERS 5 , HENDRIK VAN POPPEL 5 , ROBERT PARIDAENS 1 , PATRICK SCH Ö FFSKI 1 , ARNAUD M É JEAN 6 , VIRGINIE VERKARRE 7 , EVELYNE LERUT 8 , FLORENCE JOLY 9 , THIERRY LEBRET 10 , GW É NAELLE GRAVIS 11 , GAEL DEPLANQUE 12 , AUR É LIEN DESCAZEAUD 13 , NATHALIE RIOUX LECLERCQ 14 , VINCENT MOLINI É 15 , JEAN-JACQUES PATARD 16 , CORINE TEGHOM 17 , REZA ELAIDI 17 , JESSICA ZUCMAN-ROSSI 2,17 & ST É PHANE OUDARD 2,17 1 Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, 2 Inserm U674 G é nomique fonctionnelle des tumeurs solides, Universit é Paris-5 Ren é Descartes, Paris, France, 3 Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium, 4 Vesalius Research Center, VIB, Leuven, Belgium, 5 Department of Urology, University Hospitals Leuven, KU Leuven, Leuven, Belgium, 6 Department of Urology, Georges Pompidou European Hospital, Universit é Paris-5 Ren é Descartes, Paris, France, 7 Department of Pathology, H ô pital Necker-Enfants malades, Universit é Paris-5 Ren é Descartes, Paris, France, 8 Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium, 9 Department of Medical Oncology, Centre Fran ç ois Baclesse, Caen, France, 10 Department of Urology, H ô pital Foch, Suresnes, France, 11 Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France, 12 Department of Medical Oncology, Clinique St-Joseph, Paris, France, 13 Department of Urology, H ô pital Dupuytren, Limoges, France, 14 Department of Pathology, CHU Rennes, Rennes, France, 15 Department of Pathology, Clinique St-Joseph, Paris, France, 16 Department of Urology, H ô pital Bic ê tre, Le Kremlin-Bic ê tre, France, and 17 Department of Medical Oncology, Georges Pompidou European Hospital, Universit é Paris-5 Ren é Descartes, Paris, France Acta Oncol Downloaded from by K U Leuven on 02/20/13 Abstract
Background. There are no validated markers that predict outcome in metastatic renal cell cancer (mRCC) patients treated
with sunitinib. Recently, single nucleotide polymorphism (SNP) rs9582036 in VEGFR1 has been proposed as a predictor
of progression-free survival (PFS) and overall survival (OS) to bevacizumab in patients with pancreatic cancer and
rs7993418 in VEGFR1 as predictor for PFS in mRCC-patients treated with bevacizumab. Here, we aim to study the
impact of these SNPs in mRCC patients treated with sunitinib. Methods. We included patients with mRCC treated in 15
institutions in France and Belgium. Patients received sunitinib as fi rst-line targeted therapy. We assessed response, time-
to-tumor progression (TTP), OS, and clinical and biochemical parameters associated with outcome. We genotyped
rs9582036 and rs7993418 as well as three other surrounding SNPs in VEGFR1: rs9554320, rs9554316 and rs9513070.
Association between SNPs and treatment outcome were studied by univariate analysis and by multivariate Cox regression
using relevant clinical factors associated with TTP and OS as covariates. Findings . Ninety-one patients were included. We
found that mRCC patients with the CC-variant in rs9582036 in VEGFR1 have a poorer response rate (RR) (0% vs. 46%,
p ϭ 0.028), a poorer PFS (10 vs. 18 months, p ϭ 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS
(14 vs. 31 months, p ϭ 0.019 on univariate and 0.008 on multivariate analysis) compared to patients with the AC- and
AA-genotypes. mRCC patients with the AA-variant in rs9554320 in VEGFR1 have a poorer PFS (12 vs. 21 months,
p ϭ 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p ϭ 0.019 on univariate
Correspondence: Benoit Beuselinck, Leuven Cancer Institute, Herestraat 49, B-3000 Leuven, Belgium. Tel: ϩ 32 16 346900. Fax: ϩ 32 16 346901. E-mail: (Received 22 October 2012 ; accepted 19 January 2013 ) ISSN 0284-186X print/ISSN 1651-226X online 2013 Informa HealthcareDOI: 10.3109/0284186X.2013.770600 and 0.067 on multivariate analysis) compared to patients with the AC- and CC-genotypes. Interpretation. mRCC patients with the CC-genotype in VEGFR1 SNP rs9582036 have a poorer response rate, PFS and OS when treated with sunitinib. These fi ndings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pan-creatic cancer patients. Prospective validation of this SNP is warranted. Clear cell RCC is characterized by an inactivated fi ve criteria are part of the Memorial Sloan-Kettering Cancer Center (MSKCC) score, which categorize Inactivation of the VHL- gene leads to elevated protein patients into a favorable, intermediate, and poor levels of hypoxia-induced factor- α which upregulates prognosis group [6]. These established clinical and vascular endothelial growth factor (VEGF) and biochemical markers are indicators of the general platelet-derived growth factor (PDGF) expression. condition of the patient and the extension or stage Targeted therapies directed against some of these pro- teins have signifi cantly improved progression-free sur- Recently, a number of studies have proposed that vival (PFS) of patients with metastatic RCC (mRCC) genetic variability in genes involved in sunitinib phar- as compared to historical treatment options. Sunitinib macokinetics and pharmacodynamics alter the effi - malate is an orally administered tyrosine kinase recep- cacy of sunitinib [7 – 9] or pazopanib [10] in mRCC tor inhibitor (TKI) that targets VEGF-receptor (VEGFR) -1, -2 and -3, PDGF-receptor (PDGFR)- α HIF1A, PDGFRA, VEGFR2, VEGFR3, FGFR2, and and - β , KIT, FLT-3, colony stimulating factor-1 recep- IL8 to sunitinib effi cacy . Other studies have shown tor, and RET. In a randomized controlled trial suni- links between polymorphisms in genes involved in tinib signifi cantly prolonged the PFS (11 vs. 5 months, VEGF-dependent-angiogenesis and outcome in p Ͻ 0.001) as compared to interferon- α [1,2]. Median patients treated with bevacizumab [11]. Bevacizumab, a humanized monoclonal antibody that binds to tively. Sunitinib is currently a standard treatment in VEGF, was the fi rst anti-VEGF-specifi c drug to be RCC, but other anti-VEGFR and anti-PDGFR- approved for clinical use. When used together with targeted TKIs like sorafenib, pazopanib and axitinib standard therapies, bevacizumab is effective in several are also used in different stages of the disease. cancers such as metastatic colorectal [12], non-small Although roughly 50% of RCC patients receiving cell lung [13], breast cancer [14], RCC [15], and in sunitinib experience an objective response and 43% achieve disease stabilization, 7% will experience pro- Lambrechts et al. recently showed the predictive gressive disease (PD) at fi rst evaluation due to intrin- impact of two polymorphisms in VEGFR1 , a receptor sic resistance or due to other factors [1]. Moreover, involved in VEGF-dependent tumoral angiogenesis, all patients with clinical benefi t will ultimately relapse on outcome in pancreatic cancer and RCC treated due to acquired resistance or for other reasons. The with bevacizumab. In 77 patients with pancreatic car- identifi cation of biomarkers able to predict intrinsic cinoma included in the AVITA trial (randomizing resistance could avoid unnecessary costs and side patients in arm A with gemcitabine, erlotinib, and effects, guiding alternative treatment decisions for bevacizumab and arm B with gemcitabine, erlotinib, Acta Oncol Downloaded from by K U Leuven on 02/20/13 these patients. On the other hand, the identifi cation and placebo) and treated with bevacizumab, patients of biomarkers for acquired resistance could provide with the CC-variant of rs9582036 319A Ͼ C had a novel directions to develop therapies that block resis- worse PFS (3.4 months) compared to patients with tance pathways. Although different mechanisms of resistance have been proposed [3], reliable biomark- ers predictive of sunitinib sensitivity or primary/sec- OS (4.7 months) compared to AA-carriers (10.2 Several clinical and biochemical markers linked (p ϭ 0.0015). As no effects were seen in placebo- to PFS and OS are available for sunitinib treated treated patients, the authors concluded that this SNP patients [4,5]. For PFS, these are baseline serum lac- has a predictive value [17]. Fine-mapping experi- tate dehydrogenase (LDH) level, the presence of two ments of the VEGFR1 locus identifi ed rs7993418, a or more metastatic sites, no prior nephrectomy, East- synonymous SNP affecting tyrosine 1213 in the ern Cooperative Oncology Group Performance Sta- VEGFR1 tyrosine-kinase domain, as the functional tus (ECOG PS), and baseline platelet count. For OS, variant underlying the association. This SNP causes factors include the presence of bone metastases, time a shift in codon usage, leading to increased VEGFR1 between nephrectomy and start of systemic therapy, expression and downstream VEGFR1 signaling. In 59 baseline serum LDH level, baseline hemoglobin, patients with mRCC treated with bevacizumab in the baseline calcium and baseline ECOG PS. The last AVOREN trial (randomizing patients in arm A with VEGFR1 polymorphisms and outcome in RCC treated with sunitinib bevacizumab plus interferon versus arm B with had to reach at least the fi rst response evaluation, which was usually foreseen after two treatment cycles rs7993418 correlated signifi cantly with PFS, which was 17.5 months in the TT-variants, 10.9 months in DNA was isolated from fresh frozen normal kid- the TC-variants and 14.5 months in the CC-variants ney tissue sampled during nephrectomy using the (p ϭ 0.033). Again, no effect was observed in placebo Qiaquick extraction kit (Qiagen, Valencia, CA, USA) and quantifi ed by fl uorometry (Fluoroskan Thermo Labsystems, Cergy-Pontoise, France). DNA was iso- lated from peripheral blood with the Qiagen DNA colorectal cancer patients treated with bevacizumab kit (Qiagen, Valencia, CA, USA) and fi nal DNA con- plus chemotherapy: patients with the CC-genotype centration quantifi ed with Nanodrop (Nanodrop, had 36% of objective response, meanwhile those with Wilmington, USA). High-throughput SNP genotyp- CA- and CC-genotype had respectively, 40% and ing was performed using the Sequenom MassArray 56% of objective response (p ϭ 0.048) [18]. platform (Sequenom, San Diego, CA, USA) [19]. The aim of the present study is to replicate the Genotyping analysis was performed by investigators association of these SNPs observed with bevaci- zumab therapy in pancreatic carcinoma, RCC and We genotyped rs9582036 and four surrounding colorectal carcinoma in a retrospective cohort of tagging SNPs: rs9554316, rs9513070, rs9554320 and rs7993418, the latter the underlying variant causing a higher expression of selected in the study of Lambrechts et al. [17]. Patients and methods
We defi ned TTP as the time between the fi rst day For this retrospective study, germ-line DNA samples of sunitinib treatment and the date of radiological were selected from the ‘ CIT-rein ’ RCC tumor bank. disease progression. In most cases, RECIST was This French-Belgian multicentric RCC tumor bank used. Patients who had not progressed at database contains more than 250 frozen primary kidney tumor closure were censored at last follow-up. OS was samples. We selected the samples of patients treated defi ned as the time between the fi rst day of sunitinib with sunitinib as fi rst-line anti-VEGF-targeted ther- treatment and the date of death or last date of apy and of whom frozen normal kidney tissue was follow-up. TTP was chosen above PFS because one available. For 11 additional patients, of whom no patient died from a surgical intervention after eight frozen normal kidney tissue was available, peripheral months of sunitinib. Objective response was assessed blood was used. The protocol was approved by the medical ethics review boards of all participating insti- response, partial response (PR), stable disease (SD), tutions, and signed consent was obtained from all or PD. Patients with bone metastases only (two patients. In some cases, we used frozen biological patients) were excluded for the TTP analysis, as material originating from patients who had already bone lesions are not target lesions for RECIST. died and for whom approval for the utilization of Timing for assessments was dictated by individual remaining tissues was foreseen by the institutional Acta Oncol Downloaded from by K U Leuven on 02/20/13 All patient characteristics were tested in an uni- Eligible patients could have received cytokines as variate analysis against TTP and OS using Kaplan- systemic treatment for kidney tumors before starting Meier statistics and in the multivariate model with sunitinib as a monotherapy, but they could not have Cox-regression analysis. Fisher exact test was used received any other TKI or mammalian target of to correlate SNPs with RR. Variables with a p Յ 0.2 rapamycine (mTOR) inhibitor before starting suni- on univariate analysis were selected as covariates for tinib. Most of the patients were treated in routine multivariate Cox-regression analysis. The MSKCC clinical practice, some were included in clinical trials. score was not used in the multivariate model, as the All patients had progressive disease when sunitinib individual factors of the score were used if signifi - was started. Drug schedules, dose-reduction policy, cant on univariate analysis. Results with a p-value and the timing of radiological assessments were left of Ͻ 0.05 were considered as signifi cant in the mul- to the discretion of the attending doctors in accor- tivariate analysis. As our approach was the validation dance with current local practice guidelines. Patient of previously published results, although with characteristics considered relevant for TTP and OS another class of anti-angiogenics, no correction for analysis were the fi ve risk factors according to multiple testing was made. Statistical analyses were MSKCC prognostic criteria and additional factors conducted using GraphPad Prism 5 (GraphPad such as baseline neutrophil and platelet count, and Software, La Jolla, UCLA) and XLSTAT software the presence of liver or bone metastases. All patients (response assessment was poorly defi ned in the medical records of six patients, but they had a clini- We included 91 patients who started sunitinib cal benefi t of at least fi ve months, although it was between November 2005 and January 2012 and unclear whether the best response was either PR or closed the follow-up database in December 2012. SD). Six of 84 (7%) patients had a complete response, Table I shows the clinical characteristics of included 36/84 (37%) patients a PR, 38/84 (45%) a SD and patients. The majority of patients were of Caucasian origin . According to MSKCC prognostic criteria, Table II reports the allele frequencies of the 18% of patients were categorized into the favorable, genotyped polymorphisms in our series. Overall, the 55% in the intermediate and 27% into the poor-risk SNPs were successfully genotyped with success Ն 91% for each SNP and an overall average At the time of analysis, 62 (68%) patients had reached progression and 58 (64%) had died. The We detected a minor allele frequency of 31.3% for median follow-up was 50 months (range 1 – 75) after the C-allele in rs9582036, corresponding to the minor the start of sunitinib. Median TTP was 15.0 months allele frequency reported in the dbSNP (dbSNP build and median OS 30.0 months in the total group. The 136) database or 1000 Genomes Project (31.7%). difference with outcome on sunitinib in the pivotal Table II also reports the linkage disequilibrium (r trial (PFS 11.0 and OS 26.0 months) is likely due test) between the different SNPs showing a complete to the patient selection in our series: all the patients correlation between rs7993418 and rs9554316, but had to reach at least the fi rst evaluation by CT scan after approximately 10 weeks of treatment. More- Table III shows the clinical and biochemical over, all but one patient underwent nephrectomy. parameters associated with TTP and OS. In the mul- Best response assessment was available in 85 patients tivariate analysis for TTP, four parameters exhibited a p Յ 0.2 (baseline ECOG PS, baseline LDH activity, Table I. Patient characteristics at diagnosis and at the start of baseline neutrophil count, and the presence of bone metastases [20]) and were considered as covariates in the multivariate analysis for TTP. For OS, baseline ECOG PS, the laps of time between nephrectomy and start of systemic therapy and the presence of bone metastases were taken into account. univariate and multivariate Cox regression analysis for the SNPs in VEGFR1 for TTP and OS. Patients homozygous for the rs9582036 C-allele in VEGFR1 on univariate and 0.06 on multivariate analysis) and OS (14 vs. 31 months) (p ϭ 0.019 on univariate and 0.008 on multivariate analysis) compared to Acta Oncol Downloaded from by K U Leuven on 02/20/13 patients with the AC- and AA-genotypes, while the curves for AC- and AA-genotypes were overlapping both for PFS and OS. In the CC-carriers, there were no PRs, meanwhile in the AC- and AA-carriers, there Patients homozygous for the rs7993418 C-allele had a poorer PFS and OS compared to TC- and TT-carriers, but this difference was not statistically signifi cant. As rs7993418 was in perfect linkage dis- equilibrium with rs9554316 (see Table II), the same was observed for rs9554316 TT-carriers vs. GT- and GG-carriers. Patients with the AA-variant in rs9554320 had a poorer PFS (12 vs. 21 months) ϭ 0.0066 on univariate and 0.005 on multivariate analysis) and OS (22 vs. 34 months) (p ϭ 0.019 on univariate and 0.067 on multivariate analysis) com- ECOG PS, Eastern cooperative oncology group performance pared to CA-and CC-carriers. Finally, no impact of status; LDH, lactate dehydrogenase; MSKCC, Memorial Sloan- rs9513070 on PFS or OS could be observed. VEGFR1 polymorphisms and outcome in RCC treated with sunitinib Table II. Genotype and allele distribution of the genotyped SNPS in VEGFR1 and corelation of polymorphisms (r ² ). Discussion
mRCC patients treated with sunitinib. As sunitinib We observed a signifi cant association between SNP was used as single agent in our series, our results rs9582036 in VEGFR1, one of the molecular targets were not confounded by concomitant chemotherapy of sunitinib involved in tumoral VEGF-dependent and we could obtain signifi cant links in a series angiogenesis, and outcome (PFS, OS and RR) in involving only a limited number of patients. Table III. Baseline clinical and biochemical parameters associated with TTP and OS. Hb low [ Ͻ 11.5 g/dl (women) or Ͻ 13 g/dl (men)] (n ϭ 38) Time from nephrectomy (or initial diagnosis) to systemic Acta Oncol Downloaded from by K U Leuven on 02/20/13 Time from nephrectomy (or initial diagnosis) to systemic ECOG PS, Eastern cooperative oncology group performance status; LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center; NA, not applicable; NR, not reached; OS, overall survival; TTP, time-to-tumor progression; ULN, upper limit of normal. * The p-value was calculated by log-rank test. Note: The parameters that were considered for the multivariate analysis for TTP were baseline neutrophil count, baseline LDH and baseline ECOG PS as well as the presence of bone metastasis. The parameters that were considered for the multivariate analysis for OS were baseline ECOG PS, the laps of time between nephrectomy to systemic treatment as well as the presence of bone metastasis. Table IV. Univariate and multivariate analysis: association between SNPS and outcome. (months) (multivariate) * * (95% CI of HR) CI, confi dence interval; HR, hazard ratio; OS, overall survival; NA, not applicable; NR, not reached; ND, not done; TTP, time-to-tumor progression. * The p-value for the univariate analysis was calculated by log-rank test; * * The p-value for the multivariate analysis was the result of a Cox proportional hazards model. Note: VEGFR1 rs9582036: when analyzing AA versus AC versus CC, the TTP and OS curves for AA and AC are completely overlapping, allowing us to analyze AA ϩ AC against CC. rs7993418: all the CC-variants were also rs9582036 CC-variants. rs9554316: all the TT-variants were also rs9582036 CC-variants. rs9554320: all the rs9582036 CC-variants were rs9554320 AA-variants. For rs9513070 it was not possible to group variants, because the three curves were overlapping. Concerning rs9582036, two reports in literature, As no effects were seen in placebo-treated patients in patients with pancreatic cancer or colorectal can- and a signifi cant genotype by treatment interaction cer, treated with bevacizumab and chemotherapy, are (p ϭ 0.041) was recorded, the authors concluded that the VEGFR1 locus containing this SNP serves as a In AVITA [21], a multicenter, randomized phase predictive marker for bevacizumab treatment out- Acta Oncol Downloaded from by K U Leuven on 02/20/13 III trial, patients with metastatic pancreatic adeno- carcinoma were randomly assigned to receive gem- Hansen observed in 218 metastatic colorectal citabine and erlotinib plus either bevacizumab or cancer patients treated with bevacizumab plus che- placebo. Lambrechts et al. investigated DNA of 154 motherapy a statistically signifi cant difference in RR: AVITA-patients, of whom 77 received bevacizumab 36% of patients with the CC-genotype had objective responses, while those with CA- and AA-genotype VEGFR1 was signifi cantly associated with OS in the had 40% and 56% of objective responses, respec- bevacizumab group: median OS was 4.7 months in CC-carriers, 5.9 months in AC-carriers, and 10.2 The rs7993418 SNP was identifi ed by Lambrechts months in AA-carriers. After adjustment for neutro- et al. as the functional variant underlying the associa- phil count, C-reactive protein level, and tumor loca- tion between rs9582036 and outcome. In particular, tion, association of rs9582036 with OS showed a this SNP causes a shift in codon usage, leading to p-value of 0.002. SNP rs9582036 was also associated VEGFR1 signaling. In 59 patients with mRCC treated with PFS in bevacizumab-treated patients: AC- and with bevacizumab in the AVOREN trial [15] (ran- CC-carriers of this SNP exhibited HRs for PFS of domizing patients in arm A bevacizumab plus inter- 2.0 (95% CI 1.19 – 3.36; p ϭ 0.0091) and 4.72 (95% feron vs. arm B interferon alone), Lambrechts et al. CI 2.08 – 10.68; p ϭ 0.0002) relative to AA-carriers. found that rs7993418 correlated signifi cantly with VEGFR1 polymorphisms and outcome in RCC treated with sunitinib TTP (%): VEGFR1 rs9582036
CA + AA: 18 months
CC: 10 months
Time (months)
Subjects at risk (AA + AC genotypes)
Subjects at risk (CC genotypes)
OS (%) VEGFR1 rs9582036
CA + AA: 31 months
CC: 14 months
Time (months)
12 18 24 30 36 42 48 54
Subjects at risk (AA+AC genotypes)
84 80 69 56 43 34 28 25 17 13
Subjects at risk (CC genotypes)
Figures 1 and 2. Kaplan-Meier curves of the signifi cant associations between SNP rs9582036 and time-to-tumor progression (TTP) and Acta Oncol Downloaded from by K U Leuven on 02/20/13 overall survival (OS) in our series. P-values are the p-values from the univariate analysis. PFS, which was 17.5 months in the TT-variants, 10.9 Concerning the other surrounding polymor- months in the TC-variants and 14.5 months in the CC- VEGFR1 (rs9554316, rs9513070, and variants (p ϭ 0.033), while no effect was observed in 51 placebo treated patients. No correlation with OS was correlated with OS in the bevacizumab group of noted, but the authors explained this by the low num- AVITA, but they did not pass the p-value threshold ber of death events in their patient series and frequent post-protocol treatments with the anti-angiogenic TKIs rs9554316 favoring the GG- and GT-genotypes, sorafenib and sunitinib, which might affect association p ϭ 0.0081 for rs9513070 favoring the AA- and AG- of VEGFR1 SNPs with bevacizumab treatment out- genotypes, and p ϭ 0.0097 for rs9554320 favoring the come. Although in our series, we did notice a shorter CC- and CA-genotypes). In AVOREN, due to high PFS and OS in patients with the CC-variant, these linkage disequilibrium with rs7993418 in this results were not signifi cant. This can probably been patient series, variants rs9554316 (favoring the explained by the fact that the minor allele variant in GG- and GT-genotypes) and rs9513070 (favoring rs7993418 is less frequent than the minor allele vari- the AA- and AG-genotypes) also correlated signifi - ant in rs9582036. As a consequence, we only had four cantly with PFS in the bevacizumab group. The patients with the CC-genotype in our series. other two SNPs in the VEGFR1 locus, rs9582036 TTP (%): VEGFR1 rs9554320
AA: 12 months
CC + CA: 21 months
Time (months)
Subjects at risk (CC + CA genotypes)
Subjects at risk(AA genotypes)
OS (%) VEGFR1 rs9554320
AA: 22 months
CC + CA: 34 months
Time (months)
12 18 24 30 36 42 48 54
Subjects at risk (CC + CA genotypes) 65 63 54 45 36 30 25 23 15 12
Subjects at risk(AA genotypes)

21 18 16 11 9
Figures 3 and 4. Kaplan-Meier curves of the signifi cant associations between SNP rs9554320 and time-to-tumor progression (TTP) and overall survival (OS) in our series. P-values are the p-values from the univariate analysis. Acta Oncol Downloaded from by K U Leuven on 02/20/13 and rs9554320, were in lower linkage disequili- placebo, we cannot affi rm that rs9582036 has a predic- brium with rs7993418 and were not signifi cantly tive value. Nevertheless, given the impact both on PFS associated with PFS. In our series, the only signifi - and OS and given the fact that in bevacizumab treated cant fi ndings were the association between rs9554320 patients this SNP is a predictive marker, it is probable and PFS and OS, favoring patients with the AC- that SNP rs9582036 is also of predictive value in RCC and CC-genotype, the latter confi rming the data of The emerging evidence of the impact of SNPs in Our study has several potential limitations. First of pathways linked to pharmacokinetics and pharmaco- all, it was a retrospective analysis of patients treated in dynamics of sunitinib shows that besides acquired several centers without a central protocol dictating the genetic characteristics of tumor cells, patient’s germline treatment schedule, dose modifi cations or timing of genetic variation may also affect the effectiveness of radiological assessments. Secondly, because our patients anticancer therapy. Germline DNA has signifi cant were mainly white, the relevance of these polymor- phisms needs to be assessed in other ethnic groups, in markers in that it is inherited, fi xed, and relatively whom the described polymorphisms may be less insensitive to time and environmental factors. frequent. Finally, the major handicap of this study is If the impact of these and other SNPs on out- that due to the lack of a control group treated with come on sunitinib could be confi rmed prospectively VEGFR1 polymorphisms and outcome in RCC treated with sunitinib in independent series, scoring systems based on the Benoit Beuselinck, Alexandra Karadimou, Gabrielle combination of several unfavorable or favorable Couchy, and Joost Berkers were responsible for SNPs could be elaborated. When combining these DNA-extraction. Bart Claes and Diether Lambrechts SNPs with clinical and biochemical parameters were responsible for SNP-genotyping. Virginie linked to outcome, we will probably be able to pre- Verkarre, Vincent Molini é , Nathalie Rioux-Leclercq, dict more precisely the chance of response on suni- and Evelyne Lerut were involved in pathology review. tinib and identify primary resistant patients in order to orient them towards other therapies avoiding Thierry Lebret, Gw é naelle Gravis, Ga ë l Deplanque, unnecessary side effects and costs. We will probably also be capable of predicting more accurately PFS and thus the moment of secondary resistance. data collection and provided study materials or Contributors
recruited patients. All authors critically reviewed the This project is a common project of two kidney tumor manuscript and approved the fi nal version. banks: the CIT-rein tumor bank (Paris, France) and the University Hospitals Leuven kidney tumor bank (Leuven, Belgium). The CIT-rein project is headed Declaration of interest: The authors report no
confl icts of interest. The authors alone are respon- Jacques Patard and was part of the PNES 2007 sible for the content and writing of the paper. ( Programme National d ’ Excellence Sp é cialis é e) from Benoit Beuselinck received a grant from Fondation the INCa (Institut du Cancer). We want to thank sin- Martine Midy (Paris, France) and Fonds voor cerely for their collaboration the urologists, medical Wetenschappelijk Onderzoek Vlaanderen (Belgium). oncologists and pathologists of the next centers, whose Alexandra Karadimou received a grant from the biological material was used in the analysis: Angers: Hellenic Society of Medical Oncology (Athens, Centre Oncologique Paul Papin: Abdel Azzouzi, R é my Greece). Bart Claes is supported by the Institute é phane Triau, Pierre Bigot; Caen: Centre for the Promotion of Innovation by Science and Fran ç ois Baclesse: Henri Bensadoun, Emmanuel Technology in Flanders (IWT) and by an Emmanuel Sevin, Fran ç ois Comoz; Cr é teil: H ô pital Henri Mon- van der Schueren grant of the Vlaamse Liga tegen dor: Alexandre de la Taille, Bernard Paule, Yves Kanker. Diether Lambrechts is supported by the Stichting Tegen Kanker. Evelyne Lerut received fund- Christine Th é odore, Yves Denoux; Leuven: Univer- ing from Fonds voor Wetenschappelijk Onderzoek sity Hospitals Leuven: Hendrik Van Poppel, Evelyne Vlaanderen (Belgium) and Stichting tegen Kanker. Lerut, Joost Berkers, Pascal Wolter, Patrick Sch ö ffski, St é phane Oudard received honorarium from Novartis, Pfi zer, Roche, Sanofi -Aventis, Keocyt, Amgen, and Aur é lien Descazeaud, Julien Berger; Lyon: Centre Bayer. Patrick Sch ö ffski received honoraria from Pfi zer L é on B é rard: Marc Colombel, Sylvie N é grier, Florence and GSK for participation in educational activities in Mege-Lechevallier; Marseille: Institut Paoli-Calmettes: the context or renal cell carcinoma. Pierre Bigot Acta Oncol Downloaded from by K U Leuven on 02/20/13 received honorarium from Novartis. Jean Jacques Nantes: ICO Gauducheau: Olivier Bouchot, Fr é d é ric Patard is a consultant and principal investigator in Pfi zer trials. Gwenaelle Gravis received funds from é jean, Virginie Verkarre; Poitiers: Jacques Novartis. Benoit Beuselinck received honoraria from Irani, Jean Marc Tourani, Pierre Marie Le Villain; Amgen, Janssen and Bayer. Diether Lambrechts Rennes: Brigitte Laguerre, Jean-Jacques Patard, received research support from Hoffman-La-Roche Nathalie Rioux-Leclercq; Paris: Clinique St-Joseph: and Sanofi -Aventis to conduct research projects related Herv é Baumert, Gael Deplanque, Vincent Molini to the discovery of biomarkers for bevacizumab therapy. Strasbourg: CHRU Strasbourg: Didier Jacqmin, Diether Lambrechts is named as co-inventor on a patent Brigitte Duclos, V é ronique Lindler; Tours: CHU Tours: application which value may be affected by publication. Olivier Haillot, Claude Linassier, Franck Fetissof. The tissue collection was coordinated by the Plateforme de References
Ressources Biologiques de l ’ H ô pital Europ é en Georges Pompidou in Paris. We are grateful to Claudia De Toma for the coordination of the tissue collection. Bukowski RM , Rixe O , et al . Sunitinib versus interferon alfa in metastatic renal-cell carcinoma Benoit Beuselinck, Diether Lambrechts, Robert Paridaens, Jean-Jacques Patard, Jessica Zucman- Bukowski RM , Oudard S , et al . Overall survival and updated results for sunitinib compared with interferon alfa in patients fl uorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med 2004 ; 350 : 2335 – 42 . [3] Rini BI , Atkins MB . Resistance to targeted therapy in renal- Dowlati A , et al . Paclitaxel-carboplatin alone or with beva- cell carcinoma . Lancet Oncol 2009 ; 10 : 992 – 1000 . cizumab for non-small-cell lung cancer . N Engl J Med 2006 ; [4] Heng DY , Xie W , Regan MM , Golshayan AR , Sahi C , Eigl Prognostic factors for overall survival in patients [14] Miller K , Wang M , Gralow J , Dickler M , Cobleigh M , Perez with metastatic renal cell carcinoma treated with vascular Paclitaxel plus bevacizumab versus paclitaxel endothelial growth factor-targeted agents: Results from a large, multicenter study . J Clin Oncol 2009 ; 27 : 5794 – 9 . [5] Patil S , Figlin R , Hutson T , Michaelson MD , N é grier S , Kim [15] Escudier B , Pluzanska A , Koralewski P , Ravaud A , Bracarda ST , et al . Prognostic factors for progression free survival and S , Szczylik C , et al . Bevacizumab plus interferon alfa-2a for overall survival with sunitinib targeted therapy and with treatment of metastatic renal cell carcinoma: A randomised, cytokine as fi rst-line therapy in patients with metastatic renal double-blind phase III trial . Lancet 2007 ; 370 : 2103 – 11 . cell carcinoma . Ann Oncol 2011 ; 22 : 295 – 300 . [6] Motzer R , Bacik J , Mazumbar M . Prognostic factors for sur- et al . Phase II trial of single-agent bevacizumab followed by vival of patients with stage IV renal cell carcinoma: Memorial bevacizumab plus irinotecan at tumor progression in recur- Sloan Kettering Cancer Center experience . Clin Cancer Res rent glioblastoma . J Clin Oncol 2009 ; 27 : 740 – 5 . [17] Lambrechts D , Claes B , Delmar P , Reumers J , Mazzone M , Yesilyurt BT , et al . VEGF pathway genetic variants as biomar- kers of treatment outcome with bevacizumab: An analysis of associated with a prolonged progression-free survival in data from the AVITA and AVOREN randomised trials patients with metastatic renal cell cancer treated with sunitinib . Clin Cancer Res 2012 ; 17 : 620 – 9 . [18] Hansen TF , Christensen RD , Andersen RF , Garm Spindler [8] Garcia-Donas J , Esteban E , Leandro-Garc í a LJ , Castellano KL , Johnsson A , Jakobsen A . The predictive value of single DE , del Alba AG , Climent MA , et al . Single nucleotide pol- nucleotide polymorphisms in the VEGF system to the ymorphism associations with response and toxic effects in effi cacy of fi rst-line treatment with bevacizumab plus chem- patients with advanced renal-cell carcinoma treated with otherapy in patients with metastatic colorectal cancer: fi rst-line sunitinib: A multicentre, observational, prospective Results from the Nordic ACT trial . Int J Colorectal Dis 2012 ; study . Lancet Oncol 2011 ; 12 : 1143 – 50 . [9] Beuselinck B , Karadimou A , Lambrechts D , Claes B , Wolter P , [19] Reumers J , De Rijk P , Zhao H , Liekens A , Smeets D , Cleary J , Couchy G , et al . Single nucleotide polymorphisms associated et al . Optimized fi ltering reduces the error rate in detecting with outcome in metastatic renal cell carcinoma treated with genomic variants by short-read sequencing . J Nat Biotechnol sunitinib . Br J Cancer 2013 (accepted) . [20] Beuselinck B , Oudard S , Rixe O , Wolter P , Blesius A , Ayllon J , de Souza P , et al . Pazopanib effi cacy in renal cell carcinoma: et al . Negative impact of bone metastasis on outcome in clear Evidence for predictive genetic markers in angiogenesis-related cell renal cell carcinoma treated with sunitinib . Ann Oncol and exposure-related genes . J Clin Oncol 2011 ; 29 : 2557 – 64 . [11] Lambrechts D , Lenz H-Z , de Haas S , Carmeliet P , Scherer [21] Van Cutsem E , Vervenne WL , Bennouna J , Humblet Y , Gill S , SJ . Markers of response for the anti-angiogenic agent beva- cizumab . J Clin Oncol 2013 (accepted) . combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer . J Clin Oncol 2009 ; 27 : Hainsworth J , Heim W , et al . Bevacizumab plus irinotecan, Acta Oncol Downloaded from by K U Leuven on 02/20/13


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