VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib - a multicentric retrospective analysis

被引：44

作者：

Beuselinck, Benoit ^{[1
,2
,3
]}

Karadimou, Alexandra ^{[3
]}

Lambrechts, Diether ^{[4
,5
]}

Claes, Bart ^{[4
,5
]}

Wolter, Pascal ^{[1
,2
]}

Couchy, Gabrielle ^{[3
]}

Berkers, Joost ^{[6
]}

van Poppel, Hendrik ^{[6
]}

Paridaens, Robert ^{[1
,2
]}

Schoffski, Patrick ^{[1
,2
]}

Mejean, Arnaud ^{[7
]}

Verkarre, Virginie ^{[8
]}

Lerut, Evelyne ^{[9
]}

Joly, Florence ^{[10
]}

Lebret, Thierry ^{[11
]}

Gravis, Gwenaelle ^{[12
]}

Deplanque, Gael ^{[13
]}

Descazeaud, Aurelien ^{[14
]}

Leclercq, Nathalie Rioux ^{[15
]}

Molinie, Vincent ^{[16
]}

Patard, Jean-Jacques ^{[17
]}

Teghom, Corine ^{[18
]}

Elaidi, Reza ^{[18
]}

Zucman-Rossi, Jessica ^{[3
,18
]}

Oudard, Stephane ^{[3
,18
]}

机构：

[1] Katholieke Univ Leuven, Leuven Canc Inst, Univ Hosp Leuven, Dept Gen Med Oncol, Louvain, Belgium

[2] Katholieke Univ Leuven, Leuven Canc Inst, Univ Hosp Leuven, Expt Oncol Lab, Louvain, Belgium

[3] Univ Paris 05, INSERM, Genom Fonct Tumeurs Solides U674, Paris, France

[4] Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, Louvain, Belgium

[5] VIB, Vesalius Res Ctr, Louvain, Belgium

[6] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Urol, Louvain, Belgium

[7] Univ Paris 05, Georges Pompidou European Hosp, Dept Urol, Paris, France

[8] Univ Paris 05, Hop Necker Enfants Malad, Dept Pathol, Paris, France

[9] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Pathol, Louvain, Belgium

[10] Ctr Francois Baclesse, Dept Med Oncol, F-14021 Caen, France

[11] Hop Foch, Dept Urol, Suresnes, France

[12] Inst J Paoli I Calmettes, Dept Med Oncol, F-13009 Marseille, France

[13] Clin St Joseph, Dept Med Oncol, Paris, France

[14] Hop Dupuytren, Dept Urol, Limoges, France

[15] CHU Rennes, Dept Pathol, Rennes, France

[16] Clin St Joseph, Dept Pathol, Paris, France

[17] Hop Bicetre, Dept Urol, Le Kremlin Bicetre, France

[18] Univ Paris 05, Georges Pompidou European Hosp, Dept Med Oncol, Paris, France

来源：

ACTA ONCOLOGICA | 2014年 / 53卷 / 01期

关键词：

BEVACIZUMAB PLUS IRINOTECAN; TARGETED THERAPY; INTERFERON-ALPHA; PROGRESSION; PACLITAXEL; SURVIVAL; EFFICACY; TRIAL;

D O I：

10.3109/0284186X.2013.770600

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 first-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 = 0.028), a poorer PFS (10 vs. 18 months, p = 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS (14 vs. 31 months, p = 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 = 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p = 0.019 on univariate 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 findings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pancreatic cancer patients. Prospective validation of this SNP is warranted.

引用

页码：103 / 112

页数：10

共 21 条

[1] Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib [J].

Beuselinck, B. ;

Oudard, S. ;

Rixe, O. ;

Wolter, P. ;

Blesius, A. ;

Ayllon, J. ;

Elaidi, R. ;

Schoeffski, P. ;

Barrascout, E. ;

Morel, A. ;

Escudier, B. ;

Lang, H. ;

Zucman-Rossi, J. ;

Medioni, J. .

ANNALS OF ONCOLOGY, 2011, 22 (04) :794-800

[2]

Beuselinck B, 2013, BR J CANC

[3] Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial [J].

Escudier, Bernard ;

Pluzanska, Anna ;

Koralewski, Piotr ;

Ravaud, Alain ;

Bracarda, Sergio ;

Szczylik, Cezary ;

Chevreau, Christine ;

Filipek, Marek ;

Melichar, Bohuslav ;

Bajetta, Emilio ;

Gorbunova, Vera ;

Bay, Jacques-Olivier ;

Bodrogi, Istvan ;

Jagiello-Gruszfeld, Agnieszka ;

Moore, Nicola .

LANCET, 2007, 370 (9605) :2103-2111

[4] Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study [J].

Garcia-Donas, Jesus ;

Esteban, Emilio ;

Javier Leandro-Garcia, Luis ;

Castellano, Daniel E. ;

Gonzalez del Alba, Aranzazu ;

Angel Climent, Miguel ;

Angel Arranz, Jose ;

Gallardo, Enrique ;

Puente, Javier ;

Bellmunt, Joaquim ;

Mellado, Begona ;

Martinez, Esther ;

Moreno, Fernando ;

Font, Albert ;

Robledo, Mercedes ;

Rodriguez-Antona, Cristina .

LANCET ONCOLOGY, 2011, 12 (12) :1143-1150

[5] The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer Results from the Nordic ACT trial [J].

Hansen, Torben Frostrup ;

Christensen, Rene dePont ;

Andersen, Rikke Fredslund ;

Spindler, Karen-Lise Garm ;

Johnsson, Anders ;

Jakobsen, Anders .

INTERNATIONAL JOURNAL OF COLORECTAL DISEASE, 2012, 27 (06) :715-720

[6] Prognostic Factors for Overall Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor-Targeted Agents: Results From a Large, Multicenter Study [J].

Heng, Daniel Y. C. ;

Xie, Wanling ;

Regan, Meredith M. ;

Warren, Mark A. ;

Golshayan, Ali Reza ;

Sahi, Chakshu ;

Eigl, Bernhard J. ;

Ruether, J. Dean ;

Cheng, Tina ;

North, Scott ;

Venner, Peter ;

Knox, Jennifer J. ;

Chi, Kim N. ;

Kollmannsberger, Christian ;

McDermott, David F. ;

Oh, William K. ;

Atkins, Michael B. ;

Bukowski, Ronald M. ;

Rini, Brian I. ;

Choueiri, Toni K. .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (34) :5794-5799

[7] Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer [J].

Hurwitz, H ;

Fehrenbacher, L ;

Novotny, W ;

Cartwright, T ;

Hainsworth, J ;

Heim, W ;

Berlin, J ;

Baron, A ;

Griffing, S ;

Holmgren, E ;

Ferrara, N ;

Fyfe, G ;

Rogers, B ;

Ross, R ;

Kabbinavar, F .

NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (23) :2335-2342

[8] Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma [J].

Kreisl, Teri N. ;

Kim, Lyndon ;

Moore, Kraig ;

Duic, Paul ;

Royce, Cheryl ;

Stroud, Irene ;

Garren, Nancy ;

Mackey, Megan ;

Butman, John A. ;

Camphausen, Kevin ;

Park, John ;

Albert, Paul S. ;

Fine, Howard A. .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (05) :740-745

[9]

Lambrechts D, 2013, J CLIN ONCOL

[10] VEGF pathway genetic variants as biomarkers of treatment outcome with bevacizumab: an analysis of data from the AViTA and AVOREN randomised trials [J].

Lambrechts, Diether ;

Claes, Bart ;

Delmar, Paul ;

Reumers, Joke ;

Mazzone, Massimiliano ;

Yesilyurt, Betul T. ;

Devlieger, Roland ;

Verslype, Chris ;

Tejpar, Sabine ;

Wildiers, Hans ;

de Haas, Sanne ;

Carmeliet, Peter ;

Scherer, Stefan J. ;

Van Cutsem, Eric .

LANCET ONCOLOGY, 2012, 13 (07) :724-733

← 1 2 3 →