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Article of the Week: VEGFR1 rs9582036 as a predictive biomarker in m-ccRCC patients treated with sunitinib

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video discussing the paper.

If you only have time to read one article this week, it should be this one.

Validation of VEGFR1 rs9582036 as predictive biomarker in metastatic clear-cell renal cell carcinoma patients treated with sunitinib

Benoit Beuselinck*,,, Johnny Jean-Baptiste*,, Patrick Schoffski, Gabrielle Couchy*,Clement Meiller*,, Frederic Rolland§, Yves Allory, Steven Joniau**, Virginie Verkarre††, Reza Elaidi‡‡, Evelyne Lerut§§, Tania Roskams§§, Jean-Jacques Patard¶¶Stephane Oudard,‡‡, Arnaud Mejean***, Diether Lambrechts†††,‡‡‡ and Jessica Zucman-Rossi*,,‡‡

 

*Inserm, UMR-1162, Genomique fonctionnelle des tumeurs solides, IUH, Paris, Sorbonne Paris Cite, FacultedMedecine, Universite Paris Descartes, Paris, France, Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, §Department of Medical Oncology, Institut de Cancerologie de lOuest, Saint Herblain, Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Henri Mondor, Creteil, France, **Department of Urology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, ††Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants malades, Paris, ‡‡Department of Medical Oncology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, §§Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium, ¶¶Department of Urology, Hopital Bicetre, Le Kremlin-Bicetre, ***Department of
Urology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, †††Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, and ‡‡‡Vesalius Research Center, VIB, Leuven, Belgium

 

Abstract

Objectives

To validate vascular endothelial growth factor receptor-1 (VEGFR1) single nucleotide polymorphism (SNP) rs9582036 as a potential predictive biomarker in metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with sunitinib.

Materials and Methods

m-ccRCC patients receiving sunitinib as first-line targeted therapy were included. We assessed response rate (RR), progression-free survival (PFS), overall survival (OS), and clinical and biochemical parameters associated with outcome. We genotyped five VEGFR1 SNPs: rs9582036, rs7993418, rs9554320, rs9554316 and rs9513070. Association with outcome was studied by univariate analysis and by multivariate Cox regression. Additionally, we updated survival data of our discovery cohort as described previously.

aotwdec3-results

Results

Sixty-nine patients were included in the validation cohort. rs9582036 CC-carriers had a poorer PFS (8 vs 12 months, P = 0.02) and OS (11 vs 27 months, P = 0.003) compared to AC/AA-carriers. rs7993418 CC-carriers had a poorer OS (8 vs 24 months, P = 0.004) compared to TC/TT-carriers. rs9554320 AA-carriers had a poorer RR (0% vs 53%, P = 0.009), PFS (5 vs 12 months, P = 0.003) and OS (10 vs 25 months, P = 0.004) compared to AC/CC-carriers. When pooling patients from the discovery cohort, as described previously (n = 88), and the validation cohort, in the total series of 157 patients, rs9582036 CC-carriers had a poorer RR (8% vs 49%, P = 0.004), PFS (8 vs 14 months, P = 0.003) and OS (13 vs 30 months, P = 0.0004) compared to AC/AA-carriers. Unfavorable prognostic markers at start of sunitinib were well balanced between rs9582036 CC- and AC/AA-carriers.

Conclusion

VEGFR1 rs9582036 is a candidate predictive biomarker in m-ccRCC-patients treated with sunitinib.

Editorial: SNP of the VEGFR – a promising biomarker in mRCC

Despite earlier detection of localised renal tumours, the resultant tumour down-staging, and an ever-increasing armamentarium of systemic therapies available for metastatic RCC (mRCC), population-level RCC mortality data has failed to show significant improvement in survival. The increasing understanding of RCC biology, specifically the tyrosine kinase signalling pathway, has sparked the development and USA Food and Drug Administration (FDA)-approval of four tyrosine kinase inhibitors (TKIs) and one anti-vascular endothelial growth factor receptor (VEGFR) antibody. Additionally, immunotherapies in the form of interferon, interleukin 2 cytokine therapy and the advent of checkpoint inhibitors further expands the options for treatment of mRCC. This poses a clinical dilemma; although clinical trials are showing improved survival outcomes, there is uncertainty about to how best to sequence the available therapies. In lieu of long, expensive clinical trials exploring all possible permutations and in order to personalise therapy for specific patients, we are hopeful the exploration of biomarkers (such as the authors have performed) will fill this void and aid in the selection of therapies based on likelihood of patient response.

While studies do not seem to show a reliable correlation between von Hippel-Lindau gene status or expression levels of hypoxia-inducible factor and response to targeted therapy [1], recent exploration of single nucleotide polymorphisms (SNPs) of the VEGFR has yielded promising results with certain VEGFR1 SNPs (in particular, SNP rs9582036 with CC alleles) associated with a significantly worse overall survival when treated with a TKI [2-4]. The authors previously published on a discovery cohort of patients with mRCC treated with sunitinib and found results consistent with the aforementioned exploratory studies; the CC-variant in rs9582036 was associated with worse response rate, progression-free survival (PFS), and overall survival (14 months vs 31 months; P = 0.008) on multivariate analysis [5, 6].

This current study [7] represents their findings of a validation cohort of the potential predictive association of the VEGFR1 SNP rs9582036 in mRCC treated with sunitinib. In all, 69 patients were genotyped and clinical outcomes analysed; results were consistent with their previous discovery cohort, and in their pooled analysis of 157 patients they confirmed that the allelic status of the rs9582036 SNP was significantly associated with clinical outcomes. Patients with the CC-variant had poorer response rates (8% vs 49%), worse PFS (8 vs 14 months), and worse overall survival (13 vs 30 months).

This finding certainly could have profound implications in guiding choice of systemic therapies and exploration of the biological meaning of these SNP variants could shed light on why certain tumours or patients fail to respond to targeted therapy. However, further study is warranted. In this current study, VEGFR1 mRNA expression levels at the onset of therapy correlated positively with response to treatment; however, there was no association between the SNP genotypes explored and initial VEGFR1 expression, thus providing no clear mechanistic rationale between this association and clinical outcomes. Furthermore, this rs9582036 sub-group represented a minority (9%) of the patients studied and most patients were Caucasian, limiting the applicability of this genotyping. Additionally, the lack of a placebo control group prevents a conclusion about what to do in the case of a CC-variant rs9852036 patient, i.e. a diminished response to TKIs does not mean TKIs are necessarily ineffective, nor does it mean another therapy will be preferentially more effective.

Despite these issues, if we are to ever realise the promise of personalised medicine, it will be through efforts such as these, which explore the genetic variation in our germline (and tumour) genome that may affect treatment response and to integrate the findings of genomics and epigenomics with clinical outcomes to tailor future therapies.

Solomon L. Woldu and Vitaly Margulis
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

 

References

 

 

 

 

 

 

6 Beuselinck B, Karadimou A, Lambrechts D et al. Single- nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 2013; 108: 887900

 

 

Video: VEGFR1 rs9582036 as a predictive biomarker in m-ccRCC patients treated with sunitinib

Validation of VEGFR1 rs9582036 as predictive biomarker in metastatic clear-cell renal cell carcinoma patients treated with sunitinib

Benoit Beuselinck*,,, Johnny Jean-Baptiste*,, Patrick Schoffski, Gabrielle Couchy*,Clement Meiller*,, Frederic Rolland§, Yves Allory, Steven Joniau**, Virginie Verkarre††, Reza Elaidi‡‡, Evelyne Lerut§§, Tania Roskams§§, Jean-Jacques Patard¶¶Stephane Oudard,‡‡, Arnaud Mejean***, Diether Lambrechts†††,‡‡‡ and Jessica Zucman-Rossi*,,‡‡

 

*Inserm, UMR-1162, Genomique fonctionnelle des tumeurs solides, IUH, Paris, Sorbonne Paris Cite, FacultedMedecine, Universite Paris Descartes, Paris, France, Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, §Department of Medical Oncology, Institut de Cancerologie de lOuest, Saint Herblain, Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Henri Mondor, Creteil, France, **Department of Urology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, ††Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants malades, Paris, ‡‡Department of Medical Oncology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, §§Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium, ¶¶Department of Urology, Hopital Bicetre, Le Kremlin-Bicetre, ***Department of Urology, Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Paris, France, †††Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, and ‡‡‡Vesalius Research Center, VIB, Leuven, Belgium

 

Abstract

Objectives

To validate vascular endothelial growth factor receptor-1 (VEGFR1) single nucleotide polymorphism (SNP) rs9582036 as a potential predictive biomarker in metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with sunitinib.

Materials and Methods

m-ccRCC patients receiving sunitinib as first-line targeted therapy were included. We assessed response rate (RR), progression-free survival (PFS), overall survival (OS), and clinical and biochemical parameters associated with outcome. We genotyped five VEGFR1 SNPs: rs9582036, rs7993418, rs9554320, rs9554316 and rs9513070. Association with outcome was studied by univariate analysis and by multivariate Cox regression. Additionally, we updated survival data of our discovery cohort as described previously.

aotwdec3-results

Results

Sixty-nine patients were included in the validation cohort. rs9582036 CC-carriers had a poorer PFS (8 vs 12 months, P = 0.02) and OS (11 vs 27 months, P = 0.003) compared to AC/AA-carriers. rs7993418 CC-carriers had a poorer OS (8 vs 24 months, P = 0.004) compared to TC/TT-carriers. rs9554320 AA-carriers had a poorer RR (0% vs 53%, P = 0.009), PFS (5 vs 12 months, P = 0.003) and OS (10 vs 25 months, P = 0.004) compared to AC/CC-carriers. When pooling patients from the discovery cohort, as described previously (n = 88), and the validation cohort, in the total series of 157 patients, rs9582036 CC-carriers had a poorer RR (8% vs 49%, P = 0.004), PFS (8 vs 14 months, P = 0.003) and OS (13 vs 30 months, P = 0.0004) compared to AC/AA-carriers. Unfavorable prognostic markers at start of sunitinib were well balanced between rs9582036 CC- and AC/AA-carriers.

Conclusion

VEGFR1 rs9582036 is a candidate predictive biomarker in m-ccRCC-patients treated with sunitinib.

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