European Urology Journal 2020 WoW		CY
Working titles: 	Obesity in clear cell renal cell carcinoma- the double-edged sword.
Blog Title:   	Clear cell renal cell carcinoma: better to be fat than thin?  
Authors:  	Cissy Yong, Grant D. Stewart

Article Reference:  Sanchez, A., Furberg, H., Kuo, F., Vuong, L., Ged, Y., Patil, S., Ostrovnaya, I., Petruzella, S., Reising, A., Patel, P., Mano, R., Coleman, J., Russo, P., Liu, C.H., Dannenberg, A.J., Chan, T.A., Motzer, R., Voss, M.H., Hakimi, A.A., 2019. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study. The Lancet Oncology (in press). https://doi.org/10.1016/S1470-2045(19)30797-1

Expert Summary
The obesity paradox of some cancers remains an elusive phenomenon. Sanchez and colleagues begin to uncover the mechanisms of how obesity, an established risk factor for the development of clear cell renal cell carcinoma (ccRCC), paradoxically confers survival advantage. Patients with localised and metastatic ccRCC (mccRCC), undergoing nephrectomy or systemic therapy who were of normal weight (BMI 18.5-24.9kg/m2) or obese (BMI≥30kg/m2) were compared using clinical and molecular parameters. Significant associations between longer overall survival (OS) and obesity was observed (adjusted HR: 0.48 (COMPARZ trial); 0.68 (TCGA cohort)), confirming the obesity paradox in ccRCC. Within primary tumours, higher angiogenic scores were significantly associated with obese patients. Obesity, an established inflammatory inducer1, unexpectedly did not cause tumours to exhibit increased inflammation. Furthermore, no overall differences in tumoural immune infiltrates or gene mutational profile were associated with BMI. However, peritumour fat analysed from obese patients did harbour higher inflammatory signatures, and higher hypoxic and immune infiltration scores. This obesity-induced milieu is speculated to confer survival advantage. Firstly, increased angiogenesis within tumours potentially increases susceptibility to anti-VEGF therapies alongside increased drug delivery to target sites. Secondly, higher immune infiltrates peritumourally acts as an ‘immune reservoir’ which may be mobilised by IO agents. Overall, this study begins to deconvolute the obesity paradox in ccRCC by identifying distinct phenotypes within the tumour microenvironment (TME) i.e. tumour and perinephric fat, which may lend itself towards supporting the survival advantages observed. 

Expert Opinion
The critical role of TME in tumour behaviour is highlighted by Sanchez and colleagues2. This group propose that within the TME, a favourable milieu is established by obesity, which can be leveraged by RCC therapies to support the longer OS observed. Although validation is required, the converse is found in breast cancer where obesity may promote resistance to anti-VEGF therapies3, suggesting a tissue-specific role for obesity in cancer. Nonetheless, obesity and the associated metabolic syndrome, are increasingly prevalent and as established risk factors for RCC4, such host factors warrant further investigation into the phenotypic effects on the TME. If BMI, or measurements such as imaging-quantified visceral fat area4, can be validated as surrogate markers for obesity-altered perinephric fat, these parameters may lend themselves as stratification tools for enrolment into clinical trials, or assist decision-making in the shifting paradigm towards precision medicine. Given that EAU guidelines recommend IO agents as first line treatment in mccRCC5, this study is timely. In particular, the increased immune infiltrates in obesity-associated perinephric fat (rather than the primary tumours) acting as ‘immune reservoirs’ may confer survival advantage in obese patients with mccRCC, should be further evaluated as this may be important in individualising systemic therapies. Less clear is how these findings could be applied to patients with localised ccRCC. Adjuvant therapy in ccRCC is unproven; however, for obese patients categorised as ‘high-risk for recurrence’, is there now a hypothesis for trialling adjuvant IO therapy? Emphasis going forwards should involve validating and leveraging the TME landscape to optimise clinical management for these cohorts. 

References:
1. Deng, T et al. Annu Rev Pathol. 2016. (11), pg421-449.
2. Balkwill, FR et al. J Cell Sci. 2012,(125), pg5591.-5596.
3. Incio, J et al. Sci Transl Med. 2018, (10).
4. Zhang, GM et al. World J Surg Oncol. 2014, (12),pg236.
5. Albiges, L. et al. Eur. Urol. 2019,(76), pg151–156.

Conflict of Interest Disclosure: GDS has received educational grants from Pfizer, AstraZeneca and Intuitive Surgical, consultancy fees from Merck, Pfizer, EUSA Pharma and CMR Surgical, travel expenses from Pfizer and speaker fees from Pfizer. CY is funded by the Wellcome Trust and The Urology Foundation.

Authors: 	Miss. Cissy Yong1,2 and Mr. Grant D Stewart1,2.

Affiliations:	1Department of Surgery, University of Cambridge, Cambridge Biomedical Campus, CB2 0QQ, UK.
2Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.





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