Re: Transcriptomic Signatures Related to the Obesity Paradox in Patients with Clear Cell Renal Cell Carcinoma: A Cohort Study.

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.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