Fat Near Kidney Tumors May Explain
'Obesity Paradox'

Nick Mulcahy

January 23, 2020

Body fat near kidney tumors may be instrumental in how well cancer treatment works and the related survival of a patient, according to the authors of a new cohort study of patients with renal cell carcinoma (RCC).

In obese individuals, "perinephric" fat is denser and significantly more inflamed, which in turn may trigger an advantageous immune response, report lead author Alejandro Sanchez, MD, Huntsman Cancer Institute, University of Utah in Salt Lake City, and colleagues.

The findings lend support to — and may offer insight into — the "obesity paradox" in RCC, whereby overweight individuals are at higher risk for the disease but have better cancer outcomes compared with individuals of normal weight.

Notably, obese patients did not harbor increased inflammation within their primary tumors, contrary to the investigator's initial hypothesis. Thus, the kidney tumors are not apparently the source of the immune response to inflammation, said senior author A. Ari Hakimi, MD, Memorial Sloan Kettering Cancer Center, New York City, in a press release.

Further, there were "gene-expression differences in angiogenic and inflammatory pathways within the tumor microenvironment," including peritumoral adipose tissue, that "could help to explain the survival advantage in obese patients versus those at a normal weight in this disease setting," write the authors.

The study was published online December 20 in Lancet Oncology.

The team says their new results cannot be translated directly into clinical practice, but they hope that the differences found between the obese and normal-weight patient groups in various pathways might eventually be "leveraged" in clinical trials to improve outcomes for all patients with clear cell RCC.

In an accompanying editorial, a trio of Italian experts call the study "a crucial step forward in our comprehension of the mechanisms underlying the obesity paradox in patients with RCC."

Matteo Santoni, MD, Macerata Hospital; Alessio Cortellini, MD, St. Salvatore Hospital, L'Aquila; and Sebastiano Buti, MD, University Hospital of Parma, interpreted the authors' findings, saying that "the perinephric fat might act as a reservoir of activated cells that can be mobilized through the administration of systemic therapies." Those cells, which had increased infiltration among obese patients in the study (compared with normal-weight patients), included dendritic cells and regulatory T cells.

The study authors point out that RCC is not the only cancer with an obesity paradox, as the same holds true among patients with metastatic melanoma who have been treated with immunotherapy. (Lancet Oncol. 2018;19:310-22). The paradox also appears to hold in lung cancer immunotherapy, as reported by Medscape Medical News.

Study Details

The authors point out that the new study is restricted to patients with clear cell RCC because less is known about the tie between obesity and non-clear cell RCC.

The team assessed data from five independent clinical cohorts of adult patients with clear cell RCC who received a variety of treatments. The findings included overall survival as well as results of lab analyses. The latter included angiogenic and immunologic transcriptomic profiles of tumors and the nearby adipose tissue in both obese and normal-weight patients.

In their summary of results, the authors highlighted three patient cohorts: individuals from the COMPARZ phase 3 trial, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering (MSK) observational immunotherapy cohort.

After excluding patients from each cohort who were overweight (ie, neither obese nor normal weight), the authors reported that overall survival was longer in obese patients than in those with normal weight in two of the three groups. In the TCGA cohort (n = 93), the longer survival was seen after adjustment for stage or grade (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.22 - 0.75), and in the COMPARZ clinical trial (n = 256) after adjustment for International Metastatic RCC Database (IMDC) risk score (aHR, 0.68; 95% CI, 0.48 - 0.96).

However, in the MSK immunotherapy cohort (n = 129), the inverse association of BMI with mortality (HR, 0.54; 95% CI, 0.31 - 0.95) was not significant after adjustment for IMDC risk score (aHR, 0.72; 95% CI, 0.40 - 1.30).

The authors also reported that the tumors of obese patients "showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI."

As noted above, they also reported "increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumor." The inflammatory signatures included TNFα, IFNα, and IFNγ.

The authors also found no differences in total mutational burden among obese patients compared with patients of normal weight.

Study funding sources included a Ruth L. Kirschstein Research Service Award, an American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center for Cancer Immunotherapy, Weiss Family Kidney Research Fund, Novartis, the Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Cancer Institute.

Lancet Oncol. Published online December 20, 2019. Abstract, Editorial

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