‘Obesity paradox’ appears to fit for men with renal cell carcinoma

New York-A study from Memorial Sloan-Kettering Cancer Center, New York sheds light on the “obesity paradox” seen with renal cell carcinoma (RCC) while at the same time demonstrating the emerging value of genomics in understanding cancer and other diseases.

Obesity is a risk factor for RCC; however, obese patients diagnosed with the disease tend to have more favorable outcomes than those RCC patients with weights normal for their age and height. This is the obesity paradox. It was first noted about 9 years ago in patients undergoing dialysis for chronic kidney disease and has since been described as a phenomenon in heart failure, hypertension, coronary artery disease, and diabetes.

Dr. Russo“What we found was that patients with normal weights had a higher expression of the FASN [fatty acid synthase] gene, which was associated with faster growing tumors than those seen in obese patients,” said senior author Paul Russo, MD, professor of urology at Weill Cornell Medical College and attending surgeon at Memorial Sloan-Kettering Cancer Center.

Dr. Russo hastened to add a caveat to the findings, which were published in the Journal of the National Cancer Institute (2013; 105:1862-70).

“This is still just an association and hypothesis generating,” he told Urology Times. “We can’t say this is the mechanism or even a mechanism for virulent forms of renal cancer, and I would caution against drawing any clinical implications at this time.”

The authors looked at 2,119 patients with clear cell RCC who underwent partial or complete nephrectomy at Memorial Sloan-Kettering between 1995 and 2012. They found that compared to patients with normal body mass index, overweight patients (BMI 25 to <30 kg/m²) had a 39% lower chance of presenting with more advanced kidney cancer at diagnosis; obese patients (BMI >30 kg/m²) had a 35% lower chance. Higher BMI was also associated with a lower cancer stage and milder grade. Obese patients also had a lower risk of cancer-specific mortality, although this effect was not independent of tumor stage and grade.

Dr. Russo said that the technological approach to identifying involved genes might be as important as the results.

“I think one of the noteworthy aspects of this study is the use of genomics as a tool to give us insights into the complexity of cancer, even within populations with the same disease. Obese people are somehow protected, and there seems to be a gene associated with that protection,” he said.

The Memorial Sloan-Kettering team’s molecular epidemiologist, Helena Furberg, MSPH, PhD, and co-author Ari Hakimi, MD, conducted a genomic analysis of 126 patients drawn from the overall cohort using the Tumor Cancer Genome Atlas. They found that the gene FASN was significantly up-regulated in normal-weight patients and down-regulated in obese patients, and that the up-regulation was associated with a higher incidence of cancer-specific death. FASN is considered a metabolic oncogene and is associated with aggressive disease and poor prognosis in several cancers, including prostate and colon cancer.

The authors noted that other studies have found pharmacologic inhibition of FASN reduced RCC tumor growth in vitro.

Detection bias to blame?

When the obesity paradox in RCC was first described, some hypothesized that the reason cancer was being diagnosed more frequently in overweight patients was detection bias. The patients were getting diagnosed earlier because they were getting increased medical attention. Lower cancer-specific mortality was said to be a consequence of early detection.

However, among the conclusions advanced by the authors of the current study was that, “The decreased mortality observed among obese clear cell RCC patients may not merely be explained by detection bias or weight loss but that tumors developing in obese patients may be more indolent based on genetic factors than those in normal-weight patients.”

Dr. Russo said that these and other studies are demonstrating that specific cancers are revealing substantial genetic variability both within a given subtype of renal cancer (ie, clear cell carcinoma) and even within different regions of a renal cancer in a given patient. Understanding the genetic profile of a given patient’s tumor, which may vary widely from another patient’s tumor despite similar pathologic features, may one day create opportunities for “personalized” therapeutic strategies.

“This research is very preliminary at present, but the molecular genetic tools being developed in today’s research laboratories reveal the great complexities of the cancer problem, which in turn creates the kind of mechanistic insights that may lead to new drugs to fight cancer. I think the next few years will yield exciting therapeutic dividends,” said Dr. Russo.UT

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