ORLANDO (FRONTLINE MEDICAL NEWS)Talk about a paradox: high body mass index is a known risk factor for renal cell carcinoma, but previous studies have shown that patients with high BMI who develop localized RCC generally present with lower grade disease and have better outcomes than normal-weight patients.

Now, investigators confirm that overweight or obese patients with metastatic renal cell carcinoma (mRCC) also tend to have a better prognosis than their leaner counterparts when treated with targeted therapies.

“We externally validate that BMI impacts the outcome of patients with metastatic kidney cancer treated with targeted therapy in terms of overall survival (OS), progression-free survival, and overall response rates,” said Dr. Laurence Albiges, a visiting scientist in the Kidney Cancer Center at the Dana-Farber/Brigham and Women’s Cancer Center, Boston.

Although the mechanism for a protective effect of excess weight is not clear, there is some evidence to suggest that fatty acid metabolism in mRCC may play a role, she said at the 2015 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

In tissues samples from The Cancer Genome Atlas (TCGA, a joint repository of the National Cancer Institute and National Human Genome Research Institute), expression of FASN, a gene that encodes for fatty acid synthase, was associated with overall survival (OS), but in other samples FASN expression was not an independent prognostic factor for OS, she said.

Investigate and verify

To clarify the role of BMI in mRCC, Dr. Albiges and colleagues looked at data from clinical trials, specimens from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), and biologic data from the TCGA.

As the group reported at the 2014 ASCO annual meeting ( Abstract 4576 ), they first looked at the effect of low BMI (< 25 kg/m2) vs. high BMI (≥ 25) in 1,975 patients with mRCC in clinical trials, and found that after adjustment for IMDC prognosis groups, higher BMI was associated with better OS (median 25.6 months vs. 17.1 months; hazard ratio, 0.84; P = .0079) and longer time to treatment failure (median 8.1 vs. 5.7 months; HR, 0.86; P = .0067).

They then, in collaboration with Pfizer Oncology, conducted an external validation study using data on 4,657 patients with mRCC treated in phase II-III clinical trials from 2003 through 2013.

After adjustment for various risk factors, they found again that BMI of 25 or greater was associated with better outcomes in terms of overall survival (23.4 vs. 14.5 months; HR, 0.830; P = .0008), progression free survival (8.2 vs. 5.5 months; HR, 0.821; P < .0001), and overall response rate (25.3% vs. 17.6; adjusted odds ratio, 1.527; P < .0001).

Dr. Albiges noted that when patients were stratified by histologic subtype, “the favorable outcome associated with high BMI was only observed in clear cell RCC.”

The investigators next looked at information from the TCGA dataset on patients with metastatic clear cell RCC to see whether there was correlation between BMI and survival and between BMI and FASN expression. Although they did not detect a significant survival advantage for higher BMI in this cohort, they did find that higher BMI was significantly associated with lower FASN expression levels (P = .034), and that FASN expression below the median level was associated with better overall survival (P = .002).

Finally, they examined biospecimens from the IMDC dataset with information about outcomes under targeted therapy. Here, they found that FASN staining was associated with prognosis groups, but was not an independent prognostic factor for OS in multivariable analysis.

“BMI, however, is associated with overall survival independently of FASN,” Dr. Albiges said.

Although the mechanisms for the effect of BMI on survival are not clear, the study supports observations that many oncologists have made in clinic, said Dr. Ulka Vaishampayan, chair of genitourinary oncology at the Karmanos Cancer Institute at Wayne State University in Detroit.

“There is obviously, I think, a clinical gestalt­ that we all have, that people who are not losing a lot of weight are in general doing better across a number of malignancies,” she said. Dr. Vaishampayan was the invited discussant.



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