In two large and distinct datasets, high body mass index (BMI) was a prognostic factor for improved overall survival (OS) and progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC), even after adjusting for known prognostic factors.
The fact that obese patients have better survival than counterparts with a lower BMI is considered paradoxical because overweight has been shown in multiple cancers to be a risk factor both for developing cancer and for worse outcomes.
"It is an interesting observation that obese patients may do better when they have stage IV disease. This builds on prior work and validates the findings in a new cohort," lead study author Toni K. Choueiri, MD, of Dana-Farber Cancer Institute/Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.
Another expert who was asked for comment agreed that the evidence is building.
Thomas Olencki, DO, a kidney cancer specialist at the Ohio State University Comprehensive Cancer Center in Columbus, said everyone initially was "incredulous" about the apparent obesity paradox in RCC, but it now has "large patient numbers, reproducibility in different cohorts, and robust statistics, demonstrating this is a real effect."
There is a plausible mechanistic explanation behind the data, said Dr Choueiri.
"The biologic rationale may be explained by alterations in the FASN [fatty acid synthase] pathway. We are trying to see if there is any therapeutic opportunity," he said. "We want to go back to the lab and explore in animal models the implication of FASN on growth of RCC tumors in combination with established standard drugs."
Dr Choueiri and colleagues' findings were reported online September 6 in the Journal of Clinical Oncology.
They investigated the impact of BMI on OS and outcomes of targeted therapy in 1975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4657 patients treated for kidney cancer in clinical trials from 2003 to 2013.
In the IMDC cohort, median OS was 25.6 months (95% confidence interval [CI], 23.2 - 28.6) in patients with high BMI (≥25 kg/m2) compared with 17.1 months (95% CI, 15.5 - 18.5) in patients with low BMI (<25 kg/m2). The adjusted hazard ratio (HR) was 0.84 (95% CI, 0.73 - 0.95).
The association of BMI with OS was evident in the intermediate- and poor-risk groups but not in the favorable group. Patients with high BMI also had longer time to treatment failure relative to their peers with low BMI in both first- and second-line treatment settings, after adjusting for prognostic factors.
The results were similar in the validation cohort, with high BMI associated with improved OS (adjusted HR, 0.83; 95% CI, 0.74 - 0.93). Median OS was 23.4 months (95% CI, 21.9 - 25.3 months) with high BMI vs 14.5 months (95% CI, 13.8 - 15.9 months) with low BMI.
There were also links between tumor FASN pathway activation (FASN gene expression and immunohistochemistry [IHC]) and BMI and survival.
Among 61 patients with metastatic RCC in the Kidney Renal Clear Cell Carcinoma clinical TCGA consortium (cTCGA) cohort, FASN gene expression inversely correlated with BMI (P = .03), and high FASN expression was associated with worse OS (15.0 months vs 36.8 months with low FASN expression; P = .002).
Among 146 patients in the IDMC cohort with metastatic RCC treated with targeted therapy, positive results on FASN staining, evident in 45 patients (31%), were more common in poor-risk (11 of 23, 48%) and intermediate-risk (20 of 59, 34%) groups compared with favorable-risk groups (5 of 30, 17%).
When stratified by FASN IHC expression, OS was 27.5 months in FASN-negative patients vs 14.5 months in FASN-positive patients (HR, 1.71; 95% CI, 1.17 - 2.51; P = .005).
Clinically Relevant Now?
These observations suggest an "integral role" for tumor fatty acid metabolism in the prognosis of patients with mRCC and "lays the groundwork for future therapeutic interventions that target the FASN pathway," Dr Choueiri and colleagues conclude.
FASN is a key enzyme involved in neoplastic lipogenesis. Overexpression of FASN is common in many cancers and confers a survival growth advantage. FASN acts as a metabolic oncogene, having been associated with poor prognosis in several types of cancer, including kidney cancer. Its downregulation in overweight and obese mRCC patients in this analysis could explain why these individuals fared better than their normal-weight peers with increased FASN expression, Dr Choueiri and colleagues say.
It is still unclear why FASN may be downregulated in the setting of overweight/obesity, but the results provide a rationale for studies aimed at determining the effects of inhibiting FASN expression in RCC, regardless of BMI, the investigators say.
In an interview with Medscape Medical News, Ohio State's Dr Olencki agrees that the role of the FASN pathway in kidney cancer "has to be looked into further; clearly it is a possible therapeutic target."
Benjamin Gartrell, MD, medical oncologist at Montefiore Medical Center, New York City, told Medscape Medical News that the idea of an obesity paradox in RCC "has been around for a while, but this study provides more data to support it, and with a bigger group of patients. I suspect the difference is not necessarily the weight of the patient per se, but it's the cancer that is more likely to develop in an overweight patient tends to have a more indolent biology."
Dr Gartrell thinks the findings have clinical relevance. "Here at the Montefiore Einstein Center for Cancer Care, one of our priorities initially when we are meeting a patient is to try to give as much prognostic information as we can, and I think now we might consider incorporating the patient's weight to the prognostic information we provide to a patient."
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