Patients with metastatic renal cell carcinoma (RCC) and a BMI of 25 or greater had significantly longer overall survival compared with patients with a BMI of less than 25, according to the results of a study published in the Journal of Clinical Oncology.
According to an examination of the fatty acid metabolism pathway, underlying biology suggests a role for the fatty acid synthase (FASN) pathway.
“We believe this work provides insight to further explore both the biology and ultimately the therapeutic approaches in patients with advanced RCC,” wrote Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues. “In glioblastoma preclinical models, inhibiting FASN with orlistat, a lipase inhibitor, induced autophagy and apoptosis and raised the question of potential therapeutic development.”
Choueiri and colleagues first reported a possible link between high BMI and favorable outcomes in patients with metastatic RCC in 2010.
“From a biologic standpoint, a recent report from The Cancer Genome Atlas (TCGA) data set identified no specific DNA alterations in clear cell RCC (ccRCC) developing in obese patients,” the researchers wrote “However, gene expression profiling identified altered fatty acid pathways in obese patients relative to normal-weight patients, with marked downregulation of FASN.”
Therefore, in this study, the researchers examined associations between BMI and RCC survival looking at the underlying biologic mechanisms. They looked at BMI in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Using a dataset from TCGA, they conducted gene expression profiling focusing on the fatty acid metabolism pathways and immunohistochemistry (IHC) staining for FASN.
In the IMDC cohort, the median overall survival was 25.6 months in patients with a high BMI compared with 17.1 months in patients with a low BMI (adjusted hazard ratio [HR], 0.84 [95% CI, 0.73–0.95]). Again, in the validation cohort, those patients with a high BMI had longer overall survival compared with patients with a low BMI (23.4 months vs 14.5 months).
Among the 61 patients with metastatic RCC in the TCGA data set, patients with a high BMI had lower FASN expression compared with the low BMI group. FASN gene expression was inversely correlated with BMI (P = .034). In addition, overall survival was longer in patients with low FASN expression (36.8 vs 15 months; P = .002).
Finally, the researchers looked at IHC samples from 146 patients with metastatic disease treated with targeted therapy. About one-third (31%) of patients had FASN staining positivity. Median overall survival was 27.5 months in FASN-negative patients compared with 14.5 months in FASN-positive patients (P = .005).
“Biologically, we used tumors from patients with metastatic RCC from the ccRCC TCGA and from the IMDC data sets and showed that FASN pathway activation (FASN gene expression and IHC staining) is associated with BMI and survival,” the researchers wrote. “This suggests an integral role for fatty acid metabolism in the prognosis of patients with metastatic RCC and lays the groundwork for future therapeutic interventions that target the FASN pathway.”