Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations

Abstract

Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC. MethodsThe impact of BMI (high BMI: $ 25 kg/m 2 v low BMI: , 25 kg/m 2 ) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors. ResultsIn the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015). ConclusionHigh BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis

“…This phenomenon, wherein higher BMI is associated with increased disease risk but confers a survival advantage in patients with established or advanced disease, has recently been described in other malignancies. 7–9 Whether this inverse relationship is causal remains poorly understood. 10 However, several features of the current study suggest a potential biological role of adiposity in metastatic melanoma patient survival.…”

“…A recent study in renal cell carcinoma in which high BMI was associated with improved outcomes with targeted therapy found that alterations in fatty acid metabolism were associated with both obesity and outcomes. 9 Given emerging evidence implicating tumor and immune cell metabolism in melanoma therapeutic response, 25 the relationship between tumor metabolism and clinical metabolic phenotype should also be explored in this disease. Analyses are ongoing examining the molecular, immunologic, and metabolic correlates of obesity in melanoma.…”

“…5,6 However, higher BMI has also been associated with improved outcomes in some cancers, 7–9 a phenomenon dubbed the “obesity paradox.” 10 The role of obesity in melanoma has not been well-studied to date. 5 Existing data suggests that obesity is associated with an increased risk of melanoma in men 11 and increased primary tumor Breslow thickness.…”

Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity

“…Hakimi et al reported that high BMI was associated with reduced RCC stage at diagnosis and improved survival on univariate analysis; however, high BMI had no relationship with cancer-specific mortality after stage and grade were controlled [21]. Albiges et al compared survival in over 5,000 subjects with metastatic RCC, and found that high BMI (BMI > 25 kg/m 2 , including both overweight and obese subjects) was associated with increased OS following targeted therapy [22]. These and other findings have led to the conclusion that an obesity paradox exists for RCC, wherein obesity defined by high BMI is associated with less advanced disease and better outcomes.…”

Circulating levels of obesity-related markers and risk of renal cell carcinoma in the PLCO cancer screening trial

“…A recent analysis of metastatic RCC patients demonstrated a positive association between excess body weight and a longer overall survival, which may be due to a decreased expression of the fatty acid synthase ( FASN ) gene in obese patients [20]. As adipose tissue is composed of fatty acids, the decreased expression of FASN is likely to influence the production of adipokines and other obesity-related markers in RCC patients and could be one of the mechanisms through which carcinogenesis occurs.…”