Obesity Paradox in RCC: Improved OS for Patients With High BMI

Toni K. Choueiri, MD

Evidence has demonstrated that obesity is a risk factor for clear cell renal cell carcinoma (RCC); however, a new report suggests that a high body mass index (BMI) is a prognostic factor for improved survival in patients with metastatic RCC who have received targeted therapy.¹

The first cohort comprised 1975 patients with metastatic RCC from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), which is a consecutive patient series from institutions in North America, Europe, and Asia. The patients had received targeted therapies, such as VEGF/VEGFR and mTOR inhibitors.

In the IMDC cohort, the median overall survival (OS) was 25.6 months (95% CI, 23.2-28.6) for patients with a high BMI compared with 17.1 months (95% CI, 15.5-18.5) for patients with a low BMI (adjusted HR, 0.84; 95% CI, 0.73-0.95). The association found between BMI and OS was present in the intermediate and poor risk groups (HR, 0.73 and 0.80, respectively), but not in the favorable group (HR, 1.05).

Patients with high BMI had improved time to treatment failure compared with low BMI in both first- and second-line therapy after adjustment for the IMDC prognostic factors.

Similar results were found in the second cohort, which was an external validation cohort. The validation cohort was a pooled analysis of prospective data from 4657 patients with metastatic RCC treated in phase II and III trials sponsored by Pfizer involving sunitinib (Sutent), temsirolimus (Torisel), and axitinib (Inlyta).

The adjusted hazard ratio for OS in this cohort was 0.83 in favor of the group of patients with a high BMI. The overall response rate was 25.3% in patients with a high BMI compared with 17.6% in patients with a low BMI (adjusted odds ratio, 1.53). Both the overweight (BMI, 25 to <30 kg/m²) and obese (BMI ≥ 30 kg/m²) groups tended to have prolonged progression-free survival and OS in the first- and second line settings.

In order to investigate the underlying biologic differences associated with different BMI groups, the authors focused on the role of the fatty acid synthase (FASN) pathway in patients with metastatic RCC. FASN expression is considered a metabolic oncogene in multiple tumor models, and it has previously been reported to be associated with poor prognosis in several tumor types, including RCC.

The researchers used available genomic data of mRNA expression from patients who were part of the Kidney Renal Clear Cell Carcinoma clinical TCGA consortium. A total of 61 patients with metastatic RCC were identified in this cohort. Patients in the high BMI group (n = 39) had lower FASN expression compared with the low BMI group (n = 22; P = .03), and high FASN was associated with worse OS (median, 15 vs 36.8 months for high FASN vs low FASN, respectively).

In a final analysis, the researchers used samples from the IMDC cohort to assess the relationship between BMI and FASN IHC expression. Tissue mircroarrays were used from 146 patients with metastatic RCC who had received targeted therapy.

FASN staining positivity, which was recorded in 45 (31%) cases overall, was more frequently detected in poor (11/23; 48%) and intermediate (20/59; 34%) risk groups compared with the favorable risk group (5/30; 17%; P-trend = .02). When stratified by FASN IHC expression, OS was 27.5 months (95% CI, 19.3-36.7) in FASN-negative patients versus 14.5 months (95% CI, 10.4-20.5) in FASN-positive patients (HR, 1.71; 95% CI, 1.17-2.51; P = .005). However, the authors noted that, “The adjusted HR of FASN was reduced to 1.28 (95% CI, 0.84-1.95) in the multivariable model, with adjustment of IMDC risk group and BMI.”

In contrast, when adjusted for IMDC risk groups and FASN, BMI remained associated with OS (adjusted HR, 0.44; 95% CI, 0.29-0.66), and this correlation was observed in both FASN-negative (HR, 0.39; 95% CI, 0.24-0.64) and FASN-positive groups (HR, 0.55; 95% CI, 0.27-1.13; P-interaction = .434).

Several hypotheses have been proposed to explain the association between a high BMI and improved survival outcomes. Nishihara et al2 suggested that the correlation can be reconciled by disease heterogeneity, such that the longer survival among obese patients compared with normal-weight patients is due to a less aggressive disease subtype. The current findings support this theory because FASN gene expression was found to be downregulated in obese patients compared with patients who had a normal BMI. Moreover, higher FASN expression was associated with worse survival.

“This data seems more specific to RCC, where obesity seems to portend a favorable prognosis in metastatic disease,” Toni K. Choueiri, MD, senior author of the study and clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, said in an interview with OncLive.

The results of the study pave the way for further exploration of the biology of this association as well as therapeutic approaches that may come of it.

“We plan to take our findings back to the laboratory to discover any therapeutic implications around the FASN pathway,” said Choueiri.

References

1. Albiges L, Hakimi AA, Xie W, et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations [published online September 6, 2016]. J Clin Oncol. doi:10.1200/JCO.2016.66.7311.
2. Nishihara R, VanderWeele TJ, Shibuya K, et al. Molecular pathological epidemiology gives clues to paradoxical findings. Eur J Epidemiol. 2015. 30(10):1129-1135.

The authors of the study, which was published in the Journal of Clinical Oncology, investigated both the clinical and biologic effects of BMI on treatment outcomes in 2 distinct cohorts of patients with metastatic RCC. A high BMI was defined as >25 kg/m², and a low BMI was defined as <25 kg/m².