Individuals with obesity who were diagnosed with locally advanced or metastatic clear cell renal cell carcinoma achieved longer overall survival than patients of normal weight in select groups of an independent cohort study, which evaluated overall survival and the transcriptomic differences in the primary tumor and peritumoral adipose tissue in adult patients with metastatic clear cell renal cell carcinoma.
Individuals considered to be obese who were diagnosed with locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) achieved longer overall survival (OS) than patients of normal weight in select groups of an independent cohort study, which evaluated OS and the transcriptomic differences in the primary tumor and peritumoral adipose tissue in adult patients with ccRCC.
After excluding some patients based on pretreatment body mass index (BMI) measurement, 256 patients from the phase III COMPARZ study (68%), 93 patients from a cohort of The Cancer Genome Atlas (TCGA), and 129 participants from a Memorial Sloan Kettering Cancer Center (MSKCC) cohort (64%) were included in the OS analysis. The results of the analysis showed a longer OS in patients with a BMI of >30 kg/m² who were enrolled in both the COMPARZ study, following adjustment for International Metastatic RCC Database (IMDC) risk score (0.68, 0.48-0.96), and in the TCGA cohort (adjusted HR 0.41, 95% CI 0.22-0.75) than patients of normal weight (BMI of 18.524.9 kg/m²). In the MSKCC cohort, there was no significant relationship between BMI and mortality (HR 0.54, 95% CI 0.31-0.95) once an adjustment for IMDC risk score (adjusted HR 0.72, 95% CI 0.40-1.30) was applied.
Angiogenesis z scores were impacted by BMI, according to the analysis of transcriptomic differences in patients who were obese compared with patients who were normal weight. The COMPARZ trial cohort showed upregulation in hypoxia, TGF-β, epithelialmesenchymal transition, and angiogenesis signaling pathways. The analysis also included immune deconvolution with published immune cell signatures, which revealed that there was no significant difference in immune infiltration score, macrophage, neutrophil, overall myeloid immune cell, or T-cell infiltration scores between patients with obesity and patients of normal weight.
In the COMPARZ cohort, patients with obesity had a higher volume of infiltrating plasmacytoid dendritic cells than patients of a normal weight, which was not the case for patients in the TCGA cohort. Additionally, the difference in the tumor immune microenvironment was minimal in patients with obesity compared with patients of normal weight. No differences in the total mutational burden or frequency ofPBRM1,BAP1, orTP53mutations were observed inpatients with obesity compared with those of normal weight.
The TCGA cohort did not show significant changes in immune checkpoint expression in patients with obesity compared with patients of normal weight (P= .32). Changes in PD-L1 protein staining by immunohistochemistry were also insignificant.
In the MSKCC cohort, investigators looked at the degree of hypoxia in peritumoral fat specimens to determine how it is associated with immune infiltration. The analysis showed that in patients with obesity versus patients of normal weight, there were higher hypoxia gene-expression scores near the tumor. Additionally, hypoxia was correlated with higher total immune infiltration scores and type 1 macrophage infiltration scores. However, this analysis did not show a difference in hypoxia, immune infiltration, or macrophage scores in patients with obesity compared with patients of normal weight.
The study was hypothesis-generating, and therefore, the results cannot be used in clinical practice. However, the investigators provided advice for moving this research closer to the clinical setting.
“Future studies should focus on the usefulness of body size (such as through BMI) or body composition measures as factors that are prognostic, in combination with clinicopathological and tumor-specific features (such as mutational status), and they should explore mechanisms of fattumor cross-talk that can be used to help improve patient outcomes,” the study authors wrote.
In the phase III COMPARZ trial (NCT00720941) and MSKCC cohorts, OS was defined as the time from treatment initiation to the date of death by any-cause, or of censoring on the day of the last follow-up. In the TCGA cohort, OS was defined as the time from surgery to the date of any-cause death or of censoring on the day of the last follow-up. The study also evaluated gene-expression differences in peritumoral adipose tissue and tumor tissue, as well as the tumor immune microenvironment in obese patients versus normal-weight patients.
The Fisher’s exact and χ² tests and Wilcoxon rank-sum test, or a MannWhitney test were used to evaluate transcriptomic and genomic differences between patients with obesity and patients with normal-weight patients in the study. The Kaplan–Meier method and log-rank were used to construct the survival curves. Due to a combination of patients with American Joint Committee on Cancer stage III and IV disease in the TCGA cohort, survival curves were adjusted for stage and grade. All patients in the other 2 cohorts had stage IV disease and, therefore, did not require stage and grade adjustments. IMDC risk scores were adjusted in the MSKCC cohort, however.
Based on the data in this study, the investigators interpreted that certain factors in the tumor microenvironment vary based on BMI and may be indicative of a survival advantage for patients with obesity over patients of normal weight.
Sanchez A, Furberg H, Kuo F, et al. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study [Published online December 20, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30797-1.