BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma

Abstract

BackgroundClinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies.MethodsIn this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher’s Exact test). The Kaplan–Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox’s regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC.ResultsOf 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25–30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS.ConclusionsClinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer

“…Recent retrospective studies investigating Open access the effects of obesity on immunotherapy outcomes in RCC have provided intriguing but conflicting results: that increased adiposity (defined as BMI >25 kg/m 2 ) trended toward being detrimental, 18 that obesity (BMI >30 kg/m 2 ) had no impact on outcomes in multivariate analysis, 16 or that obesity improved PFS but not OS in patients who showed primary clinical benefit. 19 We examined this issue by evaluating outcome data for all RCC patients treated with standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation at the UAB Hospital (n=54) and the UI Hospitals and Clinics (n=18). All patients had an ECOG performance status of 0-2 and none had received prior immunotherapies.…”

“… 18 However, another 2019 study of 90 RCC patients reported no difference in BMI status between patients who derived clinical benefit from anti-PD-1/PD-L1 versus those who were resistant to therapy. 19 A third study found that in RCC patients (n=203) treated with immunotherapy (any monotherapy or combination of anti-PD-1/PD-L1/CTLA-4 during clinical trials or standard of care), obesity did not alter immune infiltration or improve survival after adjusting for risk score, but instead decreased PD-L1 expression and increased angiogenesis in renal tumors. 16 Thus, further investigation of this critical issue is needed.…”

Association between body mass index and survival outcomes for cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis

“…The remaining 27 studies were subsequently reviewed and screened according to our inclusion and exclusion criteria. Finally, 13 studies [13][14][15][16][17][23][24][25][26][27][28][29][30] were included in our meta-analysis ( Fig. 1).…”

“…The diagnosed cancer types of these patients were mainly non-small cell lung cancer (NSCLC) (68.2%), melanoma (18.5%), and renal cell carcinoma (10.2%). With regard to BMI values, seven studies [13, 15-17, 24, 25, 28] stratified the BMI value into high BMI group and low BMI group by one cutoff value, four studies [14,23,27,29] stratified the BMI values into normal BMI group (18.5 < BMI ≤ 24.9), overweight group (25.0 < BMI ≤ 29.9) and obese group (BMI ≥ 30) according to the WHO definition, one study [26] used both two methods to stratify BMI value. Notably, one study [30] stratifies BMI into 3 groups (BMI < 25, 25.0 ≤ BMI < 35, BMI ≥ 35), which was neither dichotomous nor stratifying BMI into normal overweight and obese groups.…”

Biological Support to Obesity Paradox in Renal Cell Carcinoma: A Review

“…As a contradiction, an inverse trend was reported by Bergerot et al [71], where a small group of immunotherapy-treated metastatic RCC patients with low BMI had a median OS of 23.6 months compared to 19.9 months in overweight/obese patients. A study by Labadie et al [72] reported that BMI was not correlated with OS in ccRCC patients with primary resistance to immunotherapy, while the correlation was positive in immunotherapy-sensitive patients.…”