Metastatic tropism of molecularly defined clear-cell renal cell carcinoma clusters

BACKGROUND The relationship between molecular subgroups in clear-cell renal cell carcinoma (ccRCC) and metastatic tropism is poorly understood. METHODS We analyzed over 5,000 metastatic sites from 305 treatment-naive ccRCC patients in the IMmotion150 phase II clinical trial, where patients were randomized to atezolizumab, atezolizumab/bevacizumab, or sunitinib. RESULTS Angiogenic tumors (clusters 1 and 2) had a higher rate of pancreatic (21% vs. 6.9%; P = 0.002) and lower absolute number of lymph node (2.5 vs. 4.2; P = 0.006) metastases. In contrast, proliferative tumors (clusters 4 and 5) exhibited a higher absolute number of lymph node metastases (5.5 vs. 3.5; P = 0.019). Patients with pancreatic metastases receiving sunitinib had higher odds of overall response (OR, 7.13; 95% CI, 1.81–28.07; P = 0.0049) and longer progression-free survival than those without pancreatic metastases ( P = 0.02). CONCLUSION ccRCC metastatic tropism relates to molecular clusters that predict response to therapy for tumors that metastasize to the pancreas. TRIAL REGISTRATION ClinicalTrials.gov NCT01984242 FUNDING NIH grants R01CA154475 and P50CA196516. Comprehensive analysis of the kidney cancer tumor burden confirmed that the anatomic distribution of metastasis relates to molecular clusters associated to response to specific therapies.