Haitao Xu, Payal Kapur, Alana Christie, Aleksandra W. Nielsen, Averi Perny, Olivia Brandenburg, C. J. Small, Jeffrey Miyata, Hua Zhong, Courtney Roberts, Roy Elias, Vanina Toffessi Tcheuyap, Cassandra Duarte, Adrie van Bokhoven, Justine Panian, Haoran Li, Katharine A. Collier, Debra L. Zynger, Luis Meza, Benoit Beuselinck, Neeraj Agarwal, Amir Mortazavi, Sumanta Pal, Rana McKay, Elaine T. Lam, Satwik Rajaram, James Brugarolas
BACKGROUNDClear cell renal cell carcinoma (ccRCC) with pancreatic metastases (PM) is paradoxically associated with prolonged overall survival (OS), but the biological basis for this observation remains unclear.METHODSWe analyzed matched primary and metastatic samples from an international consortium of patients with PM (n = 108) and compared them with a previously characterized ccRCC cohort without PM (n = 273).RESULTSPrimary ccRCC tumors associated with PM were dominated by indolent, angiogenic phenotypes, characterized by low-grade histology and reduced mTORC1 activation (all P < 0.001). Tumors of patients with PM were often PBRM1-deficient (80.4% vs. 54.8%, P < 0.001) and rarely harbored BAP1 loss (3.7% vs. 20.7%, P < 0.001). After metastasis diagnosis, patients with PM had significantly longer median OS compared with those without PM (110 vs. 33 months, HR 0.28 [95% CI, 0.19-0.39], P < 0.001). Survival was further prolonged among patients with PBRM1 loss (143 vs. 64 months, HR 0.41 [95% CI, 0.22-0.81], P = 0.008). Notably, PM lesions were typically low-grade and PBRM1-deficient even when more aggressive and evolved clones were present in primary tumors. Finally, PBRM1 loss was associated with preferential response to angiogenesis inhibitors over immune-oncology therapy, reflected by longer time on treatment (32.1 vs. 9.1 months, HR 0.16 [95% CI, 0.06-0.39], P < 0.001).CONCLUSIONThese findings illustrate selective tropism of indolent, less-evolved, PBRM1-deficient ccRCC clones for pancreatic dissemination. This biological bias likely underlies therapeutic sensitivity and favorable survival, supporting the consideration of PBRM1 status and metastatic tropism in risk stratification and treatment selection.FUNDINGNIH Kidney Cancer SPORE grant (P50CA196516); The Cancer Prevention and Research Institute of Texas (RP220294); Endowment from Jan and Bob Pickens Distinguished Professorship in Medical Science and Brock Fund for Medical Science Chair in Pathology.