The mechanisms underlying metastatic latency in renal cell carcinoma (RCC) remain poorly understood. This study evaluated two large independent cohorts for differences in tumor biology between patients who developed metastases early (≤1 year after nephrectomy) and those with late-onset (>3 years). In the discovery cohort (n = 161), late-metastatic RCC (late-mRCC) was associated with clear cell histology (88.9% vs 78.7%), lower pathological stage (pT1-2; 40.3% vs 18.0%), and favorable histopathological features including low grade (40.0% vs 2.3%), less sarcomatoid (5.6% vs 21.8%), and reduced necrosis (37.7% vs 78.3%; all p < .02). Late-mRCC tumors exhibited increased angiogenesis (63.5% vs 19.4%) and reduced inflammation (78.8% vs 50.0%; all p < .02) profiles. Genomic driver analyses revealed comparable rates of PBRM1 and SETD2 loss in both late- and early-mRCC, while BAP1 loss was significantly less common in late-mRCC (7.5% vs 27.1%; p < .02). In multivariable models, BAP1/PBRM1/SETD2 status and tumor necrosis emerged as key discriminators of late-mRCC. These findings were confirmed in the second cohort (n = 307). Late-mRCC was enriched for fatty acid oxidation and angiogenesis pathways, supporting a less aggressive phenotype. This was further evidenced by a lower engraftment rate in murine models (0% vs 36.5%; p < .001) and significantly longer overall survival from the time of metastasis (median survival doubled, p < .001). Interestingly, late-mRCC shared genomic and phenotypic features with RCC that metastasizes to the pancreas, suggesting a common underlying biology that influences both metastatic latency and pancreatic tropism. Overall, these findings advocate for recognition of late-mRCC, due to its distinct biology and improved prognosis.
Journal of the National Cancer Institute. 2025 Mar 11 [Epub ahead of print]
Payal Kapur, Hua Zhong, Alana Christie, Haitao Xu, Qi Cai, Ellen Araj, David Kim, Jeffrey Miyata, Vanina T Tcheuyap, Colleen T Ball, David D Thiel, Alexander Parker, Samuel O Antwi, Brad C Leibovich, Zora Modrusan, John C Cheville, James Brugarolas
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA., Kidney Cancer Program at Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA., Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, 32224, FL., Department of Urology, Mayo Clinic, Jacksonville, 32224, FL., Department of Pathology, Mayo Clinic, Rochester, 55905, MN, USA., Molecular Biology Department, Genentech Inc, South San Francisco, 94080, CA, USA.