Dr Vento on the Importance of Refining the Classification of RCC to Better Account for Molecular Heterogeneity

“Having more molecularly driven subtypes is very helpful for studying these very unique non–clear cell subtypes. A lot of times we throw around this term of non-ccRCC, as if we’re referring to one disease, but we’re really referring to a lot of different diseases, and they’re all very different.”

Joseph Vento, MD, an assistant professor in the Department of Internal Medicine at The University of Texas Southwestern Medical Center, underscored the importance of refining the classification of non–clear cell renal cell carcinoma (non-ccRCC) to improve stratification of the disease's molecular heterogeneity.

Although commonly grouped under a single category, non-ccRCC encompasses a range of biologically distinct malignancies, each with unique clinical behaviors and therapeutic implications, according to Vento. Traditionally, treatment strategies for non-ccRCC have often been extrapolated from studies conducted in ccRCC, Vento explained. However, this approach overlooks the distinct biology that characterizes subtypes like papillary, chromophobe, collecting duct, translocation-associated, and medullary RCC, he noted. He emphasized that improved characterization of the molecular features and drivers underlying these entities is critical for designing more effective therapeutic strategies.

Translational research has begun to illuminate how mutational landscapes, signaling pathways, and tumor immune microenvironments differ across non–clear cell subtypes, he said. Vento noted that these insights are reshaping the understanding of disease mechanisms and informing the rationale for developing subtype-specific therapies. By correlating molecular features with clinical presentation and treatment response, investigators are moving closer to a precision medicine framework in which therapy is tailored to the underlying biology of each subtype rather than applied uniformly across all non–clear cell disease, he highlighted.

At the clinical trial level, Vento pointed to the growing importance of incorporating molecular stratification into study design. Historically, non-ccRCC has been underrepresented in prospective studies, limiting evidence-based treatment options for these rare populations, he stated. Subtype-directed trials, informed by genomic and transcriptomic data, clarify therapeutic sensitivity and aid in identifying predictive biomarkers for immunotherapy and targeted agents, he emphasized. This, he explained, represents a critical shift away from the “one-size-fits-all” approach that has long characterized the field.