SAN FRANCISCO, CA USA (UroToday.com) - Dr. Primo Lara presented an outstanding review of the last decade in renal cancer research.
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Dr. Lara provided his review in terms of a “top ten” list of successes and disappointments in renal cell carcinoma (RCC) over the past decade. The top five successes include identification of a blueprint of RCC biology, rapid drug development, improved patient, outcomes, advances in nephron-sparing surgery, and enhanced multidisciplinary collaboration. The top five disappointments include cost and access to care, combination therapy, molecular drivers not yet druggable, no predictive biomarkers, and a cure remains elusive.
A comprehensive molecular characterization of clear cell renal cell carcinoma (ccRCC) was completed last year, and ccRCC has also been confirmed as a metabolic disease. Recent additional efforts include sequencing of histone-modifying genes and whole exome sequencing which identifies frequent mutation of the SWI/SNF complex gene PBRM1 in RCC. Genetic heterogeneity confounds personalized therapy, and branched evolution limits usefulness of single biopsies. Rapid drug development has resulted in the approval of 7 new agents since 2005, truly an “embarrassment of riches.” New agents, however, have limited drug diversity, are not necessarily applicable to all histologic subtypes, and are generally for favorable/intermediate-risk disease. The optimal sequence of therapy is yet to be determined.
Introduction of a number of novel therapeutic agents has resulted in improved patient outcomes, with most agents demonstrating favorable responses and improved PFS. However, use of PFS as an endpoint has limitations, and OS has proven too difficult to improve. Advances in nephron-sparing surgery should also be trumpeted as a success over the past decade, with widespread adoption of minimally-invasive and nephron-sparing approaches. However, limited level 3 (phase 1) clinical trial data exists to support the use of robotic and MIS platforms.
Among the notable disappointments over the past decade, the predominant one is that cure remains elusive in patients with metastatic disease. Only high-dose IL2 has a shown slim chance of cure, and there are no complete responders to targeted therapy. The partial response rate is only 30% with angiogenesis inhibitors. No predictive biomarkers exist, and targeted therapies have been largely used in a non-targeted manner. Tumor-based biomarkers are confounded by tumor heterogeneity, and only clinical prognostic criteria have been validated. Blood-based markers such as LDH have been shown to be prognostic and predictive of OS.
Further, molecular drivers of pathogenesis are not yet druggable, and development of RCC drugs faces a number of development challenges. Another disappointment has been the failure of combination therapy. Unfortunately, they can lead to excess toxicity, with marginally increased effectiveness, at higher cost. Finally, cost and access to care remains a major issue for patients with RCC. Despite rampant new drug development, costs paradoxically remain high. In terms of RCC, we do not have a true free-market economy, as cost of therapy is prohibitive ($50,000 for a 10-month course of a tyrosine-kinase inhibitor).
Over the next decade, Dr. Lara suggested a number of ways to get ahead. We need to transition from light microscopy to molecular phenotyping and phylogenetic modeling. Many lessons stand to be learned from evolutionary biology. Tumor heterogeneity must be addressed, and biomarkers require identification. The metabolic basis of RCC also requires further exploitation. Drivers of RCC pathogenesis (such as VHL) should be targeted, but subclonal genetic events and new drivers should also be included. Resurrection of immunotherapy is currently ongoing, with exciting results seen with PD targeted therapy. The past decade in RCC has witnessed incredible advances in drug development and patient care. While challenges remain, we have a well-drawn roadmap for success using biology to guide drug development.
Highlights of a presentation by Primo N. Lara, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
UC Davis Comprehensive Cancer Center, Sacramento, CA USA