Kidney Cancer Biomarkers Remain Elusive

LONDON—Although clinicians have drugs that are effective in treating metastatic renal cell carcinoma (RCC), they still have no biomarkers to predict therapeutic response, Rosalie Fisher, MD, Clinical Research Fellow at the Royal Marsden Hospital in London, told attendees at the Renal and Bladder Cancer 4th National Conference.

Seven molecularly targeted drugs have been approved for use in metastatic RCC. The use of anti VEGF-R and anti mTOR treatments have targeted signalling pathways and “we have been able to extend overall survival, to greater than two years for the average patient,” said Dr. Fisher, who added that “we have entered a new era in the management of RCC.” The problem is that these drugs have limitations and “the rather dismal bottom line ... is that in RCC there are no established predictive biomarkers of therapeutic response.”

The National Institutes of Health definition of a biomarker is a characteristic that is effectively measured and evaluated as an indicator of normal biological processes, pathogenic process, or pharmacologic response to a therapeutic intervention, she noted. Dr. Fisher pointed to some well known examples routinely used in clinical medicine, such as troponins in acute coronary syndromes.

Anti VEGF-R and anti mTOR treatments sometimes work well in RCC patients and they can even work well in patients with poor performance status or poor risk features, “but all patients become resistant no matter how good their initial response, and the real lesson is that despite these types of drugs being used in clinical trials since 2002, we still have no idea why they work or how they work, and why they work in some patients and not in others.”

Current treatment for RCC is typically selected based on the licensed indication for drugs, which is based on the eligibility criteria used in pivotal phase 3 trials. “For an individual who starts on one of these agents, the benefit they will derive at the outset is really quite unpredictable,” she said.

This contrasts with other solitary types of cancers such as melonama, breast cancer, colorectal cancer, and lung treatment, Dr. Fisher said. Predictive biomarkers exist for these cancers, but not for RCC. “The reality of these drugs in the clinic is that they are toxic, so if we select at the outset those [RCC] patients who will definitely not benefit from this treatment, this would be a major advantage.”

The lack of predictive biomarkers for RCC is not for lack of trying, Dr Fisher said. Numerous studies have attempted to find useful biomarkers in RCC since 2007, but these studies often are retrospective, the number of tumor samples is very small, and the results have been conflicting. “What is only becoming obvious now, and I think this has been grossly and persistently underestimated, is that the clinical trials that you need to do to identify biomarkers are actually complex and very difficult to do.”

Despite the lack of predictive biomarkers for RCC, Dr. Fisher said she is hopeful as there are a number of biomarker initiatives underway in the U.K. and the U.S. “It is only now that we are focusing on systematic and high-quality tissue collection, which did not really occur in the earlier trials for these drugs. Will advances in genomic techniques help or hinder us in our quest to find predictive biomarkers? I don't know but we should consider the issue of tumor heterogeneity in the discovery pipeline.”

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