SAN DIEGO – Now is the time for researchers and clinicians to examine strategies and interventions for preventing prostate cancer, in the opinion of Dr. Peter H. Gann.
"In the last 12 years or so we have seen a litany of failure with regard to prostate cancer prevention in trials with clinical endpoints," Dr. Gann, professor and director of pathology research at the University of Illinois at Chicago, said during a conference sponsored by the American Association for Cancer Research and the Prostate Cancer Foundation.
Dr. Peter H. Gann
"With vitamin E supplementation, for example, we see a possible increased risk of prostate cancer, no effect with selenium and possibly and increased risk of diabetes, no effect from soy, and the potential impact of green tea polyphenols is unresolved."
Moreover, it’s conceivable that you might need to screen 1,500 average-risk patients to prevent one prostate cancer from occurring. "That means that preventive agents don’t have to be safe; they have to be incredibly safe if they’re going to be used in this way," Dr. Gann said.
He proposed five ways to advance prostate cancer prevention efforts:
• Develop better preclinical models. Canadian investigators have reported success with generating high fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development (Cancer Res. 2013 Dec. 19 [doi:10.1158/0008-5472.CAN-13-2921-T]). "One of the incredible things about this is that the transplantable cells can be obtained from needle biopsies," said Dr. Gann, who was not involved with the study. "Architecture and protein marker expression is preserved in these xenografts, as are other molecular characteristics of the tumor, which is fantastic."
An unrelated Australian study demonstrated that it’s possible to generate xenografts of the earlier low-to-moderate grade, localized tumors (Nat. Protoc. 2013;8:836-48). "Why is this exciting for us in prevention? More and more we’re thinking about not how to prevent things from the initiation stage but rather in terms of progression," Dr. Gann explained. "Being able to have individualized samples that we can study versus agents that may inhibit progression is a major opportunity, I think."
• Improve clinical trial design and infrastructure. The existing networks for prostate cancer prevention trials are largely undeveloped, unlike cooperative group networks available for therapeutic trials, according to Dr. Gann. "Many investigators with promising ideas do not have access to the clinical infrastructure or funding sources they need for translational research," he noted. "Moreover, the pros and cons of various available designs for phase II and III trials have not been adequately debated, amidst a shifting landscape in which some designs become less feasible as others become more feasible."
• Develop better risk stratification and patient targeting. What if clinicians could do a better job of sorting out who is truly at risk for prostate cancer? "Active surveillance cohorts are the most promising opportunity we have for prevention trials involving low-risk interventions," Dr. Gann said. Cumulative results from genome-wide association studies and the expected results from sequencing studies capable of identifying rare genetic variants with high penetrance hold promise for identifying populations for whom preventive strategies would have the most benefit, he added.
• Develop better interventional agents. To date, "I think we’ve taken a haphazard approach to identifying agents for prostate cancer prevention," Dr. Gann said. "With preclinical models lacking, sometimes they’re not vetted very well, either. We’re not going to be able to develop a rational approach to preventing prostate cancer until we have a better idea of how it all comes about. One idea is to do high throughput cell assay based drug screening, which we do for therapeutics but not for chemopreventive agents. The question is, do we have the right libraries of compounds and do we have the right readouts? I suggest that we can start with compounds, especially dietary agents that could inhibit 5-alpha reductase. We also need to think beyond a pharmacologic approach: studying the effects of diet and physical activity, for example."
• Establish better intermediate endpoints for phase II trials. A lack of intermediate endpoint biomarkers (IEBs) for phase II trials is creating a "phase II bottleneck," he said. "There is an ongoing explosion of opportunities provided by new biotechnology and computational methods, but converting these opportunities into validated IEBs for trials will take thought and planning."
Dr. Gann disclosed that he has received grant support from GlaxoSmithKline.