DefinedHealth

Jeffrey M. Bockman, PhD

The WHO predicts that by 2030 there will be 12 million deaths per annum worldwide due to cancer and that at least 30–40% of these could be preventable.  Even excluding those that are due to known pathogens which are preventable (e.g., vaccines such as Gardasil for HPV) and/ortreatable (e.g., vaccines and treatment of HBV), there will still remain a huge burden of advanced-stage and poor prognosis disease that will for the most part be managed with costly and often only minimally efficacious therapeutic intervention.

One approach for addressing this is earlier detection of the cancer via screening (such as with PSA), and another is identification of molecular markers of risk of disease with sufficient predictive power to justify pharmacological or surgical intervention (e.g., BRCA testing and breast/ovariancancer).  At present, however, only around 2% of the total budget of the National Cancer Institute (NCI) in the United States is directed towards cancer prevention and early detection.

Given the historical success of the industry in primary prevention in the cardiovascular space with anti-hypertensives and anti-hyperlipidemics, the question naturally arises as to whether oncology could ever support a risk-prevention market.  If so, where and when will there be a place for pharmacological interventions, assuming that, at a minimum, preventing cancer will probably require a multimodality approach that incorporates early detection through screening, the avoidance of environmental carcinogens, and lifestyle choices with respect to exercise and diet?

Pharmacological approaches to cancer prevention are particularly appealing given our current understanding of tumorigenesis, i.e., that tumors evolve through various stages over a relatively lengthy period.  Various trials have provided some support of the concept, such as the National Surgical Adjuvant Breast and Bowel Project P-1 Study (NSABP-P1) of tamoxifen in breast cancer and sulindac or celecoxib in familial adenomatous polyposis (FAP).  However, even in such trials as these, various complicating issues have been noted, such as increased risk of side effects (some life-threatening).  Several large cancer prevention trials, such as those that tested β-carotene for lung cancer prevention, have failed to show a benefit, and some have even shown increased risk of mortality.  One of the most recently reported and highly anticipated studies was the SELECT trial for prostate cancer, looking at selenium and vitamin E.  Unfortunately, selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.  And there were statistically non-significant increases in the risks of prostate cancer in the vitamin E group and type 2 diabetes mellitus in the selenium group.

In addition to efficacy and toxicity concerns, a number of other key issues will affect the commercial viability of any chemopreventive, including delivery, dosing schedule, tolerability, cost and psychological and social implications of identifying and treating
at-risk patients.  Ultimately, perhaps the most challenging aspect of developing an agent for chemoprevention will be the clinical development and regulatory pathway. Development of cancer vaccines, for example, has been stymied by the need to develop these within the advanced stage, usually refractory setting, while experimental model data suggests that earlier usage would probably be more beneficial.

Please join us as we address some of the critical issues inherent in the evolution of prevention in oncology:

• What is the current level of activity in the chemoprevention space? Who are the forerunners?
• How are trials being designed:
  • What are the endpoints for early-phase trials?
• Are there surrogate markers/biomarkers to enable such trials?
• What are the likely tumor prospects for this mode of intervention?
• What are some promising MOAs and agents?
• How will the risks and benefits be weighed?
• What strategies are companies adopting, or are they avoiding research into chemoprevention?
• What analogues can be used for modeling commercial potential?
• How big could such a market reasonably be expected to be?