Paul Workman: Drugging the Cancer Genome

What challenges exist, even for cancer prevention approaches that have been shown to be effective? Cancer prevention, in the form of chemoprevention, has had major successes, demonstrated in Phase III randomized clinical trials (RCTs). The Breast Cancer Prevention Trial showed that tamoxifen reduced the risk of breast cancer in women at high risk by Gail model criteria by 50%, even more for estrogen receptorpositive breast cancers. Other agents demonstrated in Phase III RCTs to reduce breast cancer risk include the aromatase inhibitors, anastrozole and exemestane. Many women at high risk would benefit from these agents. Clinical experience, which has been most extensive with preventive tamoxifen, has revealed a reluctance on the part of appropriate high-risk individuals and their healthcare providers to utilize this effective drug for risk reduction. The main obstacle, which has been widely investigated, appears to be concern about toxicity in these women who do not actually have cancer. This brings us full circle to the core concept of prevention raised at the beginning of this essay regarding the importance of determining the balance of benefits and harms in a healthy population. This dilemma has shown the prevention research community that we must improve our