Commentary Cancer Interception

A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma andwhich, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. Themultifaceted roles of telomeremaintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787–92. 2011 AACR. Cancer interception is the active way of combating cancer at earlier and earlier stages. Most people not working in or very familiar with the field usually think that cancer "prevention" is somewhat passive, such as smoking avoidance to prevent getting lung cancer, which is an example of primary prevention. Although this category is crucially important, other approaches are needed as well. This need is emphasized by the startling fact that now the majority of new lung cancers develop in former smokers where preventive agents appear to be more active (1). The growing science and knowledge of cancer biology and treatment are showing us ways to intercept cancers by new, active approaches. The term "cancer interception" captures this idea: to actively intercept a cancer development process before the damage is done, that is, before the full-blown advanced tumor presents in the clinic (Fig. 1). A great challenge for medicine is to let people know that the development of cancers, like heart disease, can be intercepted with risk-reducing agents, in the same way that cancers can be treated with drugs or that cardiovascular disease (CVD) can be intercepted with antihypertensive and other risk-reducing drugs. Intercepting, or actively preventing, cancer has been a hard sell heretofore, including even among people prone to exploring it for their personal health. Even educated, at-risk people have trouble with adherence to risk reduction; for example, adherence to established effective breast cancer risk–reducing agents has proven challenging despite active adherence promotion. Yet, although confronting similar challenges, risk reduction in other settings such as CVD and osteoporosis has met with widespread acceptance. Why has pharmacologic CVD risk reduction become so widely accepted, whereas pharmacologic cancer risk Author's Affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California Corresponding Author: Elizabeth H. Blackburn, Box 2200, Genentech Hall S312F, University of California San Francisco, San Francisco, CA 94143. Phone: 415-476-4912; Fax: 415-514-2913. E-mail: [email protected] doi: 10.1158/1940-6207.CAPR-11-0195 2011 American Association for Cancer Research. Cancer Prevention Research www.aacrjournals.org 787 Research. on June 24, 2017. © 2011 American Association for Cancer cancerpreventionresearch.aacrjournals.org Downloaded from reduction has not? One proposed reason is that CVD risk reduction treats measurable conditions—notably, hypertension and high cholesterol levels—that patients can follow to assess effectiveness. Cancer interception or risk reduction actually also has at least one good example of a marker of success. Aspirin can reduce the number of detectable colorectal adenomas (the measurable condition) and has been shown to reduce colorectal cancer mortality and incidence in long-term follow-up of randomized controlled CVD trials; aspirin also is associated with the reduced mortality of several other common cancers (2, 3). In this case, surgical control of colorectal adenomas has established this lesion as a biomarker of cancer risk and mortality reduction (4). Another proposed obstacle to public acceptance of cancer risk reduction is the risk of toxic effects. This concern may be allayed, in part, by a new study of celecoxib and other nonsteroidal antiinflammatory drugs (NSAID), which, like aspirin, were shown to be active in intercepting colorectal neoplasia but, unlike aspirin, to also produce adverse CV effects. The new data indicate that low-baseline CVD risk or low-baseline C-reactive protein level eliminates the risk of NSAID-associated CVD toxicity (5). This example, furthermore, emphasizes another important concept: More "personalized" cancer interception may be the most effective. It is notable that CVD risk reduction with antihypertensive agents also has risks of substantial toxicity. Nevertheless, these proposed reasons have a sound basis and speak to a lack of effective public education about the parallels of cancer risk reduction with CVD risk reduction, and the need to remedy this lack (6). Cancer interception has never been more desirable or necessary. In the United States, for example, 44% of men and 38% of women will develop cancer in their lifetimes. Eighty-four percent of all cases are diagnosed after age 60; 31% of all cases are diagnosed after age 80. The population is aging, and an increased fraction of the population in the United States and world is reaching cancer-prone ages. Early detection increases cancer diagnosis rates. Treatment has improved, increasing the life spans of cancer patients; survivors are at increased cancer risk. These factors all point to a significantly increasing cancer burden that can only be A