Chemoprevention of Skin Cancers

Introduction

Skin cancers account for half of all cancers in the United States (US). In a review of Medicare claims data from 1992 to 1995 in the US, non-melanoma skin cancer (NMSC) was the fifth most costly cancer to treat overall, despite the relatively low per patient cost of treatment. The burden of melanoma has also continued to increase, with the lifetime risk of getting melanoma in 2009 being about 1 in 50 for whites, and, more concerning, a significantly increased number of melanomas since the 1990s among women, with thicker melanomas, truncal melanomas, and later-stage disease in general. Successful primary prevention (prevention of disease onset) of NMSC or melanoma could dramatically reduce this burden. As a result, there has been growing interest in additional prevention approaches. In NMSCs, chemoprevention strategies have become standard in clinical practice, while in melanoma, chemoprevention is a growing area of research. We review the current data on chemoprevention strategies for NMSCs and highlight evolving areas of research in melanoma chemoprevention.

History of chemoprevention

The concept of chemoprevention, originated by Sporn et al. in 1976, has been defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer. This concept fundamentally changed ideas about cancer, allowing the exploration of interventions that could prevent disease progression. Lippman and Hong further refined the concept of chemoprevention, emphasizing the importance of cancer delay; for example, ‘Chemopreventive success will be measured in part by periods of delayed cancer development, morbidity, and mortality.’

Principles and rationale for chemoprevention of non-melanoma skin cancers

The most important risk factor in the development of NMSC is sun exposure. Characteristic gene mutations in p53 and the Patched/Smoothened pathway are often noted in lesions of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), respectively. Whereas SCC is linked to cumulative sun exposure, BCC is related to intermittent and possibly childhood sun exposure. Thus, primary prevention of NMSC at the most basic level includes limiting total sun exposure and responsible behavioral modifications during episodes of intermittent exposure. Application of sunscreen with combined UVA and UVB protection, avoiding sun exposure during peak hours, and wearing protective clothing are all essential elements in reducing one's exposure to damaging ultraviolet radiation. The data supporting such recommendations, unfortunately, are weak and sometimes contradictory. Nonetheless, sunscreen use and responsible sun exposure are considered beneficial in reducing skin cancer risk.

Once DNA photodamage has already been established, preventing progression to NMSC theoretically depends on removing premalignant cells, preventing additional oncogenic mutations, repairing existing DNA damage, inhibiting downstream effects of oncogenes, or restoring functionality to lost tumor suppressor genes.

Treatment of actinic keratoses (AKs; see Chapter 10 ), the most clinically evident premalignant lesion of NMSC, is an important focus of skin cancer prevention. Recent data from the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial suggest that the risk of progression of AK to primary SCC (invasive or in situ) increases slowly over time, being 0.60% at 1 year and 2.57% at 4 years. Of note, approximately 65% of all primary SCCs and 36% of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs.

Although grossly abnormal and altered cells can be detected clinically (AKs, NMSC), ‘normal-appearing’ skin adjacent to such lesions likely shares at least some of the same oncogenic mutations. The concept of field cancerization explains how a field of genetically altered cells, within which one or more cells acquire further mutations and progress to form a unique NMSC, may develop from a single mutant cancer stem cell. Treatment of the AK or NMSC which develops within this field may serve more as a temporizing measure than a cure. As we learn more about cancer biology in the skin, focusing on field therapy may become even more important ( Table 8.1 ).