Association Between Statin Use and Risk for Keratinocyte Carcinoma in the Veterans Affairs Topical Tretinoin Chemoprevention Trial

Context Statins are pharmacologically pleiotropic. Some studies suggest that these agents may prevent keratinocytecarcinoma. Contribution In this analysis of data from a Veterans Affairs trial of topical tretinoin for prevention of skin cancer, 37% of 1037 participants at high risk for keratinocyte carcinoma were taking statins. During a median follow-up of 3.5 years, half of the participants had keratinocyte carcinoma. Analyses showed no statistically significant associations between statin use and risk for keratinocyte carcinoma. Caution Confidence bounds around the measures of associations were wide. Implication Evidence that statins prevent keratinocyte carcinoma is inconclusive. The Editors Keratinocyte carcinoma consists of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) and is the most common cancer in the United States, with more than 1 million cases occurring in 2006 (1). Basal cell carcinoma causes substantial illness, including local tissue destruction and disfigurement (2, 3). Squamous cell carcinoma metastasizes more frequently than BCC, leading to an elevated mortality risk, particularly in elderly persons (4, 5). Few effective strategies exist for preventing keratinocyte carcinoma. The most important preventive measure is regular sunscreen use (6). Statins reduce cardiovascular morbidity and mortality (711) but are pharmacologically pleiotropic, with preliminary evidence showing beneficial effects in other diseases, including dementia (12, 13), fractures (14, 15), and multiple sclerosis (16, 17). Statins may also prevent cancer by inhibiting the mevalonate pathway (18, 19). This pathway promotes synthesis of downstream nonsterol isoprenoid derivatives that may block apoptosis and promote tumor growth, angiogenesis, and tumor metastasis (2023). Data on whether statins prevent cancer have been inconclusive, with some studies showing no effect (24) and others suggesting that they are beneficial (25). These conflicting findings may be due in part to varying effects of statins on cancer in different tissue types or locations (26). We aimed to estimate the association between statin use and new lesions of keratinocyte carcinoma in the Veterans Affairs (VA) Topical Tretinoin Chemoprevention (VATTC) trial sample. The trial followed participants closely and provided standardized and complete assessments of outcomes and potential confounders. Methods Setting and Participants We conducted a cohort study by linking data from the VATTC trial and the VA Pharmacy Benefits Management database. Details of the VATTC trial have been published elsewhere (27, 28). The VATTC was a randomized, multicenter, double-blind, vehicle-controlled trial of topical tretinoin, 0.1%, applied to the face and ears for prevention of keratinocyte carcinoma in high-risk veterans conducted from November 1998 to November 2004 at 6 VA medical centers. The study centers were chosen for participation on the basis of factors related to their suitability for serving as centers in the overall randomized trial but were geographically distributed throughout the United States. The 6 locations were Chicago, Illinois; Durham, North Carolina; Miami, Florida; Long Beach, California; Phoenix, Arizona; and Oklahoma City, Oklahoma. Table 1 lists the trial's exclusion criteria. Table 1. Exclusion Criteria in the Veterans Affairs Topical Tretinoin Chemoprevention Trial Eligible veterans were at least 18 years of age, received care at 1 of the 6 participating VA centers, and had 2 or more keratinocyte carcinomas in the 5 years before enrollment (n= 1131). Study personnel received signed informed consent from all participants before enrollment. The 8 relevant institutional review boards approved the study protocol and procedures. We excluded 52 participants without pharmacy claims in the Pharmacy Benefits Management database. We also excluded 42 participants who initiated statin therapy during follow-up, leading to a final sample of 1037 veterans (Figure 1). Figure 1. Study flow diagram. VATTC = Veterans Affairs Topical Tretinoin Chemoprevention. * Includes 98 statin users and 331 nonusers. Outcome Ascertainment The primary outcome was the first occurrence of keratinocyte carcinoma (BCC or invasive SCC) on the face or ears. We did not count recurrent lesions. We chose to combine BCC and SCC, despite certain etiologic differences (such as lag time after ultraviolet exposure, association with genetic mutations, and relation to immunosuppression and human papillomavirus exposure), because they are both skin cancers derived from epidermal cells, the primary cause of both is ultraviolet sun exposure, and their therapies (both pharmacologic and surgical) are nearly identical. Because of the similarities of BCC and SCC, we hypothesized that the statins would penetrate each type of cancer equally, leading to similar pharmacologic activity across tumor types and a similar reduction in the rate of BCC and SCC that would be only minimally affected by their etiologic differences. Study dermatologists conducted physical examinations at baseline and every 6 months during follow-up. One of 2 central reference dermatopathologists read each biopsy specimen of the face and ears. Both central dermatopathologists read 10% of all biopsy specimens for a VATTC reliability substudy (27), which showed high reliability for diagnosis of BCC (= 0.88) and substantial agreement for diagnosis of invasive SCC (= 0.62) (Appendix Table). Appendix Table. Reliability of Diagnoses of Keratinocyte Carcinoma Between Reference Dermatopathologists Among a 10% Random Sample in the Veterans Affairs Topical Tretinoin Chemoprevention Trial Exposure to Statins We derived medication use information from the VA Pharmacy Benefit Management database for VATTC participants who used an outpatient VA pharmacy from 29 September 1998 to 15 November 2004. The Pharmacy Benefits Management database contains claims for all prescription transactions from every VA site (29). More than 99% of prescriptions in the Veterans Health Information Systems and Technology Architecturethe VA gold standardare recorded in the Pharmacy Benefits Management database (4). We matched the Pharmacy Benefits Management data to VATTC data. We categorized participants according to their use of statins at their randomization date. We considered participants exposed if they had used any statin (simvastatin, atorvastatin, fluvastatin, lovastatin, or pravastatin) at the date of randomization, although under the VA system at the time, simvastatin and lovastatin were the primary agents used. Because participant accrual occurred throughout the first 4 years of the trial, we had a varying amount of pharmacy claims available before each person was randomly assigned, but had no data before 1998. We hypothesized that statin use at randomization represented long-term use, an assumption supported by an analysis of duration of use on the basis of the available data. Forty-two participants initiated statin therapy during VATTC follow-up. We excluded initiators because we considered the duration of statin use to be too short to have an effect on the outcome and because there were too few initiators to estimate an effect of short-term use reliably. We estimated the average daily dose of statins by dividing the product of the dose per tablet and the dispensed quantity by the total days of supply dispensed for each prescription claim. We assumed that simvastatin, atorvastatin, fluvastatin, and pravastatin are equipotent. Potential Confounders We considered factors that may affect risk for keratinocyte carcinoma to be potential confounders, including age; sex; race or ethnicity; education; smoking history; sun exposure history; psoriasis; eczema; inflammatory acne; rhinophyma; the number of actinic keratoses at baseline; the number of previous keratinocyte carcinomas; sunscreen use; sun avoidance behaviors; and measures of sun sensitivity, which included variables on hair color, skin color, freckling, reaction to first summer sun exposure without sunscreen, skin oiliness, the year-round presence of tan lines, and the Charlson Comorbidity Index score (3034). We also considered use of tanning beds, chemical peels, 5-fluorouracil, immunosuppressants, nonsteroidal anti-inflammatory agents, other cholesterol-lowering medications, or angiotensin-converting enzyme inhibitors as potential confounders (35, 36). The primary VATTC intervention, topical tretinoin, did not confound our estimates; hence, it is not included in our final Cox regression and propensity score models. The VATTC personnel ascertained measures of potential confounders at baseline and at follow-up visits, including measures of sun sensitivity and exposure. The study investigators' questions about these exposures related to various points in the participants' lives, including early childhood, adolescence, and intervals throughout adulthood (for example, age 18 years, age 40 to 60 years, or in the 5 years before enrollment). This allowed for adjustment of potential confounders that may have exerted a causal effect at different relevant etiologic periods. Baseline clinical examinations included standardized scales of photodamage, counts and relative intensity of precancerous and other clinically relevant lesions, and questions about the average number of hours spent in the sun at different points in the participants' lives. Other questions ascertained the proportion of time spent in the sun that participants used sun-avoiding techniques (for example, wearing a hat), the annual frequency of sunburns at different life stages, and the presence of previous diagnoses (for example, eczema). During follow-up, study investigators measured what proportion of time participants used their study sunscreen, had sunburns, or were exposed to other potential keratinocyte carcinoma causes (such as tanning beds). The degree of missing data was low (approximately 2% on variables used) and varied with litt