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Invasive squamous cell carcinoma (SCC) of the skin is one of the most common cancers in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. We sought to determine the risk factors for invasive SCC on the face or ears in a high-risk population comprising 1,131 veterans in the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial. Participants were required to have been diagnosed with at least two keratinocyte carcinomas (KCs) in the 5 years prior to enrollment. The median duration of follow-up was 3.7 years. Twenty-three percent of the participants developed a new invasive SCC, and the cumulative risk of invasive SCC was 30% at 5 years. The following factors independently predicted for new invasive SCCs: number of invasive SCCs and number of in situ SCCs in the 5 years prior to enrollment, actinic keratoses count at enrollment, a history of ever use of topical 5-fluorouracil, and total occupational time spent outdoors. In contrast, the use of angiotensin-convering enzyme inhibitors or angiotensin receptor blockers during the study and a history of warts anywhere on the body were found to protect against new invasive SCCs. These independent predictors remained the same for all SCCs (invasive and in situ combined). The number of basal cell carcinomas in the 5 years prior to enrollment, sunburns, sun sensitivity, and recreational sun exposure were not associated with new SCCs. These findings identify key risk factors for additional SCCs in patients with multiple prior KCs, and suggest that a history of warts may be associated with reduced SCC risk.

Keratinocyte carcinoma (KC) is the most common cancer in the United States, with no proven means for prevention other than systemic retinoids, which have significant toxicity, and sunscreen. Topical tretinoin has been used for KC chemoprevention, although this use is unproven. Hence, we conducted the randomized Veterans Affairs Topical Tretinoin Chemoprevention Trial of high-dose topical tretinoin for KC prevention. We randomized 1,131 patients to topical 0.1% tretinoin or a matching vehicle control for 1.5-5.5 years. The primary outcomes were time to development of new basal cell carcinoma (BCC) and new invasive squamous cell carcinoma (SCC) on the face or ears. The effects were not significant (P=0.3 for BCC and P=0.4 for SCC). The proportions of the tretinoin and control groups who developed a BCC at 5 years were 53 and 54% and an invasive SCC at 5 years were 28 and 31%. These differences (95% confidence intervals) were: for BCC, 1.0% (-6.5, 8.6%); for SCC, 3.6% (-3.1, 10.3%). No differences were observed in any cancer-related end points or in actinic keratosis counts. The only quality of life difference was worse symptoms in the tretinoin group at 12 months after randomization. This trial in high-risk patients demonstrates that high-dose topical tretinoin is ineffective at reducing risk of KCs.

Basal cell carcinoma (BCC) is the most common cancer in the United States today, and patients who have had one are likely to have multiple carcinomas over time. Predictors of new BCCs on the face and ears among those at very high risk have not been studied in detail. We sought to do so prospectively in the context of a 6-year trial. We found that the number of BCCs in the prior 5 years was the most important predictor. Age, sun sensitivity, occupational sun exposure before the age of 30 years (but not afterward), lower educational level, history of eczema, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and more sunscreen use in the week, but not the 6 months, before enrollment were also independent predictors, but sunburns, baseline sun exposure, and other sun-protective measures, other skin cancers, and actinic keratoses were not. None of the eczema patients had a history of topical calcineurin use. The cumulative risk of BCC was 55% at 5 years. These findings document the key risk factors in this very high-risk population, suggesting that the history of eczema may increase the risk in those at high risk and that early sun exposure is important even in this group, and underscoring the need for chemopreventive strategies.