Ingenol mebutate-mediated reduction in p53-positive keratinocytes in skin cancerization field directly correlates with clinical response in patients with multiple actinic keratoses.

Abstract

UV radiation represents the main risk factor for non-melanoma skin cancers. Chronic UV exposure induces 'p53 patches', i.e. clonal outgrowths of keratinocytes with high nuclear expression of mutated p53, which might progress to actinic keratosis (AK) and ultimately squamous cell carcinomas (SCCs). Analysis of ingenol mebutate gel (150 and 500mcg/g) effects in the reduction in 'p53 patches' inside skin cancerization field (CF) in patients with multiple AKs of face/scalp or trunk/extremities, in order to investigate whether the expected reduction in p53+ keratinocytes might have a direct role in the long-term AK reduction in treated areas. We enrolled n=10 patients, treated with ingenol mebutate and evaluated at 2 and 6months after treatment. We observed clinical responses in the majority of patients (n=7), with AK reduction or complete clearance (n=6 and n=1, respectively). Notably, two patients did not respond to the treatment, and in one patient, after initial partial response, new lesion was recorded. In untreated skin CF samples (n=3), we observed numerous p53+ keratinocytes, similar to those observed in invasive SCC samples (53.56±8.79 and 74.34±22.05, respectively; P=0.2). After treatment, we observed a variable p53+ keratinocyte reduction in CF samples at 2months (24.67±31.19; P=0.19). Importantly, the amount of p53+ keratinocytes strongly and directly correlated with AK number (R2 =0.81). Untreated skin CF expresses high level of p53+ keratinocytes as invasive SCC. Ingenol mebutate is able to reduce p53+ keratinocytes with variable efficacy, this reduction degree directly correlating with clinical efficacy.