Associations of Statins and Diabetes with Diagnosis of Ulcerated Cutaneous Melanoma

Abstract

Ulcerated primary melanomas are associated with an inflammatory tumor microenvironment. We hypothesized that systemic proinflammatory states and anti-inflammatory medications are also associated with a diagnosis of ulcerated melanoma. In a cross-sectional study of 787 patients with newly diagnosed clinical stage IB or II melanoma, we estimated odds ratios for the association of proinflammatory factors (high body mass index, diabetes, cardiovascular disease, hypertension, and smoking) or the use of anti-inflammatory medications (statins, aspirin, corticosteroids, and nonsteroidal anti-inflammatory drugs), with ulcerated primary melanoma using regression models and subgroup analyses to control for melanoma thickness and mitotic rate. On the basis of information from 194 patients with ulcerated and 593 patients with nonulcerated primary melanomas, regular statin users had lower likelihood of a diagnosis of ulcerated primary melanoma (odds ratio 0.67, 95% confidence interval 0.45-0.99), and this association remained after adjusting for age, sex, thickness, and mitosis. When analysis was limited to melanomas that were ≤2 mm thick and had ≤2 mitoses/mm (40 ulcerated; 289 without ulceration), patients with diabetes had significantly raised odds of diagnosis of ulcerated melanoma (odds ratio 2.90, 95% confidence interval 1.07-7.90), adjusted for age, sex, body mass index, and statin use. These findings support our hypotheses that statin use is inversely associated, and diabetes is positively associated, with ulcerated melanoma.

Statins may reduce disease recurrence in patients with ulcerated primary melanoma

“…In favour of this hypothesis is our previous finding that melanoma ulceration (a highly inflamed 12,[24][25][26] and proliferative phenotype associated with higher recurrence and death) 5 is less common among long-term statin users. 11 In our current study we observed that reduction of recurrence by statins appeared strongest in ulcerated tumours, suggesting that in those developing ulcerated melanomas despite exposure to statins, the tumour and/or its environment were tempered by the drug. Limitations include the relatively short follow-up time, although our rates of first recurrence are consistent with those in reports from other populations.…”

“…Statins prevent the conversion of HMG-CoA to mevalonate, thereby reducing the downstream products necessary for critical cellular functions. 10 Disruption of these processes in melanoma cells by statins has been shown to reduce growth and metastasis in vitro 14,15 and in animal 16,17 and cohort 11,19 studies. We propose that statins render the tumour and its microenvironment less susceptible to tumour spread by inhibiting common pathways associated with tumour inflammation, ulceration and metastasis.…”

“…8 Statins also reduce production of mevalonate and its downstream products, which play important roles in cancer biology by inhibiting pathways required for growth and metastasis. 9,10 We recently described the lower likelihood of statin users compared with nonusers being diagnosed with ulcerated melanomas, 11 hypothesizing that statins inhibit the inflammatory pathways associated with tumour ulceration. 12 Based on in vitro [13][14][15] and animal models, 16,17 it is further possible that the statins, which are anti-inflammatory, inhibit growth and progression of melanoma cells.…”

Combination therapy with dacarbazine and statins improved the survival rate in mice with metastatic melanoma

“…In addition, it has been indicated that statins suppress tumor metastasis via suppression of small GTPases Stine et al, 2016;Tsubaki, Takeda, Kino, Obata, et al, 2015;Wolfe et al, 2015). It has also been suggested that patients treated with statins have a lower likelihood of developing ulcerated primary melanoma (von Schuckmann et al, 2017).…”

Survival and Glycemic Control in Patients With Coexisting Melanoma and Diabetes Mellitus

“…A more recently recognized risk factor may be diabetes mellitus (DM), a very common disease [4,5]. A recent study reported a positive association between DM and ulcerated melanoma [6]. Microvascular disease coupled with the proinflammatory environment of DM might account for this association.…”