Relation of statin use with non-melanoma skin cancer: prospective results from the Women's Health Initiative

Ange Wang, Marcia L Stefanick, Kristopher Kapphahn, Haley Hedlin, Manisha Desai, Jo Ann E Manson, Howard Strickler, Lisa Martin, Jean Wactawski-Wende, Michael Simon, Jean Y Tang, Ange Wang, Marcia L Stefanick, Kristopher Kapphahn, Haley Hedlin, Manisha Desai, Jo Ann E Manson, Howard Strickler, Lisa Martin, Jean Wactawski-Wende, Michael Simon, Jean Y Tang

Abstract

Background: The relationship between statin use and non-melanoma skin cancer (NMSC) is unclear with conflicting findings in literature. Data from the Women's Health Initiative (WHI) Observational Study and WHI Clinical Trial were used to investigate the prospective relationship between statin use and NMSC in non-Hispanic white (NHW) postmenopausal women.

Methods: The WHI study enrolled women aged 50-79 years at 40 US centres. Among 133,541 NHW participants, 118,357 with no cancer history at baseline and complete medication/covariate data comprised the analytic cohort. The association of statin use (baseline, overall as a time-varying variable, duration, type, potency, lipophilicity) and NMSC incidence was determined using random-effects logistic regression models.

Results: Over a mean of 10.5 years of follow-up, we identified 11,555 NMSC cases. Compared with participants with no statin use, use of any statin at baseline was associated with significantly increased NMSC incidence (adjusted odds ratio (ORadj) 1.21; 95% confidence interval (CI): 1.07-1.35)). In particular, lovastatin (OR 1.52; 95% CI: 1.08-2.16), simvastatin (OR 1.38; 95% CI: 1.12-1.69), and lipophilic statins (OR 1.39; 95% CI: 1.18-1.64) were associated with higher NMSC risk. Low and high, but not medium, potency statins were associated with higher NMSC risk. No significant effect modification of the statin-NMSC relationship was found for age, BMI, smoking, solar irradiation, vitamin D use, and skin cancer history.

Conclusions: Use of statins, particularly lipophilic statins, was associated with increased NMSC risk in postmenopausal white women in the WHI cohort. The lack of duration-effect relationship points to possible residual confounding. Additional prospective research should further investigate this relationship.

Trial registration: ClinicalTrials.gov NCT00000611.

Figures

Figure 1
Figure 1
Sample size for WHI OS+CT analytic cohort.

References

    1. Arnspang S, Pottegard A, Friis S, Clemmensen O, Andersen KE, Hallas J, Gaist D (2014) Statin use and risk of nonmelanoma skin cancer: a nationwide study in Denmark. Br J Cancer 112(1): 153–156.
    1. Asgari MA, Tang J, Epstein EH, Chren MM, Warton EM, Quesenberry CP, Go AS, Friedman GD (2009) Statin use and risk of basal cell carcinoma. J Am Acad Dermatol 61(1): 66–72.
    1. Bjerre LM, LeLorier J (2001) Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med 110(9): 716–723.
    1. Blais L, Desgagne A, LeLorier J (2000) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer – a nested case–control study. Arch Intern Med 160(15): 2363–2368.
    1. Chan KKW, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9(1): 10–19.
    1. Christenson LJ, Borrowman TA, Vachon CM, Tollefson MM, Otley CC, Weaver AL, Roenigk RK (2005) Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 294(6): 681–690.
    1. Collins R, Armitage J, Parish S, Sleight P, Peto R, Collaborati HPS (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326): 7–22.
    1. Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI, Porter FD, Beachy PA (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 33(4): 508–513.
    1. Corcoran RB, Scott MP (2006) Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 103(22): 8408–8413.
    1. Curiel TJ (2007) Tregs and rethinking cancer immunotherapy. J Clin Invest 117(5): 1167–1174.
    1. Gallagher RP, Hill GB, Bajdik CD, Fincham S, Coldman AJ, McLean DI, Threlfall WJ (1995) Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 131(2): 157–163.
    1. Gniadecki R (2004) Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis. Biochem Biophys Res Commun 320(1): 165–169.
    1. Goldstein MR, Mascitelli L, Pezzetta F (2009. a) The double-edged sword of statin immunomodulation. Int J Cardiol 135(1): 128–130.
    1. Goldstein MR, Mascitelli L, Pezzetta F (2009. b) Statins, regulatory T cells, and pediatric graft coronary artery disease. Pediatr Transplant 13(1): 139–140.
    1. Graaf MR, Beiderbeck AB, Egberts ACG, Richel DJ, Guchelaar HJ (2004) The risk of cancer in users of statins. J Clin Oncol 22(12): 2388–2394.
    1. Gray DT, Suman VJ, Su WP, Clay RP, Harmsen WS, Roenigk RK (1997) Trends in the population-based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992. Arch Dermatol 133(6): 735–740.
    1. Haukka J, Sankila R, Klaukka T, Lonnqvist J, Niskanen L, Tanskanen A, Wahlbeck K, Tiihonen J (2010) Incidence of cancer and statin usage—record linkage study. Int J Cancer 126(1): 279–284.
    1. Hussain SK, Sundquist J, Hemminki K (2009) The effect of having an affected parent or sibling on invasive and in situ skin cancer risk in Sweden. J Invest Dermatol 129(9): 2142–2147.
    1. Jagtap D, Rosenberg CA, Martin LW, Pettinger M, Khandekar J, Lane D, Ockene I, Simon MS (2012) Prospective analysis of association between use of statins and melanoma risk in the Women's Health Initiative. Cancer 118(20): 5124–5131.
    1. Jang TJ (2008) Prevalence of Foxp3 positive T regulatory cells is increased during progression of cutaneous squamous tumors. Yonsei Med J 49(6): 942–948.
    1. Karagas MR, Greenberg ER, Spencer SK, Stukel TA, Mott LA (1999) Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire Skin Cancer Study Group. Int J Cancer 81(4): 555–559.
    1. Kuoppala J, Lamminpaa A, Pukkala E (2008) Statins and cancer: a systematic review and meta-analysis. Eur J Cancer 44(15): 2122–2132.
    1. Li X, Wu XB, Chen Q (2014) Statin use is not associated with reduced risk of skin cancer: a meta-analysis. Br J Cancer 110(3): 802–807.
    1. Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER (2000) Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 136(8): 1007–1011.
    1. Mascitelli L, Pezzetta F, Goldstein MR (2010) The epidemic of nonmelanoma skin cancer and the widespread use of statins: Is there a connection? Dermato-Endocrinology 2(1): 37–38.
    1. Mausner-Fainberg K, Luboshits G, Mor A, Maysel-Auslender S, Rubinstein A, Keren G, George J (2008) The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis 197(2): 829–839.
    1. National Cancer Institute (2012) Cancer Trends Progress Report – 2011/2012Update. National Cancer Institute, Bethesda, MD, USA.
    1. Nardi G, Lhiaubet-Vallet V, Leandro-Garcia P, Miranda MA (2011) Potential phototoxicity of rosuvastatin mediated by its dihydrophenanthrene-like photoproduct. Chem Res Toxicol 24(10): 1779–1785.
    1. Peto R, Emberson J, Landray M, Baigent C, Collins R, Clare R, Califf R (2008) Analyses of cancer data from three ezetimibe trials. N Engl J Med 359(13): 1357–1366.
    1. Rodriguez-Pazos L, Sanchez-Aguilar D, Rodriguez-Granados MT, Pereiro-Ferreiros MM, Toribio J (2010) Erythema multiforme photoinduced by statins. Photodermatol Photoimmunol Photomed 26(4): 216–218.
    1. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, Coldiron BM (2010) Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146(3): 283–287.
    1. Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934): 1383–1389.
    1. Sekhon JS (2011) ‘Multivariate and Propensity Score Matching Software with automated balance optimization: the matching package for R.'. J Stat Softw 42(7): 1–52.
    1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr., Tomaselli GF American College of Cardiology/American Heart Association Task Force on Practice G (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129(25, Suppl 2): S1–45.
    1. Tang JY, So PL, Epstein EH Jr (2007) Novel Hedgehog pathway targets against basal cell carcinoma. Toxicol Appl Pharmacol 224(3): 257–264.
    1. Toth PP, Morrone D, Weintraub WS, Hanson ME, Lowe RS, Lin J, Shah AK, Tershakovec AM (2012) Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks. Int J Clin Pract 66(8): 800–812.
    1. van Dam RM, Huang Z, Rimm EB, Weinstock MA, Spiegelman D, Colditz GA, Willett WC, Giovannucci E (1999) Risk factors for basal cell carcinoma of the skin in men: results from the health professionals follow-up study. Am J Epidemiol 150(5): 459–468.
    1. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361(12): 1164–1172.
    1. WHI Investigators (1998) Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 19(1): 61–109.
    1. Wu J, Wong WW, Khosravi F, Minden MD, Penn LZ (2004) Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Res 64(18): 6461–6468.
    1. Zhang A, Elmets CA (2010) Drug-induced photosensitivity. eMedicine. Available at: (accessed 15 September 2015).

Source: PubMed

Подписаться