Photosensitizing Antihypertensive Drug Use and Risk of Cutaneous Squamous Cell Carcinoma K.A. Su,1,2 L.A. Habel,3 N.S. Achacoso,3 G.D. Friedman,3 M.M. Asgari1,2 1 Massachusetts General Hospital, Harvard Medical School, Boston, M.A., U.S.A. 2 Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, M.A., U.S.A. 3 Kaiser Permanente Northern California, Oakland, C.A., U.S.A. British Journal of Dermatology. DOI: 10.111/bjd.16713

Dr. Katherine A. Su

Introduction What’s already known? Certain antihypertensive drugs are photosensitizing, heightening reactivity of the skin to sunlight. Photosensitizing antihypertensive drugs may act as carcinogens by triggering: phototoxic reactions: produce DNA damage photoallergic reactions: produce chronic inflammation Photosensitizing antihypertensive drugs have been associated with lip cancer, but their impact on cutaneous squamous cell carcinoma (cSCC) risk is unclear.

Objective To examine the association between antihypertensive drug use and cSCC risk among a cohort of non- Hispanic whites with hypertension enrolled in a comprehensive integrated healthcare delivery system in northern California.

Methods Study Design: Retrospective cohort study, 1997-2012 Study Setting: Kaiser Permanente Northern California Study Population: 28,357 non-Hispanic whites with hypertension enrolled in the Research Program in Genes and Environmental Health

Methods Exposure: Pharmacy-dispensed antihypertensive drug Photosensitizing Alpha-2 receptor agonists Diuretics (loop, potassium-sparing, thiazide, combination) Unknown photosensitizing Angiotensin converting enzyme inhibitors Calcium channel blockers Vasodilators Other combinations Non-photosensitizing Alpha-blockers Beta-blockers Central agonists Angiotensin receptor blockers

Methods Outcome: Pathologically-verified cSCC Statistical Analysis: Cox modelling Covariates: Age Sex Cigarette use Charlson Comorbidity Index Healthcare utilization Surveillance measure Length of health plan membership Survey year Prior cSCC Prior actinic keratosis Prior photosensitizing antihypertensive drug use

Results: Cohort characteristics Overall (n=28,357) Ever use of Non-use of ADs (n=1,530) Photosensitizing ADs (n=17,946) Non-photosensitizing ADs (n=19,092) Unknown photosensitizing ADs (n=17,345) Age (at cohort entry): Mean (±SD) 69.1 (10.6) 69.3 (10.4) 69.9 (10.2) 70.1 (10.2) 67.9 (12.7) Sex, n (%)   Male 12,382 (43.7) 7,268 (40.5) 8,952 (46.9) 8,193 (47.2) 652 (42.6) Female 15,975 (56.3) 10,678 (59.5) 10,140 (53.1) 9,152 (52.8) 878 (57.4) Prior cSCC, n (%) Yes 2,228 (7.9) 1,329 (7.4) 1,487 (7.8) 1,352 (7.8) 217 (14.2) No 26,129 (92.1) 16,617 (92.6) 17,605 (92.2) 15,993 (92.2) 1,313 (85.8) Prior photosensitizing AD use, n (%) 20,994 (74.0) 16,189 (90.2) 14,244 (74.6) 12,921 (74.5) 791 (51.7) 7,363 (26.0) 1,757 (9.8) 4,848 (25.4) 4,424 (25.5) (48.3) AD: antihypertensive drug

Results: Hazard ratios for cSCC among cohort members Treatment (after cohort entry) cSCC, n (%) Person-years of follow-up Unadjusted HR (95% CI) Adjusted HR (95% CI) Overall (n=28,357) 3,010 (100) 144,215   Non-use of ADs (n=1,530) 371 (12.3) 19,222 1.00 (Reference) Ever use of photosensitizing ADs (n=17,946) 1,720 (57.1) 76,881 1.21 (1.12, 1.31) 1.17 (1.07, 1.28) Ever use of non-photosensitizing ADs (n=19,092) 1,862 (61.9) 83,414 1.23 (1.14, 1.33) 0.99 (0.91, 1.07) Ever use of unknown photosensitizing ADs (n=17,345) 1,717 (57.0) 73,300 1.35 (1.25, 1.46) 1.11 (1.02, 1.20) AD: antihypertensive drug

AD: antihypertensive drug Results: Hazard ratios for cSCC based on number of prescriptions for ADs filled Treatment (after cohort entry) cSCC cases, n (%) Person-years of follow-up Unadjusted HR (95% CI) Adjusted HR Non-use of ADs 371 (12.3) 19,222 1.00 (Reference) Use of photosensitizing ADs   1-7 fills 862 (28.6) 40,173 1.17 (1.06, 1.28) 1.12 (1.02, 1.24) 8-15 fills 610 (20.3) 27,071 1.21 (1.09, 1.35) 1.19 (1.06, 1.34) 16+ fills 248 (8.2) 9,637 1.42 (1.21, 1.66) 1.41 (1.20, 1.67) Use of non-photosensitizing ADs 768 (25.5) 36,284 1.18 (1.07, 1.30) 0.99 (0.89, 1.09) 625 (20.8) 27,326 1.27 (1.14, 1.41) 1.02 (0.92, 1.14) 469 (15.6) 19,804 1.30 (1.14, 1.47) 0.95 (0.83, 1.07) Use of unknown photosensitizing ADs 782 (26.0) 34,182 1.33 (1.21, 1.46) 1.12 (1.02, 1.23) 561 (18.6) 23,649 1.37 (1.23, 1.53) 1.12 (1.01, 1.25) 374 (12.4) 15,469 1.38 (1.21, 1.57) 1.06 (0.93, 1.21) AD: antihypertensive drug

Discussion This large cohort study examined the association between antihypertensive drug use and cSCC risk. This study suggests that use of photosensitizing antihypertensive drugs is associated with a 17% higher risk of cSCC compared with non-use. There was a modest increase in cSCC risk with increasing number of prescriptions for photosensitizing antihypertensive drugs.

Conclusions What does this study add? This study provides support for an increased cSCC risk among individuals treated with photosensitizing antihypertensive drugs. Patients taking photosensitizing antihypertensive drugs may benefit from education on safe sun practices and closer screening for cSCC.

Ninah S. Achacoso (not pictured) Research Team Katherine A. Su Laurel A. Habel Gary D. Friedman Maryam M. Asgari Ninah S. Achacoso (not pictured)

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