Use of Hydrochlorothiazide and Risk of Melanoma and Nonmelanoma Skin Cancer

Rouette, Julie; Yin, Hui; Pottegård, Anton; Nirantharakumar, Krishnarajah; Azoulay, Laurent

doi:10.1007/s40264-020-01015-1

Cited by 29 publications

(30 citation statements)

References 26 publications

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“…Results for KC in BIFAP were generally similar to results from a Danish study, 8 in which high use of HCTZ increased the risk of BCC by 1.3 times (1.1 times in BIFAP) and the risk of SCC by four (1.7 times in BIFAP). Recently, studies from the United Kingdom (UK) also using a primary care database, 11–13 showed similar results. In these studies HCTZ was related to KC too, especially to SCC.…”

Section: Discussionmentioning

confidence: 71%

“…However, most findings were not directly comparable mainly due to differences in the study methods used and study‐specific limitations. Recently, several studies have found an increased risk of skin and lip cancer related to high cumulative doses of hydrochlorothiazide (HCTZ) in populations from Denmark, 7–9 Iceland, 10 United Kindom 11–13 and Australia, 14 but not in a population from Taiwan 15 …”

Section: Introductionmentioning

confidence: 99%

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Use of hydrochlorothiazide and risk of skin cancer in a large nested case‐control study in Spain

León‐Muñoz

Duarte‐Salles

Llorente

et al. 2021

Pharmacoepidemiology and Drug

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Purpose Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population. Methods Two parallel nested case‐control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk‐set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). Results In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26–1.34) in SIDIAP and 1.20 (1.12–1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02–1.21]) than for SCC (1.71 [1.45–2.02]). A dose–response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09–1.43) in SIDIAP and 0.85 (0.64–1.13) in BIFAP. Conclusions In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose–response pattern.

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Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Use of hydrochlorothiazide and risk of skin cancer in a large nested case‐control study in Spain

León‐Muñoz

Duarte‐Salles

Llorente

et al. 2021

Pharmacoepidemiology and Drug

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“…Our study demonstrates that human keratinocytes chronically coexposed with UVA and HCTZ, but not with HCTZ alone, develop a dysplastic morphology, and acquire molecular characteristics of an oncogenic transformation, thus providing biologically plausible mechanisms ( Figure 7 ) for the increased risk of NMSCs observed in patients taking HCTZ [ 2 , 3 , 5 – 9 ].…”

Section: Discussionmentioning

confidence: 91%

“…On these bases, the European Medicine Agency Pharmacovigilance Risk Assessment Committee, recommended to amend the Summary of Product Characteristics for HCTZ containing products with special warnings and precautions [ 4 ]. Thereafter, data from the World Health Organization pharmacovigilance database VigiBase and case–control studies confirmed this association [ 5 – 9 ]. Very recently, the Food and Drug Administration also approved changes to the HCTZ drug label to inform patients about this risk ( https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-label-changes-hydrochlorothiazide-describe-small-risk-non-melanoma-skin-cancer#:~:text=%5B8%2F20%2F2020%5D,HCTZ%20use%20and%20to%20encourage ).…”

Section: Introductionmentioning

confidence: 95%

Hydrochlorothiazide Use and Risk of Nonmelanoma Skin Cancers: A Biological Plausibility Study

Bigagli

Cinci

D’Ambrosio

et al. 2021

Oxidative Medicine and Cellular Longevity

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Recent studies reported the association between increased risk of nonmelanoma skin cancers (NMSCs) and the use of hydrochlorothiazide (HCTZ), one of the most commonly prescribed diuretic, antihypertensive drug, over the world. Although HCTZ is known to be photosensitizing, the mechanisms involved in its potential prophotocarcinogenic effects remain unclear. Under acute exposure, therapeutically relevant concentrations of HCTZ (70, 140, and 370 ng/mL) amplified UVA-induced double-strand breaks, oxidative DNA, and protein damage in HaCaT human keratinocytes, and this effect was associated to a defective activity of the DNA repair enzyme, OGG1. Oxidative damage to DNA, but not that to proteins, was reversible within few hours. After chronic, combined exposure to HCTZ (70 ng/mL) and UVA (10 J/cm2), for 9 weeks, keratinocytes acquired a dysplastic-like phenotype characterized by a multilayered morphology and alterations in cell size, shape, and contacts. At the ultrastructural level, several atypical and enlarged nuclei and evident nucleoli were also observed. These transformed keratinocytes were apoptosis resistant, exhibited enhanced clonogenicity capacity, increased DNA damage and inflammation, defective DNA repair ability, and increased expression of the oncogene ΔNp63α and intranuclear β-catenin accumulation (a hallmark of Wnt pathway activation), compared to those treated with UVA alone. None of these molecular, morphological, or functional effects were observed in cells treated with HCTZ alone. All these features resemble in part those of preneoplastic lesions and NMSCs and provide evidence of a biological plausibility for the association among exposure to UVA, use of HCTZ, and increased risk of NMSCs. These results are of translational relevance since we used environmentally relevant UVA doses and tested HCTZ at concentrations that reflect the plasma levels of doses used in clinical practice. This study also highlights that drug safety data should be followed by experimental evaluations to clarify the mechanistic aspects of adverse events.

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“…Although the literature is not entirely consistent, we and others have reported markedly elevated risks of cutaneous squamous cell carcinoma (cSCC) among high users of hydrochlorothiazide (HCTZ) 1–7 . This is biologically plausible, since HCTZ is photosensitizing 8 and cSCC is strongly associated with cumulative sun exposure 9 …”

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confidence: 86%

Hydrochlorothiazide and risk of melanoma subtypes

Habel

Achacoso

Fireman

et al. 2021

Pharmacoepidemiology and Drug

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Background Hydrochlorothiazide (HCTZ), a common diuretic known to be photosensitizing and previously associated with non‐melanoma skin cancer, was recently reported to be associated with two melanoma subtypes, nodular and lentigo, among residents of Denmark. Our goal was to examine whether Danish findings could be replicated in a US cohort, using a similar study design and analysis. Methods Among non‐Hispanic White enrollees of Kaiser Permanente Northern California, we conducted an analysis of 9176 melanoma cases and 264 781 controls, matched on age, sex and time in health plan. We examined use of HCTZ prior to cancer diagnosis (cases) or comparable date for controls, categorized as never use, ever use and high use (≥50 000 mg). Electronic health records provided data on prescriptions, cancer diagnoses, and covariates. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for education, income and number of dermatology, internal medicine and urgent care visits. Results We observed a small increase in risk of melanoma, all types combined, associated with high use (≥50 000 mg) of HCTZ (OR = 1.11, 95% CI 1.00–1.23) and no evidence of a dose–response. Risk was more elevated for lentigo subtype (OR = 1.57, 95% CI 1.01–2.42). The somewhat elevated risk for nodular subtype was not statistically significant (OR = 1.22, 95% CI 0.78–1.90). There was very little association of high use with the superficial spreading subtype (OR = 1.05, 95% CI 0.80–1.37). Conclusions Our findings support a recent report of an association between high use of HCTZ and increased risk of the lentigo subtype of melanoma.

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Use of Hydrochlorothiazide and Risk of Melanoma and Nonmelanoma Skin Cancer

Cited by 29 publications

References 26 publications

Use of hydrochlorothiazide and risk of skin cancer in a large nested case‐control study in Spain

Use of hydrochlorothiazide and risk of skin cancer in a large nested case‐control study in Spain

Hydrochlorothiazide Use and Risk of Nonmelanoma Skin Cancers: A Biological Plausibility Study

Hydrochlorothiazide and risk of melanoma subtypes

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