Use of anti-androgenic 5α-reductase inhibitors and risk of oesophageal and gastric cancer by histological type and anatomical sub-site

ABSTRACT BACKGROUND To investigate if anti-androgenic medications 5α-reductase inhibitors (5-ARIs) decrease the risk of developing oesophageal and gastric tumours, analysed by histological

type and anatomical sub-site. METHODS A Swedish population-based cohort study between 2005 and 2018 where men using 5-ARIs were considered exposed. For each exposed participant, ten male

age-matched non-users of 5-ARIs (non-exposed) were included. Multivariable Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, calendar year,

smoking, non-steroidal anti-inflammatory drugs/aspirin use, and statins use. Further adjustments were made depending on the tumour analysed. RESULTS The cohort included 191,156 users of

5-ARIs and 1,911,560 non-users. Overall, the use of 5-ARIs was not associated with any statistically significantly reduced risk of oesophageal or cardia adenocarcinoma (adjusted HR 0.92, 95%

CI 0.82–1.02) or gastric non-cardia adenocarcinoma (adjusted HR 0.90, 95% CI 0.80–1.02). However, the use of 5-ARIs indicated a decreased risk of oesophageal or cardia adenocarcinoma among

obese or diabetic participants (adjusted HR 0.55, 95% CI 0.39–0.80) and a reduced risk of oesophageal squamous cell carcinoma (adjusted HR 0.49, 95% CI 0.37–0.65). CONCLUSION Users of 5-ARIs

may have a decreased risk of developing oesophageal or cardia adenocarcinoma among those obese or diabetic, and a decreased risk of oesophageal squamous cell carcinoma. SIMILAR CONTENT

BEING VIEWED BY OTHERS MENOPAUSAL HORMONE THERAPY AND RISK OF OESOPHAGEAL ADENOCARCINOMA IN A POPULATION-BASED COHORT STUDY Article 20 October 2021 DIFFERENTIAL ASSOCIATION BETWEEN

CUMULATIVE DOSE OF 5Α-REDUCTASE INHIBITORS AND MORTALITY Article Open access 31 March 2025 RISK OF ESOPHAGEAL AND GASTRIC ADENOCARCINOMA IN MEN RECEIVING ANDROGEN DEPRIVATION THERAPY FOR

PROSTATE CANCER Article Open access 29 June 2021 BACKGROUND Oesophageal and gastric cancers are the 6th and 2nd leading causes, respectively, of cancer-related deaths globally [1]. The main

histological types of oesophageal cancer, i.e. adenocarcinoma and squamous cell carcinoma, have distinct aetiology. Adenocarcinoma is the dominant histological type (>95%) of gastric

cancer, but the anatomical sub-sites cardia and non-cardia gastric adenocarcinoma have different aetiology [2, 3]. Oesophageal and cardia adenocarcinoma share the main risk factors of

gastro-oesophageal reflux disease and obesity, while tobacco smoking and alcohol overconsumption are the main risk factors for oesophageal squamous cell carcinoma [2]. _Helicobacter pylori_

infection is the main risk factor for gastric non-cardia adenocarcinoma, but does not increase the risk of cardia adenocarcinoma, and decreases the risk of oesophageal adenocarcinoma [4].

Oesophageal and cardia adenocarcinoma are characterised by a strong and unexplained male predominance with a 6-to-1 male-to-female ratio in Europe and up to 9-to-1 in North America [5, 6].

The role of sex hormones in the aetiology of these tumours is supported by a 16-year delayed onset in women compared with men, and associations with circulating sex hormone levels

[7,8,9,10]. Oesophageal squamous cell carcinoma and gastric non-cardia adenocarcinoma are also overrepresented in men, but the male predominance is weaker and is largely explained by sex

differences in the prevalence of the main risk factors [4, 11, 12]. The medications 5α-reductase inhibitors (5-ARIs) have anti-androgenic properties and are widely used against benign

prostatic hyperplasia. They inhibit the 5α-reductase enzyme and reduce the conversion of testosterone to the more potent androgen dihydrotestosterone [13,14,15]. The only previous study that

has investigated 5-ARIs use and risk of oesophageal and gastric cancer indicated risk reductions, but that study did not separately analyse histological types or sub-sites of these tumours

[16]. This study aimed to test the hypothesis that the use of 5-ARIs decreases the risk of oesophageal and gastric cancer, independent of tumour histology and anatomical sub-site, but that

the risk is particularly decreased for oesophageal and cardia adenocarcinoma. METHODS DESIGN This was a nationwide Swedish population-based cohort study of men between July 1, 2005 and

December 31, 2018, where exposure to 5-ARIs was examined in relation to the risk of developing the outcomes of oesophageal or gastric cancer. The source population was all male Swedish

residents aged 18 years or older who were included in the Swedish Prescribed Drugs and Health Cohort (SPREDH), which has been presented in detail in a cohort description [17]. In brief,

SPREDH combines data from four national Swedish health data registries: Prescribed Drug Registry, Patient Registry, Cancer Registry and Cause of Death Registry. These registries achieved

complete nationwide coverage well before the study period, and the linkage of individuals’ data between multiple registries was enabled by the unique personal identity number, assigned to

each resident in Sweden at birth or immigration. SPREDH included 8,269,978 adults with at least one record of a selected commonly prescribed medication during the study period. The data used

for the present study were basic characteristics, prescribed and dispensed medications, healthcare utilisation, diagnoses, and dates and causes of death. Individuals were excluded if they

had any previous diagnosis of oesophageal cancer, gastric cancer, or male genital cancers (including prostate cancer), or had undergone oesophagectomy or gastrectomy before cohort entry

(details provided in Supplementary Table 1). EXPOSURE The exposure was at least two dispensed records of the 5-ARIs finasteride or dutasteride during the study period. These medications were

identified from the Swedish Prescribed Drug Registry by their anatomical therapeutic chemical (ATC) classification codes (Supplementary Table 2). For each exposed participant, ten

individuals unexposed to 5-ARIs were randomly selected from SPREDH and matched by age (±1 year) at cohort entry (2nd 5-ARI purchase). Non-users of 5-ARIs were censored if the first

dispensation of any 5-ARI was recorded. Non-users were shifted to the exposed group at any second dispensed record of 5-ARIs. All participants were followed up until the date of any of the

outcomes, death or the end of the study period (December 31, 2018), whichever occurred first. OUTCOMES Among a total of three outcomes, the main outcome was oesophageal or cardia

adenocarcinoma. These tumours were combined because of their adjacent anatomical positioning, shared aetiology and similarly strong male predominance. The secondary outcomes were oesophageal

squamous cell carcinoma and gastric non-cardia adenocarcinoma. All cancer diagnoses were identified from the Cancer Registry by the diagnosis codes in the International Classification of

Diseases, 7th version (ICD-7) (150 for oesophageal cancer, 151.1 for cardia cancer, and 151 excluding 151.1 for gastric non-cardia cancer) and histology codes in the WHO/HS/CANC/24

classification (096 for adenocarcinoma and 146 for squamous cell carcinoma). COVARIATES There were nine covariates in total: age (continuous), calendar year (continuous), gastro-oesophageal

reflux disease (yes or no), obesity or diabetes (yes or no), tobacco smoking or smoking-related diagnoses (yes or no), alcohol overconsumption-related diagnoses (yes or no), _Helicobacter

pylori_ eradication treatment (yes or no), use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin (yes or no), and use of statins (yes or no). The combined covariate obesity and

diabetes diagnoses were used as a proxy for obesity because the obesity diagnosis was under-recorded in the Patient Registry and the vast majority (81.9%) of diabetes patients are overweight

[18]. Diagnoses confirmed within 10 years before cohort entry were searched for in the Patient Registry. _Helicobacter pylori_ eradication treatment was defined by a record of a specific

eradication package in the Prescribed Drug Registry during the study period and was treated as a time-varying variable. Use of NSAIDs/aspirin and statins were defined by at least two

dispensed records of these medications in the Prescribed Drug Registry within one year before cohort entry. STATISTICAL ANALYSIS Cox proportional hazards regression was performed to estimate

the risks of the study outcomes in 5-ARI users compared with non-users of 5-ARI, providing hazard ratios (HR) with 95% confidence intervals (CI). Both crude and multivariable models were

applied. The multivariable models were tailored for each outcome, but all models were adjusted for five covariates: Age, calendar year, tobacco smoking or smoking-related diagnoses, use of

NSAIDs/aspirin, and use of statins. In addition to these adjustments, the analyses of oesophageal or cardia adenocarcinoma were adjusted for gastro-oesophageal reflux disease, obesity or

diabetes, and _Helicobacter pylori_ eradication treatment; analyses of gastric non-cardia adenocarcinoma adjusted for obesity or diabetes and _Helicobacter pylori_ eradication treatment; and

analyses of oesophageal squamous cell carcinoma adjusted for alcohol overconsumption-related diagnoses. Stratified analyses were performed for oesophageal or cardia adenocarcinoma (main

outcome) by age (dichotomised by the median value), gastro-oesophageal reflux disease (yes and no), obesity or diabetes (yes and no), _Helicobacter pylori_ eradication treatment (yes and

no), tobacco smoking or smoking-related diagnoses (yes and no), and type of 5-ARIs (finasteride and dutasteride). We also tested the possible interaction of the use of 5-ARIs with each of

these covariates by adding a multiplicative interaction term in the Cox regression. All models met the proportional-hazard assumption on the basis of Schoenfeld residuals. Two sensitivity

analyses were performed to assess the robustness of the results: one excluding those individuals who entered the cohort in 2005 (the first year) and had less than 6 months of drug history,

which was done in order to assess new 5-ARI users (incident users); and another that censored individuals who developed any cancer (except for non-malignant melanoma; ICD-7 codes 140-209

excluding 191 in the Cancer Registry) before the outcomes under study. An experienced biostatistician (GS) followed a detailed study protocol and used the statistical software Stata (Release

16, StataCorp, College Station, TX) when performing the data management and statistical analyses. All analyses were two-sided. RESULTS STUDY PARTICIPANTS The study included 191,156 users of

5-ARIs, together accumulating 1,094,334 exposed person-years at risk. These were compared with 1,911,560 non-users of 5-ARIs who contributed to a total of 9,874,357 unexposed person-years.

The mean duration of 5-ARI use was 3.8 years (interquartile range 0.61–6.11 years). The two groups had similar characteristics, except for a slightly higher prevalence of gastro-oesophageal

reflux disease and _Helicobacter pylori_ eradication treatment and a lower prevalence of alcohol overconsumption-related diagnoses in the 5-ARIs users (Table 1). Among users of 5-ARIs 33.7%

had no record of benign prostatic hyperplasia diagnosis compared to 78.9% in the non-user group (Supplementary Table 4). RISK OF OESOPHAGEAL OR CARDIA ADENOCARCINOMA A total of 345 users of

5-ARIs and 3328 non-users were diagnosed with oesophageal or cardia adenocarcinoma during the follow-up. The use of 5-ARIs was associated with a slightly decreased point estimate of

oesophageal or cardia adenocarcinoma, although the association was not statistically significant (adjusted HR 0.92, 95% CI 0.82–1.02) (Table 2). In the stratified analyses, the use of 5-ARIs

was associated with decreased HRs in participants with obesity or diabetes (adjusted HR 0.55, 95% CI 0.39–0.80). No such statistically significant associations were found in the stratified

analyses by age, gastro-oesophageal reflux disease, _Helicobacter pylori_ treatment, or tobacco smoking or smoking-related diagnoses, although all point estimates were below 1 (Table 3). The

point estimates were similar for users of finasteride only (adjusted HR 0.91, 95% CI 0.81–1.03) and dutasteride only (adjusted HR 0.95, 95% CI 0.73–1.24) (Table 4). RISK OF OESOPHAGEAL

SQUAMOUS CELL CARCINOMA The risk of oesophageal squamous cell carcinoma was lower in users of 5-ARIs than in non-users (adjusted HR 0.49, 95% CI 0.37–0.65) (Table 2). RISK OF GASTRIC

NON-CARDIA ADENOCARCINOMA The use of 5-ARIs was associated with a slightly decreased point estimate of gastric non-cardia adenocarcinoma, but this was not statistically significant (adjusted

HR 0.90, 95% CI 0.80–1.02) (Table 2). SENSITIVITY ANALYSES The HRs for all outcomes remained virtually unchanged in the sensitivity analyses excluding participants entering the cohort in

2005 and without at least 6 months of drug history and also in analyses with censoring of participants who developed any cancer during follow-up (Table 5). DISCUSSION This study suggests a

decreased risk of oesophageal or cardia adenocarcinoma in men using 5-ARIs with obesity or diabetes diagnoses. The use of 5-ARIs was also associated with a decreased risk of oesophageal

squamous cell carcinoma. Among the strengths of the study are the population-based design, the complete follow-up, and high-quality and prospectively collected data that allowed adjustment

for several covariates and stratified analyses. Confounding remains a limitation of this observational study. However, confounding by indication should not be a major issue because 5-ARIs

and their indication of prostatic hyperplasia are not associated with the factors associated with any of the studied tumours. Moreover, the results were adjusted for all main risk factors,

which did not influence the risk estimates. Yet, due to the lack of detailed data on several risk factors for oesophageal or gastric cancer, e.g. severity of gastro-oesophageal reflux

disease and duration and intensity of tobacco smoking, residual confounding cannot be dismissed. Because we used the combined covariate of obesity and diabetes as a proxy for the

under-recorded obesity data, we were not able to examine the specific interaction of 5-ARIs use with obesity and/or diabetes. Due to the inherent time-related bias in observational

pharmaco-epidemiological studies, particularly because the duration of use or accumulated exposure closely correlate with the follow-up, we did not assess the duration of 5-ARIs use in

relation to the risk of oesophageal or gastric cancer. Despite the large size of the cohort, another limitation was a limited statistical power in some of the analyses. To our knowledge,

only one previous study has investigated the associations between 5-ARIs use and the risk of oesophageal and gastric cancer. A Scottish nested case-control study found a reduced overall risk

of oesophageal and gastric cancer among users of the 5-ARI _finasteride_ (adjusted OR 0.68, 95% CI 0.50–0.94), but no association remained when oesophageal cancer and gastric cancer were

analysed separately [16]. That study lacked data on histological types of the tumours and made no distinction between the sub-sites cardia and non-cardia gastric cancer. In contrast, the

present study separately analysed histological types and anatomical sub-sites, which is warranted considering the major differences in aetiology and strengths of the male predominance

between these tumours. An obvious decreased risk of oesophageal or cardia adenocarcinoma was observed in 5-ARI users with obesity or diabetes. This finding suggests interactions between

obesity and sex hormonal exposures. Obesity is a well-established risk factor for these tumours and obesity decreases circulating levels of testosterone and dihydrotestosterone [19,20,21].

As indicated by two recent prospective studies, low testosterone levels may increase the risk of oesophageal and cardia adenocarcinoma [9, 10]. Because 5-ARIs decrease levels of

dihydrotestosterone with a compensatory effect leading to increased testosterone levels, it is possible that the obese individuals with lowered testosterone levels are more likely to benefit

from the potential protective anti-carcinogenic effect of normal or elevated testosterone levels. Yet, the mechanisms are unclear, especially for dihydrotestosterone which is more potent

than testosterone in binding to androgen receptors. However, this has not been associated with a risk of oesophageal or cardia adenocarcinoma [10]. A substantially reduced risk of

oesophageal squamous cell carcinoma was observed in 5-ARIs users. It has been suggested that sex hormonal factors may play a role also in the aetiology of this tumour. Several studies have

reported the expression of androgen receptors in oesophageal squamous cell carcinoma tissue and in vitro studies have shown that testosterone can induce the proliferation of oesophageal

squamous cell carcinoma cell lines [22,23,24,25]. However, the epidemiologic evidence regarding associations between sex hormonal exposures and oesophageal squamous cell carcinoma is limited

and inconclusive [26,27,28,29,30,31]. The present study indicates the role of anti-androgenic exposure in the aetiology of this cancer. The results also suggested a weak association between

the use of 5-ARIs and the risk of gastric non-cardia adenocarcinoma, although this was not statistically significant. Pre-clinical studies have indicated a limited role of sex hormones in

gastric carcinogenesis [32,33,34], and the results of the current study do not support any strong risk reduction associated with 5-ARI use. In conclusion, this population-based cohort study

indicates that 5-ARI use is associated with a decreased risk of oesophageal or cardia adenocarcinoma in individuals with obesity or diabetes and a decreased risk of oesophageal squamous cell

carcinoma, while no clear risk reduction was found for gastric non-cardia adenocarcinoma. The available evidence is currently too limited to support any changes in clinical practice or

prompt any randomised clinical trials, but more large cohort studies examining the associations between 5-ARI use and the risk of oesophageal and gastric cancer are warranted. DATA

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matrix metalloproteinase 9. Oncotarget. 2014;5:10584–95. Article  Google Scholar  Download references FUNDING This study was funded partly by the Swedish Cancer Society (grant number

190043), Swedish Research Council (grant number 2019-00209) and Grant of Science and Technology Development of Fujian Province, China (grant numbers 2019L3006, 2020L2009). Open access

funding provided by Karolinska Institute. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet,

Karolinska University Hospital, Stockholm, Sweden Sirus Rabbani, Giola Santoni, Jesper Lagergren & Shao-Hua Xie * School of Cancer and Pharmaceutical Sciences, King’s College London,

London, UK Jesper Lagergren * School of Public Health and Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China Shao-Hua Xie Authors *

Sirus Rabbani View author publications You can also search for this author inPubMed Google Scholar * Giola Santoni View author publications You can also search for this author inPubMed 

Google Scholar * Jesper Lagergren View author publications You can also search for this author inPubMed Google Scholar * Shao-Hua Xie View author publications You can also search for this

author inPubMed Google Scholar CONTRIBUTIONS All authors designed the study. JL and SX collected the data for the study. GS analysed the data. SR interpreted the results and drafted the

paper. All listed authors revised the paper and approved the final version of the article, including the authorship list. SX is the guarantor of this work and, as such, had full access to

all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. CORRESPONDING AUTHOR Correspondence to Shao-Hua Xie. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study was approved by the Regional Ethical Review Board in

Stockholm (reference number 2018/271-32). The study was performed in accordance with the Declaration of Helsinki. CONSENT TO PUBLISH Not applicable. ADDITIONAL INFORMATION PUBLISHER’S NOTE

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copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Rabbani, S., Santoni, G.,

Lagergren, J. _et al._ Use of anti-androgenic 5α-reductase inhibitors and risk of oesophageal and gastric cancer by histological type and anatomical sub-site. _Br J Cancer_ 127, 892–897

(2022). https://doi.org/10.1038/s41416-022-01872-w Download citation * Received: 01 March 2021 * Revised: 14 May 2022 * Accepted: 26 May 2022 * Published: 17 June 2022 * Issue Date: 01

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