Use of 5-alpha reductase inhibitors and risk of gastrointestinal cancers in men with benign prostatic hyperplasia: A population-based cohort study.

Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.

Hormone replacement therapy and cancer mortality in women with 17 site-specific cancers: a cohort study using linked medical records.

BACKGROUND: There is limited evidence on the safety of Hormone Replacement Therapy (HRT) in women with cancer. Therefore, we systematically examined HRT use and cancer-specific mortality in women with 17 site-specific cancers. METHODS: Women newly diagnosed with 17 site-specific cancers from 1998 to 2019, were identified from general practitioner (GP) records, hospital diagnoses or cancer registries in Scotland, Wales and England. Breast cancer patients were excluded because HRT is contraindicated in breast cancer patients. The primary outcome was time to cancer-specific mortality. Time-dependent Cox regression models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer-specific mortality by systemic HRT use. RESULTS: The combined cancer cohorts contained 182,589 women across 17 cancer sites. Overall 7% of patients used systemic HRT after their cancer diagnosis. There was no evidence that HRT users, compared with non-users, had higher cancer-specific mortality at any cancer site. In particular, no increase was observed in common cancers including lung (adjusted HR = 0.98 95% CI 0.90, 1.07), colorectal (adjusted HR = 0.79 95% CI 0.70, 0.90), and melanoma (adjusted HR = 0.77 95% CI 0.58, 1.02). CONCLUSIONS: We observed no evidence of increased cancer-specific mortality in women with a range of cancers (excluding breast) receiving HRT.

Antiplatelet drugs and breast cancer risk in a large nationwide Danish case-control study.

Low-dose aspirin has been hypothesized to prevent cancer risk by inhibiting platelet aggregation. However, the anti-cancer effect of low-dose aspirin has recently been questioned and its effect on breast cancer development remains unclear. The impact of other antiplatelet drugs on breast cancer risk has rarely been evaluated. Thus, this study aimed to investigate the associations between breast cancer risk and antiplatelet drug use in a nationwide nested case-control study. From the Danish healthcare registries, we identified as cases all women with invasive breast cancer diagnosis between 2001 and 2018 (n = 68 852). The date of diagnosis corresponded to the index date. We matched cases to 10 population controls on age and calendar time, using risk set sampling. Controls were assigned the same index date as their matched case. We used the prescription registry to identify exposure to low-dose aspirin, clopidogrel and dipyridamole. We defined ever use of antiplatelet drugs as at least two prescriptions filled up to 1 year before the index date. We applied conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for breast cancer associated with the use of antiplatelet drugs, overall, by breast cancer subtype and by cumulative dose. Twelve percent of women had ever been exposed to low-dose aspirin, 2% to clopidogrel and 2% to dipyridamole. In multivariable models, breast cancer risk was not associated with ever use of low-dose aspirin (OR = 1.00 [0.97-1.03]), clopidogrel (OR = 0.93 [0.87-1.00]), and dipyridamole (OR = 1.02 [0.94-1.10]), compared with never use, and there was no evidence of a dose-response relation. However, we found an inverse association between dipyridamole use and breast cancer risk among women aged <55 years old, with suggestion of a dose-response relationship (OR per 1000 Defined Daily Doses = 0.72 [0.54-0.95]). Associations did not differ by breast cancer histological type, estrogen receptor status or clinical stage at diagnosis. Overall, the findings from this study do not support the use of antiplatelet drugs for breast cancer prevention.

Exposure to Ranitidine and Risk of Bladder Cancer: A Nested Case-Control Study.

INTRODUCTION: Ranitidine has been shown to contain the carcinogen N-nitrosodimethylamine and increase urinary N-nitrosodimethylamine in humans. We investigated whether ranitidine use is associated with increased bladder cancer risk. METHODS: A nested case-control study was conducted within the Primary Care Clinical Informatics Unit Research database which contains general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to 5 controls (based on age, sex, general practice, and date of registration). Ranitidine, other histamine-2 receptor agonists, and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for comorbidities and smoking. RESULTS: There were 3,260 cases and 14,037 controls. There was evidence of an increased risk of bladder cancer in ranitidine users, compared with nonusers (fully adjusted OR = 1.22; 95% CI 1.06-1.40), which was more marked with use for over 3 years of ranitidine (fully adjusted OR = 1.43; 95% CI 1.05-1.94). By contrast, there was little evidence of any association between proton pump inhibitor use and bladder cancer risk based on any use (fully adjusted OR = 0.98; 95% CI 0.88-1.11) or over 3 years of use (fully adjusted OR = 0.98; 95% CI 0.80-1.20). DISCUSSION: In this large population-based study, the use of ranitidine particularly long-term use was associated with an increased risk of bladder cancer. Further studies are necessary to attempt to replicate this finding in other settings.

Hormone replacement therapy in women with cancer and risk of cancer-specific mortality and cardiovascular disease: a protocol for a cohort study from Scotland and Wales.

BACKGROUND: Hormone replacement therapy (HRT) is widely used and has proven benefits for women with menopausal symptoms. An increasing number of women with cancer experience menopausal symptoms but the safety of HRT use in women with cancer is unclear. There are particular concerns that HRT could accelerate cancer progression in women with cancer, and also that HRT could increase the risk of cardiovascular disease in such women. Therefore, our primary aim is to determine whether HRT use alters the risk of cancer-specific mortality in women with a range of common cancers. Our secondary objectives are to investigate whether HRT alters the risk of second cancers, cardiovascular disease, venous thromboembolism and all-cause mortality. METHODS: The study will utilise independent population-based data from Wales using the SAIL databank and Scotland based upon the national Prescribing Information System. The study will include women newly diagnosed with common cancers from 2000 to 2016, identified from cancer registries. Women with breast cancers will be excluded. HRT will be ascertained using electronic prescribing in Wales or dispensing records in Scotland. The primary outcome will be time to cancer-specific mortality from national mortality records. Time-dependent cox regression models will be used to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer specific death in HRT users compared with non-users after cancer diagnosis after adjusting for relevant confounders, stratified by cancer site. Analysis will be repeated investigating the impact of HRT use immediately before cancer diagnosis. Secondary analyses will be conducted on the risk of second cancers, cardiovascular disease, venous thromboembolism and all-cause mortality. Analyses will be conducted within each cohort and pooled across cohorts. DISCUSSION: Our study will provide evidence to inform guidance given to women diagnosed with cancer on the safety of HRT use and/or guide modifications to clinical practice.

Weight-lowering Effects of Glucagon-like Peptide-1 Receptor Agonists and Detection of Breast Cancer Among Obese Women with Diabetes.

BACKGROUND: It has been proposed that the weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may improve detection of breast cancer in patients undergoing this treatment. We aimed to determine whether the weight-lowering effects of GLP-1 RAs are associated with an increased detection of breast cancer among obese women with type 2 diabetes. METHODS: Using the UK Clinical Practice Research Datalink, we conducted a propensity score-matched cohort study among female obese patients with type 2 diabetes newly treated with antidiabetic drugs between 1 January 2007 and 31 January 2018. New users of GLP-1 RAs (n = 5,510) were matched to new users of second- to third-line noninsulin antidiabetic drugs (n = 5,510). We used time-dependent Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with different GLP-1 RA maximal weight loss categories (<5%, 5%-10%, >10%). RESULTS: Breast cancer incidence gradually increased with GLP-1 RA maximal weight loss categories, with the highest HR observed for patients achieving at least 10% weight loss (HR = 1.8, 95% CI = 1.1, 2.8). In secondary analyses, the HR for >10% weight loss was highest in the 2-3 years since treatment initiation (HR = 2.9, 95% CI = 1.2, 6.9). CONCLUSIONS: In this population-based study, the detection of breast cancer gradually increased with GLP-1 RA weight loss categories, particularly among those achieving >10% weight loss. These results are consistent with the hypothesis that substantial weight loss with GLP-1 RAs may improve detection of breast cancer among obese patients with type 2 diabetes.

The Risk of Cardiovascular Disease in Prostate Cancer Patients Receiving Androgen Deprivation Therapies.

BACKGROUND: Androgen deprivation therapy (ADT), with a proven role in prostate cancer management, has been associated with various cardiovascular diseases. However, few studies have investigated these associations by type of ADT, particularly for newer ADTs such as the gonadotropin-releasing hormone (GnRH) antagonist degarelix. We investigated the risk of cardiovascular disease by type of ADT in a real-world setting. METHODS: We identified men newly diagnosed with prostate cancer, from 2009 to 2015, from the Scottish Cancer Registry and ADTs from the nationwide Prescribing Information System. Cardiovascular events were based upon hospitalization (from hospital records) or death from cardiovascular disease (from death records). We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular events with time-varying ADT exposure, comparing ADT users with untreated patients, after adjusting for potential confounders, including prior cardiovascular disease. RESULTS: The cohort contained 20,216 prostate cancer patients, followed for 73,570 person-years, during which there were 3,853 cardiovascular events. ADT was associated with a 30% increase in cardiovascular events (adjusted HR = 1.3; 95% CI = 1.2, 1.4). This reflected increases in cardiovascular events associated with GnRH agonists (adjusted HR = 1.3; 95% CI = 1.2, 1.4), degarelix (adjusted HR = 1.5; 95% CI = 1.2, 1.9), but not bicalutamide monotherapy (adjusted HR = 1.0; 95% CI = 0.82, 1.3). CONCLUSIONS: There were increased risks of cardiovascular disease with the use of GnRH agonists and degarelix, but not with bicalutamide monotherapy. This is the first study to observe increased cardiovascular risks with degarelix, but the cause of this association is unclear and merits further investigation.

Post-diagnostic antipsychotic use and cancer mortality: a population based cohort study.

BACKGROUND: Many antipsychotics elevate prolactin, a hormone implicated in breast cancer aetiology however no studies have investigated antipsychotic use in patients with breast cancer. This study investigated if antipsychotic use is associated with an increased risk of cancer-specific mortality among breast cancer patients. METHODS: A cohort of 23,695 women newly diagnosed with a primary breast cancer between 1st January 1998 and 31st December 2012 was identified from the UK Clinical Practice Research Datalink linked to English cancer-registries and followed for until 30th September 2015. Time-dependent Cox proportional hazards models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer-specific mortality comparing use of antipsychotics with non-use, overall, and by prolactin elevating activitiy. Analyses were repeated restricting to patients with a history of severe mental illness to control for potential confounding by indication. RESULTS: In total 848 patients were prescribed an antipsychotic and of which 162 died due to their breast cancer. Compared with non-use, antipsychotic use was associated with an increased risk of breast-cancer specific mortality (HR 2.25, 95%CI 1.90-2.67), but this did not follow a dose response relation. Restricting the cohort to patients with severe mental illness attenuated the association between antipsychotic use and breast cancer-specific mortality (HR 1.11, 95%CI 0.58-2.14). CONCLUSIONS: In this population-based cohort of breast cancer patients, while the use of antipsychotics was associated with increased breast cancer-specific mortality, there was a lack of a dose response, and importantly null associations were observed in patients with severe mental illness, suggesting the observed association is likely a result of confounding by indication. This study provides an exemplar of confounding by indication, highlighting the importance of consideration of this important bias in studies of drug effects in cancer patients.

Prognosis following surgical resection versus local excision of stage pT1 colorectal cancer: A population-based cohort study.

AIMS: To evaluate patient management following stage pT1 colorectal cancer (CRC) diagnosis, and to determine if surgical resection improved outcome compared with local excision, within a population-based study. METHODS: Data were collected from the Northern Ireland Cancer Registry. Cases of stage pT1 CRC diagnosed from 2007 to 2012 were identified. Analyses were conducted using Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for cancer-specific and all-cause mortality for individuals undergoing formal surgery versus local excision. RESULTS: 394 patients with pT1 CRC were included. Of these, 37.1% were treated by local resection, 36.8% had biopsy followed by surgery and 26.1% had local excision followed by surgery. There were 60 deaths over a mean 4.8 years of follow-up, including 10 CRC-specific deaths. An additional 12 patients had a CRC recurrence or metastases during follow-up. Of the CRC-specific deaths or recurrences, 27.3% had local excision only. Individuals treated by formal surgery did not have a reduced risk of CRC-specific death (adjusted HR = 1.51, 95% CI 0.29, 7.89), but did have a reduced risk of all-cause mortality (adjusted HR = 0.51 95% CI 0.30, 0.87) compared with those undergoing local excision only. CONCLUSIONS: Patients with stage pT1 CRC undergoing formal surgery had a reduced risk of all-cause mortality compared with those treated by local excision only. However, this was not explained by a reduced risk of recurrence/disease-free survival or CRC death, and suggests that the observed benefits may simply reflect selection of a healthier patient population in the formal surgery group.

Use of proton pump inhibitors and risk of pancreatic cancer.

PURPOSE: Preclinical studies have suggested that proton pump inhibitors (PPIs) may increase pancreatic cancer risk; however, epidemiological studies are few, with conflicting results. This spurred us to evaluate whether PPI use is associated with an increased risk of pancreatic cancer in a large population-based study. METHODS: We conducted a nationwide case-control study using data from Danish demographic and health care registries. All patients with a first cancer diagnosis of pancreatic cancer between 2000 and 2015 were identified from the Danish Cancer Registry and age-matched, sex-matched, and calendar-matched 1:20 to population controls using risk set sampling. Conditional logistic regression was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer associated with PPI use, adjusting for potential confounders. Secondary analyses examined dose-response patterns and associations with individual PPIs as well as with histamine-2-receptor antagonists. RESULTS: Ever use of PPIs occurred among 27.8% of 6921 pancreatic cancer cases and 25.4% of 34 695 matched controls, yielding a neutral adjusted OR of 1.04 (95% CI 0.97-1.11). Odds ratios were also close to unity in analyses of high use of PPIs (≥1000 DDDs; OR, 0.92 95% CI 0.80-1.07). There was no evidence of a dose-response relationship, with ORs close to unity across categories, including for those with the highest cumulative use (>2000 DDDs; OR, 1.03 95% CI 0.84-1.26). Analyses of subgroups as well as individual types of PPI and of histamine-2-receptor antagonists use also returned neutral associations. CONCLUSIONS: In this large nationwide case-control study, PPI use was not associated with an increased risk of pancreatic cancer.