Menopausal hormone therapy and breast cancer risk: a population-based cohort study of 1.3 million women in Norway.

BACKGROUND: It is important to monitor the association between menopausal hormone therapy (HT) use and breast cancer (BC) risk with contemporary estimates, and specifically focus on HT types and new drugs. METHODS: We estimated hazard ratios (HR) of BC risk according to HT type, administration route and individual drugs, overall and stratified by body mass index (BMI), molecular subtype and detection mode, with non-HT use as reference. RESULTS: We included 1,275,783 women, 45+ years, followed from 2004, for a median of 12.7 years. Oral oestrogen combined with daily progestin was associated with the highest risk of BC (HR 2.42, 95% confidence interval (CI) 2.31-2.54), with drug-specific HRs ranging from Cliovelle®: 1.63 (95% CI 1.35-1.96) to Kliogest®: 2.67 (2.37-3.00). Vaginal oestradiol was not associated with BC risk. HT use was more strongly associated with luminal A cancer (HR 1.97, 95% CI 1.86-2.09) than other molecular subtypes, and more strongly with interval (HR 2.00, 95% CI: 1.83-2.30) than screen-detected (HR 1.33, 95% CI 1.26-1.41) BC in women 50-71 years. HRs for HT use decreased with increasing BMI. CONCLUSIONS: The use of oral and transdermal HT was associated with an increased risk of BC. The associations varied according to HT type, individual drugs, molecular subtype, detection mode and BMI.

Low-Dose Aspirin and Prevention of Colorectal Cancer: Evidence From a Nationwide Registry-Based Cohort in Norway.

INTRODUCTION: To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC). METHODS: In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use. RESULTS: We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period. DISCUSSION: In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.

Low-dose aspirin, statins, and metformin and survival in patients with breast cancers: a Norwegian population-based cohort study.

BACKGROUND: Previous studies assessed the prognostic effect of aspirin, statins, and metformin in breast cancer (BC) patients, with inconclusive results. METHODS: We performed a nationwide population-based cohort study to evaluate if post-diagnostic use of low-dose aspirin, statins, and metformin was associated with BC-specific survival. Women aged ≥ 50 years and diagnosed with BC in 2004-2017, who survived ≥ 12 months after diagnosis (follow-up started 12 months after diagnosis), were identified in the Cancer Registry of Norway. The Norwegian Prescription Database provided information on prescriptions. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between post-diagnostic use and BC-specific survival, overall and by oestrogen receptor (ER) status. RESULTS: A total of 26,190 patients were included. Of these, 5324 (20%), 7591 (29%), and 1495 (6%) were post-diagnostic users of low-dose aspirin, statins, and metformin, respectively. The median follow-up was 6.1 years, and 2169 (8%) patients died from BC. HRs for use, compared to no use, were estimated at 0.96 (95% CI 0.85-1.08) for low-dose aspirin (ER+: HR = 0.97, 95% CI 0.83-1.13; ER-: HR = 0.97, 95% CI 0.73-1.29, p value for interaction = 0.562), 0.84 (95% CI 0.75-0.94) for statins (ER+: HR = 0.95, 95% CI 0.82-1.09; ER-: HR = 0.77, 95% CI 0.60-1.00, p value for interaction = 0.259), and 0.70 (95% CI 0.51-0.96) for metformin (compared to use of non-metformin antidiabetics) (ER+: HR = 0.67, 95% CI 0.45-1.01; ER-: HR = 1.62, 95% CI 0.72-3.62, p value for interaction = 0.077). CONCLUSION: We found evidence supporting an association between post-diagnostic use of statins and metformin and survival, in patients with BC. Our findings indicate potential differences according to ER status.

Antimuscarinics and lung cancer survival: A Norwegian population-based cohort study.

OBJECTIVES: Epidemiological studies have reported an association between antimuscarinics and reduced risk of cancer, including lung cancer (LC). However, the potential association between antimuscarinic use and LC prognosis has not previously been assessed. In a large population-based cohort, we aimed to investigate the association between the use of antimuscarinics and LC-specific survival. MATERIALS AND METHODS: Norwegian residents, aged ≥ 50 years, and diagnosed with LC between 2005 and 2018, were identified in the Cancer Registry of Norway, and information on filled prescriptions was obtained from the Norwegian Prescription Database. We used Cox proportional hazard models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between peri-diagnostic and post-diagnostic use of antimuscarinics and LC-specific survival. RESULTS: We included 26,693 patients with incident primary invasive LC. Of these, 466 (1.7 %) were peri-diagnostic users, and 877 (3.3 %) were post-diagnostic users of antimuscarinics, respectively. During a median follow-up of nine months, 18,088 (67.8 %) patients died due to LC. In the overall LC population, the HRs for the association between the use of antimuscarinics, compared to no use, were estimated at 1.01 (95 %CI: 0.90-1.12) for peri-diagnostic use, and 0.84 (95 %CI: 0.77-0.92) for post-diagnostic use. The association with post-diagnostic use was observed in many subgroups defined by sex, age, smoking status, histopathology, and stage, except for patients with unspecified or other histopathology than small cell LC and non-small cell LC, and for patients with local disease. The association was observed in patients treated with chemotherapy (HR = 0.75, 95 %CI: 0.64-0.88), but not in those not treated with chemotherapy (HR = 1.00, 95 %CI: 0.86-1.17; p for interaction: 0.007). CONCLUSION: Our results suggest a possible association between use of antimuscarinics and longer LC-specific survival. More studies are warranted to investigate the use of antimuscarinics to possibly prolong LC prognosis.

Low-dose aspirin and risk of breast cancer: a Norwegian population-based cohort study of one million women.

Several studies evaluated the association between aspirin use and risk of breast cancer (BC), with inconsistent results. We identified women aged ≥ 50 years residing in Norway between 2004 and 2018, and linked data from nationwide registries; including the Cancer Registry of Norway, the Norwegian Prescription Database, and national health surveys. We used Cox regression models to estimate the association between low-dose aspirin use and BC risk, overall and by BC characteristics, women's age and body mass index (BMI), adjusting for sociodemographic factors and use of other medications. We included 1,083,629 women. During a median follow-up of 11.6 years, 257,442 (24%) women used aspirin, and 29,533 (3%) BCs occurred. For current use of aspirin, compared to never use, we found an indication of a reduced risk of oestrogen receptor-positive (ER +) BC (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.92-1.00), but not ER-negative BC (HR = 1.01, 95%CI: 0.90-1.13). The association with ER + BC was only found in women aged ≥ 65 years (HR = 0.95, 95%CI: 0.90-0.99), and became stronger as the duration of use increased (use of ≥ 4 years HR = 0.91, 95%CI: 0.85-0.98). BMI was available for 450,080 (42%) women. Current use of aspirin was associated with a reduced risk of ER + BC in women with BMI ≥ 25 (HR = 0.91, 95%CI: 0.83-0.99; HR = 0.86, 95%CI: 0.75-0.97 for use of ≥ 4 years), but not in women with BMI < 25.Use of low-dose aspirin was associated with reduced risk of ER + BC, in particular in women aged ≥ 65 years and overweight women.

Real-world effectiveness of HPV vaccination against cervical neoplasia among birth cohorts ineligible for routine vaccination.

Human papillomavirus (HPV) vaccine effectiveness may differ between settings. Here we present the first real-world effectiveness study of HPV vaccination on high-grade cervical lesions from Norway, among women who received HPV vaccine outside the routine program. We performed an observational study of all Norwegian women born 1975 to 1996 and retrieved individual data from nationwide registries on HPV vaccination status and incidence of histologically verified high-grade cervical neoplasia during 2006 to 2016. We estimated the incidence rate ratio (IRR) and 95% confidence intervals (CI) for vaccination vs no vaccination by Poisson regression stratified by age at vaccination <20 years and ≥20 years. The cohort consisted of 832 732 women, of which 46 381 (5.6%) received at least one dose of HPV vaccine by the end of 2016. The incidence rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) increased with age regardless of vaccination status and was highest at age 25 to 29, at 637/100 000 among unvaccinated women, 487/100 000 among women vaccinated before age 20 and 831/100 000 among women vaccinated at age 20 or older. The adjusted IRR of CIN2+ between vaccinated and unvaccinated women was 0.62 (95% CI: 0.46-0.84) for women vaccinated below age 20, and 1.22 (95% CI: 1.03-1.43) for women vaccinated at age 20 or older. These findings indicate that HPV vaccination among women too old to be eligible for routine HPV vaccination is effective among women who are vaccinated below age 20 but may not have the desired impact among women who are vaccinated at age 20 or older.

Association between use of low-dose aspirin and detection of colorectal polyps and cancer in a screening setting.

BACKGROUND: The possible protective effect of aspirin on risk of colorectal cancer (CRC) is still highly debated. METHODS: We used data from Bowel Cancer Screening in Norway, a trial randomizing individuals from general population, aged 50-74 years, to flexible sigmoidoscopy or faecal immunochemical test (FIT), to study the association between aspirin use and detection of CRC and two CRC precursors: adenomas and advanced serrated lesions (ASL). Prescriptions of low-dose aspirin were obtained from Norwegian prescription database. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 64,889 screening participants (24,159 sigmoidoscopy, 40,730 FIT), 314 (0.5%) had CRC, 6,208 (9.6%) adenoma and 659 (1.0%) ASL. Overall and short-term use (<3 years) of low-dose aspirin, versus no use, were not associated with any colorectal lesion. Long-term use (≥3 years) was associated with lower detection of CRC (overall OR 0.66, 95%CI 0.46-0.93; sigmoidoscopy: 0.56, 0.33-0.97; FIT: 0.72, 0.45-1.15), adenomas in sigmoidoscopy arm (overall OR 0.95, 95%CI 0.87-1.03; sigmoidoscopy: 0.89, 0.80-0.99; FIT: 1.03, 0.89-1.18), but not ASLs. We did not observe significant differences in the effect of aspirin according to the location of colorectal lesions. CONCLUSION: Our results suggest that long-term use of aspirin might have a protective effect against adenomas and colorectal cancer, but not ASLs.

Night shift work and risk of aggressive prostate cancer in the Norwegian Offshore Petroleum Workers (NOPW) cohort.

BACKGROUND: Night shift work may acutely disrupt the circadian rhythm, with possible carcinogenic effects. Prostate cancer has few established risk factors though night shift work, a probable human carcinogen, may increase the risk. We aimed to study the association between night shift work and chlorinated degreasing agents (CDAs) as possible endocrine disrupters in relation to aggressive prostate cancer as verified malignancies. METHODS: We conducted a case-cohort study on 299 aggressive prostate cancer cases and 2056 randomly drawn non-cases in the Norwegian Offshore Petroleum Workers cohort (1965-98) with linkage to the Cancer Registry of Norway (1953-2019). Work history was recorded as years with day, night, and rollover (rotating) shift work, and CDA exposure was assessed with expert-made job-exposure matrices. Weighted Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for aggressive prostate cancer, adjusted for education and year of first employment, stratified by 10-year birth cohorts, and with 10, 15, and 20 years of exposure lag periods. RESULTS: Compared with day work only, an increased hazard of aggressive prostate cancer (HR = 1.86, 95% CI 1.18-2.91; P-trend = 0.046) was found in workers exposed to ≥19.5 years of rollover shift work. This persisted with longer lag periods (HR = 1.90, 95% CI 0.92-3.95; P-trend = 0.007). The exposure-hazard curve for a non-linear model increased linearly (HRs ≥1.00) for 18-26 years of rollover shift work. No association was found with CDA exposure. CONCLUSIONS: Long-term exposure to rollover shift work may increase the hazard of aggressive prostate cancer in offshore petroleum workers.

Downstaging and survival after Neoadjuvant chemotherapy for bladder cancer in Norway; a population-based study.

BACKGROUND: Neoadjuvant chemotherapy (NAC) before radical cystectomy is associated with pathological downstaging (DS) and improved overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC). Population-based studies have not unequivocally shown improved survival. The aim of this population-based study was to evaluate the effect of NAC on DS and OS in Norwegian patients with MIBC. METHODS: Patients in the Cancer Registry of Norway undergoing radical cystectomy (2008-2015) with or without NAC diagnosed with MIBC between 2008 and 2012 were included. Follow-up data were available until 31 December 2019. Logistic regression estimated the odds of DS with NAC, and a Cox model investigated the effect of DS on OS. Cox models, a mediator analysis and an instrumental variable approach were used to investigate the effect of NAC on OS. RESULTS: A total of 575 patients were included. NAC was administered to 82 (14%) patients. Compared to cystectomy only, NAC increased the proportion (43% vs. 22%) and the odds of DS (OR 2.51, CI 1.37-4.60, p = 0.003). Independent of NAC, the proportion of pN0 was higher in patients with DS (89% vs. 60%) and DS yielded a 78% mortality risk reduction (HR 0.22, CI 0.15-0.34, p = 1.9∙10-12), compared to patients without DS. We did not find an association between NAC and OS, neither by Cox regression (HR 1.16, CI 0.80-1.68, p = 0.417) nor by an instrumental variable approach (HR = 0.56, CI = 0.07-4.57, p = 0.586). The mediation analysis (p = 0.026) confirmed an indirect effect of NAC on OS through DS. Limitations include limited information of the primary tumour, details of NAC treatment and treatment indications. CONCLUSIONS: NAC increases the probability of DS and is indirectly associated to OS. DS is related to the absence of regional lymph node metastases and is associated with an OS benefit. Improved staging and biomarkers are needed to identify patients most likely to achieve DS and to benefit from NAC.

Impact of the Mobile Game FightHPV on Cervical Cancer Screening Attendance: Retrospective Cohort Study.

BACKGROUND: The wide availability of mobile phones has made it easy to disseminate health-related information and make it accessible. With gamification, mobile apps can nudge people to make informed health choices, including attending cervical cancer screening. OBJECTIVE: This matched retrospective cohort study examined the association between exposure to the FightHPV mobile app gamified educational content and having a cervical exam in the following year. METHODS: Women aged 20 to 69 years who signed an electronic consent form after downloading the FightHPV app in 2017 (intervention group) were matched 1:6 with women of the same age and with the same screening history (reference group) in 2015. To estimate the impact of exposure to the FightHPV app, we estimated cumulative incidence and hazard ratios (HRs) with 95% CIs. We used data from the Norwegian Cervical Cancer Screening Program database and Statistics Norway to determine screening participation and outcomes, respectively. RESULTS: We matched 3860 women in the control group to 658 women in the intervention group; 6 months after enrollment, 29.6% (195/658) of the women in the intervention group and 15.21% (587/3860) of those in the reference group underwent a cervical exam (P<.01). Women exposed to the FightHPV app were 2 times more likely to attend screening (adjusted HR 2.3, 95% CI 2.0-2.7), during which they were 13 times more likely to be diagnosed with high-grade abnormality (adjusted HR 12.7, 95% CI 5.0-32.5) than the women in the reference group. CONCLUSIONS: Exposure to the FightHPV app significantly increased cervical cancer screening attendance across the various analyses and improved detection of women with high risk for cervical cancer. For the first time, we demonstrated the effectiveness of gamification combined with mobile technology in cancer prevention by empowering women to make active health-related decisions. Gamification can significantly improve the understanding of complicated scientific concepts behind interventions and increase the acceptance of proposed cancer control measures.

ß-blockers and breast cancer survival by molecular subtypes: a population-based cohort study and meta-analysis.

BACKGROUND: The association between use of ß-blockers and breast cancer (BC) prognosis has been investigated in several observational studies, with conflicting results. We performed a nationwide cohort study and a meta-analysis to investigate the association, and assess if it varied between molecular subtypes of BC. METHODS: We identified women aged ≥50 years with BC diagnosed between 2004 and 2018 in Norway. We used Cox regression models to estimate the association between ß-blocker use at diagnosis and BC-specific survival, overall and by molecular subtype. We performed a meta-analysis of observational studies that reported molecular subtype-specific estimates of this association. RESULTS: We included 30,060 women, of which 4461 (15%) used ß-blockers. After a median follow-up of 5.1 years, 2826 (9%) died of BC. Overall, ß-blocker use was not associated with BC-specific survival (hazard ratio [HR] = 1.07; 95% confidence interval [CI]: 0.97-1.19). We found an association only in triple-negative BC (TNBC) patients (HR = 0.66; 95% CI: 0.47-0.91). This was confirmed in the meta-analysis: ß-blocker use was associated with progression/recurrence-free (HR = 0.58; 95% CI: 0.38-0.89) and BC-specific survival (HR = 0.74; 95% CI: 0.55-1.00) in TNBC patients only. CONCLUSION: In our cohort of BC patients and in the meta-analysis, ß-blocker use was associated with prolonged BC-specific survival only in TNBC patients.

Menopausal hormone therapy and melanoma risk in the Australian longitudinal study on women's health.

New evidence on the association between use of menopausal hormone therapy and increased risk of cutaneous melanoma (CM) is emerging. In the Australian Longitudinal Study on Women's Health, we followed 18,850 postmenopausal women for a median of 13.2 years, and observed 356 incident CMs. We found an indication of an association between use of unopposed oestrogen therapy and CM risk (hazard ratio (HR) 1.26; 95% confidence interval (CI) 0.98, 1.61), and no association between use of oestrogen-progestin therapy and CM risk (HR 0.99; 95% CI 0.37, 2.67). More studies are needed to elucidate the potential impact of different types of hormone therapy on CM risk.

Use of non-cancer drugs and survival among patients with pancreatic adenocarcinoma: a nationwide registry-based study in Norway.

BACKGROUND: The prognosis of pancreatic cancer is poor and new treatment strategies are urgently needed. To identify non-cancer drugs that could be re-purposed for cancer, we investigated the association between the use of selected drugs and cancer-specific mortality in a nationwide cohort of pancreatic cancer patients. MATERIAL AND METHODS: The study is based on linkage between the Cancer Registry of Norway and the Norwegian Prescription Database, comprising 2614 pancreatic cancer patients diagnosed between 2007 and 2014. We evaluated the association between use at diagnosis of a pre-defined list of non-cancer drugs, including metformin, antihypertensives, and statins, and pancreatic cancer-specific mortality, using Cox regression. Patients were defined as users of a particular drug if it was prescribed before diagnosis, and the prescription covered the date of diagnosis. RESULTS: In total, 2096 (80.2%) patients died from pancreatic cancer; median survival was 6 months. Statin users (n = 621) had lower mortality (hazard ratio (HR): 0.86; 95% confidence interval (CI) 0.76-0.97) compared to non-users (n = 1993). This association was more pronounced (P-heterogeneity 0.062) in users of hydrophilic (n = 37, HR: 0.61; 95% CI 0.42-0.90) than lipophilic (n = 587, HR: 0.87; 95% CI 0.78-0.98) statins. An indication for lower mortality (HR: 0.85; 95% CI 0.69-1.05) was observed in users of non-selective beta-blockers (n = 113) compared to non-users (n = 2501). Notably, when compared to users of other antihypertensives (n = 643), users of non-selective beta-blockers (n = 40) had lower mortality (HR 0.67; 95% CI 0.47-0.96). The use of other drugs, including selective beta-blockers and metformin, was not associated with mortality. CONCLUSION: The findings suggest an association between the use of statins and non-selective beta-blockers and reduced pancreatic cancer mortality, and add to the literature supporting the design of randomised clinical trials to evaluate those drugs in the management of pancreatic cancer.

A New Procedure to Assess When Estimates from the Cumulative Link Model Can Be Interpreted as Differences for Ordinal Scales in Quality of Life Studies.

PURPOSE: Assessing the clinical importance of an exposure effect on a quality of life (QoL) score often requires quantifying the effect in terms of a difference in scores. Using the linear regression model (LRM) for this purpose assumes the ordinal score is a proxy for an underlying continuous variable, but the analysis offers no assessment for the validity of the assumption. We propose an approach that assesses the proxy assumption and estimates the exposure effect by using the cumulative link model (CLM). PATIENTS AND METHODS: CLM is a well-established regression model that assumes an ordinal score is an ordered category generated from applying thresholds to a latent continuous variable. Our approach assesses the proxy assumption by testing whether these thresholds are equidistant. We compared the performance of CLM and LRM using simulated ordinal data and illustrated their application to the effect of time since diagnosis on five subscales of fatigue among breast cancer survivors measured using the Multidimensional Fatigue Inventory. RESULTS: CLM had good performance in estimating the difference in means with simulated ordinal data satisfying the proxy assumption, even when the outcome had only a few categories. When the proxy assumption was inadequate, both the CLM and LRM had biased estimates with poor coverage. The proxy assumption was appropriate for four of the five subscales in our real data application to fatigue scores, which highlighted the importance of assessing the proxy assumption to avoid reporting invalid estimates in terms of the difference in scores. CONCLUSION: The proxy assumption is critical to the interpretation of the exposure effect on the difference in mean QoL scores. CLM offers a valid test for the presence of an association, a method for assessing the proxy assumption, and when the assumption is adequate, an assessment for clinical significance using the difference in means.

Metformin use and lung cancer survival: a population-based study in Norway.

BACKGROUND: We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. METHODS: The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005-2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. RESULTS: Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62-0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47-0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73-0.95), in patients with SCC (HR = 0.75; 95%CI 0.57-0.98), regional stage LC (HR = 0.74; 95%CI 0.59-0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38-0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. CONCLUSIONS: Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.

Drug Use and Cancer Risk: A Drug-Wide Association Study (DWAS) in Norway.

BACKGROUND: Population-based pharmaco-epidemiologic studies are used to assess postmarketing drug safety and discover beneficial effects of off-label drug use. We conducted a drug-wide association study (DWAS) to screen for associations between prescription drugs and cancer risk. METHODS: This registry-based, nested case-control study, 1:10 matched on age, sex, and date of diagnosis of cases, comprises approximately 2 million Norwegian residents, including their drug history from 2004 to 2014. We evaluated the association between prescribed drugs, categorized according to the anatomical therapeutic chemical (ATC) classification system, and the risk of the 15 most common cancer types, overall and by histology. We used stratified Cox regression, adjusted for other drug use, comorbidity, county, and parity, and explored dose-response trends. RESULTS: We found 145 associations among 1,230 drug-cancer combinations on the ATC2-level and 77 of 8,130 on the ATC4-level. Results for all drug-cancer combinations are presented in this article and an online tool (https://pharmacoepi.shinyapps.io/drugwas/). Some associations have been previously reported, that is, menopausal hormones and breast cancer risk, or are likely confounded, that is, chronic obstructive pulmonary diseases and lung cancer risk. Other associations were novel, that is, inverse association between proton pump inhibitors and melanoma risk, and carcinogenic association of propulsives and lung cancer risk. CONCLUSIONS: This study confirmed previously reported associations and generated new hypotheses on possible carcinogenic or chemopreventive effects of prescription drugs. Results from this type of explorative approach need to be validated in tailored epidemiologic and preclinical studies. IMPACT: DWAS studies are robust and important tools to define new drug-cancer hypotheses.See related commentary by Wang and Gadalla, p. 597.

Prediagnostic serum 25-hydroxyvitamin D and melanoma risk.

Previous studies of serum 25-hydroxyvitamin D (25(OH)D) in relation to melanoma have shown conflicting results. We conducted a nested case-control study of 708 cases and 708 controls, using prediagnostically collected serum, to study 25(OH)D and melanoma risk in the population-based Janus Serum Bank Cohort. Stratified Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for ultraviolet radiation (UVR) indicators and stratified by ambient UVB of residence and body mass index (BMI). Non-linear associations were studied by restricted cubic splines. Missing data were handled with multiple imputation by chained equations. We found an HR of melanoma risk of 1.01 (95% CI: 0.99, 1.04) and an HRimputed of 1.02 (95% CI: 1.00, 1.04) per 5-nmol/L increase. The spline model showed exposure-risk curves with significantly reduced melanoma risk between 60 and 85 nmol/L 25(OH)D (reference 50 nmol/L). Non-significant J-shaped curves were found in sub-analyses of subjects with high ambient UVB of residence and of subjects with BMI < 25 kg/m2. Our data did not yield persuasive evidence for an association between 25(OH)D and melanoma risk overall. Serum levels within the medium range might be associated with reduced risk, an association possibly mediated by BMI.

Robust estimation of the effect of an exposure on the change in a continuous outcome.

BACKGROUND: The change in two measurements of a continuous outcome can be modelled directly with a linear regression model, or indirectly with a random effects model (REM) of the individual measurements. These methods are susceptible to model misspecifications, which are commonly addressed by applying monotonic transformations (e.g., Box-Cox transformation) to the outcomes. However, transforming the outcomes complicates the data analysis, especially when variable selection is involved. We propose a robust alternative through a novel application of the conditional probit (cprobit) model. METHODS: The cprobit model analyzes the ordered outcomes within each subject, making the estimate invariant to monotonic transformation on the outcome. By scaling the estimate from the cprobit model, we obtain the exposure effect on the change in the observed or Box-Cox transformed outcome, pending the adequacy of the normality assumption on the raw or transformed scale. RESULTS: Using simulated data, we demonstrated a similar good performance of the cprobit model and REM with and without transformation, except for some bias from both methods when the Box-Cox transformation was applied to scenarios with small sample size and strong effects. Only the cprobit model was robust to skewed subject-specific intercept terms when a Box-Cox transformation was used. Using two real datasets from the breast cancer and inpatient glycemic variability studies which utilize electronic medical records, we illustrated the application of our proposed robust approach as a seamless three-step workflow that facilitates the use of Box-Cox transformation to address non-normality with a common underlying model. CONCLUSIONS: The cprobit model provides a seamless and robust inference on the change in continuous outcomes, and its three-step workflow is implemented in an R package for easy accessibility.