Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer.

Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti-diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD = 9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD = 3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85, 95% CI = 0.82-0.88) but among men with T2DM, those on metformin had no decrease (HR = 0.96, 95% CI = 0.77-1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73, 95% CI = 0.55-0.98), compared to men with T2DM not on anti-diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR = 1.11, 95% CI = 0.95-1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.

Dietary patterns and prostate cancer risk: report from the population based ULSAM cohort study of Swedish men.

Dietary pattern analyses have increased the possibilities to detect associations between diet and disease. However, studies on dietary pattern and prostate cancer are scarce. Food intake data in the Uppsala Longitudinal Study of Adult Men cohort was determined by 7-day food records. Adherence to a modified Mediterranean Diet Score (mMDS) and a low carbohydrate-high protein (LCHP) score were grouped as low, medium, or high in the whole study population (n = 1,044) and in those identified as adequate reporters of energy intake (n = 566), respectively. Prostate cancer risk was analyzed with Cox proportional hazard regression (median follow-up 13 years) and competing risk of death was considered. There were no associations between dietary patterns and prostate cancer (n = 133) in the whole study population. Among adequate reporters the mMDS was not associated with prostate cancer (n = 72). The LCHP score was inversely related to prostate cancer in adequate reporters, adjusted hazard ratios; 0.55 (0.32-0.96) for medium and 0.47 (0.21-1.04) for high compared to low adherent participants (P-for-trend 0.04). Risk relations were not attributable to competing risk of death. In this study, a LCHP diet was associated with lower prostate cancer incidence. Relations emerged in adequate reporters, underscoring the importance of high-quality dietary data.

Chemotherapeutic drug sensitivity of primary cultures of epithelial ovarian cancer cells from patients in relation to tumour characteristics and therapeutic outcome.

BACKGROUND: A number of chemotherapeutic drugs are active in epithelial ovarian cancer (EOC) but so far choice of drugs for treatment is mostly empirically based. Testing of drug activity in tumour cells from patients might provide a rationale for a more individualised approach for drug selection. MATERIAL AND METHODS: Sensitivity of EOC to chemotherapeutic drugs was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to tumour histology, treatment status and clinical tumour response. RESULTS: For most EOC standard drugs serous high grade and clear cell EOC were the most sensitive subtypes and the mucinous tumours the most resistant subtype. Docetaxel, however, tended to show the opposite pattern. Samples from previously treated patients tended to be more resistant than those from treatment naïve patients. The activity of cisplatin correlated with that of other drugs with the exception of docetaxel. Tumour samples from two sites in the same patient at the same occasion showed similar cisplatin sensitivity in contrast to samples taken at different occasions. Samples from patients responding in the clinic to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 83-100% and 55-83% ranges, respectively. CONCLUSIONS: Assessment of EOC tumour cell drug sensitivity in vitro provides clinically relevant and potentially useful information for the optimisation of drug treatment.

Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area.

PURPOSE: Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs. METHODS: In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus. RESULTS: ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA's ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8-31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals). CONCLUSIONS: The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.

Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up.

BACKGROUND: Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se. METHODS: ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms. RESULTS: In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (≤80 µg/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa. CONCLUSIONS: S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue.

Remdesivir in the COVID-19 Pandemic: An Analysis of Spontaneous Reports in VigiBase During 2020.

INTRODUCTION: The safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs). OBJECTIVE: This study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing on remdesivir, including a disproportionality analysis (DA) of ADRs. METHODS: A dedicated algorithm enabled retrieval of all COVID-19 treatment-specific ICSRs. A severity algorithm based on co-reported medicines and symptoms enabled selection of tocilizumab with its well established safety profile as comparator for remdesivir. Descriptive statistics were used for general ICSR demographics for all COVID-19-specific medicines, remdesivir and tocilizumab individually and furthermore to present treatment patterns of medicines co-reported with remdesivir. A COVID-19 indication-focused DA was deployed to minimize confounding from underlying polysymptomatic disease. RESULTS: 14,574 COVID-19-related ICSRs were entered into VigiBase during 2020. Remdesivir was the most common medicine reported. Of 4944 remdesivir ICSRs, where tocilizumab was not co-reported, 93% described remdesivir as the sole suspect medicine. Sixty percent of ICSRs concerned males, median age was 63 years and the majority originated from the Americas (72%). In 1089 (21%) of remdesivir ICSRs, data indicated severe/critical disease. Co-reported medicines peaked during the first 3 days of remdesivir treatment. The DA for the established tocilizumab and the new remdesivir were mainly in line with the safety profiles for both medicines but suggested new safety concerns. The most reported ADRs for remdesivir represented liver dysfunction, kidney injury, death and bradycardia. CONCLUSION: Global COVID-19-related ADR reporting proved useful in providing information on ADRs as well as on treatment patterns in this patient group. Indication-focused disproportionality analysis, together with the use of a comparator with a known safety profile, proved effective in identifying known safety information and suggested new safety concerns for remdesivir.

Sex Differences in Reported Adverse Drug Reactions to COVID-19 Drugs in a Global Database of Individual Case Safety Reports.

INTRODUCTION: In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir). OBJECTIVE: Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences. METHOD: We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020. RESULTS: In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs. CONCLUSION: Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.

Disproportionality Analysis for Pharmacovigilance Signal Detection in Small Databases or Subsets: Recommendations for Limiting False-Positive Associations.

INTRODUCTION: Uncovering safety signals through the collection and assessment of individual case reports remains a core pharmacovigilance activity. Despite the widespread use of disproportionality analysis in signal detection, recommendations are lacking on the minimum size of databases or subsets of databases required to yield robust results. OBJECTIVE: This study aims to investigate the relationship between database size and robustness of disproportionality analysis, with regards to limiting spurious associations. METHODS: Three types of subsets were created from the global database VigiBase: random subsets (500 replicates each of 11 fixed subset sizes between 250 and 100,000 reports), country-specific subsets (all 131 countries available in the original VigiBase extract) and subsets based on the Anatomical Therapeutic Chemical classification. For each subset, a spuriousness rate was computed as the ratio between the number of drug-event combinations highlighted by disproportionality analysis in a permuted version of the subset and the corresponding number in the original subset. In the permuted data, all true reporting associations between drugs and adverse events were broken. Subsets with fewer than five original associations were excluded. Additionally, the set of disproportionately over-reported drug-event combinations in three specific countries at three different time points were clinically assessed for labelledness. These time points corresponded to database sizes of less than 10,000, 5000 and 1000 reports, respectively. All disproportionality analysis was based on the Information Component (IC), implemented as IC025 > 0. RESULTS: Spuriousness rates were below 0.15 for all 110 included countries regardless of subset size, with only seven countries (6%) exceeding the empirical threshold of 0.10 observed for large subsets. All 21 excluded countries had < 500 reports. For random subsets containing 3000-5000 or more reports, the higher end of observed spuriousness rates was close to 0.10. In the clinical assessment, the proportion of labelled or otherwise known drug-event combinations was very high (87-100%) across all countries and time points studied. CONCLUSIONS: To mitigate the risk of highlighting spurious associations with disproportionality analysis, a minimum size of 500 reports is recommended for national databases. For databases or subsets that are not country-specific, our recommendation is 5000 reports. This study does not consider sensitivity, which is expected to be poor in smaller databases.

A Feasibility Study of Drug-Drug Interaction Signal Detection in Regular Pharmacovigilance.

INTRODUCTION: Adverse drug reactions related to drug-drug interactions cause harm to patients. There is a body of research on signal detection for drug interactions in collections of individual case reports, but limited use in regular pharmacovigilance. OBJECTIVE: The aim of this study was to evaluate the feasibility of signal detection of drug-drug interactions in collections of individual case reports of suspected adverse drug reactions. METHODS: This study was conducted in VigiBase, the WHO global database of individual case safety reports. The data lock point was 31 August 2016, which provided 13.6 million reports for analysis after deduplication. Statistical signal detection was performed using a previously developed predictive model for possible drug interactions. The model accounts for an interaction disproportionality measure, expressed suspicion of an interaction by the reporter, potential for interaction through cytochrome P450 activity of drugs, and reported information indicative of unexpected therapeutic response or altered therapeutic effect. Triage filters focused the preliminary signal assessment on combinations relating to serious adverse events with case series of no more than 30 reports from at least two countries, with at least one report during the previous 2 years. Additional filters sought to eliminate already known drug interactions through text mining of standard literature sources. Preliminary signal assessment was performed by a multidisciplinary group of pharmacovigilance professionals from Uppsala Monitoring Centre and collaborating organizations, whereas in-depth signal assessment was performed by experienced pharmacovigilance assessors. RESULTS: We performed preliminary signal assessment for 407 unique drug pairs. Of these, 157 drug pairs were considered already known to interact, whereas 232 were closed after preliminary assessment for other reasons. Ten drug pairs were subjected to in-depth signal assessment and an additional eight were decided to be kept under review awaiting additional reports. The triage filters had a major impact in focusing our preliminary signal assessment on just 14% of the statistical signals generated by the predictive model for drug interactions. In-depth assessment led to three signals communicated with the broader pharmacovigilance community, six closed signals and one to be kept under review. CONCLUSION: This study shows that signals of adverse drug interactions can be detected through broad statistical screening of individual case reports. It further shows that signal assessment related to possible drug interactions requires more detailed information on the temporal relationship between different drugs and the adverse event. Future research may consider whether interaction signal detection should be performed not for individual adverse event terms but for pairs of drugs across a spectrum of adverse events.

Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemia.

OBJECTIVES: Gefitinib inhibits epidermal growth factor receptor (EGFR) signalling, but may also act by non-EGFR dependent mechanisms. We have investigated the activity of gefitinib in haematological tumour cells, in particular acute myeloblastic leukaemia (AML). METHODS: Cytotoxic activity of gefitinib, alone or in combination with standard anti-leukaemic drugs, was assessed by the short-term fluorometric microculture cytotoxicity assay in tumour cells from 117 patients representing five haematological and five non-haematological malignancies. In AML, the EGFR status was analysed by immunochemistry. Gefitinib-induced apoptosis was investigated in a subset of AML samples, as well as in the leukaemia cell line MV-4-11, using a multiparametric high content screening assay. To confirm activation of caspase-3 in cells treated with gefitinib, a blocking test was carried out in which MV4-11 cells were pretreated with the specific caspase inhibitor DEVD-FMK. RESULTS: Gefitinib showed highest cytotoxic activity in AML (n = 19) with many samples being sensitive at concentrations achievable in clinical practice (<10 microM), and no difference between previously untreated and relapsed patients. No correlation between the activity of gefitinib and standard antileukaemic drugs (cytarabine, doxorubicin, etoposide) was observed. Combining gefitinib with these drugs resulted in mainly additive or synergistic (etoposide) effects, with no evidence of sequence dependency. The AML cells did not express the EGFR. Gefitinib induced apoptosis, which was at least partly mediated by activation of the caspase-3 pathway. CONCLUSION: In vitro, gefitinib has significant cytotoxic activity in AML by inducing apoptosis through non-EGFR dependent pathways.

Desloratadine and depression, a drug safety signal based on worldwide spontaneous reporting of side effects.

OBJECTIVE: Desloratadine, a third-generation antihistamine, is claimed to cause fewer central nervous system (CNS) adverse drug reactions (ADRs) than antihistamines of the first- and second-generation. While literature is inconclusive regarding the possible CNS effects, symptoms like somnolence and hallucinations are acknowledged ADRs of desloratadine, indeed suggesting some passage of this drug across the blood-brain barrier. Depression is currently not described as an ADR in the approved desloratadine product labelling. MATERIALS AND METHODS: In a joint signal detection workshop with the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb, case reports of suspected drug-ADR associations were analysed. RESULTS: Forty-nine unique case reports of desloratadine associated with depression or depressed mood were detected in the WHO global ADR database. In these reports, the median time to onset of depression was three days. Most patients recovered after withdrawal of desloratadine, and in five patients the symptoms of depression recurred after re-administration of desloratadine. CONCLUSION: We hypothesize that desloratadine may enter the CNS and that it hence in rare cases may cause a clinically relevant state of depression, a relation that patients and their treating physicians should be made aware of.

Safety Concerns Reported by Patients Identified in a Collaborative Signal Detection Workshop using VigiBase: Results and Reflections from Lareb and Uppsala Monitoring Centre.

INTRODUCTION: Patient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries. OBJECTIVE: Our objective was to explore the contribution of patient reports to global signal detection in VigiBase. METHODS: Data were retrieved from VigiBase in September 2016. Drug-event-combination series were restricted to those with >50% patient reports, defined as reporter type "Consumer/non-health professional" per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a "signal." RESULTS: Of the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments. CONCLUSIONS: Safety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance.

ADR Reporting by the General Public: Lessons Learnt from the Dutch and Swedish Systems.

Consumer reporting of adverse drug reactions (ADRs) has existed in several countries for decades, but throughout Europe the role of consumers as a source of information on ADRs has not been fully accepted until recently. In Europe, The Netherlands and Sweden were among the first countries to implement consumer reporting well before it was mandated by law throughout the EU. Consumer reporting is an integral part of the spontaneous reporting systems in both The Netherlands and Sweden, with yearly numbers of reports constantly increasing. Consumer reporting forms and handling procedures are essentially the same as for healthcare professional reporting; the message in the reports, not the type of messenger, is what is of importance. Studies have established the significant contribution of consumer reporting to ADR signal detection. Combining all reports regardless of reporter type is recommended since it yields the largest critical mass of reports for signal detection. Examples of signals where consumer reports have been of crucial importance for signal detection are electric shock-like sensations associated with the use of duloxetine, and persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. An example of consumer reporting significantly strengthening a detected signal is Pandemrix(®) (influenza H1N1 vaccine)-induced narcolepsy. Raising public awareness of ADR reporting is important, but time- and resource-consuming. The minimum effort taken should be to passively inform consumers, e.g. via stakeholders' homepages and via drug product information leaflets. Another possibility of reaching out to this target group could be through co-operation with other (non-government) organizations. Information from consumer reports may give a new perspective on ADRs via the consumers' unfiltered experiences. Consumers' views may change the way the benefit-harm balance of drugs is perceived and assessed today, and, being the ultimate users of drugs, consumers could have a relevant influence in the regulatory decision-making processes for drugs. All stakeholders in pharmacovigilance should embrace this new valuable source of information.

Cytotoxic activity of a new lipid formulation of doxorubicin in cell lines and primary tumor cells.

BACKGROUND: Liposomal formulations of the anthracyclines are being developed to circumvent toxicity and prolong effect. The current study investigates the in vitro activity of a novel doxorubicin micelle formulation, containing a vehicle designed to release pharmacologically active subcomponents. MATERIALS AND METHODS: The cytotoxicity of doxorubicin formulated in a vehicle containing C4 (N-docosahexaenoyl-O-phospho-2-aminoethanol) and C11 (N-all trans-retinoyl-O-phospho-L-tyrosine) was measured in a panel of human tumor cell lines, 19 primary cultures of human tumor cells and 5 lymphocyte preparations. RESULTS AND CONCLUSION: At the tested ratio between doxorubicin and C4/C11 (1:50), C4/C11 contributed significantly to the in vitro toxicity. However, the molar EC50-values were lower for doxorubicin than for C4/C11. Synergistic interactions between doxorubicin and C4/C11 were evident in a majority of the cell types studied. C4/C11 increased the cellular load of the fluorescent Pgp substrate calcein. To further investigate the possible benefits of the new formulation, in vivo studies are ongoing.

The metabolic syndrome and the risk of prostate cancer under competing risks of death from other causes.

BACKGROUND: Associations between metabolic syndrome (MetS) components and prostate cancer development have not been studied comprehensively; results have been divergent. Using the National Cholesterol Education Program Adult Treatment panel III (NCEP) and International Diabetes Federation (IDF) definitions of the MetS, we investigated such associations taking competing risks of death into consideration. METHODS: In the prospective Uppsala Longitudinal Study of Adult Men of 2,322 Caucasian men with 34 years of follow-up baseline, MetS measurements at age 50 years were used. Cumulative incidence of prostate cancer and death with/without the MetS were calculated. Competing risk of dying was taken into account by calculating the conditional probability of prostate cancer with/without the MetS. RESULTS: Two hundred and thirty-seven prostate cancers were identified. Prostate cancer probability by age 80 years with baseline MetS compared with without MetS was nonsignificantly higher [5.2 percent units (confidence interval (CI), -0.8% to 11.3%; NCEP); 2.7 percent units (CI, -2.7% to 8.0%; IDF)]; cumulative incidence proportions of death was significantly higher [19.3 percent units (CI, 13.4-25.3%; NCEP); 15.3 percent units (CI, 9.5-21.1%; IDF)]; and conditional probability of prostate cancer considering death from other causes was significantly higher [7.3 percent-units (CI, 0.2-14.5%); odds ratio of 1.64 (CI, 1.03-2.23; NCEP)] and nonsignificantly higher [5.0 percent-units (CI, -1.6% to 11.6%); odds ratio of 1.43 (CI, 0.89-1.90; IDF]. CONCLUSIONS: The MetS by the NCEP definition is associated with prostate cancer, taking the competing risk of early death from other causes into account. IMPACT: The results further highlight the public health effect of the increasing prevalence of MetS and the importance of considering competing risks when studying risk factors for cancer.