Genetic variants and social benefit receipt in premenopausal women with breast cancer treated with docetaxel: a Danish population-based cohort study.

PURPOSE: Breast cancer patients' need for social benefits may increase following taxane-based chemotherapy, due to long-lasting side effects. Specific single nucleotide polymorphisms (SNPs) may mediate such side effects. We investigated the association between SNPs related to taxane metabolism, transport, toxicity, or DNA and neural repair, and receipt of social benefits. METHODS: From the Danish Breast Cancer Group, we identified premenopausal women diagnosed with stage I-III breast cancer during 2007-2011 and treated with docetaxel-based chemotherapy. We genotyped 21 SNPs from archived breast tumors using TaqMan assays. We ascertained social benefit payments from 1 year before to 5 years after diagnosis, using nationwide, administrative registry data. For each week, we categorized women as receiving health-related benefits (including sick leave and disability pension), labor market-related benefits (including unemployment benefits), or as being self-supporting. We computed rate ratios (RRs) of social benefit receipt for variant carriers (heterozygotes plus homozygotes) vs. non-carriers, using negative binominal regression with robust variance estimation. RESULTS: Among 2430 women, 12% received health-related benefits before diagnosis, 80% at diagnosis, and ~ 24% 2 to 5 years after diagnosis. Labor market-related benefits were uncommon (3-6%). All RRs were near-null and/or imprecise. CONCLUSION: We found no clinically meaningful impact of the selected SNPs on social benefit receipt among premenopausal breast cancer survivors treated with docetaxel.

Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.

AIM: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. METHODS: In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. RESULTS: Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5). CONCLUSIONS: Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.

Screening of substance use in pregnancy: A Danish cross-sectional study.

INTRODUCTION: There is a paucity of objectively verified data on substance use among Danish pregnant women. We estimated the prevalence of substance use including alcohol and nicotine among the general population of Danish pregnant women. MATERIAL AND METHODS: In this anonymous, national, cross-sectional, descriptive study, pregnant women were invited when attending an ultrasound scan between November 2019 and December 2020 at nine Danish hospitals. Women submitted a urine sample and filled out a questionnaire. Urine samples were screened on-site with a qualitative urine dipstick for 15 substances including alcohol, nicotine, opioids, amphetamines, cannabis, and benzodiazepines. All screen-positive urine samples underwent secondary quantitative analyses with gold standard, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results were compared to questionnaire information to analyze the validity of self-reporting and to examine possible cross-reactions. RESULTS: A total of 1903 of 2154 invited pregnant women participated (88.3%). The prevalence of dipstick-positive urine samples was 25.0%. 44.0% of these were confirmed positive, resulting in a total confirmed prevalence of 10.8%. The prevalence of nicotine use was 10.1%-and for all other substances, <0.5%. Nicotine use was more prevalent among younger pregnant women, while other substance use appeared evenly distributed over age groups. Self-reporting of use of nicotine products was high (71.1%), but low for cannabis and alcohol intake (0% and 33.3%, respectively). Prescription medication explained almost all cases of oxycodone, methylphenidate, and benzodiazepine use. CONCLUSIONS: Substance use among pregnant women consisted mainly of nicotine. Dipstick screening involved risks of false negatives and false positives. Except for alcohol intake and cannabis use, dipstick analyses did not seem to provide further information than self-reporting. LC-MS/MS analyses remain gold standard, and future role of dipstick screenings should be discussed.

Treatment patterns of antidepressants in children and adolescents in Scandinavia.

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5-17 years) during 2007-2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007-2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation.

A critical appraisal of controlled studies investigating malformation risks following pregabalin use in early pregnancy.

In March 2022, the Summary of Product Characteristics for the Lyrica brand of pregabalin was updated with warnings regarding malformation risks. This literature review and critical appraisal aims to explore whether these Summary of Product Characteristics updates are justified and provide clarity on the risk-benefit balance for pregabalin use in early pregnancy. A literature review was conducted in May 2022 to identify English language comparative studies of any design providing data about first trimester maternal pregabalin use and malformation risk. Five observational comparative cohort studies using data from 9 distinct datasets were located. Collectively these studies described at least 5300 unique pregabalin exposed pregnancies, with 4900 exposed in at least the first trimester. Three studies investigated overall major malformation risks, and 4 investigated specific malformation risks. The available evidence was found to be conflicting and generally of low quality, probably influenced by bias and data confounding, with no clear pattern of specific malformations observed. Findings from the largest study suggested absolute risks of major malformation of 4.8-5.6%, relative to a background risk of approximately 4%. Due to study methodology limitations, the available data were judged to only provide low quality evidence suggestive of a possible and unconfirmed small increased risk that cannot be solely attributed to foetal pregabalin exposure. This literature review and critical appraisal indicates that the Lyrica product literature updates are insufficiently substantiated and could result in confusion and misinformed clinical risk-benefit decision making.

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark.

PURPOSE: Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. METHODS: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. RESULTS: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98). CONCLUSION: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Changing characteristics over time of individuals receiving COVID-19 vaccines in Denmark: A population-based descriptive study of vaccine uptake.

AIMS: The Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake and characteristics of COVID-19 vaccine recipients in Denmark. METHODS: Using nationwide healthcare registries, we identified all Danish residents ⩾5 years of age who received at least one dose of a COVID-19 vaccine from 27 December 2020-29 January 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups and vaccination priority groups, and described characteristics of vaccine recipients during two-month-intervals and in vaccination priority groups. RESULTS: By 29 January 2022, 88%, 86% and 64% of Danish residents ⩾5 years (n=5,562,008) had received a first, second and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84%). Uptake ranged from 48% in 5-11-year-olds to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs 3.7-4.6% in later periods) and diabetes (9.3-12% vs 0.91-2.4% in later periods). CONCLUSIONS: We document substantial changes over time in, for example, age, sex and medical history of COVID-19 vaccine recipients. Though these results are related to the differential vaccine rollout in Denmark, similar findings are probable in other countries and should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Hypoxia-inducible factor-1α expression and breast cancer recurrence in a Danish population-based case control study.

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence. METHODS: In this population-based case-control study, we included women diagnosed with stage I-III breast cancer between 1985 and 2001, aged 35-69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER-/TAM-). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence. RESULTS: HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER-/TAM- stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER-/TAM- OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER-/TAM- stratum. CONCLUSION: In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER- breast cancer.

Socioeconomic position and prognosis in premenopausal breast cancer: a population-based cohort study in Denmark.

BACKGROUND: To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality. METHODS: We conducted a cohort study nested in the ProBeCaRe (Predictors of Breast Cancer Recurrence) cohort (n = 5959). We identified all premenopausal women aged 18-55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007-2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate, or high), income (low, medium, or high), and employment status (employed, unemployed, or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs), and used Poisson regression to compute incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of recurrence and death. We stratified on estrogen receptor (ER) status/tamoxifen to evaluate interaction. RESULTS: Our study cohort included 2616 women; 286 (CIP 13%) experienced recurrence and 223 (CIP 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased 5-year risks of recurrence (IRR 1.45, 95% CI 1.11-1.89) and mortality (IRR 1.83, 95% CI 1.32-2.52). Furthermore, we observed increased 5-year mortality in women with low education (IRR 1.49, 95% CI 0.95-2.33), low income (IRR 1.37, 95% CI 0.83-2.28), unemployment (IRR 1.61, 95% CI 0.83-3.13), or health-related work absenteeism (IRR 1.80, 95% CI 1.14-2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen. Overall analyses (follow-up max. 10 years) provided similar results. CONCLUSIONS: Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence.

Use of hypnotic drugs among children, adolescents, and young adults in Scandinavia.

BACKGROUND: Hypnotic use in children and adolescents is controversial. OBJECTIVE: To describe the use of hypnotic drugs (melatonin, z-drugs, and sedating antihistamines) among 5- to 24-year-old Scandinavians during 2012 to 2018. METHODS: Aggregate-level data were obtained from public data sources in Sweden, Norway, and Denmark. We calculated annual prevalence (users/1000 inhabitants) stratified by age group, sex, and country. Quantity of use (Defined Daily Dose (DDD)/user/day) was estimated for Norway and Denmark. RESULTS: Melatonin was the most commonly used hypnotic, and its use increased markedly from 2012 to 2018, particularly among females and 15- to 24-year-old individuals. Sweden had the highest increase in use (6.5 to 25/1000) compared with Norway (10-20/1000) and Denmark (5.7-12/1000). The annual prevalence of sedating antihistamine use was also highest in Sweden, reaching 13/1000 in 2018 in comparison to 7.5/1000 in Norway and 2.5/1000 in Denmark. Z-drug use decreased in all countries toward 2018, dropping to 3.5/1000 in Sweden, 4.4/1000 in Norway, and 1.7/1000 in Denmark. The quantity of hypnotic use in Norway and Denmark was 0.8-1.0 DDD/user/day for melatonin in 2018, as compared to 0.1-0.3 for z-drugs and antihistamines. CONCLUSION: The use of melatonin and sedating antihistamines increased among young Scandinavians during 2012-2018, and the increase was twice as high in Sweden compared with Norway and Denmark. In addition, Sweden had the highest use of sedating antihistamines. The Scandinavian variation of hypnotic use could reflect differences in frequency of sleep problems between populations or variation of healthcare access or clinical practice between countries.