Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort.

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.

Joint Effect of Alcohol Consumption and Educational Level on Alcohol-related Medical Events: A Danish Register-based Cohort Study.

BACKGROUND: Alcohol-related mortality is more pronounced in lower than in higher socioeconomic groups in Western countries. Part of the explanation is differences in drinking patterns. However, differences in vulnerability to health consequences of alcohol consumption across socioeconomic groups may also play a role. We investigated the joint effect of alcohol consumption and educational level on the rate of alcohol-related medical events. METHODS: We pooled seven prospective cohorts from Denmark that enrolled 74,278 men and women age 30-70 years (study period, 1981 to 2009). We measured alcohol consumption at baseline using self-administrated questionnaires. Information on highest attained education 1 year before study entry and hospital and mortality data on alcohol-related medical events were obtained through linkage to nationwide registries. We performed analyses using the Aalen additive hazards model. RESULTS: During follow-up (1,085,049 person-years), a total of 1718 alcohol-related events occurred. The joint effect of very high alcohol consumption (>21 [>28] drinks per week in women [men]) and low education on alcohol-related events exceeded the sum of their separate effects. Among men, we observed 289 (95% confidence interval = 123, 457) extra events per 100,000 person-years owing to education-alcohol interaction (P < 0.001). Similarly, among women, we observed 239 (95% confidence interval = 90, 388) extra events per 100,000 person-years owing to this interaction (P < 0.001). CONCLUSIONS: High alcohol consumption is associated with a higher risk of alcohol-related medical events among those with low compared with high education. This interaction may be explained by differences in vulnerability and drinking patterns across educational groups.See video abstract at, http://links.lww.com/EDE/B267.

Health care resource utilization and characteristics of patients with eosinophilic asthma in secondary health care in Finland.

Background: Eosinophilic airway inflammation is common in asthma patients and appears to be associated with severe exacerbations and loss of asthma control. Objective: To describe the resource utilization and clinical characteristics of patients with eosinophilic asthma. Design: Asthma patients ≥18 years with ≥1 blood eosinophil count in secondary care (South West Finland) during 2003‒2013 were included. Clinical characteristics (age, lung function, body mass index, and comorbidities) and asthma-related resource utilization (hospital admissions, outpatient visits, and emergency room [ER] visits) were retrieved. Resource utilization rates were compared for patients with blood eosinophil ≤ or >300 cells/µL, using adjusted negative binomial regression models. Results: Overall, 4,357 eligible patients were identified (mean age 60 years, females 68%), of which 1,927 (44%) had >300 eosinophil cells/µL blood. Patients with ≤300 and >300 eosinophil counts, exhibited similar clinical characteristics, including advanced age, poor lung function, and overweight. Comorbidities such as pneumonia, sinusitis, and nasal polyps, were more frequent among those with >300 eosinophil cells/µL blood compared with patients with lower counts. Eosinophil counts >300 cells/µL were associated with greater hospital admissions (rate ratio [RR] [95% confidence interval CI]: 1.13 [1.02;1.24]) and outpatient visits (RR [95% CI]: 1.11 [1.03;1.20]) compared with patients with lower eosinophil counts. Rates of ER visits were similar between the patient groups (RR [95% CI]: 0.99 [0.87;1.12]). Conclusions: Hospital admissions and outpatient visits occurred more often for patients with eosinophil counts >300 cells/µL, than for patients with lower eosinophil counts. Routine blood eosinophil screening might be useful to identify patients with an eosinophilic phenotype eligible for more targeted treatments.

Differential Burden of Rare and Common Variants on Tumor Characteristics, Survival, and Mode of Detection in Breast Cancer.

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes-or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR.

Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: A nationwide register-based cohort study in Denmark.

BACKGROUND AND AIM: Opioid analgesics are often effective for pain management, but may cause constipation. The aim of this study was to determine healthcare resource use and costs in non-cancer and cancer patients with opioid-induced constipation (OIC). METHODS: This was a nationwide register-based cohort study including patients ≥18 years of age initiating ≥4 weeks opioid therapy (1998-2012) in Denmark. A measure of OIC was constructed based on data from Danish national health registries, and defined as ≥1 diagnosis of constipation, diverticulitis, mega colon, ileus/subileus, abdominal pain/acute abdomen or haemorrhoids and/or ≥2 subsequent prescription issues of laxatives. Total healthcare resource utilization and costs (including pharmacy dispense, inpatient-, outpatient-, emergency room- and primary care) were estimated according to OIC status, opioid treatment dosage and length, gender, age, marital status, and comorbidities using Generalised Linear Model. RESULTS: We identified 97169 eligible opioid users (77568 non-cancer and 19601 patients with a cancer diagnosis). Among non-cancer patients, 15% were classified with OIC, 10% had previous constipation, and 75% were without OIC. Patients characteristics of non-cancer OIC patients showed a higher frequency of strong opioid treatment (69% versus 41%), long-term opioid treatment (1189 days versus 584 days), advanced age (73 years versus 61 years), and cardiovascular disease (31% versus 19%) compared to those without OIC (P<0.001 for all comparisons). Non-cancer patients with OIC had 34% higher total healthcare costs compared to those without OIC (P<0.001) after adjusting for age, gender, opioid usage, marital status and comorbidities. Among cancer patients, 35% were classified with OIC, 14% had previous constipation, and 51% were without OIC. A higher proportion of cancer patients with OIC were continuous opioid users (85% versus 83%) and strong opioid users (97% versus 85%), compared to those without OIC (P<0.001 for both comparisons). Further, the mean number of days on opioids were higher for cancer patients with versus without OIC (329 days versus 238 days, P<0.001). Total healthcare costs were 25% higher for cancer patients with versus without OIC (P<0.001) after adjusting for age, gender, opioid usage, marital status and comorbidities. CONCLUSIONS: The results of this nationwide study based on real life data suggested that both non-cancer patients and cancer patients suffering from opioid-induced constipation (OIC) may have higher healthcare resource utilization and higher associated costs compared to those without OIC. IMPLICATIONS: Reducing the number of OIC patients has potential cost savings for the health care system. Special attention should be on patients at potential high risk of OIC, such as strong and long-term opioid treatment, advanced age, and concomitant cardiovascular disease.

Opioid-induced constipation, use of laxatives, and health-related quality of life.

BACKGROUND AND AIMS: Real-life data on laxative use in patients suffering from opioid-induced constipation (OIC) are very limited, and many OIC patients are only using over the counter laxatives to resolve their constipation. Our aim was to describe laxative utilization and quality of life in participants in Norway who ever experienced OIC. METHODS: This was a cross-sectional online survey conducted between 27th of June and 3rd of July 2014 among participants above 18 years with self-reported OIC and who had agreed to receive information from the pharmacy chain (Boots A/S, Norway). The questionnaire comprised a series of multiple choice, close-ended, and free text questions on abdominal symptoms, laxative use and health-related quality of life. RESULTS: A total of 417 participants met the study eligibility criteria: (1) treated with opioid for a minimum of 4 weeks, (2) actively accepted participation, and (3) confirmed ever experiencing OIC and in addition completed the survey. Among the eligible participants, 86% were females, 85% were younger than 60 years of age, and 57% were currently suffering OIC. More than half of the currently constipated participants were experiencing moderate to very severe abdominal bloating (63%), abdominal pain (55%) and/or pain during bowel movement (50%). Less than every fourth participant (23%) had consulted health care professionals (HCPs) about their constipation. Up to 39% reported that they handled their OIC by self-management, e.g., bought laxative, reduced the dose and/or changed opioid without consulting HCP or pharmacy. Less than half (48%) of the laxative users were satisfied with the laxative they were using to relieve their constipation. The EQ-5D health-related quality of life score was mean (SD): 0.587 (0.272). Although not statistically significant (p=0.067), there was a tendency of lower quality of life among the participants who were currently constipated compared with those not currently constipated (difference of mean EQ-5D: 0.629-0.555=0.074). A significantly lower (p=0.001) quality of life was found among participants who were dissatisfied with their laxative [mean (SD): 0.424 (0.350)] than among those who were satisfied or neither satisfied nor dissatisfied [mean (SD): 0.628 (0.235) and 0.673 (0.155), respectively]. CONCLUSIONS: The results suggest a high degree of moderate to very severe abdominal symptoms, a high degree of self-management of opioid-induced constipation, a low degree of satisfaction with laxative, and low health-related quality of life of patients suffering from chronic pain necessitating long-term opioid treatment, subsequent constipation and laxatives use. IMPLICATIONS: Patients suffering from OIC with low quality of life and remaining symptoms despite use of two or more laxatives are a vulnerable patient group in need of optimized healthcare management, who also might benefit from more specific and innovative therapy.

Symptoms and quality of life in patients with chronic obstructive pulmonary disease treated with aclidinium in a real-life setting.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a progressive disease with symptoms that can have a major impact on patients' physical health. The aim of this study was to evaluate quality of life (QoL), symptom severity and dyspnoea in COPD patients treated with aclidinium up to 24 weeks. METHODS: In this prospective non-interventional multicentre study (198 centres in Sweden, Denmark, and Norway), COPD patients (age ≥40 years) who started treatment with aclidinium (initial therapy, change of treatment, or add-on therapy) could be included. Health-related QoL was obtained by COPD assessment test (CAT). Symptoms were evaluated on a 6-point Likert scale. The modified Medical Research Council (mMRC) Dyspnoea Scale was used as a simple grading system to assess the level of dyspnoea/shortness of breath from0 to 4. Patients on treatment with aclidinium who completed baseline and at least one follow-up visit (week 12 or 24) were included in the study population. RESULTS: Overall, 1,093 patients were enrolled (mean 69 years, 54% females), one-third had ≥1 exacerbation the year prior to baseline. At enrolment, 48% were LAMA naïve. Mean (standard deviation, SD) CAT score decreased from 16.9 (7.7) at baseline to 14.3 (7.3) at week 24 (p<0.01) with a decrease in all individual CAT items (p<0.05). Mean difference in morning and night-time symptoms from baseline to week 24 was -0.60 (SD 2.51) and -0.44 (SD 2.48), respectively (both p<0.001). Mean (SD) mMRC Dyspnoea Scale changed from 1.6 (1.0) at baseline to 1.5 (1.0) at week 24 (p<0.001). CONCLUSION: In this observational study of a Nordic real-life COPD population, treatment with aclidinium was associated with a clinically important improvement in QoL and morning and night-time symptoms, most pronounced in the LAMA naïve group. However, there is still room for improvement in the management of symptomatic COPD patients.