Surgical practice patterns and outcomes in T2 and T3 gallbladder cancer: a population-based study.

BACKGROUND: The extent of resection required in advanced gallbladder cancer is controversial. We aimed to describe the management and outcomes in patients with resected stage T2 and T3 gallbladder cancer. METHODS: In this population-based study, all T2 and T3 gallbladder cancer cases from Jan. 1, 2002, to Mar. 31, 2012, were identified from the Ontario Cancer Registry; pathology reports were linked and abstracted. The type of resection was classified as extended (cholecystectomy + liver resection, with or without bile duct resection) or simple (cholecystectomy only). We used Kaplan-Meier survival analysis to model time to death and evaluated factors associated with overall survival using the Cox proportional hazards regression model. RESULTS: A total of 370 patients were included, 232 with T2 disease and 138 with T3 disease. The proportions who underwent extended resection were 24.1% (56/232) and 37.0% (51/138), respectively. The unadjusted 5-year overall survival rates for simple and extended resection were 39.7% and 49.5%, respectively, for T2 disease (p = 0.03), and 13.5% and 22.8%, respectively, for T3 disease (p = 0.05). In adjusted analysis, extended resection significantly improved overall survival among patients with T2 disease (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.97), whereas higher grade of differentiation, presence of lymphovascular invasion and positive lymph nodes led to worse survival. Extended resection was not associated with improved survival in the T3 group; however, in subgroup analysis stratified by lymph node status, a trend toward improved overall survival with extended resection was seen in node-negative patients (HR 0.20, 95% CI 0.03-1.06). CONCLUSION: Extended resection improved overall survival in T2 disease regardless of nodal status but appeared most beneficial in node-negative T3 disease. The finding that extended resection was offered only to a small proportion of eligible patients highlights the need for improved knowledge translation at national surgical meetings.

A descriptive cost-analysis of MYX.1/MCRN003, a phase 2 clinical trial evaluating high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone in relapsed and refractory multiple myeloma.

BACKGROUND: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data. METHODS: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020). RESULTS: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27-$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs - $162 471.65/pt or $11 251.50/pt per cycle. Fifty-six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange. CONCLUSIONS: High-dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice-weekly carfilzomib-based regimens.

Factors predicting missing instruments in three cancer randomized clinical trials.

PURPOSE: Missing patient-reported outcome (PRO) data can seriously threaten the validity of randomized clinical trials (RCTs). Identifying which factors predict missing instruments may help researchers develop strategies to prevent it from happening. This study examined the association of factors with time to the first missing instrument after randomization in three cooperative group RCTs. METHODS: We performed descriptive analyses and Cox proportional hazards regressions for three RCTs selected from the Canadian Cancer Trials Group: MA17 (breast cancer), PR7 (prostate cancer), and LY12 (non-Hodgkin's lymphoma). The outcome was the time from randomization to the first missing instrument. Variables for 15 factors were used as covariates based on availability and previously-reported putative associations with missing PRO data. RESULTS: Nine percent of 1352 subjects on MA17, 37% of 923 subjects on PR7, and 59% of 477 subjects on LY12 had a missing instrument. Twenty-five percent of subjects on MA17 had first missing instrument within 4.6 years. The median time to first missing instrument was: not observed for MA17, 7.3 years for PR7, 0.12 years for LY12. Cox regression revealed statistically significant independent associations with outcome for only five factors: baseline age (PR7) and level of well-being (LY12), and centre level of activity (LY12), presence of post-graduate residency training program (MA17, PR7), and centre geographic location (PR7, LY12). CONCLUSION: Many factors reported to have association with missing instruments do not seem to predict time to the first missing instrument after randomization in RCTs. Context is important in understanding the few that may.

Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial.

PURPOSE: To examine associations between the UGT2B17 gene deletion and exemestane metabolites, and commonly reported side effects (fatigue, hot flashes, and joint pain) among postmenopausal women participating in the MAP.3 chemoprevention trial. METHODS: The analytical samples for the UGT2B17 analysis comprised 1752 women on exemestane and 1721 women on placebo; the exemestane metabolite analysis included 1360 women on exemestane with one-year serum samples. Both the UGT2B17 gene deletion and metabolites were measured in blood. The metabolites were conceptualized as a ratio (17-DHE-Gluc:17-DHE). Symptoms were assessed using the CTCAE v4.0 at approximately 1-year intervals. Log-binomial regression was used to examine the associations between UGT2B17 deletion, exemestane metabolites and each side effect at 1 and up to 5-year follow-up, adjusting for potential confounders. RESULTS: Among individuals on exemestane with the UGT2B17 gene deletion (i.e., lower detoxification), a higher risk of severe fatigue (RR = 2.59 95% CI: 1.14-5.89) was observed at up to 5-year follow-up. Among individuals on placebo, those with the UGT2B17 gene deletion had a higher risk of any fatigue (RR = 1.39, 95% CI: 1.02-1.89) at year 1. A lower metabolite ratio (poor detoxification) was associated with a higher risk of any fatigue, hot flashes and joint pain at year 1 (fatigue: RR = 1.89, 95% CI: 1.16-3.09; hot flashes: RR = 1.77, 95% CI: 1.40-2.24; joint pain: RR = 2.05, 95% CI: 1.35-3.12); similar associations were observed at 5-year follow-up. CONCLUSION: Variation in the metabolism of exemestane through the UGT2B17-mediated pathway is associated with subsequent risk of commonly reported symptoms in MAP.3.

Associations between occupational exposure to benzene, toluene and xylene and risk of lung cancer in Montréal.

BACKGROUND: Benzene, toluene and xylene (BTX) are aromatic hydrocarbons with inconclusive evidence of lung carcinogenicity. The aim of this research was to assess the associations between occupational exposures to BTX agents and lung cancer. METHODS: In a population-based case-control study of lung cancer, occupational histories were obtained and exposures were assessed by experts. Unconditional multivariate logistic regression was used to estimate ORs and 95% CIs, among men, between various metrics of occupational exposure to BTX and lung cancer, while adjusting for established and possible risk factors. RESULTS: Considerable overlap was found between occupational exposure to BTX, where the majority of exposed participants were exposed to all three chemicals. Lung cancer was associated with exposure to benzene (OR=1.35; 95% CI 0.99 to 1.84), toluene (OR=1.31; 95% CI 0.99 to 1.74) and xylene (OR=1.44; 95% CI 1.03 to 2.01). While these results were adjusted for smoking and other recognised and possible lung cancer risk factors, they were not mutually adjusted among the three BTX agents. CONCLUSIONS: Our study provides suggestive evidence that occupational exposure to one or more of the BTX agents may be associated with lung cancer.

A systematic review and development of a classification framework for factors associated with missing patient-reported outcome data.

BACKGROUND/AIMS: Missing patient-reported outcome data can lead to biased results, to loss of power to detect between-treatment differences, and to research waste. Awareness of factors may help researchers reduce missing patient-reported outcome data through study design and trial processes. The aim was to construct a Classification Framework of factors associated with missing patient-reported outcome data in the context of comparative studies. The first step in this process was informed by a systematic review. METHODS: Two databases (MEDLINE and CINAHL) were searched from inception to March 2015 for English articles. Inclusion criteria were (a) relevant to patient-reported outcomes, (b) discussed missing data or compliance in prospective medical studies, and (c) examined predictors or causes of missing data, including reasons identified in actual trial datasets and reported on cover sheets. Two reviewers independently screened titles and abstracts. Discrepancies were discussed with the research team prior to finalizing the list of eligible papers. In completing the systematic review, four particular challenges to synthesizing the extracted information were identified. To address these challenges, operational principles were established by consensus to guide the development of the Classification Framework. RESULTS: A total of 6027 records were screened. In all, 100 papers were eligible and included in the review. Of these, 57% focused on cancer, 23% did not specify disease, and 20% reported for patients with a variety of non-cancer conditions. In total, 40% of the papers offered a descriptive analysis of possible factors associated with missing data, but some papers used other methods. In total, 663 excerpts of text (units), each describing a factor associated with missing patient-reported outcome data, were extracted verbatim. Redundant units were identified and sequestered. Similar units were grouped, and an iterative process of consensus among the investigators was used to reduce these units to a list of factors that met the guiding principles. The list was organized on a framework, using an iterative consensus-based process. The resultant Classification Framework is a summary of the factors associated with missing patient-reported outcome data described in the literature. It consists of 5 components (instrument, participant, centre, staff, and study) and 46 categories, each with one or more sub-categories or examples. CONCLUSION: A systematic review of the literature revealed 46 unique categories of factors associated with missing patient-reported outcome data, organized into 5 main component groups. The Classification Framework may assist researchers to improve the design of new randomized clinical trials and to implement procedures to reduce missing patient-reported outcome data. Further research using the Classification Framework to inform quantitative analyses of missing patient-reported outcome data in existing clinical trials and to inform qualitative inquiry of research staff is planned.

Lifetime moderate-to-vigorous physical activity and ER/PR/HER-defined post-menopausal breast cancer risk.

PURPOSE: To assess the relationship of moderate-to-vigorous physical activity (MVPA) in leisure-time, household, and occupational domains across the total lifetime and in four age periods with breast cancer risk, as defined by estrogen receptor (ER)/progesterone receptor (PR) status and ER/PR/human epidermal growth factor-2 (HER2) status, among post-menopausal women. METHODS: Data were from 692 women with incident breast cancer and 644 controls in the Canadian Breast Cancer Study, a case-control study of women aged 40-80 years in British Columbia and Ontario. Mean metabolic equivalent (MET)-hours/week for questionnaire-assessed leisure-time, household, and occupational MVPA were calculated for the total lifetime and four age periods (12-17, 18-34, 45-49, and ≥50 years). Odds ratios (ORs) for the relationships between domain-specific MVPA at each lifetime period and risks of ER/PR-defined and ER/PR/HER2-defined breast cancers were estimated using polytomous logistic regression. Trend tests for dose-response relationships were calculated for the ORs across increasing tertiles of mean MET-hours/week of MVPA. RESULTS: Total lifetime leisure-time MVPA was associated with reduced risk of ER-/PR- breast cancer in a dose-response fashion (p trend = 0.014). In contrast, total lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer (p trend < 0.001). When further stratified by HER2 status, the effect of leisure-time MVPA appeared confined to HER2- breast cancers, and the effect of household MVPA did not differ according to HER2 status. Similar trends were observed when stratified by age period. CONCLUSIONS: Lifetime leisure-time MVPA appeared to be associated with reduced risk of ER-/PR-/HER2- breast cancers and lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer, regardless of HER2 status.

Cervical Infection With Vaccine-Associated Human Papillomavirus (HPV) Genotypes as a Predictor of Acquisition and Clearance of Other HPV Infections.

BACKGROUND: Recent birth cohorts vaccinated against human papillomavirus (HPV) may be protected against up to 4 genotypes (HPV-6, -11, -16, and -18). If natural competition exists between these and other HPV types, then the prevalence of other types may increase after vaccination. METHODS: Cohort information from 3 studies was used to compare acquisition and clearance of 30 different HPV types (individually and grouped by species), according to infection status with vaccine-targeted types at baseline and the time of the index infection, respectively. Hazard ratios (HRs) were adjusted for predictors of multiple-type infection. RESULTS: Among 3200 females across all studies, 857 were infected with HPV at baseline, and 994 acquired new infections during follow-up. Females infected with HPV-16 were at higher risk of acquiring other α-9 HPV types (HR, 1.9; 95% confidence interval [CI], 1.2-3.0) but at similar risk of clearing existing α-9 HPV infections (HR, 0.9; 95% CI, .7-1.3). Females infected with vaccine-targeted types were generally at higher risk of acquiring additional types (HRs, > 1.0) and at equal risk of clearing existing infections. Accounting for multiple comparisons, none of the HRs of < 1.0 or >1.0 were statistically significant in our analyses of acquisition or clearance. CONCLUSIONS: Vaccine-targeted HPV types do not appear to compete with other types, suggesting that HPV type replacement is unlikely to occur.

Genetic variation in vitamin D-related genes and risk of breast cancer among women of European and East Asian descent.

Studies of vitamin D-related genetic variants and breast cancer have been inconsistent. This study aimed to investigate associations of vitamin D-related polymorphisms and breast cancer risk among European and East Asian women and potential interactions with menopausal status and breast tumour subtypes. Data from a case-control study of breast cancer (1037 cases and 1050 controls) were used to assess relationships between 21 polymorphisms in two vitamin D-related genes (GC and VDR) and breast cancer risk. Odds ratios were calculated in stratified analyses of European and East Asian women, using logistic regression in an additive genetic model. An interaction term was used to explore modification by menopausal status. Polytomous regression was used to assess heterogeneity by breast tumour subtype. False discovery rate adjustments were conducted to account for multiple testing. No association was observed between GC or VDR polymorphisms and breast cancer risk. Modification of these relationships by menopausal status was observed for select polymorphisms in both Europeans (VDR rs4328262 and rs11168292) and East Asians (GC rs7041 and VDR rs11168287). Heterogeneity by tumour subtype was seen for three VDR polymorphisms (rs1544410, rs7967152 and rs2239186) among Europeans, in which associations with ER-/PR-/HER2+ tumours, but not with other subtypes, were observed. In conclusion, associations between vitamin D-related genetic variants and breast cancer were not observed overall, although the relationships between vitamin D pathway polymorphisms and breast cancer may be modified by menopausal status and breast tumour subtype.

Global genomic diversity of human papillomavirus 6 based on 724 isolates and 190 complete genome sequences.

UNLABELLED: Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution. IMPORTANCE: This study established the largest database of globally circulating HPV6 genomic variants and contributed a total of 130 new, complete HPV6 genome sequences to available sequence repositories. Two HPV6 variant lineages and five sublineages were identified and showed some degree of association with geographical location, anatomical site of infection/disease, and/or gender. We additionally identified several HPV6 lineage- and sublineage-specific SNPs to facilitate the identification of HPV6 variants and determined a representative region within the L2 gene that is suitable for HPV6 whole-genome-based phylogenetic analysis. This study complements and significantly expands the current knowledge of HPV6 genetic diversity and forms a comprehensive basis for future epidemiological, evolutionary, functional, pathogenicity, vaccination, and molecular assay development studies.

Exemestane for breast-cancer prevention in postmenopausal women.

BACKGROUND: Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. METHODS: In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. RESULTS: A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. CONCLUSIONS: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).

A case-control study of lifetime light intensity physical activity and breast cancer risk.

PURPOSE: Physical activity reduces breast cancer risk, although most evidence is for activity in the moderate-to-vigorous intensity range. The effect of light intensity physical activity (LIPA) is unknown. We aimed to determine the association between self-reported lifetime LIPA and pre- and post-menopausal breast cancer risk. Our secondary objective was to analyze risk stratified by estrogen and progesterone tumor receptor status. METHODS: Data were from a case-control study of 1,110 incident breast cancer cases (388 pre-menopausal; 722 post-menopausal) and 1,172 controls (442 pre-menopausal; 730 post-menopausal) recruited at two Canadian sites. Lifetime leisure-time, household, and occupational physical activity and covariates were assessed by questionnaire. Mean minutes per day of LIPA for each of the age periods 12-17, 18-34, 35-49, ≥50, and the total lifetime were calculated. Odds ratios were calculated using unconditional logistic regression for overall breast cancer risk and using polytomous logistic regression for estrogen receptor (ER)/progesterone receptor (PR)-defined tumor subtypes and were adjusted for moderate-to-vigorous physical activity and other confounders. RESULTS: LIPA was not associated with breast cancer risk at any age period across the life course: odds ratio (OR) = 0.81; 95 % CI 0.53-1.24 for pre-menopausal women and OR = 0.87; 95 % CI 0.64-1.19 for post-menopausal women in the highest vs. lowest categories of total lifetime LIPA. No heterogeneity in risk by ER/PR tumor status was observed. CONCLUSIONS: Our results suggest that light intensity physical activity is not associated with breast cancer risk reduction. This finding is important for physical activity recommendations for breast cancer prevention.

Quality and readability of online information and materials on post-surgery breast seroma.

Aims/Background Seroma formation is the most common complication following breast surgery. However, there is little evidence on the readability of online patient education materials on this issue. This study aimed to assess the accessibility and readability of the relevant online information. Methods This systematic review of the literature identified 37 relevant websites for further analysis. The readability of each online article was assessed through using a range of readability formulae. Results The average Flesch-Reading Ease score for all patient education materials was 53.9 (± 21.9) and the average Flesch-Kincaid reading grade level was 7.32 (± 3.1), suggesting they were 'fairly difficult' to read and is higher than the recommended reading level. Conclusion Online patient education materials regarding post-surgery breast seroma are at a higher-than-recommended reading grade level for the public. Improvement would allow all patients, regardless of literacy level, to access such resources to aid decision-making around undergoing breast surgery.

Human papillomavirus type 52 polymorphism and high-grade lesions of the uterine cervix.

The association between polymorphism of human papillomavirus type 52 (HPV52) and high-grade cervical intraepithelial neoplasia (CIN2,3) was investigated in Canadian women. HPV-52-positive endocervical specimens collected from 216 women selected from a total of 3,614 participants recruited in two case-control and two cohort studies conducted in Canada, were further analyzed by PCR-sequencing of the LCR and E6 gene. Overall, the HPV52 LCR prototype was detected more frequently in Caucasian women (69 of 132, 52.3%, 95% confidence interval (CI): 43.8%-60.6%) than in non-Caucasian women (15 of 48, 31.3%, 95% CI 19.9%-45.4%). In two cohort studies, HPV52 prototype was detected in seven of 15 (46.7%, 95% CI 24.8-69.9) HPV52 persistent infections and 14 of 35 (40.0%, 95% CI 25.5-56.5) transient infections (p = 0.76). In two case-control studies, 30 participants did not have CIN, 18 had low-grade CIN (CIN1), 64 had CIN2,3, seven had cervical cancer and the diagnosis was undefined for 27 women. Variant MTL-52-LCR-02 was detected more frequently in women with cancer (28.6%, 95% CI 7.6%-64.8%) than in women without cancer or CIN2,3 (0%, 95% CI 0.0%-9.2%; p = 0.015). CIN2,3 risk was significantly associated with a deletion at nucleotide position 7695 in the LCR (OR 4.9, 95% CI 1.2-20.8), the T7744C variation in the LCR (OR 5.7, 95% CI 1.1-32.0), and the K93R variation in E6 (OR 6.9, 95% CI 1.3-36.8), after adjusting for age, detection of HPV16 or 18 and study site. These findings indicate that HPV52 polymorphism influences risk of CIN-2,3 and possibly invasive cancer.

Moderate-to-vigorous intensity physical activity across the life course and risk of pre- and post-menopausal breast cancer.

Moderate-to-vigorous intensity physical activity (MVPA) reduces breast cancer risk, although the effects of MVPA in different settings across the life course and how they may differ by menopausal status are unclear. This gap was addressed using data from a case-control study of 1,110 incident breast cancer cases and 1,172 cancer-free controls, frequency matched by age, from Vancouver and Kingston, Canada. In Vancouver, cases were recruited from the British Columbia Cancer Registry and controls from the Screening Mammography Program of British Columbia and in Kingston cases and controls were recruited from a breast assessment center. Lifetime leisure-time, household, and occupational MVPA energy expenditures were assessed in an open-ended questionnaire and mean weekly metabolic equivalent hours (MET-h/week) were calculated for the age periods 12-17, 18-34, 35-49, and ≥50 years and for the total lifetime. Odds ratios were estimated separately for pre- and for post-menopausal women using unconditional logistic regression. Among post-menopausal women, each of >22.9 MET-h/week of mean lifetime leisure-time MVPA (equivalent to running for 3 h) and >61.1 MET-h/week of mean lifetime household MVPA (equivalent to 24 h of moderate household work) reduced breast cancer risk by 40 %, compared to 0 MET-h/week of each. The respective ORs were 0.63 (95 % CI 0.42-0.94) and 0.58 (95 % CI 0.43-0.79). Among post-menopausal women, leisure-time MVPA after age 35 was more strongly associated with reduced breast cancer risk than MVPA in early life, while household MVPA was associated with reduced risk at all adulthood age periods. The weekly volume of leisure-time MVPA required to reduce post-menopausal breast cancer risk was consistent with amount recommended in the World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention.

Increased risk of breast cancer associated with long-term shift work in Canada.

OBJECTIVES: Long-term night work has been suggested as a risk factor for breast cancer; however, additional studies with more comprehensive methods of exposure assessment to capture the diversity of shift patterns are needed. As well, few previous studies have considered the role of hormone receptor subtype. METHODS: Relationships between night shift work and breast cancer were examined among 1134 breast cancer cases and 1179 controls, frequency-matched by age in Vancouver, British Columbia, and Kingston, Ontario. Self-reported lifetime occupational histories were assessed for night shift work, and hormone receptor status obtained from tumour pathology records. RESULTS: With approximately one-third of cases and controls ever employed in night shift work, associations with duration demonstrated no relationship between either 0-14 or 15-29 years, while an association was apparent for ≥30 years (OR=2.21, 95% CI 1.14 to 4.31). This association with long-term night shift work is robust to alternative definitions of prolonged shift work, with similar results for both health and non-health care workers. CONCLUSIONS: Long-term night shift work in a diverse mix of occupations is associated with increased breast cancer risk and not limited to nurses, as in most previous studies.

Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial.

BACKGROUND: Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. METHODS: In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. FINDINGS: 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002). INTERPRETATION: 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. FUNDING: Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).

Alcohol-associated Liver Disease Is Now the Most Common Indication for Liver Transplant Waitlisting Among Young American Adults.

BACKGROUND: Mortality from cirrhosis is increasing and is the highest among young adults with alcohol-associated liver disease (ALD). The aim of this study was to describe rates of liver transplant (LT) waitlisting stratified by age, sex, and cirrhosis etiology. METHODS: Retrospective population-based study from 2003 to 2018 using the Scientific Registry of Transplant Recipients database. Adults newly registered on the LT waitlist were included, and age at listing was dichotomized to ±40 y. Annual standardized incidence proportions of LT waitlisting by age group, sex, and etiology were calculated using census data. Changes in annual rates were described with Poisson regression. RESULTS: A total of 209 399 unique individuals were included, 10 326 (5%) <40 y at listing. In those <40 y of age, listing increased most for ALD (4-fold increase) followed by nonalcoholic fatty liver disease (NAFLD; 2-fold increase). Compared to young adult males, young females were more likely to be listed for ALD and less likely to be listed for NAFLD. In those ≥40 y of age, listings increased most for ALD (2-fold increase) and NAFLD (2-fold increase). Hepatitis C virus increased from 2003 to 2013 and declined post-2014 in the ≥40-y age group. CONCLUSIONS: LT waitlisting is increasing substantially in young Americans, driven primarily by ALD. These data support ongoing efforts to identify adolescents and young adults with early stages of ALD where interventions can be implemented to prevent the development of cirrhosis and liver-related complications.

One Fraction Size Does Not Fit All: Patient Preferences for Hypofractionated Radiation Therapy From a Discrete Choice Experiment.

PURPOSE: Hypofractionated external beam radiation therapy (EBRT) is a standard of care option for localized prostate cancer. To inform clinical practice we quantified patients' preferences for convenience, efficacy, and toxicity risks, of conventional, moderate hypofractionation, and stereotactic radiation therapy regimens. METHODS AND MATERIALS: We used a discrete choice experiment with a voluntary sample consisting of patients treated with EBRT for localized prostate cancer at our academic cancer center. In 2019, 58 participants, mean (SD) age of 72.9 (7.1) years, agreed to complete an in-person 1:1 discrete choice experiment. Each participant made 12 choices between 2 unique EBRT scenarios, each described by 5 attributes: (1) treatment time; (2) fiducial markers; and risk of (3) prostate specific antigen recurrence; (4) acute and (5) late GI or GU toxicity. Patient preferences were estimated using mixed multinomial logistic regression, and prespecified subgroups with conditional logistic regression. RESULTS: All attributes were statistically significant, thus influenced participants' choices. Risks of prostate specific antigen recurrence (ß = -2.581), late (ß = -1.854), and acute (ß = -1.005) toxicity were most important to participants (P < .001 for each), followed by EBRT length (ß = -0.728; P = .017) and fiducial marker implantation (ß = -0.563; P = .004). Older (ß = -0.063; 95% confidence interval, -0.12, -0.01) and rural (ß = -0.083; 95% CI -0.14, -0.02) participants significantly preferred shorter EBRT and were less willing-to-extend treatment to reduce toxicity risk. CONCLUSIONS: Patients with prostate cancer place importance on EBRT attributes, and some are willing to trade-off increased risk of toxicity for improved convenience. Our findings promote shared clinical decision-making because patients are interested in learning about the trade-offs involved.

Reproductive Outcomes in Young Breast Cancer Survivors Treated (15-39) in Ontario, Canada.

We conducted a population-based, retrospective, matched-cohort study to examine the impact of breast cancer diagnosis and treatment on fertility outcomes. Relative risks of infertility, childbirth, premature ovarian insufficiency (POI; age < 40) and early menopause (age < 45) were calculated using modified Poisson regression. Our primary cohort included young women (15-39) with early stage BC diagnosed 1995-2014. Five cancer-free patients were matched to each BC patient by birth year and census subdivision. The BC cohort was further divided by treatment with chemotherapy vs. no chemotherapy treatment. 3903 BC patients and 19,515 cancer-free women. BC patients treated with chemotherapy were at increased risk of infertility (RR 1.81; 95% CI 1.60-2.04), and POI (RR 6.25; 95% CI 5.15-7.58) and decreased childbirth (RR 0.85; 95% CI 0.75-0.96), compared to women without cancer. BC patients who did not receive chemotherapy were also at increased risk of infertility (RR 1.80 95% CI 1.48-2.18) and POI (RR 2.12 95% CI 1.37-3.28). All young BC survivors face an increased risk of diagnosed infertility and POI relative to women without cancer, independent of chemotherapy. These results emphasize the importance of pre-treatment fertility counselling for young women diagnosed with BC.