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Purpose The Ontario Breast Screening Program (OBSP) offers free screening mammograms every 2 years, to women aged 50–74. Study objectives were to determine demographic characteristics associated with the adherence to OBSP and if women screened in the OBSP have a lower stage at diagnosis than non-screened eligible women. Methods We used the Ontario cancer registry (OCR) to identify 48,927 women, aged 51–74 years, diagnosed with breast cancer between 2010 and 2017. These women were assigned as having undergone adherent screening (N = 26,108), non-adherent screening (N = 6546) or not-screened (N = 16,273) in the OBSP. We used multinomial logistic regression to investigate the demographic characteristics associated with screening behaviour, as well as the association between screening status and stage at diagnosis. Results Among women with breast cancer, those living in rural areas (versus the largest urban areas) had a lower odds of not being screened (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.68, 0.78). Women in low-income (versus high-income) communities were more likely not to be screened (OR 1.42, 95% CI 1.33, 1.51). When stratified, the association between income and screening status only held in urban areas. Non-screened women were more likely to be diagnosed with stage II (OR 1.91, 95% CI 1.82, 2.01), III (OR 2.96, 95% CI 2.76, 3.17), or IV (OR 8.96, 95% CI 7.94, 10.12) disease compared to stage I and were less likely to be diagnosed with ductal carcinoma in situ (DCIS) (OR 0.91, 95% CI 0.84–0.98). Conclusions This study suggests that targeting OBSP recruitment efforts to lower income urban communities could increase screening rates. OBSP adherent women were more likely to be diagnosed with earlier stage disease, supporting the value of this initiative and those like it.

Given the controversy over the effectiveness of age-based breast cancer (BC) screening, offering risk-stratified screening to women may be a way to improve patient outcomes with detection of earlier-stage disease. While this approach seems promising, its integration requires the buy-in of many stakeholders. In this cross-sectional study, we surveyed Canadian healthcare professionals about their views and attitudes toward a risk-stratified BC screening approach. An anonymous online questionnaire was disseminated through Canadian healthcare professional associations between November 2020 and May 2021. Information collected included attitudes toward BC screening recommendations based on individual risk, comfort and perceived readiness related to the possible implementation of this approach. Close to 90% of the 593 respondents agreed with increased frequency and earlier initiation of BC screening for women at high risk. However, only 9% agreed with the idea of not offering BC screening to women at very low risk. Respondents indicated that primary care physicians and nurse practitioners should play a leading role in the risk-stratified BC screening approach. This survey identifies health services and policy enhancements that would be needed to support future implementation of a risk-stratified BC screening approach in healthcare systems in Canada and other countries.

Studies have suggested a link between prenatal maternal acetaminophen use and adverse developmental outcomes in children. However, there exists a knowledge gap regarding overall cognitive development and use of acetaminophen, especially concerning the timing of use in pregnancy. This study aimed to characterize the relationship between maternal acetaminophen use and cognitive development at 4 years.This analysis included data collected throughout pregnancy and delivery from women in the Ontario Birth Study prospective cohort from 2013 to 2019 and from the NIH Toolbox Early Childhood Cognition battery administered to 4-year-old children between 2018 and 2021 (n = 436). The exposure was maternal acetaminophen use and the primary outcome was a cognition composite score. The relationship between exposure and outcome was determined using Poisson regression with a robust error variance.We did not observe any association between maternal acetaminophen intake any time before or during pregnancy and low cognition composite score of offspring. The IRR of suboptimal overall cognition was 1.38 (0.78-2.45), 1.22 (0.67-2.22), 0.80 (0.44-1.47), and 1.56 (0.74-3.29) for maternal use of acetaminophen before, in early, late, or overall pregnancy, respectively.Current data do not provide evidence to support a relationship of maternal acetaminophen use during pregnancy with adverse cognitive effects at 4 years.Acetaminophen use during pregnancy may influence the risk of child neurocognitive disorders, but there is conflicting evidence of its relationship to sub-clinical measures of cognitive development such as executive function. The study design allowed us to examine the role of timing of acetaminophen use in its relationship with cognitive development, based on a validated and standardized tablet-administered instrument for children, instead of a teacher or parent report. We did not observe a clear relationship between maternal acetaminophen use at different timepoints during pregnancy and child cognitive development.

To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a “texture risk score” using pre-treatment mammograms in a case–control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation = 1.25, 95% CI 1.01–1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.

Background Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined. Objectives The purpose of this study was to report CAD risk among participants in the Women’s Environmental Cancer and Radiation Epidemiology Study. Methods A total of 1,583 women who were, Central Illustration

With combination antiretroviral therapy (ART) and increased longevity, cancer is a leading cause of morbidity among people with HIV. We characterized trends in cancer burden among people with HIV in Ontario, Canada, between 1997 and 2020.We conducted a population-based, retrospective cohort study of adults with HIV using linked administrative health databases from Jan. 1, 1997, to Nov. 1, 2020. We grouped cancers as infection-related AIDS-defining cancers (ADCs), infection-related non-ADCs (NADCs) and infection-unrelated cancers. We calculated age-standardized incidence rates per 100 000 person-years with 95% confidence intervals (CIs) using direct standardization, stratified by calendar period and sex. We also calculated limited-duration prevalence.Among 19 403 adults living with HIV (79% males), 1275 incident cancers were diagnosed. From 1997-2000 to 2016- 2020, we saw a decrease in the incidence of all cancers (1113.9 [95% CI 657.7-1765.6] to 683.5 [95% CI 613.4-759.4] per 100 000 person-years), ADCs (403.1 [95% CI 194.2-739.0] to 103.8 [95% CI 79.2-133.6] per 100 000 person-years) and infection-related NADCs (196.6 [95% CI 37.9-591.9] to 121.9 [95% CI 94.3-154.9] per 100 000 person-years). The incidence of infection-unrelated cancers was stable at 451.0 per 100 000 person-years (95% CI 410.3-494.7). The incidence of cancer among females increased over time but was similar to that of males in 2016-2020.Over a 24-year period, the incidence of cancer decreased overall, largely driven by a considerable decrease in the incidence of ADC, whereas the incidence of infection-unrelated cancer remained unchanged and contributed to the greatest burden of cancer. These findings could reflect combination ART-mediated changes in infectious comorbidity and increased life expectancy; targeted cancer screening and prevention strategies are needed.

Purpose. The Ontario Breast Screening Program (OBSP) offers free screening mammograms every two years, to women aged 50-74. Study objectives were to determine demographic characteristics associated with adherence to OBSP and if women screened in OBSP have a lower stage at diagnosis than non-screened eligible women. Methods. We used the Ontario Cancer Registry (OCR) to identify 51,617 women, aged 50-74, diagnosed with breast cancer between 2010-2017. These women were assigned as screened (N=33,821) or non-screened (N=17,796) in OBSP. We used logistic regression to investigate the demographic characteristics associated with non-screening behaviour. We used multinomial regression to examine the association between screening status and stage at diagnosis.Results. Among women with breast cancer, those living in rural areas (versus the largest urban areas) had a lower odds ratio (OR) of not being screened (OR: 0.76, 95%CI: 0.72-0.81). Women in low income (versus high income) communities were more likely not to be screened (OR: 1.35, 95%CI: 1.27-1.43). When stratified, the association between income and screening status only held in urban areas. Non-screened women were more likely to be diagnosed stage II (OR: 1.76, 95%CI: 1.68-1.85), III (OR: 2.73, 95%CI: 2.56-2.92), or IV (OR: 6.93, 95%CI: 6.24-7.69) disease compared to stage I and were less likely to be diagnosed with ductal carcinoma in-situ (DCIS) (OR: 0.90, 95%CI: 0.85-0.96). Conclusions. This study suggests that targeting OBSP recruitment efforts to lower income urban communities could increase screening rates. OBSP adherent women were more likely to be diagnosed at earlier stages, supporting the value of this initiative and those like it.

Evidence is mounting that cigarette smoking contributes to second primary contralateral breast cancer (CBC) risk. Whether radiation therapy (RT) interacts with smoking to modify this risk is unknown. In this multicenter, individually matched, case-control study, we examined the association between RT, smoking, and CBC risk. The study included 1521 CBC cases and 2212 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2008 aged younger than 55 years. Absorbed radiation doses to contralateral breast regions were estimated with thermoluminescent dosimeters in tissue-equivalent anthropomorphic phantoms, and smoking history was collected by interview. Rate ratios (RRs) and 95% confidence intervals (CIs) for CBC risk were estimated by multivariable conditional logistic regression. There was no interaction between any measure of smoking with RT to increase CBC risk (eg, the interaction of continuous RT dose with smoking at first breast cancer diagnosis [ever/never]: RR = 1.00, 95% CI = 0.89 to 1.14; continuous RT dose with years smoked: RR = 1.00, 95% CI = 0.99 to 1.01; and continuous RT dose with lifetime pack-years: RR = 1.00, 95% CI = 0.99 to 1.01). There was no evidence that RT further increased CBC risk in young women with first primary breast cancer who were current smokers or had smoking history.

Population‐level identification of children and youth with ASD is essential for surveillance and planning for required services. The objective of this study was to develop and validate an algorithm for the identification of children and youth with ASD using administrative health data. In this retrospective validation study, we linked an electronic medical record (EMR)‐based reference standard, consisting 10,000 individuals aged 1–24 years, including 112 confirmed ASD cases to Ontario administrative health data, for the testing of multiple case‐finding algorithms. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and corresponding 95% confidence intervals (CI) were calculated for each algorithm. The optimal algorithm was validated in three external cohorts representing family practice, education, and specialized clinical settings. The optimal algorithm included an ASD diagnostic code for a single hospital discharge or emergency department visit or outpatient surgery, or three ASD physician billing codes in 3 years. This algorithm's sensitivity was 50.0% (95%CI 40.7–88.7%), specificity 99.6% (99.4–99.7), PPV 56.6% (46.8–66.3), and NPV 99.4% (99.3–99.6). The results of this study illustrate limitations and need for cautious interpretation when using administrative health data alone for the identification of children and youth with ASD. Lay Summary We tested algorithms (set of rules) to identify young people with ASD using routinely collected administrative health data. Even the best algorithm misses more than half of those in Ontario with ASD. To understand this better, we tested how well the algorithm worked in different settings (family practice, education, and specialized clinics). The identification of individuals with ASD at a population level is essential for planning for support services and the allocation of resources. Autism Res 2021, 14: 1037–1045. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.

The identification of genetic variation that directly impacts infection susceptibility to SARS-CoV-2 and disease severity of COVID-19 is an important step towards risk stratification, personalized treatment plans, therapeutic, and vaccine development and deployment. Given the importance of study design in infectious disease genetic epidemiology, we use simulation and draw on current estimates of exposure, infectivity, and test accuracy of COVID-19 to demonstrate the feasibility of detecting host genetic factors associated with susceptibility and severity in published COVID-19 study designs. We demonstrate that limited phenotypic data and exposure/infection information in the early stages of the pandemic significantly impact the ability to detect most genetic variants with moderate effect sizes, especially when studying susceptibility to SARS-CoV-2 infection. Our insights can aid in the interpretation of genetic findings emerging in the literature and guide the design of future host genetic studies. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-020-00818-2.

Health care professionals are expected to take on an active role in the implementation of risk-based cancer prevention strategies. This study aimed to explore health care professionals' (1) self-reported familiarity with the concept of polygenic risk score (PRS), (2) perceived level of knowledge regarding risk-stratified breast cancer (BC) screening, and (3) preferences for continuing professional development.A cross-sectional survey was conducted using a bilingual-English/French-online questionnaire disseminated by health care professional associations across Canada between November 2020 and May 2021.A total of 593 professionals completed more than 2 items and 453 responded to all questions. A total of 432 (94%) participants were female, 103 (22%) were physicians, and 323 (70%) were nurses. Participants reported to be unfamiliar with (20%), very unfamiliar (32%) with, or did not know (41%) the concept of PRS. Most participants reported not having enough knowledge about risk-stratified BC screening (61%) and that they would require more training (77%). Online courses and webinar conferences were the preferred continuing professional development modalities.The study indicates that health care professionals are currently not familiar with the concept of PRS or a risk-stratified approach for BC screening. Online information and training seem to be an essential knowledge transfer modality.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder requiring significant health and educational resources for affected individuals. A reference standard for ASD was generated from an existing population-based cohort of 10,000 children and youth aged 1-24 years who were randomly selected for chart abstraction from 29,256 patients from 119 family physicians. We developed and validated an algorithm to identify children and youth with ASD within an electronic medical record system (N = 80,237, aged 1-24 years) in order to examine the prevalence of comorbidities and quantify health system utilization within the cohort. We identified 1,062 children and youth with ASD representing a prevalence of 1.32%. Compared to individuals without ASD, those with ASD had a higher prevalence of asthma, were more likely to visit a specialist, undergo surgery, and be hospitalized for psychiatric reasons. Children and youth with ASD in Ontario have complex health system needs, illustrated through a significant burden of comorbidities and increased health system utilization. LAY SUMMARY: Our paper generates population-based estimates of health system use by children and youth with ASD, who have a higher burden of comorbidities than the general population. We developed a case-finding algorithm and applied it in electronic medical records to create a cohort of children and youth with ASD, thereby generating an important resource to further study the health care needs of individuals with ASD.

Purpose: Dysregulation of the receptor activator of nuclear factor κB (RANK) pathway may contribute to the pathogenesis of BRCA1-associated breast cancer. Specifically, lower levels of osteoprotegerin (OPG), an endogenous inhibitor of RANK-ligand (RANKL) that competes with RANK for RANKL binding, have been reported among women with pathogenic or likely pathogenic variant (mutation) in the BRCA1 gene. It has been suggested that lower OPG levels may be associated with an increased risk of breast cancer, proposing that OPG may serve as a biomarker for breast cancer risk. Whether OPG is associated with estimated breast cancer risk remains unknown. The goal of this study was to evaluate the relationship between OPG and the estimated risk of breast cancer in women with a BRCA1 mutation. Methods: Women were eligible for inclusion if they had a BRCA1 mutation, were between ages 18 and 79, had a pedigree, had no prior history of cancer, had not undergone prophylactic bilateral mastectomy and provided a blood sample available for OPG analysis. Detailed information on various risk factors (i.e., reproductive, hormonal, family history) was collected using biennial questionnaires. An enzyme-linked immunosorbent assay was used to quantify serum OPG levels (pg/mL). Risk of breast cancer was estimated using Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 6 incorporated in the CanRisk tool. The relationship between OPG and estimated lifetime (up to age 80) and ten-year (age 40–50) risks of breast cancer was evaluated using quantile regression analyses. Analyses were further stratified by age (≤50 vs >50 years). Results: A total of 539 women were included in the analysis. The median age at blood collection was 39 years (18–77 years). For lifetime breast cancer risk, a 1 standard deviation (SD; 38.40 pg/ml) increase in OPG level was associated with a 5.4% lower risk at the 25th percentile (P ≤ 0.001), a 4.2% lower risk at the 50th percentile (P ≤ 0.001), and a 1.5% lower risk at the 75th percentile (P ≤ 0.001). For ten-year breast cancer risk, a 1 SD increase in OPG level was associated with a 1.2% lower risk at the 25th percentile (P ≤ 0.001), a 0.8% lower risk at the 50th percentile (P ≤ 0.001), and a 0.8% lower risk at the 75th percentile (P = 0.005). The association between OPG and both estimated risks did not vary in the analysis stratified by age (≤50 vs >50 years). Conclusion: Higher circulating OPG levels were associated with significantly lower estimated lifetime and ten-year risks of BRCA1-associated breast cancer. These associations were stronger for women at a lower risk of developing lifetime breast cancer. Further research is needed to determine whether integrating circulating OPG levels can improve existing risk prediction models. These data contribute to ongoing interest in the role of RANK signaling in mammary tumorigenesis. Inhibiting RANK signaling may therefore be a potential target for breast cancer prevention in women with a BRCA1 mutation and other high-risk populations. Citation Format: Sarah S. Park, Tasnim Zaman, Shana J. Kim, Jennifer D. Brooks, Andy K. O. Wong, Jan Lubiński, Steven A. Narod, Leonardo Salmena, Joanne Kotsopoulos. Association between circulating osteoprotegerin levels and estimated risk of BRCA1-associated breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P037.

Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes—preterm birth, low birthweight, and small for gestational age—are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use. Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age. Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen use

Thrombocytosis is associated with cancer progression and death for many cancer types. It is unclear if platelet count is also associated with cancer survival. We conducted a cohort study of 112,231 adults in Ontario with a diagnosis of cancer between January 2007 and December 2016. We included patients who had a complete blood count (CBC) completed in the 30 days prior to their cancer diagnosis. Subjects were assigned to one of three categories according to platelet count: low (≤25th percentile), medium (>25 to

In risk-stratified cancer screening, multiple risk factors are incorporated into the risk assessment. An individual’s estimated absolute cancer risk is linked to risk categories with tailored screening recommendations for each risk category. Absolute risk, expressed as either remaining lifetime risk or shorter-term (five- or ten-year) risk, is estimated from the age at assessment. These risk estimates vary by age, however, some clinical guidelines (e.g., enhanced breast cancer surveillance guidelines) and ongoing personalised breast screening trials, stratify women based on absolute risk thresholds that do not vary by age. We examine an alternative approach in which the risk thresholds used for risk stratification vary by age and consider the implications of using age-independent risk thresholds on risk stratification. We demonstrate that using an age-independent remaining lifetime risk threshold approach could identify high-risk younger women but would miss high-risk older women, whereas an age-independent 5-year or 10-year absolute risk threshold could miss high-risk younger women and classify lower-risk older women as high risk. With risk misclassification, women with an equivalent risk level would be offered a different screening plan. To mitigate these problems, age-dependent absolute risk thresholds should be used to inform risk stratification.

Purpose: BRCA1 mutation carriers face a very high lifetime risk of developing breast cancer. Dysregulation of the receptor activator of nuclear factor κB (RANK) pathway has been implicated in the pathogenesis of BRCA1-associated breast cancer. In addition, lower levels of osteoprotegerin (OPG), the decoy receptor for RANK-ligand, have been reported among women with a BRCA1 mutation and may be associated with an increased risk of breast cancer. Thus, inhibition of RANK signaling represents a potential target for prevention, and furthermore, OPG levels may be a biomarker of subsequent cancer risk. Whether non-genetic exposures also influence circulating levels of OPG in these high-risk women is not known. Therefore, the goal of this study was to evaluate reproductive, hormonal, and lifestyle correlates of OPG levels in BRCA1 mutation carriers. Methods: Eligible women included BRCA1 mutation carriers enrolled in a longitudinal study, aged 18 years or older, without a history of cancer, and with a serum sample available. All women completed a baseline questionnaire at the time of enrolment and a follow-up questionnaire every two years thereafter to collect detailed information on various exposures (i.e., reproductive, hormonal, and lifestyle) and outcomes. Serum OPG levels (pg/ml) were measured using an enzyme-linked immunosorbent assay (ELISA). Generalized linear models were used to evaluate the associations of various reproductive, hormonal, and lifestyle exposures at the time of blood collection with serum OPG and to estimate adjusted means. Results: A total of 828 women were included in the current analysis. Older age was associated with significantly higher OPG levels (60 years, 79.04 vs. 82.01 pg/ml; Ptrend < 0.0001). Current vs. never smoking was also associated with significantly higher OPG levels (87.69 vs. 73.48 pg/ml; Pcat < 0.0001). There were no significant associations between other exposures and levels of OPG (P ≥ 0.17). Findings were similar in the analyses stratified by menopausal status. Conclusion: The results from this study suggest that non-genetic factors likely have a minimal impact upon serum OPG among women with a BRCA1 mutation. Further studies are needed to explore other potential correlates of OPG (i.e., diet, supplement use) and to elucidate whether integration of circulating OPG levels may improve existing risk prediction models. Citation Format: Sarah S. Park, Tasnim Zaman, Shana J. Kim, Jennifer D. Brooks, Andy K. Wong, Jan Lubiński, Steven A. Narod, Leonardo Salmena, Joanne Kotsopoulos. Reproductive, hormonal and lifestyle correlates of circulating osteoprotegerin levels in women with a BRCA1 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5896.

Objective. To assess if body mass index (BMI) and high waist circumference (HWC) are associated with testing positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods. 9,386 UK Biobank study participants tested for SARS-CoV-2 from March 16th 2020 to June 29th 2020 were analyzed. A forward model building approach was used to estimate adjusted risk ratios (RR) and 95% confidence intervals (95% CI). Analyses were stratified by age due to a significant first-order interaction between age and HWC. Results. Approximately 17% (n = 1,577) of participants tested positive for SARS-CoV-2. BMI category had a linear association with testing positive for SARS-CoV-2 among participants

Risk-stratified screening for breast cancer (BC) is increasingly considered as a promising approach. However, its implementation is challenging and needs to be acceptable to women. We examined Canadian women’s attitudes towards, comfort level about, and willingness to take part in BC risk-stratified screening. We conducted an online survey in women aged 30 to 69 years in four Canadian provinces. In total, 4293 women completed the questionnaire (response rate of 63%). The majority of women (63.5% to 72.8%) expressed favorable attitudes towards BC risk-stratified screening. Most women reported that they would be comfortable providing personal and genetic information for BC risk assessment (61.5% to 67.4%) and showed a willingness to have their BC risk assessed if offered (74.8%). Most women (85.9%) would also accept an increase in screening frequency if they were at higher risk, but fewer (49.3%) would accept a reduction in screening frequency if they were at lower risk. There were few differences by province, however, outcomes varied by age, education level, marital status, income, perceived risk, history of BC, prior mammography, and history of genetic test for BC (all p ≤ 0.01). Risk-based BC screening using multifactorial risk assessment appears to be acceptable to most women. This suggests that the implementation of this approach is likely to be well-supported by Canadian women.

Background As cannabis consumption is increasing globally, including among pregnant women, there is a critical need to understand the effects of cannabis on fetal development and birth outcomes. We had two objectives: to determine 1) the factors associated with self-reported cannabis use in the pre/early-pregnancy period, and 2) whether cannabis use is associated with low birth weight, preterm birth, or small size for gestational age (GA) infants. Methods Maternal questionnaire and birth outcome data was gathered from 2229 women and 1778 singleton infants in the Ontario Birth Study, a hospital-based prospective cohort study (2013–2019). Women self-reported cannabis use within 3 months of learning their pregnancy status. Multivariable linear and logistic regression was conducted to 1) identify factors associated with cannabis use, and 2) determine the associations between cannabis use with the selected birth outcomes. Results Cannabis use increased in the cohort over time. Women who reported cannabis use (N = 216) were more likely to be younger and more likely to use alcohol, tobacco, and prescription pain medication, although most did not. These women had infants born at lower average birth weights and had 2.0 times the odds of being small for GA (95% confidence interval: 1.3, 3.3) after multivariable adjustment for socioeconomic factors and other substance use. Conclusion Our results suggest that women who use cannabis around the time of conception have higher odds of having infants that are small for gestational age. Targeted clinical messaging may be most applicable to women actively trying to conceive.

Objective To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC). Methods The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0, Highlights • Radiation treatment is associated with increased contralateral breast cancer risk in some women. • Reproductive status at the time of treatment may modify this relationship. • Some evidence that pregnancy after radiation treatment increases contralateral breast cancer risk.

Background It has been suggested that cardiorespiratory fitness (CRF) may be used to identify those at greatest risk for severe COVID-19 illness. However, no study to date has examined the association between CRF and COVID-19. The objectives of this study were to determine whether CRF is independently associated with testing positive with or dying from COVID-19. Methods This is a prospective cohort study of 2,690 adults from the UK Biobank Study that were followed from March 16th, 2020 to July 26th, 2020. Participants who were tested for COVID-19 and had undergone CRF assessment were examined. CRF was estimated (eCRF) and categorized as low (th percentile), moderate (20th to 80th percentile) and high (≥80th percentile) within sex and ten-year age groups (e.g. 50–60 years). Participants were classified as having COVID-19 if they tested positive (primarily PCR tests) at an in-patient or out-patient setting as of July 26, 2020. Participants were classified as having died from COVID-19 if the primary or underlying cause of death was listed ICD-10 codes U071 or U072 by June 30th, 2020. Adjusted risk ratios (aRR) and 95% confidence intervals (CI) were estimated and a forward model building approach used to identify covariates. Findings There was no significant association between eCRF and testing positive for COVID-19. Conversely, individuals with moderate (aRR = 0.43, 95% CI: 0.25, 0.75) and high fitness (aRR = 0.37, 95% CI: 0.16, 0.85) had a significantly lower risk of dying from COVID-19 than those with low fitness. Conclusions While eCRF was not significantly associated with testing positive for COVID-19, we observed a significant dose-response between having higher eCRF and a decreased risk of dying from COVID-19. This suggests that prior gains in CRF could be protective against dying from COVID-19 should someone develop the virus.

The identification of genetic variation that directly impacts infection susceptibility and disease severity of COVID-19 is an important step towards risk stratification, personalized treatment plans, therapeutic and vaccine development and deployment. Given the importance of study design in infectious disease genetic epidemiology, we use simulation and draw on current estimates of exposure, infectivity and test accuracy of COVID-19 to demonstrate the feasibility of detecting host genetic factors associated with susceptibility and severity with published COVID-19 study designs. We demonstrate why studying susceptibility to SARS-CoV-2 infection could be futile at the early stages of the pandemic. Our insights can aid in the interpretation of genetic findings emerging in the literature and guide the design of future host genetic studies.

Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01; BRCA1/2 pathogenic variant carriers with RT: RR = 4.46, 95% CI = 2.96 to 6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT: RR = 0.38, 95% CI = 0.09 to 1.55; carriers of ATM rare missense variants of uncertain significance with RT: RR = 2.98, 95% CI = 1.31 to 6.80). Further mechanistic studies will aid clinical decision-making related to RT.

This case-control study evaluates the association of an elevated platelet count with risk of cancer by cancer type and time from a complete blood count test to cancer diagnosis., Key Points Question Is a high platelet count associated with an increased risk of cancer? Findings In this nested case-control study of 8 917 187 Ontario residents who had 1 or more routine complete blood count tests performed, an elevated platelet count was associated with a diagnosis of cancer within 10 years after the blood test. The magnitude of the association varied by cancer type and time elapsed since the blood test. Meaning The findings suggest that a high platelet count is associated with increased cancer risk., Importance Individuals with cancer often have an elevated platelet count at the time of diagnosis. The extent to which an elevated platelet count is an indicator of cancer is unclear. Objective To evaluate the association of an elevated platelet count with a cancer diagnosis. Design, Setting, and Participants This nested case-control study included Ontario residents enrolled in the provincial health insurance plan who had 1 or more routine complete blood count (CBC) tests performed between January 1, 2007, and December 31, 2017, with follow-up through December 31, 2018. Case patients were individuals with a new cancer diagnosis during the observation period. Eligible control individuals were cancer free before the date of diagnosis for a case patient to whom they were matched. One case patient was matched to 3 controls based on sex, age, and health care use patterns. Data were analyzed from September 24, 2020, to July 13, 2021. Exposures Case patients and controls were assigned to 1 of 5 exposure groups based on age- and sex-specific platelet count distributions in the control population: very low (≤10th percentile), low (>10th to 25th percentile), medium (>25th to

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women. This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N = 118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density. Compared to women with "minimal" BPE, those who had "marked" BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, ptrend across all categories = 0.001; 150% increase, ptrend = 0.001; and 158% increase, ptrend = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast.

Introduction Advances in breast cancer screening and treatment have led to an increasing number of breast cancer survivors. The objective of this study was to determine the impact of comorbidities on self-reported quality of life (QOL) and emotional health following a breast cancer diagnosis and treatment. Methods Women with a personal history of breast cancer (N = 3,372) were identified from the cross-sectional Canadian Partnership Against Cancer (CPAC) Experiences of Cancer Patients in Transitions Survey. Multinomial (nominal) logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the relationship between burden of comorbidities and overall QOL and emotional health (very poor/poor, fair, good, very good). Results Of the 3,372 participants, 57% reported at least one chronic condition at the time of breast cancer diagnosis. As the number of chronic conditions at diagnosis increased, the odds of reporting worse quality of life and emotional health following treatment also increased. Specifically, compared to women reporting very good QOL, for each additional chronic condition, women reported significantly higher odds of reporting good (OR = 1.22, 95% CI: 1.12, 1.32), fair (OR = 1.76, 95% CI: 1.58, 1.96), or poor/very poor (OR = 2.31, 95% CI: 1.86, 2.88) QOL. Similarly, for each additional comorbidity, women reported significantly higher odds of reporting good (OR = 1.17, 95% CI: 1.07, 1.28), fair (OR = 1.63, 95% CI: 1.46, 1.82), or poor/very poor (OR = 2.17, 95% CI: 1.81, 2.60) emotional health, relative to very good emotional health. Conclusion Breast cancer survivors coping with a high comorbidity burden experience worse overall QOL and emotional health following treatment. This highlights the importance of integrating information on comorbidities into survivorship care to improve the experience and overall outcomes of patients with complex needs.

Background: Oral contraceptive use is associated with a significantly reduced risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. To date, there have been no prospective analyses of this relationship, and the impact of other types of contraception (e.g. intrauterine device (IUD), implant, patch, injection) on BRCA-associated ovarian cancer risk is unknown. The goal of this study is to prospectively evaluate the relationship between types of contraception and ovarian cancer incidence in women with a BRCA1 or BRCA2 mutation. Methods: The longitudinal study included 3,298 eligible BRCA1/2 mutation carriers. Self-reported information regarding contraceptive use, including medication name, start year, end year, duration of use and method of administration were collected by biennial questionnaire. Women were classified according to history of contraceptive use (ever/never), duration of use, contraceptive method, calendar year of initiation and time since last use. Time-dependent Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer associated with each contraceptive method. Results: There were 84 incident ovarian cancer cases diagnosed over a mean follow-up period of 5.1 years. There was no significant association between ever use of an IUD (HR: 0.78; 95% CI: 0.28-2.14) and risk of ovarian cancer compared to IUD never users. Ongoing analyses will focus on the relationships between other contraceptive methods, formulations and duration of use on ovarian cancer risk, further stratified by histology and site of origin. Conclusions: Preliminary findings from this prospective analysis suggest that IUD use may not be protective among BRCA1/2 mutation carriers. Ongoing results will elucidate the impact of contraceptive formulation and method on ovarian cancer risk to inform clinical recommendations surrounding the use of contraceptive agents for chemoprevention in high risk women. Citation Format: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos. Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 878.

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention.

Alcohol drinking and, to a lesser extent, cigarette smoking are risk factors for a first primary breast cancer. Information on these behaviours at diagnosis may contribute to risk prediction of contralateral breast cancer (CBC) and they are potentially modifiable. The WECARE Study is a large population-based case-control study of women with breast cancer where cases (N=1521) had asynchronous CBC and controls (N=2212), matched on survival time and other factors, had unilateral breast cancer (UBC). Using multivariable conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CI), we examined the risk of CBC in relation to drinking and smoking history at and following first diagnosis. We adjusted for treatment, disease characteristics, and other factors. There was some evidence for an association between CBC risk and current drinking or current smoking at the time of first breast cancer diagnosis, but the increased risk occurred primarily among women exposed to both (RR=1.62, 95% CI 1.24-2.11). CBC risk was also elevated in women who both smoked and drank alcohol after diagnosis (RR=1.54, 95% CI 1.18-1.99). In the subset of women with detailed information on amount consumed, smoking an average of ≥10 cigarettes per day following diagnosis was also associated with increased CBC risk (RR=1.50, 95% CI 1.08-2.08; p-trend=0.03). Among women with a diagnosis of breast cancer, information on current drinking and smoking could contribute to the prediction of CBC risk. Women who both drink and smoke may represent a group who merit targeted lifestyle intervention to modify their risk of CBC. This article is protected by copyright. All rights reserved.

This case-control study assesses the association of a genetic risk score based on variants in a DNA repair pathway with risk of a second primary contralateral breast cancer after radiation therapy for a first breast cancer., Key Points Question Is a genetic risk score comprising variants in a DNA repair pathway associated with risk of developing a second primary contralateral breast cancer among women who underwent radiation therapy for a primary breast cancer? Findings In this case-control study including 3732 women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years, a genetic risk score comprising variants in a DNA repair pathway was associated with increased risk of a subsequent radiation-associated contralateral breast cancer. Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%. Meaning This genetic risk score may be a helpful tool to guide treatment for young women with breast cancer., Importance Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood. Objective To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer. Design, Setting, and Participants This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women’s Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019. Exposures Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median. Main Outcomes and Measures The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency. Results A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%. Conclusions and Relevance This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

Author(s): Antoniou, Antonis; Anton-Culver, Hoda; Borowsky, Alexander; Broeders, Mireille; Brooks, Jennifer; Chiarelli, Anna; Chiquette, Jocelyne; Cuzick, Jack; Delaloge, Suzette; Devilee, Peter; Dorval, Michael; Easton, Douglas; Eisen, Andrea; Eklund, Martin; Eloy, Laurence; Esserman, Laura; Garcia-Closas, Montserrat; Goldgar, David; Hall, Per; Knoppers, Bartha Maria; Kraft, Peter; La Croix, Andrea; Madalensky, Lisa; Mavaddat, Nasim; Mittman, Nicole; Nabi, Hermann; Olopade, Olufunmilayo; Pashayan, Nora; Schmidt, Marjanka; Shieh, Yiwey; Simard, Jacques; Stover-Fiscallini, Allison; Tice, Jeffrey A; Van't Veer, Laura; Wenger, Neil; Wolfson, Michael; Yau, Christina; Ziv, Elad

Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes-preterm birth, low birthweight, and small for gestational age-are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use.Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age.Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen useonce/week was associated with small for gestational age, adjusted relative risk (aRR) = 1.46 (95% CI 1.02, 2.11). Acetaminophen use ≥once/week was associated with both small for gestational age, RR = 1.82 (95% CI 1.12, 2.94), and low birthweight, aRR = 2.16 (95% CI 1.02, 4.54). Acetaminophen use during pregnancy was not associated with the examined outcomes.Prepregnancy acetaminophen use may be associated with higher risk of adverse birth outcomes.

Background Tamoxifen treatment greatly reduces a woman’s risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. Methods Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5–0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. Results Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20–55% reduced RR of CBC (AS = 2, RR = – 0.81, 95% CI 0.62–1.06; AS = 1.5, RR = 0.45, 95% CI 0.30–0.68; and AS = 1, RR = 0.55, 95% CI 0.40–0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59–1.96; and AS = 0, RR = 1.17, 95% CI 0.58–2.35) (p for homogeneity = – 0.02). Conclusion This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC. Electronic supplementary material The online version of this article (10.1186/s13058-018-1083-y) contains supplementary material, which is available to authorized users.

Purpose To compare the clinical, imaging, and histopathologic features of breast cancers detected at screening magnetic resonance (MR) imaging, screening mammography, and those detected between screening examinations (interval cancers) in women at high risk. Materials and Methods This retrospective institutional review board-approved, HIPAA-compliant review of 7519 women at high risk for breast cancer who underwent screening with MR imaging and mammography between January 2005 and December 2010 was performed to determine the number of screening-detected and interval cancers diagnosed. The need for informed consent was waived. Medical records were reviewed for age, risk factors (family or personal history of breast cancer, BRCA mutation status, history of high-risk lesion or mantle radiation), tumor histopathologic results, and time between diagnosis of interval cancer and most recent screening examination. The χ(2) test and logistic regression methods were used to compare the features of screening MR imaging, screening mammography, and interval cancers. The Wilcoxon signed-rank test was used to calculate P values. Results A total of 18 064 screening MR imaging examinations and 26 866 screening mammographic examinations were performed. Two hundred twenty-two cancers were diagnosed in 219 women, 167 (75%) at MR imaging, 43 (19%) at mammography, and 12 (5%) interval cancers. Median age at diagnosis was 52 years. No risk factors were associated with screening MR imaging, screening mammography, or interval cancer (P > .06). Cancers found at screening MR imaging were more likely to be invasive cancer (118 of 167 [71%]; P < .0001). Of the 43 cancers found at screening mammography, 38 (88%) manifested as calcifications and 28 (65%) were ductal carcinoma in situ. Interval cancers were associated with nodal involvement (P = .005) and the triple-negative subtype (P = .03). Conclusion In women at high risk for breast cancer who underwent screening with mammography and MR imaging, invasive cancers were more likely to be detected at MR imaging, whereas most cancers detected at screening mammography were ductal carcinoma in situ. Interval cancers were found infrequently and were more likely to be node positive and of the triple-negative subtype. (©) RSNA, 2016.

PURPOSE: Breast fibroglandular tissue (FGT), as visualized on a mammogram (mammographic density, MD), is one of the strongest known risk factors for breast cancer. FGT is also visible on breast MRI, and increased background parenchymal enhancement (BPE) in the FGT has been identified as potentially a major breast cancer risk factor. The aim of this exploratory study was to examine the biologic basis of BPE. METHODS: We examined the unaffected contra-lateral breast of 80 breast cancer patients undergoing a prophylactic mastectomy before any treatment other than surgery of their breast cancer. BPE was classified on the BI-RADS scale (minimal/ mild/moderate/marked). Slides were stained for microvessel density (MVD), CD34 (another measure of endothelial density), glandular tissue within the FGT and VEGF. Spearman correlations were used to evaluate the associations between BPE and these pathologic variables. RESULTS: In pre-menopausal patients, BPE was highly correlated with MVD, CD34 and glandular concentration within the FGT, and the pathologic variables were themselves highly correlated. The expression of VEGF was effectively confined to terminal duct lobular unit (TDLU) epithelium. The same relationships of the four pathologic variables with BPE were seen in post-menopausal patients, but the relationships were much weaker and not statistically significant. CONCLUSION: The strong correlation of BPE and MVD together with the high correlation of MVD with glandular concentration seen in pre-menopausal patients indicates that increased breast cancer risk associated with BPE in pre-menopausal women is likely to result from its association with increased concentration of glandular tissue in the FGT. The effective confinement of VEGF expression to the TDLUs shows that the signal for MVD growth arises directly from the glandular tissue. Further studies are needed to understand the basis of BPE in post-menopausal women.

IntroductionAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) that presents with a high degree of heterogeneity (e.g., co-occurrence of other NDDs and other co-morbid conditions), contributing to differential health system needs. Genetics are known to play an important role in ASD and may be associated with different disease trajectories. Objectives and ApproachIn this proof of principle project, our objective is to link >2,200 children with a confirmed diagnosis of a NDD from the Province of Ontario Neurodevelopmental (POND) Study to administrative health data and electronic medical record (EMR) data in order to identify subgroups of ASD with unique health system trajectories. POND includes detailed phenotype and whole genome sequencing (WGS) data. Identified subgroups will be characterized based on clinical phenotype and genetics. To meet this goal, consideration of WGS-specific privacy and data issues is needed to implement processes which are above and beyond traditional requirements for analyzing individual-level administrative health data. ResultsLinkage of WGS data with administrative health data is an emerging area of research. As such it has presented a number of initial challenges for our study of ASD. Privacy concerns surrounding the use of WGS data and rare-variant analysis are of particular importance. Practical issues required the need for analysts with expertise in administrative data, EMR data and genetic analyses, and specialized software and sufficient processing power to analyze WGS data. Transdisciplinary discussions of the scope and significance of research questions addressed through this linkage were crucial. The identification of genetic determinants of phenotypes and trajectories in ASD could support targeted early interventions; EMR linkage may inform algorithms to identify ASD in broader populations. These approaches could improve both patient outcome and family experience. Conclusion/ImplicationsAs the cost of genetic sequencing decreases, WGS data will become part of the routine clinical management of patients. Linkage of WGS, EMR and administrative data has tremendous potential that has largely not been realized; including population-level ASD research to improve our ability to predict long-term outcomes associated with ASD.

Purpose The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.