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Purpose: We developed a web-based education intervention as an alternative to predisclosure education with a genetic counselor (GC) to reduce participant burden and provider costs with return of genetic research results., Methods: Women at three sites who participated in 11 gene discovery research studies were contacted to consider receiving cancer genetic research results. Participants could complete predisclosure education through web education or with a GC. Outcomes included uptake of research results, factors associated with uptake, and patient-reported outcomes., Results: Of 819 participants, 178 actively (21.7%) and 167 passively (20.4%) declined return of results; 474 (57.9%) were enrolled. Most (60.3%) received results although this was lower than the 70% uptake we hypothesized. Passive and active decliners were more likely to be Black, to have less education, and to have not received phone follow-up after the invitation letter. Most participants selected web education (88.5%) as an alternative to speaking with a GC, but some did not complete or receive results. Knowledge increased significantly from baseline to other time points with no significant differences between those who received web versus GC education. There were no significant increases in distress between web and GC education., Conclusion: Interest in web-based predisclosure education for return of genetic research results was high although it did not increase uptake of results. We found no negative patient-reported outcomes with web education, suggesting that it is a viable alternative delivery model for reducing burdens and costs of returning genetic research results. Attention to attrition and lower uptake of results among Black participants and those with less formal education are important areas for future research.

Background: Socioeconomic status (SES) at birth is associated with breast cancer risk. Whether this association is driven by changes in breast tissue composition (BTC) prior to adulthood remains unclear., Methods: We used multivariable linear regression models to examine whether SES at birth is associated with BTC in adolescence and adulthood using data from a New York City cohort of daughters (n = 165, 11-20 years) and mothers (n = 160, 29-55 years). We used maternal-reported data on daughters' household income and maternal education at birth, analyzed individually and in combination (SES index). Women also reported their own mothers' education at birth. We used optical spectroscopy to evaluate BTC measures that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized breast cancer risk factor., Results: Being in the highest versus lowest category of the SES index was associated with lower lipid content [βadjusted (βadj) = -0.80; 95% confidence interval (CI), -1.30 to -0.31] and higher collagen content (βadj = 0.54; 95% CI, 0.09-0.99) in adolescence. In women with a body mass index (BMI) <30 kg/m2, higher maternal education at birth (≥ vs. < high school degree) was associated with lower lipid content (βadj = -0.57; 95% CI, -0.97 to -0.17), higher water content (βadj = 0.70; 95% CI, 0.26-1.14), and higher optical index (βadj = 0.53; 95% CI, 0.10-0.95)., Conclusions: This study supports that SES at birth is associated with BTC in adolescence and adulthood, although the latter association may depend on adult BMI., Impact: Further research is needed to identify the socially patterned early life factors influencing BTC., (©2023 American Association for Cancer Research.)

Objective: Women with breast cancer have an increased risk of primary ovarian cancer (BR→OV), and women with ovarian cancer have an increased risk of primary breast cancer (OV→BR). This systematic review summarizes risk factors for developing BR→OV and OV→BR., Methods: We searched PubMed and Embase until June 2022., Results: We identified 23 articles meeting our inclusion criteria. Studies observed a lower risk of BR→OV for Black versus White women, alcohol consumption, radiotherapy and hormone therapy, BRCA2 versus BRCA1, and ER/PR positive versus negative breast tumors, and a higher risk with family history of breast/ovarian cancer, triple negative versus luminal breast cancer, and higher grade breast tumors. There was an increased risk of OV→BR with family history of cancer., Conclusions: Tumor characteristics, and genetic and familial factors are associated with risk of BR→OV and OV→BR. These results could aid clinicians in decision-making for breast and ovarian cancer patients, including risk-reducing strategies., Competing Interests: Declaration of Competing Interest Dr. Wright has received royalties from UpToDate and research support from Merck. All other authors have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: In the United States, Hispanic-Latino children reach puberty earlier on average than non-Hispanic white children. Yet among U.S. Hispanic/Latino children, pubertal timing comparisons between immigrant generations have not been made, hence we examined whether pubertal timing differs by immigrant generational status, independent of BMI and acculturation measures., Methods: Cross-sectional data on 724 boys and 735 girls, aged 10-15 years, from the Hispanic Community Children's Health Study/Study of Latino (SOL) Youth, were used to predict the median ages of thelarche, pubarche, and menarche in girls, and pubarche and voice change in boys, using Weibull survival models, while adjusting for SOL center, BMI, and acculturation., Results: In girls, the first generation began thelarche earlier than second and third generations (median age [years] [95% confidence interval]: 7.4 [6.1, 8.8] vs. 8.5 [7.3, 9.7] and 9.1 [7.6, 10.7], respectively), but began menarche later (12.9 [12.0,137] vs. 11.8 [11.0, 12.5] and 11.6 [10.6, 12.6], respectively). Pubertal timing and tempo for boys did not differ by generational status., Conclusions: First-generation U.S. Hispanic/Latino girls had the earliest thelarche, latest menarche and longest pubertal tempo, compared to second and third generations. Factors beyond BMI and acculturation may account for the differences in pubertal timing by generational status of U.S. Hispanic/Latino girls., (© 2023 Wiley Periodicals LLC.)

Lay Abstract: Little is known about factors related to the increased risk for gastrointestinal symptoms in adults with an autism spectrum disorder (ASD), while the negative impact of gastrointestinal symptoms is evident. Especially, the relationship between gastrointestinal symptoms and psychological, behavioural, and biological risk factors in adults with ASD (traits) is unclear. Autistic peer support workers and autism-advocates also emphasised the importance of identifying risk factors, because of the high prevalence of gastrointestinal problems in people with ASD. Therefore, our study investigated which psychological, behavioural, and biological factors are associated with gastrointestinal symptoms in adults with ASD or with autistic traits. We analysed data from 31,185 adults in the Dutch Lifelines Study. Questionnaires were used to evaluate the presence of an autism spectrum disorder diagnosis, autistic traits, gastrointestinal symptoms, psychological and behavioural factors. Biological factors were examined with body measurements. We found that not only adults with ASD but also adults with higher levels of autistic traits were at increased risk for gastrointestinal symptoms. Adults with ASD who experienced psychological problems (psychiatric problems, worse perceived health, chronic stress) had a higher risk for gastrointestinal symptoms than adults with ASD without these psychological problems. Moreover, adults with higher levels of autistic traits were less physically active, which was also associated with gastrointestinal symptoms. In conclusion, our study highlights the relevance of identifying psychological problems and evaluating physical activity when trying to help adults with ASD or autistic traits and gastrointestinal symptoms. This suggests that healthcare professionals should be more aware of behavioural and psychological risk factors when evaluating gastrointestinal symptoms in adults with ASD (traits).

Background: People who give care to autistic individuals (autism-caregivers) experience higher levels of caregiver strain than people who provide care for individuals with other chronic conditions (non-autism-caregivers). This places them at higher risk for psychological, behavioural and physical health concerns. The aim of this study is to delineate psychological, behavioural, and physical aspects of caregiver strain in autism-caregivers compared to non-autism-caregivers., Methods: We included 3354 adult caregivers from the general population in the Netherlands participating in the second assessment (January, 1, 2014-December, 31, 2017) of the Lifelines Cohort. In this cohort study, using multivariable regression adjusted for age, sex, and socioeconomic status, we analysed psychological (anxiety and depression based on a Mini International Neuropsychiatric Interview, and self-reported stress and perceived health), behavioural (questionnaire-assessed physical activity, alcohol use, and smoking), and physical aspects (body mass index, waist circumference, and leukocyte-counts) of caregiver strain in autism-caregivers (n = 722) compared with non-autism-caregivers (n = 2632)., Findings: Autism-caregivers reported more stress (OR 3.61, 95% CI 2.60-4.99). Both anxiety (OR 1.85, 95% CI 1.37-2.49) and depressive disorders (OR 1.83, 95% CI 1.17-2.86) were more common in autism-caregivers than in non-autism-caregivers. Perceived health, physical activity, alcohol use, and smoking were not different between autism- and non-autism-caregivers. In autism-caregivers, lymphocyte- and monocyte-counts were lower than in non-autism-caregivers., Interpretation: In this large cohort, autism-caregivers had worse psychological health than non-autism-caregivers. Moreover, autism-caregiving might be associated with an altered immune balance. These findings underline the higher caregiver strain in autism-caregivers compared to other caregivers. This calls for increased support to autism-caregivers., Funding: Lifelines has been funded by the Dutch government., Competing Interests: The authors declare not having any conflict of interest., (© 2023 The Author(s).)

Research methods to study risk factors and prevention of breast cancer have evolved rapidly. We focus on advances from epidemiologic studies reported over the past two decades addressing scientific discoveries, as well as their clinical and public health translation for breast cancer risk reduction. In addition to reviewing methodology advances such as widespread assessment of mammographic density and Mendelian randomization, we summarize the recent evidence with a focus on the timing of exposure and windows of susceptibility. We summarize the implications of the new evidence for application in risk stratification models and clinical translation to focus prevention-maximizing benefits and minimizing harm. We conclude our review identifying research gaps. These include: pathways for the inverse association of vegetable intake and estrogen receptor (ER)-ve tumors, prepubertal and adolescent diet and risk, early life adiposity reducing lifelong risk, and gaps from changes in habits (e.g., vaping, binge drinking), and environmental exposures., (Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.)

Environmental exposure to polycyclic aromatic hydrocarbons (PAH) has been shown to be associated with chronic disease outcomes through multiple mechanisms including altered regulation of the transcription factor peroxisome proliferator-activated receptor gamma (Ppar) γ. Because PAH exposure and Pparγ each have been associated with mammary cancer, we asked whether PAH would induce altered regulation of Pparγ in mammary tissue, and whether this association may underlie the association between PAH and mammary cancer. Pregnant mice were exposed to aerosolized PAH at proportions that mimic equivalent human exposures in New York City air. We hypothesized that prenatal PAH exposure would alter Pparγ DNA methylation and gene expression and induce the epithelial to mesenchymal transition (EMT) in mammary tissue of offspring (F1) and grandoffspring (F2) mice. We also hypothesized that altered regulation of Pparγ in mammary tissue would associate with biomarkers of EMT, and examined associations with whole body weight. We found that prenatal PAH exposure lowered Pparγ mammary tissue methylation among grandoffspring mice at postnatal day (PND) 28. However, PAH exposure did not associate with altered Pparγ gene expression or consistently with biomarkers of EMT. Finally, lower Pparγ methylation, but not gene expression, was associated with higher body weight among offspring and grandoffspring mice at PND28 and PND60. Findings suggest additional evidence of multi-generational adverse epigenetic effects of prenatal PAH exposure among grandoffspring mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Deep learning techniques, including convolutional neural networks (CNN), have the potential to improve breast cancer risk prediction compared to traditional risk models. We assessed whether combining a CNN-based mammographic evaluation with clinical factors in the Breast Cancer Surveillance Consortium (BCSC) model improved risk prediction., Methods: We conducted a retrospective cohort study among 23,467 women, age 35-74, undergoing screening mammography (2014-2018). We extracted electronic health record (EHR) data on risk factors. We identified 121 women who subsequently developed invasive breast cancer at least 1 year after the baseline mammogram. Mammograms were analyzed with a pixel-wise mammographic evaluation using CNN architecture. We used logistic regression models with breast cancer incidence as the outcome and predictors including clinical factors only (BCSC model) or combined with CNN risk score (hybrid model). We compared model prediction performance via area under the receiver operating characteristics curves (AUCs)., Results: Mean age was 55.9 years (SD, 9.5) with 9.3% non-Hispanic Black and 36% Hispanic. Our hybrid model did not significantly improve risk prediction compared to the BCSC model (AUC of 0.654 vs 0.624, respectively, p = 0.063). In subgroup analyses, the hybrid model outperformed the BCSC model among non-Hispanic Blacks (AUC 0.845 vs. 0.589; p = 0.026) and Hispanics (AUC 0.650 vs 0.595; p = 0.049)., Conclusion: We aimed to develop an efficient breast cancer risk assessment method using CNN risk score and clinical factors from the EHR. With future validation in a larger cohort, our CNN model combined with clinical factors may help predict breast cancer risk in a cohort of racially/ethnically diverse women undergoing screening., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Peripheral blood mononuclear cells (PBMCs) are a useful model for biochemical assays, particularly for etiological studies. We describe here a method for measuring DNA repair capacity (DRC) in archival cryogenically preserved PBMCs. To model DRC, we measured γ-H2AX repair kinetics in thawed PBMCs after irradiation with 3 Gy gamma rays. Time-dependent fluorescently labeled γ-H2AX levels were measured at five time points from 1 to 20 h, yielding an estimate of global DRC repair kinetics as well as a measure of unrepaired double strand breaks at 20 h. While γ-H2AX levels are traditionally measured by either microscopy or flow-cytometry, we developed a protocol for imaging flow cytometry (IFC) that combines the detailed information of microscopy with the statistical power of flow methods. The visual imaging component of the IFC allows for monitoring aspects such as cellular health and apoptosis as well as fluorescence localization of the γ-H2AX signal, which ensures the power and significance of this technique. Application of a machine-learning based image classification improved flow cytometry fluorescent measurements by identifying apoptotic cells unable to undergo DNA repair. We present here DRC repair parameters from 18 frozen archival PBMCs and 28 fresh blood samples collected from a demographically diverse cohort of women measured in a high-throughput IFC format. This thaw method and assay can be used alone or in conjunction with other assays to measure etiological phenotypes in cryogenic biobanks of PBMCs., (© 2023 International Society for Advancement of Cytometry.)

Introduction: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes., Patients and Methods: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change., Results: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m 2 , 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m 2 , 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively)., Conclusion: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population., (© 2023. The Author(s).)

Background: The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH)., Methods: Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n = 4,557) or post-diagnosis (n = 1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted HR and 95% confidence intervals (CI)., Results: Women in the highest versus lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74-1.04; Ptrend = 0.12) for HEI-2015; 0.82 (0.69-0.97; Ptrend = 0.02) for AHEI; 0.73 (0.59-0.92; Ptrend = 0.02) for aMED; and 0.78 (0.65-0.94; Ptrend = 0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index <25 kg/m2 and women with hormone receptor positive tumors., Conclusions: Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer., Impact: Adherence to a healthy diet may improve survival of women with breast cancer., (©2023 American Association for Cancer Research.)

Background: Earlier onset of breast development (thelarche) is associated with increased breast cancer risk. Identifying modifiable factors associated with earlier thelarche may provide an opportunity for breast cancer risk reduction starting early in life, which could especially benefit girls with a greater absolute risk of breast cancer due to family history., Methods: We assessed associations of maternal pre-pregnancy body mass index (BMI), physical activity during pregnancy, gestational weight gain and daughters' weight and length at birth with age at thelarche using longitudinal Weibull models in 1031 girls in the Lessons in Epidemiology and Genetics of Adult Cancer from Youth (LEGACY) Girls Study-a prospective cohort of girls, half of whom have a breast cancer family history (BCFH)., Results: Girls whose mothers had a pre-pregnancy BMI of ≥25 and gained ≥30 lbs were 57% more likely to experience earlier thelarche than girls whose mothers had a pre-pregnancy BMI of <25 and gained <30 lbs [hazard ratio (HR) = 1.57, 95% CI: 1.16, 2.12]. This association was not mediated by childhood BMI and was similar in girls with and without a BCFH (BCFH: HR = 1.41, 95% CI: 0.87, 2.27; No BCFH: HR = 1.62, 95% CI: 1.10, 2.40). Daughters of women who reported no recreational physical activity during pregnancy were more likely to experience earlier thelarche compared with daughters of physically active women. Birthweight and birth length were not associated with thelarche., Conclusion: Earlier thelarche, a breast cancer risk factor, was associated with three potentially modifiable maternal risk factors-pre-pregnancy BMI, gestational weight gain and physical inactivity-in a cohort of girls enriched for BCFH., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Incidence of early-onset colorectal cancer (EOCRC; e.g., diagnosed before age 50) in the United States has increased substantially since the 1990s but the underlying reasons remain unclear., Methods: We examined the ecologic associations between dietary factors and EOCRC incidence in adults aged 25-49 during 1977-2016 in the United States, using negative binomial regression models, accounting for age, period, and race. The models also incorporated an age-mean centering (AMC) approach to address potential confounding by age. We stratified the analysis by sex and computed incidence rate ratio (IRR) for each study factor. Study factor data (for 18 variables) came from repeated national surveys; EOCRC incidence data came from the Surveillance Epidemiology, and End Results Program., Results: Results suggest that confounding by age on the association with EOCRC likely existed for certain study factors (e.g., calcium intake), and that AMC can alleviate the confounding. EOCRC incidence was positively associated with smoking [IRR (95% confidence interval (CI): 1.17 (1.10-1.24) for men; 1.15 (1.09-1.21) for women] and alcohol consumption [IRR (95% CI), 1.08 (1.04-1.12) for men; 1.08 (1.04-1.11) for women]. No strong associations were found for most other study factors (e.g., fiber and calcium)., Conclusions: Alcohol consumption was positively associated with EOCRC and has increased among young adults since the 1980s, which may have contributed to the EOCRC incidence increases since the 1990s. The AMC approach may help alleviate age confounding in similar ecologic analyses., Impact: Increases in alcohol consumption may have contributed to the recent increases in colorectal cancer incidence among young adults. See related commentary by Ni et al., p. 164., (©2022 American Association for Cancer Research.)

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1 , BRCA2 and other high-risk genes with known penetrance.

Background: Dense breast notification (DBN) legislation aims to increase a woman's awareness of her personal breast density and the implications of having dense breasts for breast cancer detection and risk. This information may adversely affect women's breast cancer worry, perceptions of risk, and uncertainty about screening, which may persist over time or vary by sociodemographic factors. We examined short- and long-term psychological responses to DBN and awareness of breast density (BD)., Methods: In a predominantly Hispanic New York City screening cohort (63% Spanish-speaking), ages 40-60 years, we assessed breast cancer worry, perceived breast cancer risk, and uncertainties about breast cancer risk and screening choices, in short (1-3 months)- and long-term (9-18 months) surveys following the enrollment screening mammogram (between 2016 and 2018). We compared psychological responses by women's dense breast status (as a proxy for DBN receipt) and BD awareness and examined multiplicative interaction by education, health literacy, nativity, and preferred interview language., Results: In multivariable models using short-term surveys, BD awareness was associated with increased perceived risk (odds ratio (OR) 2.27, 95% confidence interval (CI) 0.99, 5.20 for high, OR 2.19, 95% CI 1.34, 3.58 for moderate, vs. low risk) in the overall sample, and with increased uncertainty about risk (OR 1.97 per 1-unit increase, 95% CI 1.15, 3.39) and uncertainty about screening choices (OR 1.73 per 1-unit increase, 95% CI 1.01, 2.9) in Spanish-speaking women. DBN was associated with decreased perceived risk among women with at least some college education (OR 0.32, 95% CI 0.11, 0.89, for high, OR 0.50, 95% CI 0.29, 0.89, for moderate vs. low risk), while those with a high school education or less experienced an increase (OR 3.01, 95% CI 1.05, 8.67 high vs. low risk). There were no associations observed between DBN or BD awareness and short-term breast cancer worry, nor with any psychological outcomes at long-term surveys., Conclusions: Associations of BD awareness and notification with breast cancer-related psychological outcomes were limited to short-term increases in perceived breast cancer risk dependent on educational attainment, and increases in uncertainty around breast cancer risk and screening choices among Spanish-speaking women., (© 2022. The Author(s).)

Indications for genetic testing for inherited cancer syndromes are expanding both in the academic and the community setting. However, only a fraction of individuals who are candidates for testing pursue this option. Therefore, it is important to understand those factors that impact the uptake of genetic testing in individuals affected and unaffected with cancer. A successful translation of genomic risk stratification into clinical care will require that providers of this information are aware of the attitudes, perceived risks and benefits, and concerns of individuals who will be considering testing. The purpose of this study was to assess beliefs, attitudes and preferences for genetic risk information, by personal characteristics of women affected and unaffected by breast cancer enrolled in the Breast Cancer Family Registry Cohort. Data for this analysis came from eight survey questions, which asked participants (N = 9,048, 100% female) about their opinions regarding genetic information. Women reported that conveying the accuracy of the test was important and were interested in information related to personal level of risk, finding out about diseases that could be treated, and information that could be helpful to their families. Young women were most interested in how their own health needs might be impacted by genetic test results, while older women were more interested in how genetic information would benefit other members of the family. Interest in how the genetic test was performed was highest among Asian and Hispanic women. Women affected with breast cancer were more likely to report feeling sad about possibly passing down a breast cancer gene, while unaffected women were more uncertain about their future risk of cancer. The variety of informational needs identified has implications for how genetic counselors can tailor communication to individuals considering genetic testing., (© 2022 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Objective: To evaluate the risks, benefits, and utility of testing for adult-onset hereditary breast and ovarian cancer (HBOC) in adolescents and young adults., Study Design: We evaluated interest in genetic testing of adolescents for adult-onset HBOC genes through semistructured interviews with mothers and adolescents who had previously participated in breast cancer research or had pursued (mothers) clinical testing for HBOC., Results: The majority of mothers (73%) and daughters (75%) were interested in the daughter having genetic testing and were motivated by the future medical utility and current social utility of relieving anxiety and allowing them to prepare. Mothers and daughters both reported that approximately 3 years in the future was the best time to test the daughter regardless of the current age of the daughter. Overall, both mothers and daughters expressed the importance of the involvement of the mother to provide educational and emotional support but ultimately it was the daughter's decision to test. Balancing the independence and maturity of the daughter while reinforcing communication and support within the dyad was a prominent theme throughout the interviews., Conclusions: There is interest among some high-risk adolescents and young adults to engage in genetic counseling and undergo testing. Providing pretest and posttest genetic counseling, assessing preferences for parent involvement, and offering psychosocial support may be important if genetic testing for HBOC is offered to adolescents and young adults before age 25 years., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Risk-based genetic tests are often used to determine cancer risk, when to initiate screening, and frequency of screening, but rely on interest in genetic testing. We examined overall interest in genetic testing for cancer risk assessment and willingness to change behavior, and whether these are affected by demographic or socioeconomic factors.We conducted a community needs health survey in 2019 among primary care and cancer patients, family members and community members in New York City. We used univariable analysis and relative risk regression to examine interest in genetic cancer risk testing and willingness to modify lifestyle behaviors in response to an informative genetic test.Of the 1225 participants, 74.0% (n = 906) expressed interest in having a genetic test to assess cancer risk. Interest in genetic testing was high across all demographic and socioeconomic groups; reported interest in genetic testing by group ranged from 65.0 (participants aged 65 years and older) to 83.6% (participants below federal poverty level). Among the 906 participants that reported interest in genetic testing, 79.6% were willing to change eating habits, 66.5% to change exercise habits, and 49.5% to lose weight in response to an informative genetic test result.Our study reveals that interest in genetic testing for cancer risk is high among patients and community members and is high across demographic and socioeconomic groups, as is the reported willingness to change behavior. Based on these results, we recommend that population-based genetic testing may result in greater reduction cancer risk, particularly among minoritized groups., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Given the long induction time of many cancers and the fact that modifiable risk factors (e.g., cigarette smoking) including preventive factors (e.g., human papillomavirus [HPV] vaccination, healthy dietary and physical activity patterns) are influenced in adolescence, educating adolescents about cancer causation and risk reduction may have a large impact on reducing the cancer burden. We conducted a systematic review of literature evaluating the impact of cancer education interventions on adolescent knowledge of cancer risk reduction. We searched for articles published from 2000 to 2019 and identified 33 studies meeting our criteria. Given the methodological heterogeneity across studies, we briefly assessed effectiveness but focused on examining the design of the intervention and study. The majority of studies took place outside of the United States (67%). Most studies solely addressed skin or cervical cancer (67%) with only 18% ( n = 6) discussing multiple cancers. The majority of interventions were a single-session (55%), did not involve a control or comparison group (67%), and were evaluated using a pre-test and a single post-test (61%); some studies administered multiple post-tests. Few studies (12%) investigated adolescents' knowledge of lifestyle and environmental risk factors at both the individual and community level. Most studies (94%) reported improvement in knowledge following an intervention. Our review revealed wide methodological variation and a deficit in research evaluating interventions that address multiple cancer types and risk factors. Future research should robustly test whether comprehensive cancer education for adolescents can reduce the cancer burden, particularly in communities with major cancer health disparities.

Background: Polycyclic aromatic hydrocarbons (PAHs) are endocrine-disrupting chemicals. Few studies have evaluated the association between pubertal development in girls and PAH exposures quantified by urinary biomarkers., Methods: We examined associations of urinary PAH metabolites with pubertal development in 358 girls 6-16 years of age from the San Francisco Bay Area enrolled in a prospective cohort from 2011 to 2013 and followed until 2020. Using baseline data, we assessed associations of urinary PAH metabolites with pubertal development stage. In prospective analyses limited to girls who at baseline had not yet started breast (N = 176) or pubic hair (N = 179) development or menstruation (N = 267), we used multivariable Cox proportional hazards regression to assess associations of urinary PAH metabolites with the onset of breast and pubic hair development, menstruation, and pubertal tempo (interval between the onset of breast development and menstruation)., Results: We detected PAH metabolites in >98% of girls. In cross-sectional analyses using baseline data, PAH metabolites were not associated with the pubertal development stage. In prospective analyses, higher concentrations (≥ median) of some PAH metabolites were associated with two-fold higher odds of earlier breast development (2-hydroxy naphthalene, 1-hydroxy phenanthrene, summed hydroxy phenanthrenes) or pubic hair development (1-hydroxy naphthalene) among girls overweight at baseline (body mass index-for-age percentile ≥85) compared with nonoverweight girls with lower metabolites concentrations. PAH metabolites were not associated with age at menarche or pubertal tempo., Conclusions: PAH exposures were widespread in our sample. Our results support the hypothesis that, in overweight girls, PAHs impact the timing of pubertal development, an important risk factor for breast cancer., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Heavier body mass index (BMI) is the most established predictor of earlier age at puberty. However, it is unknown whether the timing of the childhood switch to heavier BMI (age at BMI rebound) also matters for puberty., Methods: In the LEGACY Girls Study (n = 1040), a longitudinal cohort enriched with girls with a family history of breast cancer, we collected paediatric growth chart data from 852 girls and assessed pubertal development every 6 months. Using constrained splines, we interpolated individual growth curves and then predicted BMI at ages 2, 4, 6, 8 and 9 years for 591 girls. We defined age at BMI rebound as the age at the lowest BMI between ages 2 and 8 years and assessed its association with onset of thelarche, pubarche and menarche using Weibull survival models., Results: The median age at BMI rebound was 5.3 years (interquartile range: 3.6-6.7 years). A 1-year increase in age at BMI rebound was associated with delayed thelarche (HR = 0.90; 95% CI = 0.83-0.97) and menarche (HR = 0.86; 95% CI = 0.79-0.94). The magnitude of these associations remained after adjusting for weight between birth and 2 years, was stronger after adjusting for BMI at age 9, and was stronger in a subset of girls with clinically assessed breast development., Conclusions: Earlier BMI rebound is associated with earlier pubertal timing. Our observation that BMI rebound may be a driver of pubertal timing in girls with and without a family history of breast cancer provides insight into how growth and pubertal timing are associated with breast cancer risk., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Coronavirus disease of 2019 (COVD-19) continues to disrupt cancer care delivery efforts and exacerbate existing health inequities. Here we describe the impact of COVID-19 on community outreach organizations partnering with a National Cancer Institute-designated Community Outreach and Engagement (COE) office in New York City (NYC) and lessons learned from these experiences. Between July and September of 2020, we conducted 16 semi-structured interviews with community key-informants to validate and inform efforts to support community organizations in response to COVID-19. Key-informants represented organizations performing a broad range of health and cancer care activities serving historically underserved, low-income, marginalized communities of color in NYC. All interviews were recorded, transcribed, and analyzed using rapid qualitative approaches. We summarize our response to challenges raised by partnering organizations. Themes included the impact of COVID-19 on communities served, challenges faced by organizations, and solutions to address COVID-19 related challenges. The COE and community organizations had to shift priorities and adapt engagement efforts to address the more urgent needs of the community (e.g., emotional distress, food insecurity). COVID-19 disrupted traditional community engagement activities for cancer outreach-calling for creativity and innovation in the community engagement process and shift in priorities. The COE responded by maintaining ongoing dialogue with community partners, by being flexible in scope/priorities beyond cancer prevention and control, and by providing education, outreach, fundraising and other resources, and developing new partnerships to meet needs of community organizations and the populations they serve., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics., Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (n snps =5) or sedentary time (n snps =6), or accelerometer-measured (n snps =1) or self-reported (n snps =5) vigorous physical activity., Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger)., Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women., Competing Interests: Competing interests: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received honoraria from Roche, Novartis and Pfizer. AWK declares research funding to her institution from Myriad Genetics for an unrelated project (funding dates 2017-2019). SL declares grants and honoraria paid to her institution from Amgen, Novartis, Pfizer, Roche, and, outside the submitted work, grants and/or honoraria paid to her institution from AbbVie, Celgene, Seattle Genetics, PrIME/Medscape, Daiichi-Sankyo, Lilly, Samsung, BMS, Puma, Immunomedics, AstraZeneca, Pierre Fabre, Merck, GlaxoSmithKlein, EirGenix, and Bayer, and personal fees from Chugai; SL also has a patent EP14153692.0 pending. UM declares stock ownership in Abcodia Ltd. RAM has been a consultant for Pharmavite. No other authors have conflicts to declare., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The National Cancer Institute (NCI) has established an online repository of evidence-based cancer control programs (EBCCP) and increasingly calls for the usage of these EBCCPs to reduce the cancer burden. To inventory existing EBCCPs and identify remaining gaps, we summarized NCI's EBCCPs relevant to reducing breast cancer risk with an eye towards interventions that address multiple levels of influence in populations facing breast cancer disparities. For each program, the NCI EBCCP repository provides the following expert panel determined summary metrics: (a) program ratings (1-5 scale, 5 best) of research integrity, intervention impact, and dissemination capability, and (b) RE-AIM framework assessment (0-100%) of program reach, effectiveness, adoption, and implementation. We quantified the number of EBCCPs that met the quality criteria of receiving a score of ≥3 for research integrity, intervention impact, and dissemination capability, and receiving a score of ≥50% for available RE-AIM reach, effectiveness, adoption, and implementation. For breast cancer risk reduction, we assessed the presence and quality of EBCCPs related to physical activity (PA), obesity, alcohol, tobacco control in early life, breastfeeding, and environmental chemical exposures. Our review revealed several major gaps in EBCCPs for reducing the breast cancer burden: (1) there are no EBCCPs for key breast cancer risk factors including alcohol, breastfeeding, and environmental chemical exposures; (2) among the EBCPPs that exist for PA, obesity, and tobacco control in early life, only a small fraction (24%, 17% and 31%, respectively) met all the quality criteria (≥3 EBCCP scores and ≥50% RE-AIM scores) and; (3) of those that met the quality criteria, only two PA interventions, one obesity, and no tobacco control interventions addressed multiple levels of influence and were developed in populations facing breast cancer disparities. Thus, developing, evaluating, and disseminating interventions to address important risk factors and reduce breast cancer disparities are needed.

This study compared different approaches to measuring breast density and breast tissue composition (BTC) in adolescent girls (n = 42, aged 14-16 years) and their mothers (n = 39, aged 36-61 years) from a cohort in Santiago, Chile. Optical spectroscopy (OS) was used to measure collagen, water, and lipid concentrations, which were combined into a percent breast density index (%BDI). A clinical dual-energy X-ray absorptiometry (DXA) system calibrated to measure breast density provided percent fibroglandular volume (%FGV) from manually delineated images. After digitizing mammogram films, the percent mammographic breast density (%MBD) was measured using computer-assisted software. Partial correlation coefficients (r partial ) were used to evaluate associations between breast density measures and BTC from these three different measurement approaches, adjusting for age and body mass index. %BDI from OS was associated with %FGV from DXA in adolescent girls (r partial  = 0.46, p-value = 0.003), but not in mothers (r partial  = 0.17, p-value = 0.32). In mothers, %FGV from DXA was associated with %MBD from mammograms (r partial  = 0.60, p-value < 0.001). These findings suggest that data from OS, DXA, and mammograms provide related but distinct information about breast density and BTC. Future studies should explore how the information provided by these different devices can be used for breast cancer risk prediction in cohorts of adolescent girls and women., (© 2022. The Author(s).)

Purpose: The American Cancer Society (ACS) published an updated Guideline for Cancer Prevention (ACS Guideline) in 2020. Research suggests that adherence to the 2012 ACS Guideline might lower breast cancer risk, but there is limited evidence that this applies to women at increased familial and genetic risk of breast cancer., Methods: Using the Breast Cancer Family Registry (BCFR), a cohort enriched for increased familial and genetic risk of breast cancer, we examined adherence to three 2020 ACS Guideline recommendations (weight management (body mass index), physical activity, and alcohol consumption) with breast cancer risk in 9615 women. We used Cox proportional hazard regression modeling to calculate hazard ratios (HRs) and 95% confidence intervals (CI) overall and stratified by BRCA1 and BRCA2 pathogenic variant status, family history of breast cancer, menopausal status, and estrogen receptor-positive (ER +) breast cancer., Results: We observed 618 incident invasive or in situ breast cancers over a median 12.9 years. Compared with being adherent to none (n = 55 cancers), being adherent to any ACS recommendation (n = 563 cancers) was associated with a 27% lower breast cancer risk (HR = 0.73, 95% CI: 0.55-0.97). This was evident for women with a first-degree family history of breast cancer (HR = 0.68, 95% CI: 0.50-0.93), women without BRCA1 or BRCA2 pathogenic variants (HR = 0.71, 95% CI: 0.53-0.95), postmenopausal women (HR = 0.63, 95% CI: 0.44-0.89), and for risk of ER+ breast cancer (HR = 0.63, 95% CI: 0.40-0.98)., Discussion: Adherence to the 2020 ACS Guideline recommendations for BMI, physical activity, and alcohol consumption could reduce breast cancer risk for postmenopausal women and women at increased familial risk., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Growing evidence links adolescent exposures to cancer risk later in life, particularly for common cancers like breast. The adolescent time period is also important for cancer risk reduction as many individual lifestyle behaviors are initiated including smoking and alcohol use. We developed a cancer risk-reduction educational tool tailored for adolescents that focused on five modifiable cancer risk factors. To contextualize risk factors in adolescents' social and physical environments, the intervention also focused on structural barriers to individual- and community-level change, with an emphasis on environmental justice or the fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income with respect to the development, implementation, and enforcement of environmental laws, regulations, and policies. The educational tool consisted of a 50-min module that included an introduction to cancer biology including genetic susceptibility and environmental interactions, cancer burden in the local community, and risk reduction strategies. The module also included an interactive activity in which adolescent students identify cancer risk factors and brainstorm strategies for risk reduction at both the individual and community level. We administered the module to 12 classes of over 280 high school and college students in New York City. Cancer risk reduction strategies identified by the students included family- or peer-level strategies such as team physical activity and community-level action including improving parks and taxing sugary foods. We developed a novel and interactive cancer risk-reduction education tool focused on multiple cancers that can be adopted by other communities and educational institutions., (© 2021. American Association for Cancer Education.)

Background: Polycyclic aromatic hydrocarbons (PAH), which are found in air pollution, have carcinogenic and endocrine disrupting properties that might increase breast cancer risk. PAH exposure might be particularly detrimental during pregnancy, as this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes. In this study, we tested the hypothesis that ambient PAH exposure during pregnancy is associated with breast tissue composition, measured one to two decades later, in adolescent daughters and their mothers., Methods: We conducted a prospective analysis using data from a New York City cohort of non-Hispanic Black and Hispanic mother-daughter dyads (recruited 1998-2006). During the third trimester of pregnancy, women wore backpacks containing a continuously operating air sampling pump for two consecutive days that measured ambient exposure to eight carcinogenic higher molecular weight nonvolatile PAH compounds (Σ8 PAH) and pyrene. When daughters (n = 186) and mothers (n = 175) reached ages 11-20 and 29-55 years, respectively, optical spectroscopy (OS) was used to evaluate measures of breast tissue composition (BTC) that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized risk factor for breast cancer. Multivariable linear regression was used to evaluate associations between ambient PAH exposure and BTC, overall and by exposure to household tobacco smoke during pregnancy (yes/no). Models were adjusted for race/ethnicity, age, and percent body fat at OS., Results: No overall associations were found between ambient PAH exposure (Σ8 PAH or pyrene) and BTC, but statistically significant additive interactions between Σ8 PAH and household tobacco smoke exposure were identified for water content and optical index in both daughters and mothers (interaction p values < 0.05). Σ8 PAH exposure was associated with higher water content (β daughters  = 0.42, 95% CI = 0.15-0.68; β mothers  = 0.32, 95% CI = 0.05-0.61) and higher optical index (β daughters  = 0.38, 95% CI = 0.12-0.64; β mothers  = 0.38, 95% CI = 0.12-0.65) in those exposed to household tobacco smoke during pregnancy; no associations were found in non-smoking households (interaction p values < 0.05)., Conclusions: Exposure to ambient Σ8 PAH and tobacco smoke during pregnancy might interact synergistically to impact BTC in mothers and daughters. If replicated in other cohorts, these findings might have important implications for breast cancer risk across generations., (© 2022. The Author(s).)

Importance: To promote the identification of women carrying BRCA1/2 variants, the US Preventive Services Task Force recommends that primary care clinicians screen asymptomatic women for an increased risk of carrying a BRCA1/2 variant risk., Objective: To examine the effects of patient and clinician decision support about BRCA1/2 genetic testing compared with standard education alone., Design, Setting, and Participants: This clustered randomized clinical trial was conducted at an academic medical center including 67 clinicians (unit of randomization) and 187 patients. Patient eligibility criteria included women aged 21 to 75 years with no history of breast or ovarian cancer, no prior genetic counseling or testing for hereditary breast and ovarian cancer syndrome (HBOC), and meeting family history criteria for BRCA1/2 genetic testing., Interventions: RealRisks decision aid for patients and the Breast Cancer Risk Navigation Tool decision support for clinicians. Patients scheduled a visit with their clinician within 6 months of enrollment., Main Outcomes and Measures: The primary end point was genetic counseling uptake at 6 months. Secondary outcomes were genetic testing uptake at 6 and 24 months, decision-making measures (perceived breast cancer risk, breast cancer worry, genetic testing knowledge, decision conflict) based upon patient surveys administered at baseline, 1 month, postclinic visit, and 6 months., Results: From December 2018 to February 2020, 187 evaluable patients (101 in the intervention group, 86 in the control group) were enrolled (mean [SD] age: 40.7 [13.2] years; 88 Hispanic patients [46.6%]; 15 non-Hispanic Black patients [8.1%]; 72 non-Hispanic White patients [38.9%]; 35 patients [18.9%] with high school education or less) and 164 (87.8%) completed the trial. There was no significant difference in genetic counseling uptake at 6 months between the intervention group (20 patients [19.8%]) and control group (10 patients [11.6%]; difference, 8.2 percentage points; OR, 1.88 [95% CI, 0.82-4.30]; P = .14). Genetic testing uptake within 6 months was also statistically nonsignificant (13 patients [12.9%] in the intervention group vs 7 patients [8.1%] in the control group; P = .31). At 24 months, genetic testing uptake was 31 patients (30.7%) in intervention vs 18 patients (20.9%) in control (P = .14). Comparing decision-making measures between groups at baseline to 6 months, there were significant decreases in perceived breast cancer risk and in breast cancer worry (standard mean differences = -0.48 and -0.40, respectively)., Conclusions and Relevance: This randomized clinical trial did not find a significant increase in genetic counseling uptake among patients who received patient and clinician decision support vs those who received standard education, although more than one-third of the ethnically diverse women enrolled in the intervention underwent genetic counseling. These findings suggest that the main advantage for these high-risk women is the ability to opt for screening and preventive services to decrease their cancer risk., Trial Registration: ClinicalTrials.gov Identifier: NCT03470402.

Purpose: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management., Methods: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment., Results: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers., Conclusion: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs., Competing Interests: Timothy R. RebbeckHonoraria: AstraZeneca (I)Consulting or Advisory Role: AstraZeneca (I) Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise. Norbert ArnoldHonoraria: AstraZeneca Åke BorgHonoraria: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, AstraZeneca Sandrine CaputoResearch Funding: AstraZeneca/France (Inst) Wendy K. ChungConsulting or Advisory Role: RegeneronResearch Funding: Biogen Chrystelle ColasConsulting or Advisory Role: AstraZeneca/Merck, Pfizer Miguel de la HoyaConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca D. Gareth EvansHonoraria: AstraZeneca Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche George FountzilasStock and Other Ownership Interests: GENPREX Inc (I), ARIAD (I), Deciphera Pharmaceuticals Inc (I), Daiichi Sankyo, RFL Holdings, FORMYCONHonoraria: AstraZenecaConsulting or Advisory Role: Pfizer, Roche, NovartisSpeakers' Bureau: Roche (I), LEO Pharma (I), Pfizer (I)Travel, Accommodations, Expenses: Merck (I), Pfizer (I), K.A.M Oncology/Hematology (I) Megan FronePatents, Royalties, Other Intellectual Property: Receive royalties for being a codeveloper of CancerGene Connect Eric HahnenConsulting or Advisory Role: AstraZeneca Helen HansonHonoraria: Pfizer Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy Bioanalytics, GRAILResearch Funding: GOG Foundation (Inst), NCI-NRG Oncology (Inst), Genentech/Roche (Inst)Patents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Irene KonstantopoulouSpeakers' Bureau: AstraZenecaResearch Funding: AstraZeneca Ava KwongHonoraria: Stryker, AstraZeneca Taiwan Limited, Roche Singapore, Pfizer, AstraZeneca Hong Kong Ltd Joanne Ngeow Yuen YieResearch Funding: AstraZeneca Rita K. SchmutzlerHonoraria: AstraZeneca, Clovis, MSD/AstraZenecaConsulting or Advisory Role: AstraZeneca, MSD/AstraZenecaResearch Funding: Amgen Leigha SenterConsulting or Advisory Role: AstraZeneca/MerckSpeakers' Bureau: AstraZeneca/Merck Christian F. SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Dominique Stoppa-LyonnetHonoraria: AstraZeneca/Merck (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, Roche Sebastian A. WagnerConsulting or Advisory Role: Bayer Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. May receive royalties if commercialization is realized.No other potential conflicts of interest were reported.

Background: To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer., Methods: For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy., Results: COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use., Conclusion: Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Polycyclic aromatic hydrocarbon (PAH) exposures from tobacco smoke, automobile exhaust, grilled or smoked meat and other sources are widespread and are a public health concern, as many are classified as probable carcinogens and suspected endocrine-disrupting chemicals. PAH exposures can be quantified using urinary biomarkers., Methods: Seven urinary metabolites of naphthalene, fluorene, phenanthrene, and pyrene were measured in two samples collected from girls aged 6-16 years from the San Francisco Bay Area. We used Spearman correlation coefficients (SCC) to assess correlations among metabolite concentrations (corrected for specific gravity) separately in first (n = 359) and last (N = 349) samples, and to assess consistency of measurements in samples collected up to 72 months apart. Using multivariable linear regression, we assessed variation in mean metabolites across categories of participant characteristics and potential outdoor, indoor, and dietary sources of PAH exposures., Results: The detection rate of PAH metabolites was high (4 metabolites in ≥98% of first samples; 5 metabolites in ≥95% of last samples). Correlations were moderate to strong between fluorene, phenanthrene and pyrene metabolites (SCC 0.43-0.82), but weaker between naphthalene and the other metabolites (SCC 0.18-0.36). SCC between metabolites in first and last samples ranged from 0.15 to 0.49. When classifying metabolite concentrations into tertiles based on single samples (first or last samples) vs. the average of the two samples, agreement was moderate to substantial (weighted kappa statistics 0.52-0.65). For specific metabolites, concentrations varied by age, race/ethnicity, and body mass index percentile, as well as by outdoor sources (season of sample collection, street traffic), indoor sources (heating with gas, cigarette smoke), and dietary sources (frequent use of grill, consumption of smoked meat or fish) of PAH exposures., Conclusions: Urinary PAH exposure was widespread in girls aged 6-16 years and associated with several sources of exposure. Tertile classification of a single urine sample provides reliable PAH exposure ranking., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Prior to the recommended age for population-based breast cancer screening by mammography, which ranges from 40-50 years depending on guidelines, the main way to identify higher risk women for earlier breast cancer (BC) screening to improve outcomes and discuss targeted chemoprevention is through specific clinical guidelines which are largely based on family history of breast cancer and known mutations in breast cancer susceptibility genes. The annual percent change (APC) in early-onset BC continues to rise, with the higher early-onset cancer burden and mortality continuing to be seen in non-Hispanic black (NHB) women compared to non-Hispanic white (NHW) women. Coupled with the increasing incidence overall as well as the lower percent of BC family history reported in NHB women compared with that of NHW women means that continued reliance on guidelines to identify women for genetic screening and initiation of early BC screening based largely on family history could lead to even greater BC health inequities. The similarity in the prevalence of mutations in key BC susceptibility genes between NHB and NHW women contrasts sharply to the differences in age-specific incidence rates between NHB and NHW women, supporting that there must be environmental modifiers that are contributing to the increased incidence in NHB women. This reality further argues for identifying NHB women early in adulthood through genetic testing who may benefit from tailored BC risk-reduction programs and early BC screening., (© 2022. The Author(s).)

Purpose: The nonsteroidal anti-inflammatory drug aspirin is an agent of interest for breast cancer prevention. However, it is unclear if aspirin affects mammographic breast density (MBD), a marker of elevated breast cancer risk, particularly in the context of concurrent use of medications indicated for common cardiometabolic conditions, which may also be associated with MBD., Methods: We used data from the New York Mammographic Density Study for 770 women age 40-60 years old with no history of breast cancer. We evaluated the association between current regular aspirin use and MBD, using linear regression for continuous measures of absolute and percent dense areas and absolute non-dense area, adjusted for body mass index (BMI), sociodemographic and reproductive factors, and use of statins and metformin. We assessed effect modification by BMI and reproductive factors., Results: After adjustment for co-medication, current regular aspirin use was only positively associated with non-dense area (β = 18.1, 95% CI: 6.7, 29.5). Effect modification by BMI and parity showed current aspirin use to only be associated with larger non-dense area among women with a BMI ≥ 30 (β = 28.2, 95% CI: 10.8, 45.7), and with lower percent density among parous women (β = -3.3, 95% CI: -6.4, -0.3)., Conclusions: Independent of co-medication use, current regular aspirin users had greater non-dense area with stronger estimates for women with higher BMI. We found limited support for an association between current aspirin use and mammographically dense breast tissue among parous women., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs., (© 2021. The Author(s).)

Efficient and reproducible measurements of multiple polycyclic aromatic hydrocarbon (PAH) metabolites in urinary samples are required to evaluate the complex health effects of PAH exposure. Here, we demonstrate a highly practical, automated off-line solid-phase extraction (SPE) of deconjugated hydroxylated PAHs followed by LC-MS/MS to simultaneously measure eight mono-hydroxylated PAH compounds: 1-hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, 2&3-hydroxyphenanthrene, 4-hydroxyphenanthrene and 1-hydroxypyrene. Initially, we observed low recovery rates (e.g., 16% for 1-hydroxypyrene) when using previously published methods. We optimized the procedure by choosing polymeric absorbent-based cartridges, automating the sample loading step by diluting samples with 15% methanol/sodium acetate, and most importantly, replacing acetonitrile with methanol as the eluting solvent. Optimized sample preparation has improved the recovery rates to more than 69% for analytes of interest. This improvement led to higher method sensitivity and detection frequency, especially for 1-hydroxypyrene, in all of 100 urine samples collected in the New York City site of the Legacy Girls Study. The limits of detection ranged from 7.6 pg/mL to 20.3 pg/mL using 1 mL of urine, compared to the 2 mL required in CDC, method 09-OD. The average coefficients of variance of quality control samples (n = 60) ranged between 7 and 21%; variance of repeated measurements (n = 45) was less than 10%. This efficient and reliable method for measuring PAH metabolites will greatly benefit epidemiology studies and biomonitoring programs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

DNA repair phenotype can be measured in blood and may be a potential biomarker of cancer risk. We conducted a systematic review and meta-analysis of epidemiological studies of DNA repair phenotype and cancer through March 2021. We used random-effects models to calculate pooled odds ratios (ORs) of cancer risk for those with the lowest DNA repair capacity compared with those with the highest capacity. We included 55 case-control studies that evaluated 12 different cancers using 10 different DNA repair assays. The pooled OR of cancer risk (all cancer types combined) was 2.92 (95% Confidence Interval (CI) 2.49, 3.43) for the lowest DNA repair. Lower DNA repair was associated with all studied cancer types, and pooled ORs (95% CI) ranged from 2.02 (1.43, 2.85) for skin cancer to 7.60 (3.26, 17.72) for liver cancer. All assays, except the homologous recombination repair assay, showed statistically significant associations with cancer. The effect size ranged from 1.90 (1.00, 3.60) for the etoposide-induced double-strand break assay to 5.06 (3.67, 6.99) for the γ-H2AX assay. The consistency and strength of the associations support the use of these phenotypic biomarkers; however large-scale prospective studies will be important for understanding their use related to age and screening initiation., (© 2022. The Author(s).)

We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk., Prevention Relevance: Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Despite tremendous efforts, the incidence of surgical site infection (SSI) following the surgical treatment of pediatric spinal deformity remains a concern. Although previous studies have reported some risk factors for SSI, these studies have been limited by not being able to investigate multiple risk factors at the same time. The aim of the present study was to evaluate a wide range of preoperative and intraoperative factors in predicting SSI and to develop and validate a prediction model that quantifies the risk of SSI for individual pediatric spinal deformity patients., Methods: Pediatric patients with spinal deformity who underwent primary, revision, or definitive spinal fusion at 1 of 7 institutions were included. Candidate predictors were known preoperatively and were not modifiable in most cases; these included 31 patient, 12 surgical, and 4 hospital factors. The Centers for Disease Control and Prevention definition of SSI within 90 days of surgery was utilized. Following multiple imputation and multicollinearity testing, predictor selection was conducted with use of logistic regression to develop multiple models. The data set was randomly split into training and testing sets, and fivefold cross-validation was performed to compare discrimination, calibration, and overfitting of each model and to determine the final model. A risk probability calculator and a mobile device application were developed from the model in order to calculate the probability of SSI in individual patients., Results: A total of 3,092 spinal deformity surgeries were included, in which there were 132 cases of SSI (4.3%). The final model achieved adequate discrimination (area under the receiver operating characteristic curve: 0.76), as well as calibration and no overfitting. Predictors included in the model were nonambulatory status, neuromuscular etiology, pelvic instrumentation, procedure time ≥7 hours, American Society of Anesthesiologists grade >2, revision procedure, hospital spine surgical cases <100/year, abnormal hemoglobin level, and overweight or obese body mass index., Conclusions: The risk probability calculator encompassing patient, surgical, and hospital factors developed in the present study predicts the probability of 90-day SSI in pediatric spinal deformity surgery. This validated calculator can be utilized to improve informed consent and shared decision-making and may allow the deployment of additional resources and strategies selectively in high-risk patients., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G814)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: An increased familial risk of breast cancer may be due to both shared genetics and environment. Women with a breast cancer family history may have a higher prevalence of breast cancer-related gene variants and thus increased susceptibility to environmental exposures. We evaluated whether air pollutant and breast cancer associations varied by familial risk., Methods: Sister Study participants living in the contiguous United States at enrollment (2003-2009; N = 48,453), all of whom had at least one first-degree relative with breast cancer, were followed for breast cancer. Annual NO 2 and PM 2.5 concentrations were estimated at the enrollment addresses. We predicted 1-year familial breast cancer risk using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Using Cox regression, we estimated HRs and 95% confidence intervals (CI) for associations between each pollutant dichotomized at the median and breast cancer with interaction terms to examine modification by BOADICEA score., Results: NO 2 was associated with a higher breast cancer risk among those with BOADICEA score >90th percentile (HR, 1.28; 95% CI, 1.05-1.56) but not among those with BOADICEA score ≤90th percentile (HR, 0.98; 95% CI, 0.90-1.06; P interaction = 0.01). In contrast to NO 2 , associations between PM 2.5 and breast cancer did not vary between individuals with BOADICEA score >90th percentile and ≤90th percentile ( P interaction = 0.26)., Conclusions: Our results provide additional evidence that air pollution may be implicated in breast cancer, particularly among women with a higher familial risk., Impact: Women at higher underlying breast cancer risk may benefit more from interventions to reduce exposure to NO 2 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Use of e-cigarettes and other electronic nicotine delivery systems (ENDS) is on the rise. We administered a health needs survey via email to 804 adult primary care and oncology patients at a large urban academic medical center in 2019. We examined differences in e-cigarette use by smoking status, personal history of cancer, alcohol use, and second-hand tobacco smoke exposure. Of the 804 participants, 90 (11.2%) reported ever using e-cigarettes. E-cigarette use was more prevalent in young adults (risk ratio [RR] for 18-24 years: 4.58, 95% confidence interval [95% CI] 2.05, 10.26), current smoking (RR 4.64, 95% CI 1.94, 11.07), very often/often binge drinking (RR 3.04, 96% CI 1.38, 6.73), and ≥ 1 smokers in the home (RR 3.90, 95% CI 2.10, 7.23). Binge alcohol consumption and tobacco smoking are associated with increased risk cancer. Inquiries about e-cigarette use among adults 25-40 years present providers the opportunity to also counsel young adult about reducing cancer risk., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance., (© 2022. The Author(s).)

Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear., Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes., Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions., Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction., (© 2021. The Author(s).)