Physical activity during adolescence and early adulthood and breast cancer risk before age 40 years.

BACKGROUND: Breast cancer (BC) incidence is increasing in women under age 40 years, underscoring the need for research on BC risk factors for younger women. METHODS: We used data from an international family cohort (n=26,348) to examine whether recreational physical activity (RPA) during adolescence and early adulthood are associated with BC risk before age 40. The cohort includes 2,502 women diagnosed with BC before age 40, including 2,408 diagnosed before study enrollment (68% within 5 years of enrollment). Women reported their average hours-per-week of moderate and strenuous RPA during adolescence (12-17 years) and early adulthood (25-34 years), which were converted to total age-adjusted metabolic equivalents-per-week and categorized into quartiles. We conducted attained age analyses until age 40 (follow-up time began at age 18) using Cox proportional hazards regression models adjusted for study center, race and ethnicity, and education. RESULTS: Being in the highest versus lowest quartile of RPA during adolescence and early adulthood were respectively associated with 12% [HR (95% CI): 0.88 (0.78, 0.98)] and 16% [HR (95% CI): 0.84 (0.74, 0.95) lower BC risks before age 40. Being in the highest quartile of RPA during both adolescence and early adulthood (Pearson correlation=0.52) versus neither timepoint was associated with a 22% lower risk [HR (95% CI): 0.78 (0.68, 0.89)]. CONCLUSIONS: Findings suggest that RPA during adolescence and early adulthood may lower BC risk before age 40. IMPACT: Policies promoting physical activity during adolescence and early adulthood may be important for reducing the growing burden of breast cancer in younger women.

Uptake of Cancer Genetic Services for Chatbot vs Standard-of-Care Delivery Models: The BRIDGE Randomized Clinical Trial.

Importance: Increasing numbers of unaffected individuals could benefit from genetic evaluation for inherited cancer susceptibility. Automated conversational agents (ie, chatbots) are being developed for cancer genetics contexts; however, randomized comparisons with standard of care (SOC) are needed. Objective: To examine whether chatbot and SOC approaches are equivalent in completion of pretest cancer genetic services and genetic testing. Design, Setting, and Participants: This equivalence trial (Broadening the Reach, Impact, and Delivery of Genetic Services [BRIDGE] randomized clinical trial) was conducted between August 15, 2020, and August 31, 2023, at 2 US health care systems (University of Utah Health and NYU Langone Health). Participants were aged 25 to 60 years, had had a primary care visit in the previous 3 years, were eligible for cancer genetic evaluation, were English or Spanish speaking, had no prior cancer diagnosis other than nonmelanoma skin cancer, had no prior cancer genetic counseling or testing, and had an electronic patient portal account. Intervention: Participants were randomized 1:1 at the patient level to the study groups at each site. In the chatbot intervention group, patients were invited in a patient portal outreach message to complete a pretest genetics education chat. In the enhanced SOC control group, patients were invited to complete an SOC pretest appointment with a certified genetic counselor. Main Outcomes and Measures: Primary outcomes were completion of pretest cancer genetic services (ie, pretest genetics education chat or pretest genetic counseling appointment) and completion of genetic testing. Equivalence hypothesis testing was used to compare the study groups. Results: This study included 3073 patients (1554 in the chatbot group and 1519 in the enhanced SOC control group). Their mean (SD) age at outreach was 43.8 (9.9) years, and most (2233 of 3063 [72.9%]) were women. A total of 204 patients (7.3%) were Black, 317 (11.4%) were Latinx, and 2094 (75.0%) were White. The estimated percentage point difference for completion of pretest cancer genetic services between groups was 2.0 (95% CI, -1.1 to 5.0). The estimated percentage point difference for completion of genetic testing was -1.3 (95% CI, -3.7 to 1.1). Analyses suggested equivalence in the primary outcomes. Conclusions and Relevance: The findings of the BRIDGE equivalence trial support the use of chatbot approaches to offer cancer genetic services. Chatbot tools can be a key component of sustainable and scalable population health management strategies to enhance access to cancer genetic services. Trial Registration: ClinicalTrials.gov Identifier: NCT03985852.

Use of web-based decision support to improve informed choice for chemoprevention: a qualitative analysis of pre-implementation interviews (SWOG S1904).

BACKGROUND: Women with high-risk breast lesions, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have a 4- to tenfold increased risk of breast cancer compared to women with non-proliferative breast disease. Despite high-quality data supporting chemoprevention, uptake remains low. Interventions are needed to break down barriers. METHODS: The parent trial, MiCHOICE, is a cluster randomized controlled trial evaluating the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. For this pre-implementation analysis, 25 providers participated in semi-structured interviews prior to accessing decision support tools. Interviews sought to understand attitudes/beliefs and barriers/facilitators to chemoprevention. RESULTS: Interviews with 25 providers (18 physicians and 7 advanced practice providers) were included. Providers were predominantly female (84%), white (72%), and non-Hispanic (88%). Nearly all providers (96%) had prescribed chemoprevention for eligible patients. Three themes emerged in qualitative analysis. The first theme describes providers' confidence in chemoprevention and the utility of decision support tools. The second theme elucidates barriers to chemoprevention, including time constraints, risk communication and perceptions of patients' fear of side effects and anxiety. The third theme is the need for early implementation of decision support tools. CONCLUSIONS: This qualitative study suggests that providers were interested in the early inclusion of decision aids (DA) in their chemoprevention discussion workflow. The DAs may help overcome certain barriers which were elucidated in these interviews, including patient level concerns about side effects, clinic time constraints and difficulty communicating risk. A multi-faceted intervention with a DA as one active component may be needed. TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT04496739.

Improving Cancer Care for Women Seeking Services in the Veterans Health Administration Through the Breast and Gynecological Oncology System of Excellence.

Women are the fastest growing population among Veterans and have substantial risk factors that increase their likelihood for developing cancer. To ensure that the Department of Veterans Affairs Veterans Health Administration (VHA) offers the best possible cancer care to women Veterans, it established the Breast and Gynecologic Oncology System of Excellence (BGSoE) in 2021. The BGSoE offers telehealth oncology services and a comprehensive cancer navigation program. Veterans are identified through physician referral or through the BGSoE dashboard which integrates ICD-10 codes and text mining from VA electronic health records to identify eligible Veterans with breast or gynecological cancers. Descriptive statistics, including Veteran demographics and geographical location, were derived from BGSoE dashboard data. From January 1, 2021 to March 15, 2024, the BGSoE identified a total of 7,187 incident cases of breast or gynecological cancer among living Veterans. Most cancers were breast (78%) versus gynecological cancers (22%) and 10% of Veterans with breast cancer were identified as male. The average age at diagnosis was 59 for Veterans with breast cancer and 56 for those Veterans with gynecological cancers. Among Veterans in the BGSoE, 28% identified as Black and 6% identified as Hispanic. As the prevalence of women Veterans requiring cancer-related care continues to rise, it will be essential for VHA to evaluate the equitable reach, quality, and acceptability of women-focused cancer health services. The BGSoE focuses on providing high-quality and coordinated clinical cancer care. Veterans Health Administration also established the Center for Oncology Outcomes Review and Gender (COURAGE) to evaluate the BGSoE and continue to strengthen cancer care services in VHA. Initial evaluation objectives include establishing an evidence base regarding Veterans with breast and gynecological cancers, including their experiences with cancer care in the VHA. Eventually, COURAGE will provide ongoing monitoring and evaluation to continue to grow and improve cancer care in the VHA.

Pregnancy-Related Factors and Breast Cancer Risk for Women Across a Range of Familial Risk.

Importance: Few studies have investigated whether the associations between pregnancy-related factors and breast cancer (BC) risk differ by underlying BC susceptibility. Evidence regarding variation in BC risk is critical to understanding BC causes and for developing effective risk-based screening guidelines. Objective: To examine the association between pregnancy-related factors and BC risk, including modification by a of BC where scores are based on age and BC family history. Design, Setting, and Participants: This cohort study included participants from the prospective Family Study Cohort (ProF-SC), which includes the 6 sites of the Breast Cancer Family Registry (US, Canada, and Australia) and the Kathleen Cuningham Foundation Consortium (Australia). Analyses were performed in a cohort of women enrolled from 1992 to 2011 without any personal history of BC who were followed up through 2017 with a median (range) follow-up of 10 (1-23) years. Data were analyzed from March 1992 to March 2017. Exposures: Parity, number of full-term pregnancies (FTP), age at first FTP, years since last FTP, and breastfeeding. Main Outcomes and Measures: BC diagnoses were obtained through self-report or report by a first-degree relative and confirmed through pathology and data linkages. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% CIs for each exposure, examining modification by PARS of BC. Differences were assessed by estrogen receptor (ER) subtype. Results: The study included 17 274 women (mean [SD] age, 46.7 [15.1] years; 791 African American or Black participants [4.6%], 1399 Hispanic or Latinx participants [8.2%], and 13 790 White participants [80.7%]) with 943 prospectively ascertained BC cases. Compared with nulliparous women, BC risk was higher after a recent pregnancy for those women with higher PARS (last FTP 0-5 years HR for interaction, 1.53; 95% CI, 1.13-2.07; P for interaction < .001). Associations between other exposures were limited to ER-negative disease. ER-negative BC was positively associated with increasing PARS and increasing years since last FTP (P for interaction < .001) with higher risk for recent pregnancy vs nulliparous women (last FTP 0-5 years HR for interaction, 1.54; 95% CI, 1.03-2.31). ER-negative BC was positively associated with increasing PARS and being aged 20 years or older vs less than 20 years at first FTP (P for interaction = .002) and inversely associated with multiparity vs nulliparity (P for interaction = .01). Conclusions and Relevance: In this cohort study of women with no prior BC diagnoses, associations between pregnancy-related factors and BC risk were modified by PARS, with greater associations observed for ER-negative BC.

Summary and Roadmap of Breast Cancer Research in the Veterans Affairs.

Women are the largest growing population of Veterans within the U.S. Department of Veterans Affairs (VA) Health Care System. Among women Veterans, breast cancer is the most common malignancy (30% of all cancers), yet little is known about the unique needs of women Veterans with cancer and how to provide them with high quality care. The VA health care system has initiated multiple system-wide systemic efforts, including launching the Breast and Gynecologic Cancer System of Excellence (BGSOE) to address this knowledge gap. This report summarizes the outcomes of the inaugural 2023 VA Women's Cancer Research Conference, which assembled 37 multidisciplinary clinicians, scientists, the VA and civilian partners with a shared goal of advancing VA breast cancer research. Conference objectives were to build a collective vision for improving: (1) referral patterns for breast cancer treatment and patient-level outcomes and (2) molecular and genetic testing patterns across the breast cancer continuum among women Veterans. The meeting hosted 15 speakers at the Houston VA Medical Center. Future research priorities for women Veterans with cancer were identified from discussions and a post-conference survey. We then administered a 13-question post-conference survey to conference attendees. Respondents ranked the research priorities. The survey results show that the cross-cutting cancer research priorities designed to transform cancer care for women Veterans at the VA fit into 5 broad areas of study, including (1) care quality for treatment, (2) improving treatment, (3) care quality of molecular and genetic testing, (4) risk reduction through risk assessment and germline genetic testing, and (5) establishing strategic partnerships. Our data elucidate areas for further investigation to improve the delivery of cancer care.

The Landscape of Care for Women Veterans with Cancer: An Evidence Map.

BACKGROUND: Women are the fastest growing veteran group in the US and the number of women veterans (WVs) with cancer is rising; however, little is known about this population. Cancer care for WVs is complex and it is essential to understand their unique needs and care coordination challenges to provide evidence-based care. The purpose of this review is to map the quantity, distribution, and characteristics of literature describing cancer and its treatment among WVs. METHODS: We searched MEDLINE (via PubMed), Embase (Elsevier), and Web of Science Core Collection (Clarivate) from inception through January, 2024. Publications were eligible that reported gender-specific data on any aspect of cancer care among WVs. Data was abstracted by a single investigator with over-reading. RESULTS: Forty-six reports were included; 44 were observational and 19 had a women-only sample. There were no interventional reports and no qualitative reports had a patient sample. Breast cancer was the most commonly addressed (n = 19). There were six additional reports on sex-specific cancers. Many reports used large VA databases or previous trial data, creating the potential for patient overlap between reports. Among VA-specific areas of interest, only three reports evaluated the potential implications of racial differences and only two included a transgender population. No reports examined the effects of toxic exposures on cancer. Within the NCI Cancer Control Continuum, crosscutting areas were more commonly represented; over half (25) of the reports addressed epidemiology. There were few reports on focus areas and little overlap between focus and crosscutting areas. DISCUSSION: Existing literature provides an inadequate understanding of the population of WVs with cancer. There is scant information regarding the population of WVs with cancer, their care preferences or experiences, or how to best identify and address unmet healthcare needs. It is imperative to expand research to provide evidence-based care for this population.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction.

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS313 differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313 distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

BACKGROUND: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. AIM: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. METHODS: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. RESULTS: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. CONCLUSION: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium.

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/m2, 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/m2, 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.

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival.

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09-1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words).

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants.

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.

Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

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.

Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk.

Background: Recreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs). Methods: We estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided. Results: We observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events. Conclusion: Findings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs.

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Comparing models of delivery for cancer genetics services among patients receiving primary care who meet criteria for genetic evaluation in two healthcare systems: BRIDGE randomized controlled trial.

BACKGROUND: Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential. METHODS: We are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling. DISCUSSION: BRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients. TRIAL REGISTRATION: BRIDGE is registered as NCT03985852 . The trial was registered on June 6, 2019 at clinicaltrials.gov .