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Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

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: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. Methods: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43–12.33). Results: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16–0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12–0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71–1.10). Conclusions: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable. [ABSTRACT FROM AUTHOR]

Background: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.Methods: We used the Prospective Family Cohort Study of 14 657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided.Results: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.Conclusions: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years. [ABSTRACT FROM AUTHOR]

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models. [ABSTRACT FROM AUTHOR]

Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person‐years of follow‐up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14–1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11–1.65), 1.26 (95% CI: 1.00–1.60), and 1.40 (95% CI: 1.01–1.93), for categories of full‐lifetime BOADICEA score <20%, 20 to <35%, ≥35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04–2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78–2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13–1.53) (pinteraction = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk. What's new? Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. To find out, the authors used a family‐based prospective cohort of women enriched for breast cancer family history (BCFH) to examine the association of BBD with BC risk. They observed a 30% increased BC risk associated with BBD, independent of BCFH. Previous studies have been underpowered to examine this interaction with extent of family history; this study confirms the importance of both BBD and BCFH when performing clinical risk assessment. [ABSTRACT FROM AUTHOR]

There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR = 0.68, 95% CI = 0.32 to 1.47, HR = 0.94, 95% CI = 0.70 to 1.26, and HR = 1.10, 95% CI = 0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk. [ABSTRACT FROM AUTHOR]