Differences in metabolomic profiles between Black and White women in the U.S.: Analyses from two prospective cohorts.

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences ≥ |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Racial and Ethnic Variation in Receipt and Intensity of Active Surveillance for Older Patients With Localized Prostate Cancer.

INTRODUCTION: The use of active surveillance (AS) for prostate cancer is increasing, and racial disparities have been identified in its implementation. We investigated differences by race and ethnicity in the utilization and intensity of AS by race and ethnicity among older men with low- and favorable intermediate-risk prostate cancer, with particular focus on the integration of multiparametric MRI (mpMRI) into AS protocols. METHODS: Using the Surveillance, Epidemiology, and End Results and Medicare fee-for-service linked database, we identified a cohort of men diagnosed between 2010 and 2017 with low- or favorable intermediate-risk prostate cancer. The odds of receiving AS were compared by patient race and ethnicity using multivariable logistic regression models, while the rates of usage of PSA tests, biopsy, and mpMRI within 2 years of diagnosis among men on AS were assessed using multivariable Poisson regression models. RESULTS: Our cohort included 33,542 men. The proportion of men with low-risk disease who underwent AS increased from 29.5% in 2010 to 51.7% in 2017, while the proportion among men with favorable intermediate disease grew from 11.4% to 17.2%. Hispanic (odds ratio [OR] = 0.68, 95% CI 0.58-0.79) and non-Hispanic Black men (OR = 0.78, 95% CI 0.68-0.89) were less likely to receive AS than non-Hispanic White men for low-risk disease, while non-Hispanic Black men were more likely to receive AS for favorable intermediate disease (OR = 1.21, 95% CI 1.04-1.39). Non-Hispanic Black men receiving AS underwent prostate MRI at a lower rate compared to non-Hispanic White men, regardless of whether they had low-risk (incidence rate ratio = 0.77, 95% CI 0.61-0.97) or favorable intermediate-risk (incidence rate ratio = 0.61, 95% CI 0.44-0.83) disease, respectively. CONCLUSIONS: The overall adoption of AS for low-risk prostate cancer increased among Medicare fee-for-service beneficiaries. However, a significant disparity exists for non-Hispanic Black men, as they exhibit lower rates of AS utilization. Moreover, non-Hispanic Black men are less likely to have access to novel technologies, such as mpMRI, as part of their AS protocols.

Associations of early-life and adult anthropometric measures with the expression of stem cell markers CD44, CD24, and ALDH1A1 in women with benign breast biopsies.

BACKGROUND: According to the stem cell hypothesis, breast carcinogenesis may be related to the breast stem cell pool size. However, little is known about associations of breast cancer risk factors, such as anthropometric measures, with the expression of stem cell markers in non-cancerous breast tissue. METHODS: The analysis included 414 women with biopsy-confirmed benign breast disease (BBD) in the Nurses' Health Study (NHS) and NHSII. Birthweight, weight at age 18, current weight, and current height were reported via self-administered questionnaire. Immunohistochemical staining of stem cell markers (CD44, CD24, ALDH1A1) in histopathologically normal epithelial and stromal breast tissue was quantified with an automated computational image analysis system. Linear regression was used to examine the associations of early-life and adult anthropometric measures with log-transformed stem cell marker expression, adjusting for potential confounders. RESULTS: Birthweight (≥10.0 vs. <5.5 lbs: ß [95% CI]=4.29 [1.02, 7.56]; p-trend=0.001 in stroma) and adult height (≥67.0 vs. <63.0 inch: 0.86 [0.14, 1.58]; p-trend=0.02 in epithelium and stroma combined) were positively associated with CD44 expression. Childhood body fatness was inversely (p-trend=0.03) and adult height was positively associated with CD24 expression in combined stroma and epithelium (p-trend=0.03). CONCLUSION: Our data suggest that anthropometric measures, such as birthweight, adult height, and childhood body fatness, may be associated with the stem cell expression among women with BBD. IMPACT: Anthropometric measures, such as birthweight, height, and childhood body fatness, may have long-term impacts on stem cell population in the breast.

Assessing breast arterial calcification in mammograms and its implications for atherosclerotic cardiovascular disease risk.

PURPOSE: Breast arterial calcifications (BAC) are incidentally observed on mammograms, yet their implications remain unclear. We investigated lifestyle, reproductive, and cardiovascular determinants of BAC in women undergoing mammography screening. Further, we investigated the relationship between BAC, coronary arterial calcifications (CAC) and estimated 10-year atherosclerotic cardiovascular (ASCVD) risk. METHODS: In this cross-sectional study, we obtained reproductive history and CVD risk factors from 215 women aged 18 or older who underwent mammography and cardiac computed tomographic angiography (CCTA) within a 2-year period between 2007 and 2017 at hospital. BAC was categorized as binary (present/absent) and semi-quantitatively (mild, moderate, severe). CAC was determined using the Agatston method and recorded as binary (present/absent). Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated, accounting for age as a confounding factor. ASCVD risk over a 10-year period was calculated using the Pooled Cohort Risk Equations. RESULTS: Older age, systolic and diastolic blood pressures, higher parity, and younger age at first birth (≤28 years) were significantly associated with greater odds of BAC. Women with both BAC and CAC had the highest estimated 10-year risk of ASCVD (13.30 %). Those with only BAC (8.80 %), only CAC (5.80 %), and no BAC or CAC (4.40 %) had lower estimated 10-year risks of ASCVD. No association was detected between presence of BAC and CAC. CONCLUSIONS: These findings support the hypothesis that BAC on a screening mammogram may help to identify women at potentially increased risk of future cardiovascular disease without additional cost and radiation exposure.

Associations of reproductive breast cancer risk factors with expression of stem cell markers in benign breast tissue.

Background: We investigated the associations of reproductive factors known to influence breast cancer risk with the expression of breast stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples. Methods: We included 439 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII. The data on reproductive and other breast cancer risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was performed on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as % of cells that stained positive for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of reproductive factors with a log-transformed expression of each marker (in epithelium and stroma), adjusted for other breast cancer risk factors. Results: In multivariate analysis, the time between menarche and age at first birth was inversely associated with CD44 in epithelium (ß per 5 years = -0.38, 95% CI -0.69; -0.06). Age at first birth and the time between menarche and age at first birth were inversely associated with ALDH1A1 (stroma: ß per 5 years = -0.43, 95% CI -0.76; -0.10 and ß = -0.47, 95% CI -0.79; -0.15, respectively; epithelium: ß = -0.15, 95% CI -0.30; -0.01 and ß = -0.17, 95% CI -0.30; -0.03, respectively). Time since last pregnancy was inversely associated with stromal ALDH1A1 (ß per 5 years = -0.55, 95% CI -0.98; -0.11). No associations were found for CD24. The observed associations were similar in premenopausal women. In postmenopausal women, lifetime duration of breastfeeding was inversely associated with stromal ALDH1A1 expression (ß for ≥24 vs. 0 to <1 months = -2.24, 95% CI 3.96; -0.51, p-trend = 0.01). Conclusion: Early-life reproductive factors may influence CD44 and ALDH1A1 expression in benign breast tissue.

Second Primary Breast Cancer in Young Breast Cancer Survivors.

Importance: Among women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC. Objective: To estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC. Design, Setting, and Participants: Participants were enrolled in the Young Women's Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023. Main Outcomes and Measures: The 5- and 10- year cumulative incidence of SPBC. Results: In all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70). Conclusions: Findings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.

Recreational physical activity and breast cancer risk by menopausal status and tumor hormone receptor status: results from the Nurses' Health Studies.

PURPOSE: Physical activity is associated with lower breast cancer risk, especially in postmenopausal women. Associations in premenopausal women are less well established. METHODS: We evaluated recreational physical activity and breast cancer risk in the Nurses' Health Study (NHS) and NHSII (187,278 women; n = 12,785 breast cancers; follow-up: NHS = 1986-2016, NHSII = 1989-2017) by menopausal status and estrogen (ER) and progesterone (PR) receptor status. Physical activity was evaluated as updated cumulative average of metabolic equivalent of task (MET)-h/week. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Recreational physical activity was inversely associated with breast cancer risk in pre- and postmenopausal women. Higher activity levels were associated with lower risk of ER+/PR + breast cancer in both pre- and postmenopausal women (e.g., total recreational activity, ≥ 27 vs < 3 MET-h/week, premenopausal HR = 0.83, 95%CI = (0.70-0.99), postmenopausal HR = 0.86 (0.78-0.95); pheterogeneity = 0.97). Results were attenuated with adjustment for current body mass index (BMI) among postmenopausal, but not premenopausal, women (e.g., ≥ 27 vs < 3 MET-h/week, premenopausal HR = 0.83 (0.69-0.98); postmenopausal HR = 0.95 (0.85-1.05); pheterogeneity = 0.99). In analyses of moderate-vigorous activity and breast cancer risk, no heterogeneity by menopausal status was observed (phet ≥ 0.53; e.g., ≥ 27 vs < 3 MET-h/week, ER+/PR+, premenopausal HR = 0.88 (0.69-1.11); postmenopausal HR = 0.71 (0.58-0.88). No associations were observed for ER-/PR- disease. CONCLUSIONS: Recreational physical activity was associated with lower breast cancer risk in both pre- and postmenopausal women, supporting recreational physical activity as an accessible, modifiable exposure associated with reduced breast cancer risk regardless of menopausal status.

Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Reproductive factors related to childbearing and a novel automated mammographic measure, V.

BACKGROUND: We investigated the associations between several reproductive factors related to childbearing and the variation (V) measure (a novel, objective, single summary measure of breast image intensity) by menopausal status. METHODS: Our study included 3,814 cancer-free women within the Nurses' Health Study (NHS) and NHSII cohorts. The data on reproductive variables and covariates were obtained from biennial questionnaires closest to the mammogram date. V-measures were obtained from mammographic images using a previously developed algorithm capturing the standard deviation of pixel values. We used multivariate linear regression to examine the associations of parity, age at first birth, time between menarche and first birth, time since last pregnancy, and lifetime breastfeeding duration with V-measure, adjusting for breast cancer risk factors, including percent mammographic density (PMD). We further examined if these associations were statistically accounted for (mediated) by PMD. RESULTS: Among premenopausal women, none of the reproductive factors were associated with V. Among postmenopausal women, inverse associations of parity and positive associations of age at first birth with V were mediated by PMD (percent mediated: nulliparity: 66.7%, p<0.0001; parity: 50.5%, p<0.01; age at first birth 76.1%, p<0.001) and were no longer significant in PMD-adjusted models. Lifetime duration of breastfeeding was positively associated with V (>36 vs. 0-<1 months ß=0.29, 95% CI 0.07; 0.52, p-trend<0.01), independent of PMD. CONCLUSIONS: Parity, age at first birth, and breastfeeding were associated with postmenopausal V. IMPACT: This study highlights associations of reproductive factors with mammographic image intensity.

BMI and breast cancer risk around age at menopause.

BACKGROUND: A high body mass index (BMI, kg/m2) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology. METHODS: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy. RESULTS: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO. CONCLUSION: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55.

Reproductive risk factors for breast cancer and association with novel breast density measurements among Hispanic, Black, and White women.

PURPOSE: There are differences in the distributions of breast cancer incidence and risk factors by race and ethnicity. Given the strong association between breast density and breast cancer, it is of interest describe racial and ethnic variation in the determinants of breast density. METHODS: We characterized racial and ethnic variation in reproductive history and several measures of breast density for Hispanic (n = 286), non-Hispanic Black (n = 255), and non-Hispanic White (n = 1694) women imaged at a single hospital. We quantified associations between reproductive factors and percent volumetric density (PVD), dense volume (DV), non-dense volume (NDV), and a novel measure of pixel intensity variation (V) using multivariable-adjusted linear regression, and tested for statistical heterogeneity by race and ethnicity. RESULTS: Reproductive factors most strongly associated with breast density were age at menarche, parity, and oral contraceptive use. Variation by race and ethnicity was most evident for the associations between reproductive factors and NDV (minimum p-heterogeneity:0.008) and V (minimum p-heterogeneity:0.004) and least evident for PVD (minimum p-heterogeneity:0.042) and DV (minimum p-heterogeneity:0.041). CONCLUSION: Reproductive choices, particularly those related to childbearing and oral contraceptive use, may contribute to racial and ethnic variation in breast density.

Conception and pregnancy among women with a live birth after breast cancer treatment: A survey study of young breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women of reproductive age. This study sought to explore the postcancer conception and pregnancy experience of young BC survivors to inform counseling. METHODS: In the Young Women's Breast Cancer Study (NCT01468246), a multicenter, prospective cohort, participants diagnosed at age ≤40 years with stage 0-III BC who reported ≥1 postdiagnosis live birth were sent an investigator-developed survey. RESULTS: Of 119 eligible women, 94 (79%) completed the survey. Median age at diagnosis was 32 years (range, 17-40) and at first postdiagnosis delivery was 38 years (range, 29-47). Most had stage I or II (77%) and HR+ (78%) BC; 51% were nulligravida at diagnosis. After BC treatment, most (62%) conceived naturally, though 38% used assisted reproductive technology, 74% of whom first attempted natural conception for a median of 9 months (range, 2-48). Among women with a known inherited pathogenic variant (n = 20), two underwent preimplantation genetic testing. Of 59 women on endocrine therapy before pregnancy, 26% did not resume treatment. Hypertensive disorders of pregnancy (20%) was the most common obstetrical condition. Nine percent of newborns required neonatal intensive care unit admission and 9% had low birth weight. CONCLUSION: Among women with live births after BC treatment, most conceived naturally and having a history of BC did not appear to negatively impact pregnancy complications, though the high rate of hypertensive disorders of pregnancy warrants further investigation. The prolonged period of attempting natural conception for some survivors suggests the potential need for improved understanding and counseling surrounding family planning goals after BC.

Prostate-specific antigen testing rates in high-risk populations: results from the All of Us Research Program.

BACKGROUND: Early detection of prostate cancer using prostate-specific antigen (PSA) remains controversial and disparities in the receipt of prostate cancer screening persist in the US. We sought to examine disparities in PSA testing rates among groups with higher prostate cancer risk and differential access to healthcare. METHODS: We identified a cohort of 37,706 males within the All of Us Research Program without a history of prostate cancer between the ages of 40 and 85 at time of enrollment (2017-2021). Incidence rate ratios (IRR) for the number of PSA tests received during follow-up through December 2021 were estimated using age- and multivariable-adjusted negative binomial regression models. PSA testing frequencies in the cohort were compared with population-based estimates from the 2020 Behavioral Risk Factor Surveillance System (BRFSS). RESULTS: A total of 6,486 males (17.2%) received at least one PSA test over the course of follow-up. In multivariable-adjusted models, non-Hispanic Black males received PSA tests at a 17% lower rate (IRR = 0.83, 95% CI 0.76, 0.90) than non-Hispanic White males. Higher educational attainment, higher annual income, having self-/employer-purchased insurance, having a spouse or domestic partner, and having a family history of prostate cancer were all associated with higher rates of PSA testing. The proportion of males ages 55 to 69 who received a PSA test within two years was lower in All of Us (12.4%, 95% CI 11.8-13.0%) relative to population-based estimates from the BRFSS (35.2%, 95% CI 34.2-36.3%). CONCLUSION: Absolute PSA testing rates in All of Us were lower than population-based estimates, but associations with PSA testing in the cohort mirrored previously reported disparities in prostate cancer screening. These findings highlight the importance of addressing barriers to care in order to reduce disparities in cancer screening.

Impact of age, race, and family history on COVID-19-related changes in breast cancer screening among the Boston mammography cohort study.

PURPOSE: We studied women enrolled in the Boston Mammography Cohort Study to investigate whether subgroups defined by age, race, or family history of breast cancer experienced differences in the incidence of screening or diagnostic imaging rates during the COVID-19 lockdown and had slower rebound in the incidence of these rates during reopening. METHODS: We compared the incidence of monthly breast cancer screening and diagnostic imaging rates over during the pre-COVID-19 (January 2019-February 2020), lockdown (March-May 2020), and reopening periods (June-December 2020), and tested for differences in the monthly incidence within the same period by age (< 50 vs ≥ 50), race (White vs non-White), and first-degree family history of breast cancer (yes vs no). RESULTS: Overall, we observed a decline in breast cancer screening and diagnostic imaging rates over the three time periods (pre-COVID-19, lockdown, and reopening). The monthly incidence of breast cancer screening rates for women age ≥ 50 was 5% higher (p = 0.005) in the pre-COVID-19 period (January 2019-February 2020) but was 19% lower in the reopening phase (June-December 2020) than that of women aged < 50 (p < 0.001). White participants had 36% higher monthly incidence of breast cancer diagnostic imaging rates than non-White participants (p = 0.018). CONCLUSION: The rebound in screening was lower in women age ≥ 50 and lower in non-White women for diagnostic imaging. Careful attention must be paid as the COVID-19 recovery continues to ensure equitable resumption of care.

Association and Prediction Utilizing Craniocaudal and Mediolateral Oblique View Digital Mammography and Long-Term Breast Cancer Risk.

Mammographic percentage of volumetric density is an important risk factor for breast cancer. Epidemiology studies historically used film images often limited to craniocaudal (CC) views to estimate area-based breast density. More recent studies using digital mammography images typically use the averaged density between craniocaudal (CC) and mediolateral oblique (MLO) view mammography for 5- and 10-year risk prediction. The performance in using either and both mammogram views has not been well-investigated. We use 3,804 full-field digital mammograms from the Joanne Knight Breast Health Cohort (294 incident cases and 657 controls), to quantity the association between volumetric percentage of density extracted from either and both mammography views and to assess the 5 and 10-year breast cancer risk prediction performance. Our results show that the association between percent volumetric density from CC, MLO, and the average between the two, retain essentially the same association with breast cancer risk. The 5- and 10-year risk prediction also shows similar prediction accuracy. Thus, one view is sufficient to assess association and predict future risk of breast cancer over a 5 or 10-year interval. PREVENTION RELEVANCE: Expanding use of digital mammography and repeated screening provides opportunities for risk assessment. To use these images for risk estimates and guide risk management in real time requires efficient processing. Evaluating the contribution of different views to prediction performance can guide future applications for risk management in routine care.

Influence of analytic methods, data sources, and repeated measurements on the population attributable fraction of lifestyle risk factors.

Population attributable risk (PAR%) reflects the preventable fraction of disease. However, PAR% estimates of cancer have shown large variation across populations, methods, data sources, and timing of measurements. Three statistical methods to estimate PAR% were identified from a systematic literature review: the Levin's formula, the comparative incidence rate method, and the comparative risk assessment method. We compared the variations in PAR% of postmenopausal breast cancer in the Nurses' Health Study to evaluate the influence by method choice, source of prevalence data, use of single vs repeated exposure measurements, and potential joint effects of obesity, alcohol, physical activity, fruit and vegetable intake. Across models of the three methods, the estimated PAR% using repeated measurements were higher than that using baseline measurement; overall PAR% for the baseline, simple update, and cumulative average models were 13.8%, 21.1%, 18.6% by Levin's formula; 13.7%, 28.0%, 31.2% by comparative risk assessment; and 17.4%, 25.2%, 29.3% by comparative incidence rate method. The estimated PAR% of the combination of multiple risk factors was higher than the product of the individual PAR%: 18.9% when assuming independence and 31.2% when considering the risk factors jointly. The three methods provided similar PAR% based on the same data source, timing of measurements, and target populations. However, sizable increases in the PAR% were observed for repeated measures over a single measure and for calculations based on achieving all recommendations jointly rather than individually.

Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study.

BACKGROUND: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort. METHODS: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis. RESULTS: We show that in the absence of a well powered trans-ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort. CONCLUSIONS: Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.

Genomics of ERBB2-Positive Breast Cancer in Young Women Before and After Exposure to Chemotherapy Plus Trastuzumab.

PURPOSE: Erb-B2 receptor tyrosine kinase 2 (ERBB2)-positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS: From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS: Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION: ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

Extended adjuvant endocrine therapy in a longitudinal cohort of young breast cancer survivors.

Extended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women's Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006-2016. Women with stage I-III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6-8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04-1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81-4.51; III v. I: OR: 3.73, 95%CI: 1.87-7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16-6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.