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High mammographic density is a well-established risk factor for breast cancer; however, data from Black women are limited. It is largely unknown how mammographic density is associated with breast cancer subtypes among Black women. We examined the association between percent mammographic density (PMD) and breast cancer risk among participants in the Black Women's Health Study. Digital screening mammograms were available for 363 cases and 5541 non-cases. Cumulus software was used to assess PMD. We used inverse probability of sampling weights and Cox proportional hazards models, adjusted for age and body mass index, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and by age at mammography and estrogen receptor (ER) status of the breast tumors. Multivariable models included additional breast cancer risk factors. Tests of statistical significance were 2-sided. In simple models, women in the highest quartile of PMD had 53% increased odds of breast cancer compared to those in the lowest quartile (HR 1.53; 95% CI: 1.11, 2.11). HRs were 1.37 (95% CI: 0.83, 2.24) among women <55 years of age and 1.68 (95% CI: 1.10, 2.56) among women aged ≥55 years. HRs were 1.49 (95% CI: 1.02, 2.16) for ER+ cancer and 1.45 (95% CI: 0.73, 2.87) for ER- cancer. Associations were largely unchanged in multivariable models. In this study of U.S. Black women, higher PMD was associated with ER+ and ER- breast cancer risk. Findings from this study reinforce the importance of breast density as a risk factor for breast cancer in Black women., (© 2024 UICC.)

Background: The American Cancer Society recommends physicians inform average risk women about endometrial cancer (EC) risk on reaching menopause, but new diagnoses are rising fastest in women <50 years. Educating these women about EC risks requires knowledge of risk factors. However, EC in young women is rare and challenging to study in single study populations., Methods: We included 13,846 incident EC patients (1,639 < 50 years) and 30,569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and EC risk. We created a risk score to evaluate the combined associations and population attributable fractions of these factors., Results: In younger and older women, we observed positive associations with BMI and diabetes, and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women ≥50 years (PHet<0.01). BMI was the strongest risk factor [OR≥35 vs <25 kg/m2=5.57 (95% CI:4.33-7.16) for <50 years; OR≥35 vs <25 kg/m2=4.68 (95% CI : 4.30-5.09) for ≥50 years; PHet=0.14]. Possessing ≥4 risk factors was associated with ∼9-fold increased risk in women <50 years and ∼4-fold increased risk in women ≥50 years (PHet<0.01). Together, 59.1% of ECs in women <50 and 55.6% in women ≥50 were attributable to these factors., Conclusions: Our data confirm younger and older women share common EC risk factors. Early educational efforts centered on these factors may help mitigate the rising EC burden in young women., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: High mammographic density is one of the strongest breast cancer risk factors; however, determinants of high mammographic density are understudied in Black women. We assessed growth and development factors across the lifecourse in relation to mammographic density., Methods: Within the Black Women's Health Study (BWHS), we used Cumulus software to assess percent mammographic density from digital screening mammograms for 5,905 women ages 40-74. We fit linear regression models to quantify the association of lifecourse characteristics including birth weight, childhood somatotype, age at menarche, body mass index (BMI) at age 18, height, BMI at mammography, and adulthood waist-to-hip ratio with density overall and by age. We also performed a path analysis to assess the total and mediating effects of the growth and development factors on density., Results: BMI at age 18, height, BMI at mammography, and waist-to-hip ratio were significantly and inversely associated with density. On path analysis, total effects of childhood somatotype (standardized  = -0.05, p <0.001), BMI at age 18 (standardized  = -0.13, p <0.001), BMI at mammography (standardized  = -0.22, p <0.001), and waist-to-hip ratio (standardized  = -0.04, p <0.001) were associated with density., Conclusions: Several factors across the lifecourse - greater childhood somatotype, BMI at age 18, height, BMI at mammography, and waist-to-hip ratio - were associated with lower mammographic density in this cohort of Black women., Impact: Body size closer to the time of mammography may be more meaningful in determining mammographic density, though early life adiposity also influences mammographic density.

Background: Females exposed prenatally to diethylstilbestrol (DES) have an elevated risk of cervical dysplasia, breast cancer, and clear cell adenocarcinoma (CCA) of the cervix/vagina. Testicular cancer risk is increased in prenatally exposed males. Epigenetic changes may mediate the transmission of DES effects to the next ("third") generation of offspring., Methods: Using data self-reported by third-generation females, we assessed DES in relation to the risk of cancer and benign breast and reproductive tract conditions. Using data from prenatally DES-exposed and unexposed mothers, we assessed DES in relation to cancer risk in their female and male offspring. Cancer risk was assessed by standardized incidence ratios (SIR) and 95% confidence intervals (CI); the risks of benign and malignant diagnoses were assessed by hazard ratios (HR) and 95% CI., Results: In self-reported data, DES exposure was not associated with an increased risk of overall cancer (HR 0.83; CI 0.36-1.90), breast cancer, or severe cervical dysplasia. No females reported CCA. The risk of borderline ovarian cancer appeared elevated, but the HR was imprecise (3.46; CI 0.37-32.42). Based on mothers' reports, DES exposure did not increase the risk of overall cancer (HR 0.80; CI 0.49-1.32) or of other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated (HR 1.41; CI 0.70-2.86), but the CI was wide. The risk of testicular cancer was not elevated in exposed males; no cases of prostate cancer were reported., Conclusions: To date, there is little evidence that DES is associated with cancer risk in third-generation females or males, but these individuals are relatively young, and further follow-up is needed.

Background: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors., Methods: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors., Results: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy., Conclusions: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association., Impact: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: A high body mass index (BMI, kg/m 2 ) 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., Competing Interests: Declaration of Competing Interest none., (Published by Elsevier Ltd.)

Purpose: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer., Methods: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity., Results: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( P nonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; P het = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity., Conclusion: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Background: Obesity is an established risk factor for multiple myeloma (MM). Relatively few prior studies, however, have evaluated associations in Black populations., Methods: Among 55,276 participants in the Black Women's Health Study, a prospective U.S. cohort established in 1995, we confirmed 292 incident diagnoses of MM over 26 years of follow-up. Multivariable Cox proportional hazard models, adjusted for age and putative MM risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of usual body mass index (BMI), BMI at age 18, height, and waist-to-hip ratio with MM., Results: Compared to women with a usual adult BMI < 25 kg/m 2 , the HR associated with a usual adult BMI ≥ 35 kg/m 2 was 1.38 (95% CI: 0.96, 1.98). For early adult BMI, the HR comparing women with BMI ≥ 25 vs. <25 kg/m 2 was 1.57 (95% CI: 1.08, 2.28). Women who were heavy in both early and later life had the highest risk compared to those who were lean at both time points (HR: 1.60; 95% CI: 1.02, 2.52). Height was also associated with the risk of MM; the HR per 10 cm was 1.21 (95% CI: 1.02, 1.43)., Conclusions: These results indicate that high early adult BMI is associated with a 57% increased risk of MM in Black women and potentially highlight the importance of weight control as a preventive measure., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Risk factors for monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor to multiple myeloma, are largely unknown. We hypothesized that low vitamin D levels might be associated with higher MGUS prevalence in a national cohort of U.S. Black women., Methods: We screened archived serum samples (collected 2014-2017) from 3896 randomly selected participants in the Black Women's Health Study ages 50-79 for evidence of MGUS; samples had been assayed for 25-hydroxyvitamin D [25(OH)D] shortly after blood draw. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D level and MGUS status, adjusting for age, body mass index, and season of blood draw., Results: We identified 334 MGUS cases (8.6%) in the study population. The adjusted OR comparing women with vitamin D deficiency (25(OH)D < 20 ng/mL) to those with 25(OH)D levels ≥ 30 ng/mL was 1.27 (95% CI: 0.95, 1.72)., Conclusion: MGUS was more prevalent among Black women with vitamin D deficiency compared to those with 25(OH)D ≥ 30 ng/mL; however, the association was not statistically significant. Future prospective studies are warranted to clarify the possible association between vitamin D and MGUS., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models., Methods: We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics., Results: When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC., Conclusions: Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model)., Methods: Data from the Black Women's Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls., Results: AUCs were 0.577 (95% CI 0.556-0.598) for the BWHS model and 0.584 (95% CI 0.563-0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603-0.644)., Conclusions: This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making., (© 2023. The Author(s).)

Background: Chemical hair relaxers, use of which is highly prevalent among Black women in the US, have been inconsistently linked to risk of estrogen-dependent cancers, such as breast cancer, and other reproductive health conditions. Whether hair relaxer use increases risk of uterine cancer is unknown., Methods: In the Black Women's Health Study, 44,798 women with an intact uterus who self-identified as Black were followed from 1997, when chemical hair relaxer use was queried, until 2019. Over follow-up, 347 incident uterine cancers were diagnosed. We used multivariable Cox proportional hazards regression models, adjusted for age and other potential confounders, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of hair relaxer use with risk of uterine cancer., Results: Compared to women who never used hair relaxers or used them infrequently (<4 years and ≤1-2 times/year), the HR for uterine cancer associated with heavy use (≥15 years and at least 5 times/year) was 1.18 (95% CI: 0.81, 1.71). However, among postmenopausal women, compared to never/light use, the HR for moderate use was 1.60 (95% CI: 1.01, 2.53), the HR for heavy use was 1.64 (1.01, 2.64), and the HR for ≥20 years of use regardless of frequency was 1.71 (1.08, 2.72). Results among premenopausal women were null., Conclusions: In this large cohort of Black women, long-term use of chemical hair relaxers was associated with increased risk of uterine cancer among postmenopausal women, but not among premenopausal women. These findings suggest that hair relaxer use may be a potentially modifiable risk factor for uterine cancer., 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.)

Evidence suggests that aspirin use reduces the occurrence of colorectal neoplasia. Few studies have investigated the association among Black Americans, who are disproportionately burdened by the disease. We assessed aspirin use in relation to colorectal adenoma among Black women. The Black Women's Health Study is a prospective cohort of self-identified Black American women established in 1995. Participants reported regular aspirin use on baseline and follow-up questionnaires. Beginning in 1999, participants reported undergoing a colonoscopy or sigmoidoscopy, the only procedures through which colorectal adenomas can be diagnosed. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between aspirin use and colorectal adenoma among 34 397 women who reported at least 1 colonoscopy or sigmoidoscopy. From 1997 through 2018, 1913 women were diagnosed with an adenoma. Compared to nonaspirin users, regular users had 14% (OR = 0.86, 95% CI: 0.78-0.95) lower odds of adenoma. The odds of adenoma decreased with increasing duration of aspirin use (≥10 years: OR = 0.80, 95% CI: 0.66-0.96). Initiating aspirin at a younger age was associated with a reduced adenoma occurrence (age < 40 years at initiation: OR = 0.69, 95% CI: 0.55-0.86). Regular aspirin use was associated with a decreased odds of colorectal adenoma in our study of Black women. These findings support evidence demonstrating a chemopreventive impact of aspirin on colorectal neoplasia and suggest that aspirin may be a useful prevention strategy among US Black women., (© 2023 UICC.)

Mammography enables early detection of breast cancer, a critical factor in improving treatment outcomes and breast cancer mortality. Yet, not all women benefit equally, and striking racial disparities in breast cancer mortality persist, with Black women 40% more likely to die from breast cancer compared with non-Hispanic White women. The current issue of Cancer Epidemiology, Biomarkers & Prevention presents three informative reports revealing racial and ethnic variations in mammography's performance in risk stratification, detection, and surveillance. The performance dynamics of mammography across different racial and ethnic groups highlight the urgency for additional research and innovative interventions to ensure equitable breast cancer control. We emphasize a pressing need for a comprehensive evaluation of multilevel influences on the performance and implementation of mammography in racially and ethnically diverse populations, complemented by equally urgent efforts to address factors influencing the risk of aggressive tumor subtypes and timely and effective treatment delivery. See related articles by Kerlikowske et al., p. 1524, Hubbard et al., p. 1531, Nyante et al., p. 1542., (©2023 American Association for Cancer Research.)

BACKGROUND: Black women have a disproportionately higher burden of both preeclamptic pregnancy and stroke compared with White women, but virtually all existing evidence on this possible association has been generated from women of European ancestry. METHODS: In the Black Women’s Health Study, a prospective cohort of U.S. Black women who enrolled in 1995, 42,924 participants were parous and free of cardiovascular disease at baseline. Biennial questionnaires included questions on preeclampsia, gestational hypertension, and stroke. We sought the medical records for participants who reported a stroke, and we reviewed them blinded to reproductive history. Cox proportional-hazards models, with control for potential confounders, were used to estimate hazard ratios and 95% confidence intervals (CIs). RESULTS: Over a median of 22 years of follow-up, there were 1555 incident strokes, including 310 among 4938 women with a history of hypertensive disorders of pregnancy (HDOP). The multivariable hazard ratio for stroke for women with any HDOP compared with those who had never experienced HDOP was 1.66 (95% CI, 1.46 to 1.89). Comparable hazard ratios were 1.53 (95% CI, 1.29 to 1.82) for preeclampsia and 1.81 (95% CI, 1.53 to 2.13) for gestational hypertension only. Associations were similar among women under age 55 years and those aged 55 years and older. CONCLUSIONS: In this prospective study of Black women, a history of HDOP was associated with an estimated 66% increased long-term risk of stroke. This association may contribute to the disproportionately higher stroke incidence in Black women given the higher prevalence of HDOP in this population. (Funded by the U.S. National Institutes of Health.)

Background: A central challenge to precision medicine research efforts is the return of genetic research results in a manner that is effective, ethical, and efficient. Formal tests of alternate modalities are needed, particularly for racially marginalized populations that have historically been underserved in this context., Methods: We are conducting a randomized controlled trial (RCT) to test scalable modalities for results return and to examine the clinical utility of returning genetic research results to a research cohort of Black women. The primary aim is to compare the efficacy of two communication modalities for results return: 1) a conventional modality that entails telephone disclosure by a Board-certified genetic counselor, and 2) an online self-guided modality that entails results return directly to participants, with optional genetic counselor follow-up via telephone. The trial is being conducted among participants in the Black Women's Health Study (BWHS), where targeted sequencing of 4000 participants was previously completed., Results: Several ethical, legal, and social implications (ELSI) and challenges presented, which necessitated substantial revision of the original study protocol. Challenges included chain of custody, re-testing of research results in a CLIA lab, exclusion of VUS results, and digital literacy. Bioethical principles of autonomy, justice, non-maleficence, and beneficence were considered in the design of the study protocol., Conclusion: This study is uniquely situated to provide critical evidence on the effectiveness of alternative models for genetic results return and provide further insight into the factors influencing access and uptake of genetic information among U.S. Black women., Clinicaltrials: gov: NCT04407611., 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.)

Background: Animal and experimental studies suggest circadian disruption increases colorectal cancer risk, but evidence in humans is limited. We examined night shift work, chronotype, and residential position within a time zone, proxies for circadian disruption, in relation to colorectal cancer risk., Methods: Participants in the Black Women's Health Study, a prospective cohort of 59,000 Black American women established in 1995, reported history of night shift work and chronotype on follow-up questionnaires. Residential position within a time zone was estimated using participant addresses at each questionnaire cycle. Number of colorectal cancer cases and follow-up duration varied by analysis depending on timing of exposure assessment, ranging from 204 over the 2005 to 2018 night shift work study period to 452 over the 1995 to 2018 residential position study period. Cox proportional hazards regression was used to estimate multivariable-adjusted HRs and 95% confidence intervals (CI)., Results: Compared with never having worked a night shift, working a night shift for ≥10 years was associated with increased colorectal cancer risk (HR = 1.64; 95% CI, 1.01-2.66). However, shorter duration was not. The HR for evening versus morning chronotype was 0.96 (95% CI, 0.73-1.27). Westward position of residence within a time zone was not associated with colorectal cancer risk (HR per 5-degree longitude increase: 0.92; 95% CI, 0.82-1.03)., Conclusions: Our findings suggest a possible increased risk of colorectal cancer associated with long duration night shift work; however, results require confirmation in larger studies., Impact: Circadian disruption from long-term night shift work may contribute to colorectal cancer development in Black women., (©2022 American Association for Cancer Research.)

Purpose: Women with preeclampsia are more likely to deliver preterm. Reports of inverse associations between preeclampsia and breast cancer risk, and positive associations between preterm birth and breast cancer risk are difficult to reconcile. We investigated the co-occurrence of preeclampsia/gestational hypertension with preterm birth and breast cancer risk using data from the Premenopausal Breast Cancer Collaborative Group., Methods: Across 6 cohorts, 3096 premenopausal breast cancers were diagnosed among 184,866 parous women. We estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal breast cancer risk using Cox proportional hazards regression., Results: Overall, preterm birth was not associated (HR 1.02, 95% CI 0.92, 1.14), and preeclampsia was inversely associated (HR 0.86, 95% CI 0.76, 0.99), with premenopausal breast cancer risk. In stratified analyses using data from 3 cohorts, preterm birth associations with breast cancer risk were modified by hypertensive conditions in first pregnancies (P-interaction = 0.09). Preterm birth was positively associated with premenopausal breast cancer in strata of women with preeclampsia or gestational hypertension (HR 1.52, 95% CI: 1.06, 2.18), but not among women with normotensive pregnancy (HR = 1.09, 95% CI: 0.93, 1.28). When stratified by preterm birth, the inverse association with preeclampsia was more apparent, but not statistically different (P-interaction = 0.2), among women who did not deliver preterm (HR = 0.82, 95% CI 0.68, 1.00) than those who did (HR = 1.07, 95% CI 0.73, 1.56)., Conclusion: Findings support an overall inverse association of preeclampsia history with premenopausal breast cancer risk. Estimates for preterm birth and breast cancer may vary according to other conditions of pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies., Aims: We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk., Methods and Results: Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code., Conclusion: The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Evidence of an association between plasma 25-hydroxyvitamin D [25(OH)D] levels and risk of hypertension, predominantly from studies of White individuals, suggests an inverse relationship. Limited data are available on Black individuals, who are more likely to have vitamin D deficiency. In the Black Women's Health Study (BWHS), a prospective study of 59 000 self-identified Black women from across the US, we assessed levels of a validated predicted vitamin D score in relation to incident hypertension. We followed 42 239 participants who were free of cardiovascular disease and cancer from 1995 to 2019, during which time 19 505 incident cases of hypertension were identified. Cox proportional hazards model were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of predicted vitamin D with the risk of incident hypertension. In age-adjusted analyses, there was a strong inverse dose-response association between predicted vitamin D score and hypertension risk, with an HR of .66 (95% CI: .63-.68, p trend < .0001) for the highest quartile of predicted vitamin D relative to the lowest. After control for potential confounders including body mass index, physical activity, and cigarette smoking, the HR was attenuated to .91 (95% CI: .87-.95, p trend = .002). In this prospective cohort study of Black women, predicted vitamin D score was weakly inversely associated with the incidence of hypertension. This observed association may reflect an inability to fully control for confounding factors., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology., Materials and Methods: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk., Results: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade., Conclusion: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Guidelines recommend shared decision making (SDM) for mammography screening for women ≥ 75 and not screening women with < 10-year life expectancy. High-quality SDM requires consideration of women's breast cancer (BC) risk, life expectancy, and values but is hard to implement because no models simultaneously estimate older women's individualized BC risk and life expectancy., Methods: Using competing risk regression and data from 83,330 women > 55 years who completed the 2004 Nurses' Health Study (NHS) questionnaire, we developed (in 2/3 of the cohort, n = 55,533) a model to predict 10-year non-breast cancer (BC) death. We considered 60 mortality risk factors and used best-subsets regression, the Akaike information criterion, and c-index, to identify the best-fitting model. We examined model performance in the remaining 1/3 of the NHS cohort (n = 27,777) and among 17,380 Black Women's Health Study (BWHS) participants, ≥ 55 years, who completed the 2009 questionnaire. We then included the identified mortality predictors in a previously developed competing risk BC prediction model and examined model performance for predicting BC risk., Results: Mean age of NHS development cohort participants was 70.1 years (± 7.0); over 10 years, 3.1% developed BC, 0.3% died of BC, and 20.1% died of other causes; NHS validation cohort participants were similar. BWHS participants were younger (mean age 63.7 years [± 6.7]); over 10-years 3.1% developed BC, 0.4% died of BC, and 11.1% died of other causes. The final non-BC death prediction model included 21 variables (age; body mass index [BMI]; physical function [3 measures]; comorbidities [12]; alcohol; smoking; age at menopause; and mammography use). The final BC prediction model included age, BMI, alcohol and hormone use, family history, age at menopause, age at first birth/parity, and breast biopsy history. When risk factor regression coefficients were applied in the validation cohorts, the c-index for predicting 10-year non-BC death was 0.790 (0.784-0.796) in NHS and 0.768 (0.757-0.780) in BWHS; for predicting 5-year BC risk, the c-index was 0.612 (0.538-0.641) in NHS and 0.573 (0.536-0.611) in BWHS., Conclusions: We developed and validated a novel competing-risk model that predicts 10-year non-BC death and 5-year BC risk. Model risk estimates may help inform SDM around mammography screening., (© 2023. The Author(s).)

Background: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density., Methods: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation., Results: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV., Conclusions: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk., (© 2022. The Author(s).)

Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03-1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23-4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.

Background: Epidemiologic studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating concentrations of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund (WCRF) concluded that consumption of coffee probably protects against EC., Objectives: Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors for EC., Methods: We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 EC cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate ORs and their corresponding 95% CIs. All models were adjusted for potential confounders including age, race, BMI, smoking status, diabetes status, study design, and study site., Results: Coffee drinkers had a lower risk of EC than non-coffee drinkers (multiadjusted OR: 0.87; 95% CI: 0.79, 0.95). There was a dose-response relation between higher coffee consumption and lower risk of EC: compared with non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3, and >4 cups/d were 0.90 (95% CI: 0.82, 1.00), 0.86 (95% CI: 0.78, 0.95), and 0.76 (95% CI: 0.66, 0.87), respectively (P-trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with BMI > 25 kg/m 2 ., Conclusions: The results of the largest analysis to date pooling individual-level data further support the potentially beneficial health effects of coffee consumption in relation to EC, especially among females with higher BMI., (Copyright © 2022 American Society for Nutrition.)

Background: Obesity is a risk factor for multiple myeloma (MM), yet results of prior studies have been mixed regarding the importance of early and/or later adult obesity; other measures of body composition have been less well studied., Methods: We evaluated associations of early adult (ages 18-21) and usual adult body mass index (BMI), waist circumference, and predicted fat mass with MM by pooling data from six U.S. prospective cohort studies comprising 544,016 individuals and 2756 incident diagnoses over 20-37 years of follow-up. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations, adjusted for age and other risk factors., Results: Each 5 kg/m 2 increase in usual adult BMI was associated with a 10% increased risk of MM (HR: 1.10; 95% CI: 1.05-1.15). Positive associations were also noted for early adult BMI (HR per 5 kg/m 2 : 1.14; 95% CI: 1.04-1.25), height (HR per 10 cm: 1.28; 95% CI: 1.20-1.37), waist circumference (HR per 15 cm: 1.09; 95% CI: 1.00-1.19), and predicted fat mass (HR per 5 kg: 1.06; 95% CI: 1.01-1.11)., Conclusions: These findings highlight the importance of avoidance of overweight/obesity and excess adiposity throughout adulthood as a potential MM risk-reduction strategy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Compared to white women, Black women have increased risk of developing hypertensive diseases of pregnancy (HDOP) and have a higher incidence of aggressive breast cancer subtypes. Few studies of HDOP and breast cancer risk have included large numbers of Black women. This study examined the relation of HDOP to incidence of breast cancer overall and by estrogen receptor (ER) status in Black women., Methods: We followed 42,982 parous women in the Black Women's Health Study, a nationwide prospective study of Black women. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of self-reported HDOP, including preeclampsia and gestational hypertension, with breast cancer incidence overall and by ER subtype, adjusted for age and established breast cancer risk factors., Results: Over 20 years of follow-up, we identified 2376 incident breast cancer cases. History of HDOP (11.7%) was not associated with breast cancer risk overall (HR 0.98; 95% CI 0.87, 1.11). HRs for invasive ER+ and ER- breast cancer were 1.11 (95% CI 0.93, 1.34) and 0.81 (95% CI 0.61, 1.07), respectively., Conclusions: HDOP was not associated with risk of overall breast cancer in Black women. A suggestive inverse association with ER- breast cancer may reflect an anti-tumorigenic hormone profile in HDOP, but those results require confirmation in other studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Socioeconomic and health-related factors, including comorbid illness, may affect mammography screening rates and subsequently contribute to breast cancer outcomes. We explored the association between diabetes and mammography screening, and whether this association varied between racial, ethnic, and geographic groups. Methods: Cross-sectional data from the 2012, 2014, 2016, and 2018 Behavioral Risk Factor Surveillance System were used to fit logistic regression models assessing the association between diabetes and up-to-date mammography screening in 497,600 women, aged 50-74 years. Participants were considered exposed if they responded "yes" to "(Ever told) you have diabetes?" and up to date on screening if they responded "yes" to having a mammogram within the past 2 years. Models were adjusted for age, health status, socioeconomic, and access variables. Results: The majority of participants were White (79.6%), non-Hispanic (88.9%), and up to date on screening (78.8%). Overall, 16.8% reported having diabetes. In fully adjusted models, White women with diabetes were 12% more likely to be up to date on screening (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.06-1.19) than those without diabetes. Black/African American women and those of Hispanic ethnicity with diabetes were more likely to report being up to date with mammography (OR Black : 1.28, 95% CI: 1.12-1.45; OR Hispanic : 1.19, 95% CI: 1.13-1.24) than those without. Patterns were similar across geographic regions. Conclusions: Women of ages 50-74 years with diabetes were more likely to be up to date on screening than women without diabetes. Chronic disease management may represent an opportunity to address cancer screening.

In 2022, more than 100 000 non-Hodgkin lymphoma (NHL) diagnoses are expected, yet few risk factors are confirmed. In this study, data from six US-based cohorts (568 717 individuals) were used to examine body size and risk of NHL. Over more than 20 years of follow-up, 11 263 NHLs were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) estimated associations with NHLs for adult body mass index (BMI), height, weight change, waist circumference and predicted fat mass. Adult height was broadly associated with NHL, but most strongly with B-cell NHLs among non-White participants (e.g. HR BLACK  = 2.06, 95% CI: 1.62-2.62). However, the strongest association among the anthropometric traits examined was for young adult BMI and risk of diffuse large B-cell lymphoma (DLBCL), particularly those who maintained a higher BMI into later adulthood. Individuals with BMI over 30 kg/m 2 throughout adulthood had more than double the DLBCL risk (HR = 2.67, 95% CI: 1.71-4.17) compared to BMI 18.5-22.9 kg/m 2 . Other anthropometric traits were not associated with NHL after controlling for BMI. These results suggest that sustained high BMI is a major driver of DLBCL risk. If confirmed, we estimate that up to 23.5% of all DLBCLs (and 11.1% of all NHLs) may be prevented with avoidance of young adult obesity., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

While excess weight is an established risk factor for postmenopausal breast cancer, consideration of maximum body mass index (maxBMI; BMI is calculated as weight (kg)/height (m)2) or BMI at a point in time relevant for breast carcinogenesis may offer new insights. We prospectively evaluated maxBMI and time-dependent BMI in relation to breast cancer incidence among 31,028 postmenopausal women in the Black Women's Health Study. During 1995-2015, a total of 1,384 diagnoses occurred, including 787 estrogen-receptor (ER)-positive (ER+) cases and 310 ER-negative (ER-) cases. BMI was assessed at baseline and 2, 4, 6, and 8 years before diagnosis. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with women with BMI <25, those with BMI ≥35 had increased risk of ER+ breast cancer but not ER- breast cancer. For BMI assessed 2 years before diagnosis, the HRs for ER+ breast cancer associated with maxBMI ≥35 and time-dependent BMI ≥35 were 1.42 (95% confidence interval (CI): 1.10, 1.84) and 1.63 (95% CI: 1.25, 2.13), respectively. The corresponding HR for time-dependent BMI assessed 6 years before diagnosis was 1.95 (95% CI: 1.45, 2.62). These findings suggest strong associations of BMI with risk of ER+ breast cancer in postmenopausal women, regardless of timing of BMI assessment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ambient dioxin exposure from industrial sources, excluding exposures from occupations and accidental releases/contamination, may be associated with risk of developing hepatocellular carcinoma (HCC). The objective of this study was to examine the association between county-level ambient dioxin air emissions from industrial sources and HCC risk in the US. We obtained information on 90,359 incident HCC cases diagnosed between 2000 and 2016 from population-based cancer registries across the US in the Surveillance, Epidemiology, and End Results (SEER) database. Dioxin emissions from 1987 to 2007 from a nationwide spatial database of historical dioxin-emitting facilities were linked to the SEER county of residence at diagnosis using a geographic information system (GIS). Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between county-level dioxin emissions and HCC rates adjusting for individual-level age at diagnosis, sex, race/ethnicity, year of diagnosis, SEER registry, and county-level information on health conditions, lifestyle factors, and socioeconomic status. There was no association between dioxin emissions based on the number of dioxin-emitting facilities within a county or average annual emissions within a county and HCC risk. In analyses by facility type, there were positive associations between county-level dioxin emissions from coal-fired power plants (adjusted IRR 1.09, 95% CI 1.01-1.17), but not with the number of these facilities. Similarly, positive associations for industrial boilers and sewage sludge incinerators were evident, but not consistent across both exposure metrics. Future research should incorporate individual-level data to further explore the findings suggested by these ecologic analyses., (Copyright © 2021. Published by Elsevier Inc.)

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting., Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors., Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women., Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Observational studies, mostly among White populations, suggest that low vitamin D levels increase colorectal cancer risk. African Americans, who are disproportionately burdened by colorectal cancer, often have lower vitamin D levels compared with other populations., Methods: We assessed predicted vitamin D score in relation to colorectal cancer among 49,534 participants in the Black Women's Health Study, a cohort of African American women followed from 1995 to 2017 through biennial questionnaires. We derived predicted vitamin D scores at each questionnaire cycle for all participants using a previously validated prediction model based on actual 25-hydroxyvitamin D values from a subset of participants. We calculated cumulative average predicted vitamin D score at every cycle by averaging scores from cycles up to and including that cycle. Using Cox proportional hazards regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer incidence according to predicted score quartiles., Results: Over follow-up, 488 incident colorectal cancers occurred. Compared with women in the highest quartile of predicted vitamin D score, those in the lowest had an estimated 41% (HR = 1.41; 95% CI, 1.05-1.90) higher colorectal cancer risk. Comparable HRs were 1.44 (95% CI, 1.02-2.01) for colon and 1.34 (95% CI, 0.70-2.56) for rectal cancer., Conclusions: Low vitamin D status may lead to elevated colorectal cancer risk in African American women., Impact: Our findings, taken together with established evidence that vitamin D levels are generally lower in African Americans than other U.S. groups, suggest that low vitamin D status may contribute to the disproportionately high colorectal cancer incidence among African Americans., (©2021 American Association for Cancer Research.)

Purpose: Breast cancer risk prediction models are used to identify high-risk women for early detection, targeted interventions, and enrollment into prevention trials. We sought to develop and evaluate a risk prediction model for breast cancer in US Black women, suitable for use in primary care settings., Methods: Breast cancer relative risks and attributable risks were estimated using data from Black women in three US population-based case-control studies (3,468 breast cancer cases; 3,578 controls age 30-69 years) and combined with SEER age- and race-specific incidence rates, with incorporation of competing mortality, to develop an absolute risk model. The model was validated in prospective data among 51,798 participants of the Black Women's Health Study, including 1,515 who developed invasive breast cancer. A second risk prediction model was developed on the basis of estrogen receptor (ER)-specific relative risks and attributable risks. Model performance was assessed by calibration (expected/observed cases) and discriminatory accuracy (C-statistic)., Results: The expected/observed ratio was 1.01 (95% CI, 0.95 to 1.07). Age-adjusted C-statistics were 0.58 (95% CI, 0.56 to 0.59) overall and 0.63 (95% CI, 0.58 to 0.68) among women younger than 40 years. These measures were almost identical in the model based on estrogen receptor-specific relative risks and attributable risks., Conclusion: Discriminatory accuracy of the new model was similar to that of the most frequently used questionnaire-based breast cancer risk prediction models in White women, suggesting that effective risk stratification for Black women is now possible. This model may be especially valuable for risk stratification of young Black women, who are below the ages at which breast cancer screening is typically begun., Competing Interests: Tracy BattagliaResearch Funding: American Cancer Society, Patient Centered Outcomes Research Institute, NIH NCATs (Inst) Elisa V. BanderaConsulting or Advisory Role: PfizerNo other potential conflicts of interest were reported.

Background: Research on psychosocial stress and risk of breast cancer has produced conflicting results. Few studies have assessed this relation by breast cancer subtype or specifically among Black women, who experience unique chronic stressors., Methods: We used prospective data from the Black Women's Health Study, an ongoing cohort study of 59,000 US Black women, to assess neighborhood- and individual-level psychosocial factors in relation to risk of breast cancer. We used factor analysis to derive two neighborhood score variables after linking participant addresses to US Census data (2000 and 2010) on education, employment, income and poverty, female-headed households, and Black race for all households in each residential block group. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for established breast cancer risk factors., Results: During follow-up from 1995 to 2017, there were 2167 incident invasive breast cancer cases (1259 estrogen receptor positive (ER +); 687 ER negative (ER-)). For ER- breast cancer, HRs were 1.26 (95% CI 1.00-1.58) for women living in the highest quartile of neighborhood disadvantage relative to women in the lowest quartile, and 1.24 (95% CI 0.98-1.57) for lowest versus highest quartile of neighborhood socioeconomic status (SES). For ER+ breast cancer, living in the lowest quartile of neighborhood SES was associated with a reduced risk of ER+ breast cancer (HR = 0.83, 95% CI 0.70-0.98). With respect to individual-level factors, childhood sexual abuse (sexual assault ≥ 4 times vs. no abuse: HR = 1.35, 95% CI 1.01-1.79) and marital status (married/living together vs. single: HR = 1.29, 95% CI 1.08-1.53) were associated with higher risk of ER+, but not ER- breast cancer., Conclusion: Neighborhood disadvantage and lower neighborhood SES were associated with an approximately 25% increased risk of ER- breast cancer in this large cohort of Black women, even after control for multiple behaviors and lifestyle factors. Further research is need to understand the underlying reasons for these associations. Possible contributing factors are biologic responses to the chronic stress/distress experienced by individuals who reside in neighborhoods characterized by high levels of noise, crime and unemployment or the direct effects of environmental toxins., (© 2021. The Author(s).)

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years., Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs., Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1 , BRCA2 , and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2 , PALB2 , BRCA2 , and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1 , BRCA2 , and PALB2 ., Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Amal YussufEmployment: Ambry Genetics Celine M. VachonStock and Other Ownership Interests: Exact SciencesResearch Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Tina PesaranEmployment: Ambry Genetics/Konica MinoltaTravel, Accommodations, Expenses: Ambry Genetics/Konica Minolta Irene M. OngEmployment: Propeller HealthStock and Other Ownership Interests: AyrFlo Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Jill S. DolinskyEmployment: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis OncologyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/917904 Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Background: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers., Methods: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age., Results: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77-1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68-1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23-1.00)., Conclusions: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men., Impact: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk., (©2021 American Association for Cancer Research.)

Hair relaxers and leave-in conditioners and oils, commonly used by Black/African American women, may contain estrogens or estrogen-disrupting compounds. Thus, their use may contribute to breast cancer risk. Results of the few previous studies on this topic are inconsistent. We assessed the relation of hair relaxer and leave-in conditioner use to breast cancer incidence in the Black Women's Health Study, a nationwide prospective study of Black women. Among 50 543 women followed from 1997 to 2017, 2311 incident breast cancers occurred. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression for breast cancer overall and by estrogen receptor (ER) status. For heavy use (≥15 years of use for ≥7 times/year) of hair relaxers relative to never/light use (<4 years, no more than 1-2 times/year), the multivariable HR for breast cancer overall was 1.13 (95%CI: 0.96-1.33). Duration, frequency, age at first use and number of scalp burns were not associated with overall breast cancer risk. For heavy use of hair relaxers containing lye, the corresponding HR for ER+ breast cancer was 1.32 (95% CI: 0.97, 1.80); there was no association for non-lye products. There was no association of conditioner use and breast cancer. Results of this study were largely null, but there was some evidence that heavy use of lye-containing hair relaxers may be associated with increased risk of ER+ breast cancer. Consistent results from several studies are needed before it can be concluded that use of certain hair relaxers impacts breast cancer development., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Percent mammographic density (PMD) is a strong breast cancer risk factor, however, other mammographic features, such as V, the standard deviation (SD) of pixel intensity, may be associated with risk. We assessed whether PMD, automated PMD (APD), and V, yielded independent associations with breast cancer risk. We included 1900 breast cancer cases and 3921 matched controls from the Nurses' Health Study (NHS) and the NHSII. Using digitized film mammograms, we estimated PMD using a computer-assisted thresholding technique. APD and V were determined using an automated computer algorithm. We used logistic regression to generate odds ratios (ORs) and 95% confidence intervals (CIs). Median time from mammogram to diagnosis was 4.1 years (interquartile range: 1.6-6.8 years). PMD (OR per SD :1.52, 95% CI: 1.42, 1.63), APD (OR per SD :1.32, 95% CI: 1.24, 1.41), and V (OR per SD :1.32, 95% CI: 1.24, 1.40) were positively associated with breast cancer risk. Associations for APD were attenuated but remained statistically significant after mutual adjustment for PMD or V. Women in the highest quartile of both APD and V (OR vs Q1/Q1 : 2.49, 95% CI: 2.02, 3.06), or PMD and V (OR vs Q1/Q1 : 3.57, 95% CI: 2.79, 4.58) had increased breast cancer risk. An automated method of PMD assessment is feasible and yields similar, but somewhat weaker, estimates to a manual measure. PMD, APD and V are each independently, positively associated with breast cancer risk. Women with dense breasts and greater texture variation are at the highest relative risk of breast cancer.

Purpose: We evaluated the association of percent mammographic density (PMD), absolute dense area (DA), and non-dense area (NDA) with risk of "intrinsic" molecular breast cancer (BC) subtypes., Methods: We pooled 3492 invasive BC and 10,148 controls across six studies with density measures from prediagnostic, digitized film-screen mammograms. We classified BC tumors into subtypes [63% Luminal A, 21% Luminal B, 5% HER2 expressing, and 11% as triple negative (TN)] using information on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. We used polytomous logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CI) for density measures (per SD) across the subtypes compared to controls, adjusting for age, body mass index and study, and examined differences by age group., Results: All density measures were similarly associated with BC risk across subtypes. Significant interaction of PMD by age (P = 0.001) was observed for Luminal A tumors, with stronger effect sizes seen for younger women < 45 years (OR = 1.69 per SD PMD) relative to women of older ages (OR = 1.53, ages 65-74, OR = 1.44 ages 75 +). Similar but opposite trends were seen for NDA by age for risk of Luminal A: risk for women: < 45 years (OR = 0.71 per SD NDA) was lower than older women (OR = 0.83 and OR = 0.84 for ages 65-74 and 75 + , respectively) (P < 0.001). Although not significant, similar patterns of associations were seen by age for TN cancers., Conclusions: Mammographic density measures were associated with risk of all "intrinsic" molecular subtypes. However, findings of significant interactions between age and density measures may have implications for subtype-specific risk models.

Background: Air pollution contains numerous carcinogens and endocrine disruptors which may be relevant for breast cancer. Previous research has predominantly been conducted in White women; however, Black women may have higher air pollution exposure due to geographic and residential factors., Objective: We evaluated the association between air pollution and breast cancer risk in a large prospective population of Black women., Methods: We estimated annual average ambient levels of particulate matter <2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ) and ozone (O 3 ) at the 1995 residence of 41,317 participants in the Black Women's Health Study who resided in 56 metropolitan areas across the United States. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for an interquartile range (IQR) increase in each pollutant. We evaluated whether the association varied by menopausal status, estrogen receptor (ER) status of the tumor and geographic region of residence., Results: With follow-up through 2015 (mean = 18.3 years), 2146 incident cases of breast cancer were confirmed. Higher exposure to NO 2 or O 3 was not associated with a higher risk of breast cancer. For PM 2.5 , although we observed no association overall, there was evidence of modification by geographic region for both ER- (p for heterogeneity = 0.01) and premenopausal breast cancer (p for heterogeneity = 0.01). Among women living in the Midwest, an IQR increase in PM 2.5 (2.87 μg/m 3 ), was associated with a higher risk of ER- (HR = 1.53, 95% CI: 1.07-2.19) and premenopausal breast cancer (HR = 1.32, 95% CI: 1.03-1.71). In contrast, among women living in the South, PM 2.5 was inversely associated with both ER- (HR = 0.74, 95% CI: 0.56-0.97) and premenopausal breast cancer risk (HR = 0.75, 95% CI: 0.62-0.91)., Discussion: Overall, we observed no association between air pollution and increased breast cancer risk among Black women, except perhaps among women living in the Midwestern US., (Published by Elsevier Inc.)

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants., Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed., Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1 , RAD51C , and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM , CDH1 , and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657&#95;661del5 founder pathogenic variant in NBN , were not associated with an increased risk of breast cancer., Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies., Methods: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer., Results: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer., Conclusions: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Trans fatty acid (TFA) intake persists in much of the world, posing ongoing threats to public health that warrant further elucidation. Published evidence suggests a positive association of self-reported TFA intake with non-Hodgkin lymphoma (NHL) risk., Objectives: To confirm those reports, we conducted a prospective study of prediagnosis RBC membrane TFA levels and risk of NHL and common NHL histologic subtypes., Methods: We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants with archived RBC specimens and no history of cancer at blood draw (1989-1090 and 1994-1995, respectively). We confirmed 583 incident NHL cases (332 women and 251 men) and individually matched 583 controls on cohort (sex), age, race, and blood draw date/time. We analyzed RBC membrane TFA using GLC (in 2013-2014) and expressed individual TFA levels as a percentage of total fatty acids. We used unconditional logistic regression adjusted for the matching factors to estimate ORs and 95% CIs for overall NHL risk per 1 SD increase in TFA level and assessed histologic subtype-specific associations with multivariable polytomous logistic regression., Results: Total and individual TFA levels were not associated with risk of all NHL or most subtypes. We observed a positive association of total TFA levels with diffuse large B cell lymphoma (DLBCL) risk [n = 98 cases; OR (95% CI) per 1 SD increase: 1.30 (1.05, 1.61); P = 0.015], driven by trans 18:1n-9(ω-9)/elaidic acid [OR (95% CI): 1.34 (1.08, 1.66); P = 0.007], trans 18:1n-7/vaccenic acid [OR (95% CI): 1.28 (1.04, 1.58); P = 0.023], and trans 18:2n-6t,t [OR (95% CI): 1.26 (1.01, 1.57); P = 0.037]., Conclusions: Our findings extended evidence for TFA intake and DLBCL risk but not for other NHL subtypes. Reduced TFA consumption through dietary choices or health policy measures may support prevention of DLBCL, an aggressive NHL subtype., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The size distribution of adipocytes in fat tissue provides important information about metabolic status and overall health of patients. Histological measurements of biopsied adipose tissue can reveal cardiovascular and/or cancer risks, to complement typical prognosis parameters such as body mass index, hypertension or diabetes. Yet, current methods for adipocyte quantification are problematic and insufficient. Methods such as hand-tracing are tedious and time-consuming, ellipse approximation lacks precision, and fully automated methods have not proven reliable. A semi-automated method fills the gap in goal-directed computational algorithms, specifically for high-throughput adipocyte quantification. Here, we design and develop a tool, AdipoCyze, which incorporates a novel semi-automated tracing algorithm, along with benchmark methods, and use breast histological images from the Komen for the Cure Foundation to assess utility. Speed and precision of the new approach are superior to conventional methods and accuracy is comparable, suggesting a viable option to quantify adipocytes, while increasing user flexibility. This platform is the first to provide multiple methods of quantification in a single tool. Widespread laboratory and clinical use of this program may enhance productivity and performance, and yield insight into patient metabolism, which may help evaluate risks for breast cancer progression in patients with comorbidities of obesity., Abbreviations: BMI: body mass index.

Background: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of breast cancer; however, results of epidemiological studies have been mixed. Few studies have investigated these associations among African American women., Methods: To assess the relation of aspirin use to risk of breast cancer in African American women, we conducted a prospective analysis within the Black Women's Health Study, an ongoing nationwide cohort study of 59,000 African American women. On baseline and follow-up questionnaires, women reported regular use of aspirin (defined as use at least 3 days per week) and years of use. During follow-up from 1995 through 2017, 1919 invasive breast cancers occurred, including 1112 ER+, 569 ER-, and 284 triple-negative (TN) tumors. We used age-stratified Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of aspirin use with risk of ER+, ER-, and TN breast cancer, adjusted for established breast cancer risk factors., Results: Overall, the HR for current regular use of aspirin relative to non-use was 0.92 (95% CI 0.81, 1.04). For ER+, ER-, and TN breast cancer, corresponding HRs were 0.98 (0.84, 1.15), 0.81 (0.64, 1.04), and 0.70 (0.49, 0.99), respectively., Conclusions: Our findings with regard to ER- and TN breast cancer are consistent with hypothesized inflammatory mechanisms of ER- and TN breast cancer, rather than hormone-dependent pathways. Aspirin may represent a potential opportunity for chemoprevention of ER- and TN breast cancer.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)