Background & Aims:Incidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts. Methods:Concentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography-mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men. Results:Higher concentrations of total testosterone (OR per one-unit increase in log2 = 1.77, 95% CI = 1.38-2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21-2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22-20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27-2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33-0.68). Conclusions:Higher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk. Impact and implications:This study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men.

You have accessJournal of UrologyGlobal Health/Humanitarian (MP67)1 Sep 2021MP67-18 CLINICAL CHARACTERISTICS OF PROSTATE CANCER PATIENTS IN WEST AND SOUTH AFRICA IN THE MEN OF AFRICAN DESCENT AND CARCINOMA OF THE PROSTATE (MADCAP) CONSORTIUM STUDY Mohamed Jalloh, Denzel Zhu, Ilir Agalliu, Caroline Andrews, Evan Kovac, Ben Adusei, Nana Yaa Snyper, James Mensah, Victoria Okyne, Ann Hsing, Akindele Adebiyi, Olufemi Ogunbiyi, Olayiwola Shittu, Peter Olabode, Maxwell Nwegbu, Oseremen Aisuodionoe-Shadrach, Pedro Fernandez, Hayley Irusen, Audrey Pentz, Maureen Joffe, Elvira Singh, Judith Jacobson, Alfred Neugut, Thomas Rohan, Lamine Niang, Serigne Gueye, and Timothy Rebbeck Mohamed JallohMohamed Jalloh More articles by this author , Denzel ZhuDenzel Zhu More articles by this author , Ilir AgalliuIlir Agalliu More articles by this author , Caroline AndrewsCaroline Andrews More articles by this author , Evan KovacEvan Kovac More articles by this author , Ben AduseiBen Adusei More articles by this author , Nana Yaa SnyperNana Yaa Snyper More articles by this author , James MensahJames Mensah More articles by this author , Victoria OkyneVictoria Okyne More articles by this author , Ann HsingAnn Hsing More articles by this author , Akindele AdebiyiAkindele Adebiyi More articles by this author , Olufemi OgunbiyiOlufemi Ogunbiyi More articles by this author , Olayiwola ShittuOlayiwola Shittu More articles by this author , Peter OlabodePeter Olabode More articles by this author , Maxwell NwegbuMaxwell Nwegbu More articles by this author , Oseremen Aisuodionoe-ShadrachOseremen Aisuodionoe-Shadrach More articles by this author , Pedro FernandezPedro Fernandez More articles by this author , Hayley IrusenHayley Irusen More articles by this author , Audrey PentzAudrey Pentz More articles by this author , Maureen JoffeMaureen Joffe More articles by this author , Elvira SinghElvira Singh More articles by this author , Judith JacobsonJudith Jacobson More articles by this author , Alfred NeugutAlfred Neugut More articles by this author , Thomas RohanThomas Rohan More articles by this author , Lamine NiangLamine Niang More articles by this author , Serigne GueyeSerigne Gueye More articles by this author , and Timothy RebbeckTimothy Rebbeck More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002028.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Men of African descent have the highest burden of aggressive prostate cancer (PCa). However, the clinical features of PCa within sub-Saharan Africa (SSA) are understudied. Our objective was to characterize the clinical features of men with PCa in SSA, and to compare demographic/clinical features of PCa between West (WA) and South Africa (SA). METHODS: Between 2016 and 2020, we recruited 2,588 histologically-confirmed PCa patients into a multi-center study in Senegal, Ghana, Nigeria and South Africa via the MADCaP Consortium. Participants completed a detailed questionnaire which collected information on demographics, lifestyle, PCa family history, and lower urinary symptoms (LUTS) assessed through the International Prostatism Symptom Score (IPSS); medical history and PCa clinical features were extracted through review of medical charts. We used Student t-test, Wilcoxon sign-rank test or χ2 test to compare patients’ characteristics by region. RESULTS: Among 2588 men with PCa, 1325 (51.2%) were recruited in WA and 1263 (49.8%) in SA. The majority (78.9%) of patients had high D’Amico risk PCa. PCa patients in WA were older at diagnosis (68.3±8.0 years) compared to SA patients (66.5±8.0, p<0.001). Median PSA at diagnosis was higher in WA cases (93.9, IQR: 26.5-450.9) compared to SA cases (28.5, IQR: 12.8-100.9, p<0.001). PCa cases in WA also had a higher prevalence of moderate/severe LUTS (63.7%) compared to PCa cases in SA (49.4%). Clinically invasive disease (stage T3+) was more prevalent in WA compared to SA (64.5% vs. 20.2%, p<0.001). However, the distribution of aggressive Gleason Group 4-5 PCa was similar between WA (39.9%) and SA (38.1%). The majority of patients were treated with hormone-therapy in both WA (42.2%) and SA (61.8%). However, in SA, a large proportion of patients are treated with radiation therapy (27.6%), while this treatment was rarely used in WA. CONCLUSIONS: Men in Africa present with very high-risk PCa. Patients in WA had characteristics of more advanced disease at presentation than their SA counterparts, indicated by a higher PSA, prevalence of adverse clinical features, and a greater proportion of prostatic symptoms. This data further emphasizes the need for the development of PCa screening guidelines within SSA. Source of Funding: Supported in part by the National Cancer Institute, National Institutes of Health (NIH) Grants No. U01-CA184374 and NIH 5 P30-CA06516 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e516-e517 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohamed Jalloh More articles by this author Denzel Zhu More articles by this author Ilir Agalliu More articles by this author Caroline Andrews More articles by this author Evan Kovac More articles by this author Ben Adusei More articles by this author Nana Yaa Snyper More articles by this author James Mensah More articles by this author Victoria Okyne More articles by this author Ann Hsing More articles by this author Akindele Adebiyi More articles by this author Olufemi Ogunbiyi More articles by this author Olayiwola Shittu More articles by this author Peter Olabode More articles by this author Maxwell Nwegbu More articles by this author Oseremen Aisuodionoe-Shadrach More articles by this author Pedro Fernandez More articles by this author Hayley Irusen More articles by this author Audrey Pentz More articles by this author Maureen Joffe More articles by this author Elvira Singh More articles by this author Judith Jacobson More articles by this author Alfred Neugut More articles by this author Thomas Rohan More articles by this author Lamine Niang More articles by this author Serigne Gueye More articles by this author Timothy Rebbeck More articles by this author Expand All Advertisement PDF downloadLoading ...

Abstract Background: The purpose of this study was to evaluate whether there are differences in distant recurrence rates between Black and White women with localized breast cancer who participated in NCI-sponsored clinical trials, and thus had access to state of the art oncologic care and lacked major comorbidities. Methods: We analyzed pooled data from 10 NSABP trials including 10,364 patients with localized breast cancer treated with adjuvant chemotherapy (AC, n=8147) or neoadjuvant chemotherapy (NAC, n=2217), limited to those with self-reported race that was either Black (n=1006, 10.3%) or White (n=9358, 89.7%). AC/NAC included doxorubicin and cyclophosphamide, with or without a taxane. The association between race (Black vs. White) and distant relapse-free survival (DRFS) was analyzed in the overall population and stratified by AC or NAC use. Log rank tests were used to test for differences in DRFS. Multivariate Cox regression was performed to estimate risk of distant recurrence adjusted for other prognostic covariates including age (continuous), tumor size (> 2 cm vs. < 2 cm), ER expression (positive vs. negative), and nodal status (pathologically positive for AC cohort or clinically positive for NAC cohort vs. negative). Results: In the AC cohort, 7,419 (91%) patients were White and 728 (9%) Black. In the NAC cohort, 1,939 (88%) were White and 278 (12%) Black. Black race was associated with an inferior DRFS in the combined AC/NAC cohort (Logrank p<.0001), and in both the AC and NAC cohorts (Logrank p=0.0008 and p=0.01, respectively). After adjustment for other covariates in multivariate analysis, Black race remained significantly associated with an inferior DRFS in the combined AC/NAC cohort (HR 1.17, [95% CI 1.05-1.31], p=0.004), with similar trends noted in the AC (HR 1.17 [95% CI 1.02-1.33], p=0.03) and NAC cohort (HR 1.21 [95% CI 0.98-1.45], p=0.08). When the AC cohort was analyzed by ER status, Black race was associated with worse DRFS in ER-positive disease (HR 1.32 [95% CI 1.06-1.63], p=0.02), but not ER-negative disease (HR 1.06, [95% CI 0.87-1.30], p=0.57), although there was no statistically significant interaction with ER status (p=0.15). In the NAC cohort, Black women had a higher pathologic complete response (pCR) rate (22% vs 17%, Chi-squared test p=0.03). Black race was associated with a significantly worse DRFS in patients who did not achieve pCR (HR 1.34 [95% CI 1.06-1.63], p=0.01), but not in those who had a pCR (HR 0.89 [95% CI 0.49, 1.61], p=0.71). Conclusion: We observed that Black women with localized breast cancer had higher distant recurrence rates than White women. This and other reports suggest that factors other than social determinants of health may be contributing to racial disparities in breast cancer outcome/progression, most notably in ER-positive disease and patients with residual disease after NAC. Future research is needed to help delineate the biological differences that contribute to these observations. Citation Format: Gina Kim, Jessica M. Pastoriza, Jiyue Qin, Juan Lin, George S. Karagiannis, John S. Condeelis, Greg Yothers, Thomas B. Julian, Stewart J. Anderson, David Entenberg, Thomas E. Rohan, Joseph A. Sparano, Xiaonan Xue, Maja H. Oktay. Racial disparity in localized breast cancer: Pooled analysis of NSABP trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 35.

To the Editor: Lung cancer in never-smokers may be increasing in the United States.1 To further explore these temporal trends, we estimated lung cancer mortality from 1992 to 2011, by linking the National Longitudinal Mortality Study (NLMS)2 and Tobacco Use Supplements (TUS). The NLMS is a prospective study of mortality in combined samples of the civilian noninstitutionalized population.2 NLMS is managed by the Census Bureau and consists of responses to Current Population Surveys (CPS) (response rate >90%),3 linked to mortality data from the National Death Index, which is maintained by the National Center for Health Statistics.4 The CPS supplement is a weighted, national probability sample of households that provides demographic, economic, and social information about the US population. NLMS consists of ≈3.8 million records with >550,000 deaths during 1992–2011. The TUS in CPS collects nationally representative information regarding tobacco use from ≈240,000 adults every 3–4 years since 1992.5 Participants with CPS and TUS responses were eligible for analysis. Never-smokers were defined as those having smoked ≤100 cigarettes in their lifetime. Lung cancer deaths were identified using underlying cause as the cause of death. Age-adjusted mortality rates (per 100,000; adjMRLC) and 95% confidence intervals (CIs), based on the 2000 Standard US population, were estimated using SASv9.4 (Cary, NC). Annual percentage change (APC) in adjMRLC was estimated by the best fit model using joinpoint regression (Joinpointv4.6.0.0, Bethesda, MD). We identified ≈4,900 lung cancer deaths (rounded to nearest 100 per Census regulations). A majority of deaths (86.5%) were among smokers and 13.5% among never-smokers. From 1992 to 2011, the adjMRLC was 86.5 (69.2–106.7), with rates higher among males [116.3 (96.1–139.4)] compared with females [65.6 (50.7–83.5)]. Temporal trends show rates trending downward for males [APC = −1.6 (−2.2 to −1.0)] and, conversely, upward for females [APC = 0.8 (0.3–1.2)] since 1992. Further, those who attained a high school diploma only also experienced a positive APC [=0.9 (0.4–1.3)] since 1992. The adjMRLC suggested an increase over time by ≈20% among smokers [1992–2001: 144.7 (122.1–170.3); 2002–2011: 171.3 (146.6–199.0)] and among never-smokers [1992–2001: 17.5 (10.3–27.8); 2002–2011: 20.8 (12.8–31.9)]. The increase in lung cancer mortality in never-smokers was also seen in each sex [males: 1992–2001: 17.4 (10.2–27.7); 2002–2011: 20.1 (12.3–31.0), females: 1992–2001: 17.5 (10.3–27.8); 2002–2011: 21.3 (13.2–32.5)]. This pattern was also evident among never-smokers by educational attainment [HS: 1992–2001: 10.4 (5.1–18.9); 2002–2011: 12.8 (6.8–22.0)] and annual income [<25,000: 1992–2001: 26.5 (17.4–38.7); 2002–2011: 32.3 (22.1–45.5), 25,000–39,000: 1992–2001: 13.4 (7.2–22.7); 2002–2011: 16.4 (9.4–26.5), >40,000: 1992–2001: 10.1 (4.9–18.5); 2002–2011: 12.5 (6.6–21.6)]. The NLMS-TUS linkage, a nationally representative weighted sample with oversampling of small area and minority groups, is the largest contemporary study of tobacco use and mortality in the United States. We demonstrated that age-adjusted mortality for lung cancer in never-smokers is increasing among males and females despite decreasing mortality rates for lung cancer overall since 1997. Our observed suggestion that rates among never-smokers are increasing over time is consistent with some of the prior literature.6 Our study’s prospective design allows for estimation of mortality trends, which should correlate with incidence given lung cancer’s poor prognosis. Although our lung cancer mortality estimates are consistent with previous NLMS reports,7 they are higher than other national estimates,8 potentially attributed to the increased representation of rural populations in NLMS. Our results suggest lung cancer in never-smokers is a US public health concern. Given the overlapping 95% CIs of the rates for the time periods studied, additional research is warranted to ensure sufficient statistical power to determine if lung cancer in this group is truly increasing. Potentially increasing lung cancer mortality in never smokers indicates the need to further study environmental exposures, their potential interaction with molecular drivers of lung cancer, and how they may inform potential lung cancer screening guidelines in never smokers. ACKNOWLEDGMENTS This paper is released to inform interested parties of research and to encourage discussion. Any views expressed on statistical, methodological, technical, or operational issues are those of the authors and not necessarily those of the US Census Bureau. All results have been reviewed by the Census Bureau’s Disclosure Review Board to ensure that no confidential information is released. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. H. Dean Hosgood, IIIDepartment of Epidemiology andPopulation HealthAlbert Einstein College of MedicineBronx, NY[email protected] Candace CosgroveMortality Research BranchCenter for Administrative Records Researchand Applications United States Census BureauSuitland, MD Madelyn KlugmanThomas RohanDepartment of Epidemiology andPopulation HealthAlbert Einstein College of MedicineBronx, NY Sean AltekruseEpidemiology Branch, Prevention andPopulation Sciences ProgramDivision of Cardiovascular SciencesNational Heart Lung and Blood InstituteNational Institutes of HealthBethesda, MD

Background: Within the normal BMI (body mass index (BMI) of 18.5-24.9kg/m2) category, some individuals may be at increased risk of developing obesity-related cancers. Towards this end, studies have shown positive associations between body fat, particularly in the abdominal region, and cancer-associated metabolic disturbances among normal weight individuals. However, little is known about the association between body fat distribution and risk of obesity-related cancers among normal weight individuals. Thus, in this study, we examined the association of overall and central adiposity, assessed using bioelectrical impedance (BIA)-derived and anthropometric measures, with risk of selected obesity-related cancers among normal weight persons. Methods: The study included normal weight individuals aged 40-70 years who were enrolled in the UK Biobank cohort between 2006 and 2010. BIA-derived and anthropometric body fat measures were taken at baseline by trained staff. Incident tumors were ascertained via linkage to UK cancer registries. Multivariable Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations of the body fat measures with risk of cancers of the breast, endometrium, ovary, colorectum, pancreas, and kidney, and with multiple myeloma. Results: The overall incidence of obesity-related cancers was 2.2 per 1000 person-years of follow-up (N= 2364 incident obesity-related cases among 152,489 subjects with a median follow-up time of 7 years). All measures of central and peripheral adiposity demonstrated linear positive dose-response relationships with risk of postmenopausal invasive breast cancer and with endometrial cancer. For all of the body fat measures, postmenopausal women in the highest quartile showed increased invasive breast cancer risk, after adjusting for potential confounders, compared to women in the lowest quartile, with hazard ratios ranging from 1.29 (95% CI: 1.11-1.50) for the ratio of trunk fat to leg fat mass to 1.59 (95% CI: 1.31-1.93) for trunk fat mass index (TFMI; calculated as trunk fat mass (kg)/height (m)2). For endometrial cancer, only the TFMI (HR: 1.80, 95% CI:1.12-2.88) and waist circumference (HR: 1.70, 95% CI: 1.04-2.80) were positively associated with risk. A waist-to-hip ratio in the highest quartile was also positively associated with colorectal cancer risk among males (HR: 1.56, 95% CI: 1.03-2.37). None of the body fat measures were associated with risk colorectal cancer risk among women or with risk of the remaining cancers. Conclusion: The findings of this study suggest that elevated levels of central and/or overall adiposity may be associated with increased risk of postmenopausal breast cancer, endometrial cancer and probably colorectal cancer (males), among normal weight individuals. Evaluating body composition in those with a normal BMI can potentially identify individuals at increased risk for cancer providing an opportunity for interventions to reduce risk. Citation Format: Rhonda S. Arthur, Mimi Kim, Andrew Dannenberg, Thomas Rohan. Measures of overall and central adiposity in relation to risk of obesity-related cancers among normal weight men and women in the UK Biobank [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3483.

Abstract Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60–2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10–1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04–1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09–1.17)], endometrioid [1.20 (1.10–1.32)], and clear cell [1.37 (1.18–1.58)], but not mucinous [0.99 (0.88–1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

OBJECTIVES/GOALS: There is a high burden of lung cancer in persons living with HIV (PLWH). The role that HIV status, by levels of immune function and viral load, has on survival from lung cancer is not fully understood. The study’s objectives were to assess 1) the association of HIV with survival in non-small cell lung cancer (NSCLC) and 2) prognostic factors in PLWH with NSCLC. METHODS/STUDY POPULATION: Participants were from a cohort of lung cancer patients diagnosed between 2004-2017 in the Bronx, NY, with vital status ascertainment at least annually. We compared survival from NSCLC diagnosis between HIV-negative patients (HIV-, N = 2881) and PLWH (N = 88), using Cox regression, accounting for clinical and sociodemographic factors including smoking status. In three separate comparisons to HIV-, PLWH were dichotomized by CD4 count (<200 vs. ≥200 cells/μL), CD4/CD8 ratio (median, <0.43 vs. ≥0.43) and HIV viral load (VL) suppression (<75 vs. ≥75 copies/mL). In PLWH only, we assessed the relationships of CD4 count, CD4/CD8 ratio, and VL at diagnosis with survival adjusting for age, sex, and cancer stage. CD4 count and CD4/CD8 ratio were also examined as time-varying variables using a counting process approach. RESULTS/ANTICIPATED RESULTS: PLWH were younger (median 56 years, IQR 51-52 vs. 68, IQR 60-76) and more likely to be current smokers (58% vs. 37%) at diagnosis than HIV- patients. Median survival was lower in PLWH [1.1 years, 95% confidence interval (95%CI): 0.6-1.3] than in HIV- [1.6 (1.5-1.7)]. Survival comparing PLWH with higher CD4/CD8 to HIV- was similar [hazard ratio (HR), 95%CI: 0.63 (0.37-1.07)], but those with lower CD4/CD8 experienced worse survival (HR = 1.74, 95%CI: 1.07-3.89). Among PLWH, having a CD4 count < 200 cells/μL was associated with over twice the risk of death compared to those with CD4 ≥ 200 cells/μL (HR = 2.37, 95%CI: 1.14-4.92). VL and CD4/CD8 ratio were not associated with survival. Lower time-updated CD4 count was also associated with worse survival (HR = 2.19 for CD4 <200 vs. >200 cells/μL, 95%CI: 1.16-4.13). DISCUSSION/SIGNIFICANCE OF IMPACT: Among persons with NSCLC, CD4/CD8 ratio nearest diagnosis was shown to distinguish mortality risk in PLWH compared with HIV- patients. In addition, PLWH with low CD4 had worse prognosis than PLWH who had higher CD4 counts. These results suggest HIV immune status to be an essential component influencing survival in lung cancer.

Abstract Background: Breast cancer outcomes from the Women’s Health Initiative (WHI) Estrogen plus Progestin and Estrogen-alone trials have been reported but issues remain regarding long- term, post-intervention influence on breast cancer incidence and the influence of time from menopause to hormone therapy initiation (gap time) on breast cancer findings. Design and methods: Postmenopausal women aged 50 to 79 years with no prior breast cancer and with mammogram clearance enrolled in one of two randomized clinical trials at 40 US centers from 1993 to1998, with follow up through September, 2016. The randomized, placebo-controlled trial interventions were: conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8,506) vs placebo (n = 8,102) for 5.6 years (median) for women with a uterus or CEE-alone (n = 5,310) vs placebo (n = 5,429) for 7.2 years (median) for women with prior hysterectomy. Annual mammography was mandated through the originally specified completion date in both trials (March 31, 2005). Incident breast cancers were verified by medical record review. Hazard ratios (HRs) were estimated using multi-variable Cox proportional hazards models. The primary outcome for these analyses was time-specific invasive breast cancer incidence rates. In each trial, participants were instructed to stop all study pills coincident with the publication of each trial’s results, in 2002 and 2004, respectively. Results: During the intervention period, with 238 incident breast cancers, CEE-alone significantly reduced breast cancer incidence (hazard ratio [HR] 0.76 95% confidence interval [CI] 0.58, 0.98, P = 0.04). As previously reported, subgroup analyses indicated CEE-alone was particularly beneficial for women with no prior HT use (interaction P = 0.04) and women with gap time >= 5 years (interaction P = 0.01). Post-intervention, through 16.1 years of cumulative follow-up, with 520 incident breast cancers, CEE-alone use continued to significantly reduce breast cancer incidence (HR 0.77 95% CI 0.65-0.92, P = 0.005) while subgroup differences were attenuated and were no longer statistically significant. During the intervention period, with 360 incident breast cancers, CEE plus MPA use significantly increased breast cancer incidence (HR 1.26 95% CI 1.02, 1.56, P = 0.04) with increase in breast cancer incidence greater in women with prior HT use (interaction P = 0.02) and women with gap time < 5 years (interaction P = 0.002). Post-intervention, through 18.3 years cumulative follow-up, with 1,003 incident breast cancers, CEE plus MPA continued to significantly increase breast cancer incidence (HR 1.29 95% CI 1.14, 1.47, P < 0.001) while subgroup differences were attenuated and were no longer statistically significant. Conclusions: CEE-alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions: all postmenopausal women with prior hysterectomy using CEE-alone have the potential benefit of experiencing a reduction in breast cancer incidence while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence. Citation Format: Rowan T Chlebowski, Garnet L Anderson, Aaron K Aragaki, JoAnn E Manson, Marcia Stefanick, Kathy Pan, Wendy Barrington, Lewis H Kuller, Michael S. Simon, Dorothy Lane, Karen C Johnson, Thomas E. Rohan, Margery L.S. Gass, Jane A Cauley, Electra D. Paskett, Maryam Sattari, Ross L Prentice. Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women's Health Initiative randomized trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-00.

Background: Many genetic variants have been associated with increased risk of breast cancer. In contrast, an overall healthy lifestyle has been associated with a reduced risk. However, the degree to which an overall healthy lifestyle may attenuate the impact of genetic variants on risk of breast cancer remains equivocal. In this study, we examined the association of a healthy lifestyle index (HLI) with risk of breast cancer by genetic risk groups. Methods: The study included 106,814 postmenopausal women of white descent aged 40 to 70 years who were enrolled in the UK Biobank cohort between 2006 and 2010. The HLI was based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry (ranging from 0 to 20, with the higher scores representing more favorable lifestyle). A polygenic risk score (categorized as low, intermediate and high) was generated as the sum of risk alleles weighted by the logOR of 117 breast cancer associated single nucleotide polymorphisms. A total of 1,949 incident invasive breast cancer cases were ascertained after a median follow-up of 5.7 years. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association of a healthy lifestyle risk score with risk of breast cancer by genetic risk groups. Results: Compared to women with an unfavorable lifestyle (lowest quartile), women with a favorable lifestyle (highest quartile) had a 32% reduced risk of invasive breast cancer (HR: 0.68: 0.59, 0.79). Women with high genetic risk (highest tertile) had an 86% increased risk of invasive breast cancer (1.86: 1.66, 2.08) compared to those with low genetic risk (lowest tertile). Compared with women who had an unfavorable lifestyle, a favorable lifestyle did not significantly reduce risk of invasive breast cancer among women with low genetic risk (0.80: 0.63-1.02), while women with a favorable lifestyle had 32% and 43% reduced risk of invasive breast cancer in the intermediate and high genetic risk categories, respectively (0.68: 0.53, 0.86 and 0.57; 0.44, 0.74, respectively). However, interaction between the genetic score and the lifestyle score did not achieve statistical significance (pinteraction=0.162). Conclusion: This study suggests that an overall healthy lifestyle may attenuate the impact of genetics on risk of breast cancer, particularly among women with intermediate and high genetic risk. Citation Format: Rhonda S. Arthur, Tao Wang, Thomas Rohan. The interplay between lifestyle-related factors and genetics with risk of invasive breast cancer among postmenopausal women from the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 963.

Introduction: Excess body weight characterized by higher BMI is associated with increased risk of cardiovascular disease (CVD). In individuals with normal BMI, the extent to which body fat distribution may impact CVD risk is unclear, particularly in postmenopausal women who often experience fat redistribution. Hypothesis: We hypothesized a detrimental impact of trunk fat and a favorable impact of leg fat on risk of CVD risk among postmenopausal women with normal BMI. Methods: We analyzed data from 2683 normal-weight (BMI: 18.5-24.9 kg/m 2 ) women in the Women’s Health Initiative study without known CVD at baseline (1993-1998). Body composition including whole body and regional fat mass (FM) were determined by dual-energy X-ray absorptiometry. Incident CVD events including coronary heart disease (coronary death, nonfatal myocardial infarction, or coronary revascularization) and stroke were ascertained through February 2017. Results: There were 291 incident cases of CVD during a median 17.9 years of follow-up. After multivariable adjustment, whole body FM or FM percentage was not significantly associated with CVD risk. Higher trunk FM percentage was associated with increased risk of CVD (HR comparing extreme quartiles = 1.91, 95% CI: 1.33-2.74, P -trend <0.001), while higher leg FM percentage was associated with lower risk of CVD (HR = 0.62, 95% CI: 0.43-0.89, P -trend = 0.008) ( Figure ). These associations were slightly attenuated but remained significant after further adjustment for waist circumference or waist-to-hip ratio. Higher trunk fat combined with lower leg fat was associated with particularly higher risk of CVD (HR comparing extreme groups = 3.33, 95% CI: 1.46-7.62). Similar significant associations of trunk fat and leg fat were observed for coronary heart disease but not for stroke. Conclusions: Among postmenopausal women with normal BMI, higher trunk fat was associated with increased risk of CVD, while higher leg fat was associated with decreased risk of CVD, independently of central adiposity measures.

The third category for extent of involution in Table 4 was published incorrectly in the original publication. The correct classification is ≥ 75% and the corrected Table 4 is given in the Correction article.

Abstract Background: Genome-wide association studies (GWAS) have identified associations of telomere maintenance genes with breast cancer risk. This, coupled with the recognized role of telomere dysfunction as a cancer hallmark, has motivated the need for further study of telomeres and breast cancer. Further, the meta-GWAS discovery of seven single nucleotide polymorphisms (SNPs) associated with telomere length (TL) enables the use of an aggregated genetic risk score (GRS) for TL. We hypothesized that a higher GRS (representing shorter TL) would be associated with increased risk of breast cancer, and that a strengthened association may exist between higher TL GRS and aggressive breast cancer risk. Methods: In a race/ethnically diverse sample of invasive breast cancer cases (N=1,108) and non-cases (N=20,023) from the Women’s Health Initiative, we derived an unweighted TL GRS using seven previously identified TL-associated SNPs. Women were postmenopausal and the average age at enrollment was 63.9 years. We tested TL GRS associations with overall breast cancer risk and for estrogen receptor (ER), progesterone receptor (PR), and her2/neu (HER2) status-specific breast cancer risk using Cox proportional hazards models adjusted for age and race/ethnicity (in the entire sample) and age in strata of European American (EA; N=9,796), African American (AA; N=7,504), and Hispanic American (HA; N=3,229) women. We also considered reproductive risk factors, family history of breast cancer, hormone therapy, tumor characteristics, BMI, physical activity, smoking, alcohol, and US region as potential confounders. Results: We observed a small but statistically significant association between higher TL GRS (shorter TL) and reduced risk of overall breast cancer in the entire sample (HR=0.96, 95% CI: 0.93-1.00). Results of race/ethnicity-stratified analyses for TL GRS and overall breast cancer risk were not significant. The TL GRS was independently associated with decreased risk of ER-negative, PR-positive, and HER2-positive breast cancer risk in the entire sample (HR=0.82, 95% CI: 0.71-0.94, HR=0.94, 95% CI: 0.89-0.99, and HR=0.88, 95% CI: 0.79-0.99, respectively). Similarly, the TL GRS was associated with a reduced risk of ER-negative breast cancer in AA (HR=0.79, 95% CI: 0.64-0.97) and independently with PR-positive and HER2-positive breast cancer risk in HA (HR=0.85, 95% CI: 0.75-0.97 and HR=0.79, 95% CI: 0.58-0.99, respectively). Adjustment for other covariates did not influence hazards. Conclusions: Our results suggest that higher TL GRS is associated with reduced risk of overall breast cancer and with the development of specific breast cancer subtypes, such as ER negativity and/or PR and HER2 positivity. While our focus on GWAS-implicated SNPs may not encompass the full spectrum of genes involved in TL, further studies into the potential mechanism for shorter TL and reduced breast cancer risk are needed. Citation Format: Laurie Grieshober, Jean Wactawski-Wende, Rachael Hageman Blair, Lina Mu, Leah Preus, Jing Nie, Jiali Han, Jaymie R. Meliker, Thomas Rohan, Heather M. Ochs-Balcom. Telomere length genetic risk score is associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1288. doi:10.1158/1538-7445.AM2017-1288