McCullough, Lauren E.

Abstract Breast cancer rates among women younger than 50 years-old have been steadily increasing since the mid-1990s. There is consistent evidence that use of combination estrogen and progesterone oral contraceptives (OCs)—including contemporary formulations with lower estrogen—increases breast cancer risk. It is unclear, however, if this risk varies by factors such as progestin type in the OC formulation, timing of OC use, histopathologic characteristics of the breast cancer, or individual patient characteristics. This study included premenopausal women aged <50 years and cancer-free when they enrolled in the U.S.-based American Cancer Society Cancer Prevention Study-3 cohort between 2006 and 2013 (n=101,838 women). At enrollment participants responded to a detailed life history questionnaire including questions about type, brand, duration, and recency of OC use. Incident breast cancers diagnosed between 2006-2018 were identified through cancer registry linkages (n=759). Participants were followed until the first of 1) breast cancer diagnosis, 2) age >50 years, or 3) December 31, 2018. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate associations between OC use and breast cancer risk. On average, participants were 39.3 years at baseline and were followed for 5.7 years (up to 12.3 years). Current versus never use of OCs for 10+ years was associated with a higher risk of breast cancer (10-<20 years: HR=1.46, 95% CI: 1.03-2.07; 20-<30 years: HR=1.66, 95% CI: 1.14-2.41; 30+ years HR= 2.51, 95% CI: 0.77-8.16). Cessation of OC use progressively attenuated the association down to the null 15 years after discontinuation of use (HR=1.04, 95% CI: 0.73-1.49). Associations with current OC use varied by generation of progestin in the formulation (first generation: HR=1.37, 95% CI: 0.93-2.02; second: HR=1.79, 95% CI: 1.20-2.67; third: HR=1.65, 95% CI: 1.13-2.42; fourth: HR= 0.91, 95% CI: 0.49-1.67). The strongest associations were observed for use of formulations with norgestrel: HR=2.82, 95% CI: 1.54-5.19; norgestimate: HR=1.80, 95% CI: 1.19-2.72; and levonorgestrel: HR=1.56, 95% CI: 1.00-2.43. The OC-breast cancer associations were primarily limited to localized, grade 1 or 2, and ER+ disease. Race, income, body mass index, physical activity, alcohol use, cigarette smoking, parity, and breastfeeding did not appear to modify the associations. There were also no clear differences in the associations based on age at first or last OC use or timing relative to pregnancy. Current, long-term OC use was associated with increased risk of early-onset breast cancer. These data suggest that risks may vary with progestin content, and future studies are needed to define formulations that minimize breast cancer risk while still maximizing protection against other female cancers. Citation Format: Lauren R. Teras, Emily L. Deubler, Mark E. Sherman, Clara Bodelon, Lauren E. McCullough, James M. Hodge, Sicha Chantaprasopsuk, Alpa V. Patel. Factors modifying the association between hormonal contraception and risk of early-onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3442.

Abstract Background: Crown-like structures in breast adipose tissue (CLS-B), indicative of proinflammatory conditions, are most frequently observed among obese (body mass index, BMI ≥30 kg/m2) women and may contribute to poor prognosis in this group. African-American (AA) women have disproportionately higher rates of obesity than White women, and at least one prior study suggests the prevalence of CLS-B may be higher among AA women. However, most previous studies have examined CLS-B within affected tissues, which may reflect inflammation in the tumor microenvironment, and few have examined the association between CLS-B and clinical outcomes by race. Methods: We examined the presence of CLS-B detected by CD68 immunohistochemistry in normal adjacent breast tissue from a quadrant uninvolved by tumor obtained via mastectomy among 174 African-American women and 168 White women with stage I—III breast cancer diagnosed at Emory University Hospitals (2007—2012). We also investigated associations between CLS-B and other demographic and lifestyle factors at diagnosis (e.g., BMI, smoking status, age at menarche, parity, lactation, menopausal status, hormone replacement therapy use, and family history of breast cancer). Patients were followed for an average of seven years after diagnosis for recurrence and survival. Multivariable Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) for associations between CLS-B presence and progression-free survival (PFS), controlling for BMI and other potential confounders. Results: Median age at diagnosis for both AA and White women was 54 years, with more than 60% postmenopausal among both groups. AA women were more likely than White women to be obese (52% vs. 24%) and have ER- tumors (30% vs. 12%). Presence of any CLS-B was similar between AA (32%) and White (29%) patients. In multivariable models, we did not find any association between CLS-B and race (HR=1.14, 95% CI: 0.72, 1.82) with the only statistically significant factors being BMI (≥30 vs. 18.5-<25 kg/m2: HR=4.36, 95% CI: 2.17, 8.76) and parity (1+ vs. 0 births: HR=0.43, 95% CI: 0.21, 0.91). Over follow-up, 46 breast cancer recurrences and 52 deaths (23 from breast cancer) occurred. Overall, the presence of CLS-B was not associated with PFS (multivariable HR: 0.97, 95% CI: 0.58, 1.62). When examined by race, there was a difference in the direction of the association between CLS-B and PFS among AA women (HR=1.25, 95% CI: 0.64, 2.46) compared to White women (HR=0.75, 95% CI: 0.33, 1.71), although this difference was not statistically significant (P=0.86). Conclusion: Our results show a strong, positive association between BMI and CLS-B in non-tumor tissue and an inverse association with parity. We did not observe a difference in CLS-B presence by race nor did we find CLS-B to be associated with worse progression-free survival, which is in contrast to previous studies that have examined the presence of CLS-B within specimens in close proximity to the tumor. Citation Format: Aswathy M Cheriyan, Mark E Sherman, Yuan Liu, Keerthi Gogineni, Jiaqi Liu, Jiabei He, Uma Krishnamurti, Ryan Ashiqueali, Jinjing He, Rami Yacoub, Jasmine Miller-Kleinhenz, Lauren E McCullough, Maret L Maliniak. Presence of crown-like structures in breast adipose tissue and clinical outcomes among African-American and White breast cancer patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C074.

Abstract Background: Racial disparities in breast cancer outcomes persist in the US, in which black women are more likely to die from breast cancer than white women. Despite levels of mammographic screening comparable to the US, Atlanta has a disproportionate burden of late-stage breast tumors and higher mortality rates, especially among black women. To better understand this disparity, we sought to identify tumor, treatment, and patient characteristics that may contribute to the observed differences in breast cancer mortality between black and white women in the metropolitan Atlanta area. Methods: In this study, patients were identified from the Georgia Cancer Registry. We included 4943 non-Hispanic white and 3580 non-Hispanic black women with an initial diagnosis of stage I-IV primary breast cancer between January 2010 and December 2014 in Atlanta. Cox proportional hazard regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to compare black vs. white breast cancer mortality by tumor (stage, grade, ER status, and molecular subtype), treatment (surgery type, receipt of chemotherapy, radiation, hormone therapy, and trastuzumab), and patient (insurance, marital status, SES, and location of service) characteristics. We performed a mediation analysis to evaluate the contribution of subtype, stage, and socioeconomic status (SES) as mediators on the path between race and breast cancer mortality. Results: Compared with white breast cancer patients, black women were younger with tumors that were higher stage, higher grade, and more likely to be larger, node positive and triple negative. In fully adjusted models, black women diagnosed with Luminal A subtype were 58% more likely to die of breast cancer compared to their white counterparts (HR=1.58, 95%CI 1.31-2.00). Similarly, black women with private insurance were 60% more likely to die of breast cancer (HR=1.61, 95%CI 1.25-1.98), and black women in the highest SES group were more than twice as likely to die from breast cancer (HR=2.26, 95%CI 1.26-4.06) than white women with comparable SES. The smallest disparities in breast cancer mortality by race were observed among women without insurance, in the lowest SES index, or those diagnosed with triple-negative breast cancer. The mediation analysis showed 84.8% of the effect between race and breast cancer mortality was through stage, subtype, and SES. Conclusion: Our results indicate variation in racial disparities in breast cancer mortality by tumor and patient characteristics. Consistent with previous reports, our mediation results suggest that later stage and triple-negative subtype among black women are major contributors of the observed disparity. However, our results also shed new light on the disparity, suggesting that the largest disparities are observed among women with ER+ tumors amenable to adjuvant therapies and are most pronounced among women of high SES. More research is needed to understand the drivers of disparities in these treatable tumors. Citation Format: Lindsay J. Collin, Renjian Jiang, Kevin C. Ward, Keerthi Gogineni, Preeti D. Subhedar, Mark Sherman, Mia M. Gaudet, Carmen Radecki Breitkopf, Olivia D'Angelo, Sheryl Gabram-Mendola, Jolie Siegel, Rana Aneja, Anne Gaglioti, Lauren E. McCullough. Identification of factors contributing to breast cancer mortality disparities in the metropolitan Atlanta area [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C053.

AbstractBackgroundRacial disparities in breast cancer (BC) outcomes persist where non-Hispanic black (NHB) women are more likely to die from BC than non-Hispanic white (NHW) women, and the extent of this disparity varies geographically. We evaluated tumor, treatment, and patient characteristics that contribute to racial differences in BC mortality in Atlanta, Georgia, where the disparity was previously characterized as especially large.MethodsWe identified 4943 NHW and 3580 NHB women in the Georgia Cancer Registry with stage I–IV BC diagnoses in Atlanta (2010–2014). We used Cox proportional hazard regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) comparing NHB vs NHW BC mortality by tumor, treatment, and patient characteristics on the additive and multiplicative scales. We additionally estimated the mediating effects of these characteristics on the association between race and BC mortality.ResultsAt diagnosis, NHB women were younger—with higher stage, node-positive, and triple-negative tumors relative to NHW women. In age-adjusted models, NHB women with luminal A disease had a 2.43 times higher rate of BC mortality compared to their NHW counterparts (95% CI = 1.99 to 2.97). High socioeconomic status (SES) NHB women had more than twice the mortality rates than their white counterparts (HR = 2.67, 95% CI = 1.65 to 4.33). Racial disparities among women without insurance, in the lowest SES index, or diagnosed with triple-negative BC were less pronounced.ConclusionsIn Atlanta, the largest racial disparities are observed in luminal tumors and most pronounced among women of high SES. More research is needed to understand drivers of disparities within these treatable features.