Sherman, Mark

Abstract Polycystic ovarian syndrome (PCOS) is a complex health condition associated with metabolic disturbances and infertility. Recent data suggest that the prevalence of PCOS is increasing among women globally, although the etiology of these trends is undefined. Consequently, preclinical models that better reflect the biology of PCOS are urgently needed to facilitate research that can lead to the discovery of prevention strategies or improved management. The existing animal models have several limitations as they do not reflect all the PCOS features metabolically and/or phenotypically. Therefore, there is no clear consensus on the use of appropriate animal model and selection of the most appropriate PCOS-inducing agent. To that end, we have established a Swiss albino mouse model of PCOS based on 3 weeks of daily treatment with letrozole (50 μg/day; intraperitoneal) and dehydroepiandrosterone (DHEA, 6 mg/100 g body weight; subcutaneous) in 5-week-old female mice fed on normal or high-fat diet (HFD). Mice were regularly assessed for body weight, blood glucose, and estrous cycle. Three weeks after drug administration, mice were sacrificed and assessed for blood-based metabolic parameters as well as ovarian function. Our results indicate that DHEA combined with HFD produces changes mimicking those of clinical PCOS, including elevated serum testosterone and luteinizing hormone, dyslipidemia, poor ovarian microenvironment, and development of multiple ovarian cysts, recapitulating cardinal features of PCOS. In comparison, normal diet and/or letrozole produced fewer features of PCOS. The data from the experimental models presented here can improve our understanding of PCOS, a growing concern in women’s health.

Abstract Background Mammographic breast density (MBD) decline post-tamoxifen initiation is a favorable prognostic factor in estrogen receptor (ER)–positive breast cancer (BC) and has potential utility as a biomarker of tamoxifen response. However, the prognostic value of MBD decline may vary by molecular characteristics among ER–positive patients. Methods We investigated associations between MBD decline (≥10% vs <10%) and breast cancer–specific mortality (BCSM) among ER–positive breast cancer patients aged 36-87 years at diagnosis treated with tamoxifen at Kaiser Permanente Northwest (1990-2008). Patients who died of BC (case patients; n = 62) were compared with those who did not (control patients; n = 215) overall and by tumor molecular characteristics (immunohistochemistry [IHC]–based subtype [luminal A–like: ER–positive/progesterone receptor [PR]–positive/HER2–negative/low Ki67; luminal B–like: ER–positive and 1 or more of PR–negative, HER2–positive, high Ki67] and modified IHC [mIHC]–based recurrence score of ER/PR/Ki67). Percent MBD was measured in the unaffected breast at baseline mammogram (mean = 6 months before tamoxifen initiation) and follow-up (mean = 12 months post-tamoxifen initiation). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models. All statistical tests were 2-sided. Results MBD decline was statistically significantly associated with reduced risk of BCSM overall (OR = 0.38, 95% CI = 0.15 to 0.92). This association was, however, stronger among women with aggressive tumor characteristics including luminal B–like (OR = 0.17, 95% CI = 0.04 to 0.73) vs A–like (OR = 0.74, 95% CI = 0.19 to 2.92); large (OR = 0.26, 95% CI = 0.08 to 0.78) vs small (OR = 0.41, 95% CI = 0.04 to 3.79) tumors; PR–negative (OR = 0.02, 95% CI = 0.001 to 0.37) vs PR–positive (OR = 0.50, 95% CI = 0.18 to 1.40) disease; and high (OR = 0.25, 95% CI = 0.07 to 0.93) vs low (OR = 0.44, 95% CI = 0.10 to 2.09) mIHC3 score. Conclusion The findings support MBD decline as a prognostic marker of tamoxifen response among patients with aggressive ER–positive BC phenotypes, for whom understanding treatment effectiveness is critical.

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.