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Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2− tumors may have different tumor biology and treatment response compared to postmenopausal patients. Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2− EBC in monarchE. Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated. Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician’s choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months). Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population. Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Background Uncontrolled blood pressure (BP) remains a leading cause of death in the United States. The American Medical Association developed a quality improvement program to improve BP control, but it is unclear how to efficiently implement this program at scale across multiple health systems. Methods and Results We conducted BP MAP (Blood Pressure Measure Accurately, Act Rapidly, and Partner With Patients), a comparative effectiveness trial with clinic‐level randomization to compare 2 scalable versions of the quality improvement program: Full Support (with support from quality improvement expert) and Self‐Guided (using only online materials). Outcomes were clinic‐level BP control (<140/90 mm Hg) and other BP‐related process metrics calculated using electronic health record data. Difference‐in‐differences were used to compare changes in outcomes from baseline to 6 months, between intervention arms, and to a nonrandomized Usual Care arm composed of 18 health systems. A total of 24 safety‐net clinics in 9 different health systems underwent randomization and then simultaneous implementation. BP control increased from 56.7% to 59.1% in the Full Support arm, and 62.0% to 63.1% in the Self‐Guided arm, whereas BP control dropped slightly from 61.3% to 60.9% in the Usual Care arm. The between‐group differences‐in‐differences were not statistically significant (Full Support versus Self‐Guided=+1.2% [95% CI, −3.2% to 5.6%], P =0.59; Full Support versus Usual Care=+3.2% [−0.5% to 6.9%], P =0.09; Self‐Guided versus Usual Care=+2.0% [−0.4% to 4.5%], P =0.10). Conclusions In this randomized trial, 2 methods of implementing a quality improvement intervention in 24 safety net clinics led to modest improvements in BP control that were not statistically significant. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03818659.

AbstractProblemIt is now recognized that SARS‐CoV‐2 infection and pandemic‐related stress impacts maternal health. However, their effects at the maternal‐fetal interface are still debated.Method of studyWe recruited 199 women between March 2020 and July 2021, 79 SARS‐CoV‐2+ and 120 negative (the latter exposed to pandemic stress only). We also included 40 historic controls (i.e. pre‐pandemic uncomplicated pregnancies recruited before March 2020). Placental samples were collected for protein and histological analysis.ResultsThe majority of SARS‐CoV‐2+ women were multiethnic, had higher pre‐pregnancy BMI and elevated preterm birth rate (17%) vs SARS‐CoV‐2– or historic control. Placental inflammatory profile revealed increased IL‐1Ra and CRP, independently of SARS‐CoV‐2 status, whilst MCP‐1, IL‐6 and IFNγ were elevated in the negative, but pandemic stress‐exposed, group. These changes were predominant in placentas with inflammatory lesions on histopathological analysis. Furthermore, we observed elevated immune cells (CD45+) in placentas from SARS‐CoV‐2+ and negative pregnancies vs historic controls, even when individuals with pregnancy complications were excluded.ConclusionsPlacental inflammatory profiles differed between SARS‐CoV‐2 statuses, namely exposed to pandemic stress +/‐ SARS‐CoV‐2 infection. This highlights the need to understand the differences between the effects of pandemic‐related stress and the added burden of SARS‐CoV‐2 infection on placental health.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Abstract Introduction Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and positive sinonasal bacterial cultures may be recalcitrant to topical therapy alone due to the additional local inflammatory burden associated with bacterial infection/colonization. Objective To evaluate sinonasal outcomes in CRSwNP patients with a positive perioperative bacterial culture, who were treated with postoperative intranasal corticosteroids (INCS) alone versus INCS in combination with a short-term course of oral corticosteroids (OCS). Methods This is a retrospective chart review of CRSwNP patients. A total of 59 patients met inclusion criteria, including positive perioperative bacterial culture and treatment with INCS with or without concomitant use of OCS. Two cohorts were formed based on the chosen postoperative medical treatment; 32 patients underwent postoperative INCS alone, while 27 underwent INCS plus a ≤ 2-week course of OCS. The 22-item sinonasal outcome test (SNOT-22) scores and Lund-Kennedy scores (LKS) were assessed preoperatively, and at 2-week, 4-week, and 4 to 6 months after endoscopic sinus surgery (ESS). Results There were no statistically significant differences in postoperative sinonasal symptoms or endoscopic scores between the cohorts treated with INCS plus OCS versus those prescribed INCS alone (p > 0.05). Our regression model failed to demonstrate a relationship between the use of OCS and better sinonasal outcomes at 2-week, 4-week, and 4 to 6 months after ESS (p > 0.05). Conclusion Our study suggests that in a cohort of CRSwNP patients with recent bacterial infections, the postoperative use of combined OCS and INCS did not result in a statistical improvement of endoscopic and symptomatic outcomes over INCS irrigation alone. However, both treatment groups had a clinically significant improvement based on the Minimal Clinically Important Difference.

Importance Only modest attention has been paid to the contributions of social determinants of health to atrial fibrillation (AF) risk factors, diagnosis, symptoms, management, and outcomes. The diagnosis of AF provides unique challenges exacerbated by the arrhythmia’s often paroxysmal nature and individuals’ disparate access to health care and technologies that facilitate detection. Social determinants of health affect access to care and management decisions for AF, increasing the likelihood of adverse outcomes among individuals who experience systemic disadvantages. Developing effective approaches to address modifiable social determinants of health requires research to eliminate the substantive inequities in health care delivery and outcomes in AF. Observations The National Heart, Lung, and Blood Institute convened an expert panel to identify major knowledge gaps and research opportunities in the field of social determinants of AF. The workshop addressed the following social determinants: (1) socioeconomic status and access to care; (2) health literacy; (3) race, ethnicity, and racism; (4) sex and gender; (5) shared decision-making in systemically disadvantaged populations; and (6) place, including rurality, neighborhood, and community. Many individuals with AF have multiple adverse social determinants, which may cluster in the individual and in systemically disadvantaged places (eg, rural locations, urban neighborhoods). Cumulative disadvantages may accumulate over the life course and contribute to inequities in the diagnosis, management, and outcomes in AF. Conclusions and Relevance Workshop participants identified multiple critical research questions and approaches to catalyze social determinants of health research that address the distinctive aspects of AF. The long-term aspiration of this work is to eradicate the substantive inequities in AF diagnosis, management, and outcomes across populations.