Abstract
Introduction: The advent of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has transformed the clinical practice of HR+/HER2- metastatic breast cancer. Palbociclib, ribociclib, and ...abemaciclib have been approved in conjunction with anti-estrogens, while abemaciclib has also been approved as monotherapy based on single agent activity in the MONARCH-1 trial (objective response rate/ORR: 19.7% and median progression-free-survival/PFS = 6.0 months; Dickler M et al CCR 2017). However, there is limited insight into the mechanisms governing resistance to CDK 4/6i and the potential utility of continued CDK4/6i after progression on a prior CDK 4/6i-based therapy.
Methods: We evaluated the clinical outcomes of patients with metastatic HR+/HER2- breast cancer who had received abemaciclib following an initial course of palbociclib-based therapy at our institution. In addition, we conducted genomic analysis utilizing next-generation sequencing of tissue samples and blood (cell-free DNA/cfDNA analysis) where available.
Results: From June, 2014 through July, 2018, a total of 49 patients received abemaciclib, and 14 patients had prior palbociclib exposure. One patient was deceased shortly after initiating abemaciclib and one patient was lost to follow-up. Among the 12 remaining patients, eight had sequential courses of CDK4/6-based therapy, while four patients had at least one intervening non-CDK 4/6i based regimen. At data-cutoff of 8/15/2018, five patients (41.7%) had early progression on abemaciclib (PFS equal to or less than 120 days) while three (25%) patients had ongoing benefit (PFS greater than 120 days, two of three actively on therapy). Three additional patients had recently initiated abemaciclib therapy (less than 120 days prior to current analysis). Preliminary analysis of baseline cfDNA results in patients with early progression on abemaciclib therapy after prior CDK4/6i revealed the presence of RB1 mutation, FGFR1 amplification, and TP53 mutation, among others. Additional analyses with mature clinical data (including updated PFS and ORR), toxicity assessment during secondary CDK4/6i exposure, and further analysis of genomic sequencing results will be provided at the meeting.
Conclusions: The majority of patients had early disease progression on abemaciclib after prior exposure to CDK4/6i suggesting potential cross-resistance to CDK4/6i mediated by common drivers. However, a subset of patients derived clinical benefit with continued exposure to CDK4/6i, highlighting the need for additional research to evaluate potential predictive biomarkers and guide rational utilization of continued CDK4/6 blockade in metastatic HR+/HER2- breast cancer.
Citation Format: Wander SA, Spring LM, Stein CR, Yuen M, Zangardi M, O'Shaughnessy J, Bardia A. Abemaciclib after prior palbociclib exposure in patients with metastatic hormone-receptor positive (HR+)/HER2- breast cancer abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-39.
The Electron Ion Collider (EIC) is the next generation of precision QCD facility to be built at Brookhaven National Laboratory in conjunction with Thomas Jefferson National Laboratory. There are a ...significant number of software and computing challenges that need to be overcome at the EIC. During the EIC detector proposal development period, the ECCE consortium began identifying and addressing these challenges in the process of producing a complete detector proposal based upon detailed detector and physics simulations. In this document, the software and computing efforts to produce this proposal are discussed; furthermore, the computing and software model and resources required for the future of ECCE are described.
Acne vulgaris (AV) is the eighth most common non-fatal disease globally. Previous work identified an association between AV and increased Filaggrin (FLG) expression in the follicular epidermis, but ...further work did not find a clear link between loss of function (LoF) Filaggrin gene (FLG) mutations and protection from AV. In this work we aimed to explore any association between AV and FLG LoF mutations using a cohort of genotyped Bangladeshi patients with atopic eczema (AE) in East London. Retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone clinical assessment. The Chi squared or Fisher's exact test was used to determine differences between groups. We found a significant reduction in history of AV in AE patients with FLG LoF mutations relative to AE patients without FLG mutations (p = 0.02). We showed a non-significant reduction in AV diagnosis in patients with impaired barrier function (measured by trans epidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (p = 0.02). In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV.
An up-to-date catalog of nearby galaxies considered to be hosts of binary compact objects is provided, with complete information about sky position, distance, extinction-corrected blue luminosity, ...and error estimates. With our current understanding of binary evolution, rates of formation and coalescence for binary compact objects scale with massive-star formation, and hence the (extinction-corrected) blue luminosity of host galaxies. Coalescence events in binary compact objects are among the most promising gravitational-wave sources for ground-based gravitational-wave detectors such as LIGO. Our catalog and associated error estimates are important for the interpretation of analyses carried out for LIGO, in constraining the rates of compact binary coalescence, given an astrophysical population model for the sources considered. We discuss how the notion of effective distance, created to account for the antenna pattern of a gravitational-wave detector, must be used in conjunction with our catalog. We also note that the catalog provided can be used in other astronomical analysis of populations that scale with galaxy blue luminosity.
In the High Plains, corn (Zea mays L.) is an important commodity for livestock feed. However, limited water resources and drought conditions continue to hinder corn production. Drought-tolerant (DT) ...corn hybrids could help maintain high yields under water-limited conditions, though consistent response of such hybrids is unverified. In this two-year study, the effects of three irrigation treatments were investigated for a DT and conventional maize hybrid, Pioneer AQUAMax P0876HR and Pioneer 33Y75, respectively. In 2013, the drier of the 2Â years, irrigation amounts and crop water use (ETc) were greater for the conventional hybrid, but grain water use efficiency (WUE) and harvest index were significantly greater for the DT hybrid. In 2014, grain yields and WUE were not significantly different between hybrids. However, irrigation amounts, ETc and biomass yields were greater for the conventional hybrid. Results from both years indicate that the DT hybrid required less water to maximize grain yield as compared to the conventional hybrid. Producing relatively high yields with reduced amounts of water may provide a means for producers to continue corn production in a semiarid environment with declining water supplies.
Each year, approximately 71% of new early career psychologists are women, yet no empirical research has examined the unique career adjustment needs and experiences of women early career ...psychologists. This study presents the constructivist grounded theory analysis of 22 in-depth interviews with women early career psychologists regarding their experiences of developing a career in psychology. Three primary spheres of influence on career adjustment emerged from the data: identity-based influences, experiential-focused influences, and outcome-oriented influences. These major spheres of influence are further refined into themes and subthemes that play a role in the career experiences of women early career psychologists. The impact of these themes on the women’s career trajectory is explored, and implications for research, training, policy, and practice are presented.
The ENDEAVOR IV (Randomized Comparison of Zotarolimus-Eluting and Paclitaxel-Eluting Stents in Patients with Coronary Artery Disease) trial evaluated the safety and efficacy of the ...zotarolimus-eluting stent (ZES) compared with the paclitaxel-eluting stent (PES).
First-generation drug-eluting stents have reduced angiographic and clinical restenosis, but long-term safety remains controversial. A second-generation drug-eluting stent, which delivers zotarolimus, a potent antiproliferative agent, via a biocompatible phosphorylcholine polymer on a cobalt alloy thin-strut stent has shown promising experimental and early clinical results.
This is a prospective, randomized (1:1), single-blind, controlled trial comparing outcomes of patients with single de novo coronary lesions treated with ZES or PES. The primary end point was noninferiority of 9-month target vessel failure defined as cardiac death, myocardial infarction, or target vessel revascularization.
Among a total of 1,548 patients assigned to ZES (n = 773) or PES (n = 775), at 9 months, ZES was noninferior to PES with rates of target vessel failure 6.6% versus 7.1%, respectively (p(noninferiority) < or = 0.001). There were fewer periprocedural myocardial infarctions with ZES (0.5% vs. 2.2%; p = 0.007), whereas at 12 months, there were no significant differences between groups in rates of cardiac death, myocardial infarction, target vessel revascularization, or stent thrombosis. Although incidence of 8-month binary angiographic in-segment restenosis was higher in patients treated with ZES versus PES (15.3% vs. 10.4%; p = 0.284), rates of 12-month target lesion revascularization were similar (4.5% vs. 3.2%; p = 0.228), especially in patients without planned angiographic follow-up (3.6% vs. 3.2%; p = 0.756).
These findings demonstrate that ZES has similar clinical safety and efficacy compared with PES in simple and medium complexity single de novo coronary lesions. (ENDEAVOR IV Clinical Trial; NCT00217269).
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