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NPJ Breast Cancer

Amir Sonnenblick, David Venet, Sylvain Brohée, Noam Pondé, Christos Sotiriou
Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. We developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Our analysis revealed that the pAKT pathway activation was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal-Wallis test p  < 10-10 )...
2019: NPJ Breast Cancer
Fresia Pareja, Felipe C Geyer, David N Brown, Ana P Martins Sebastião, Rodrigo Gularte-Mérida, Anqi Li, Marcia Edelweiss, Arnaud Da Cruz Paula, Pier Selenica, Hannah Y Wen, Achim A Jungbluth, Zsuzsanna Varga, Juan Palazzo, Brian P Rubin, Ian O Ellis, Edi Brogi, Emad A Rakha, Britta Weigelt, Jorge S Reis-Filho
Breast adenomyoepitheliomas (AMEs) are rare epithelial-myoepithelial neoplasms that may occasionally produce myxochondroid matrix, akin to pleomorphic adenomas (PAs). Regardless of their anatomic location, PAs often harbor rearrangements involving HMGA2 or PLAG1 . We have recently shown that the repertoire of somatic genetic alterations of AMEs varies according to their estrogen receptor (ER) status; whilst the majority of ER-positive AMEs display mutually exclusive PIK3CA or AKT1 hotspot mutations, up to 60% of ER-negative AMEs harbor concurrent HRAS Q61 hotspot mutations and mutations affecting either PIK3CA or PIK3R1 ...
2019: NPJ Breast Cancer
Stephen Johnston, Miguel Martin, Angelo Di Leo, Seock-Ah Im, Ahmad Awada, Tammy Forrester, Martin Frenzel, Molly C Hardebeck, Joanne Cox, Susana Barriga, Masakazu Toi, Hiroji Iwata, Matthew P Goetz
At the MONARCH 3 interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (AI) significantly improved progression-free survival (PFS) and objective response rate (ORR) with a tolerable safety profile as initial treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). MONARCH 3 is a randomized, phase III, double-blind study of abemaciclib/placebo (150 mg twice daily, continuous) plus nonsteroidal AI (1 mg anastrozole or 2...
2019: NPJ Breast Cancer
Vasileios Askoxylakis, Gino B Ferraro, Mark Badeaux, David P Kodack, Isabelle Kirst, Ram C Shankaraiah, Christina S F Wong, Dan G Duda, Dai Fukumura, Rakesh K Jain
The effective treatment of cerebral metastases from HER2-positive breast cancer remains an unmet need. Recent studies indicate that activated astrocytes and brain endothelial cells exert chemoprotective effects on cancer cells through direct physical interaction. Here we report that the endothelin axis mediates protection of HER2 -amplified brain metastatic breast cancers to the anti-HER2 antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Macitentan, a dual inhibitor of endothelin receptors A and B, improves the efficacy of T-DM1 against breast cancers grown in the brain...
2019: NPJ Breast Cancer
Avonne E Connor, Kala Visvanathan, Stephanie D Boone, Nader Rifai, Kathy B Baumgartner, Richard N Baumgartner
Epidemiologic studies have found that elevated insulin levels and chronic hyperglycemia among breast cancer (BC) survivors are associated with poor prognosis; few of these studies have included Hispanic women in whom diabetes is highly prevalent. We examined the associations between circulating fructosamine-a biomarker of hyperglycemia and blood glucose control, self-reported diabetes, and risk of BC-specific and all-cause mortality among Hispanic and non-Hispanic white (NHW) women diagnosed with invasive BC...
2019: NPJ Breast Cancer
Judy C Boughey, Michael D Alvarado, Rachael B Lancaster, W Fraser Symmans, Rita Mukhtar, Jasmine M Wong, Cheryl A Ewing, David A Potter, Todd M Tuttle, Tina J Hieken, Jodi M Carter, James W Jakub, Henry G Kaplan, Claire L Buchanan, Nora T Jaskowiak, Husain A Sattar, Jeffrey Mueller, Rita Nanda, Claudine J Isaacs, Paula R Pohlmann, Filipa Lynce, Eleni A Tousimis, Jay C Zeck, M Catherine Lee, Julie E Lang, Paulette Mhawech-Fauceglia, Roshni Rao, Bret Taback, Constantine Goodellas, Margaret Chen, Kevin M Kalinsky, Hanina Hibshoosh, Brigid Killelea, Tara Sanft, Gillian L Hirst, Smita Asare, Jeffrey B Matthews, Jane Perlmutter, Laura J Esserman
[This corrects the article DOI: 10.1038/s41523-018-0074-6.].
2019: NPJ Breast Cancer
Noam Pondé, Richard D Gelber, Martine Piccart
No abstract text is available yet for this article.
2019: NPJ Breast Cancer
Angelo Di Leo, Joyce O'Shaughnessy, George W Sledge, Miguel Martin, Yong Lin, Martin Frenzel, Molly C Hardebeck, Ian C Smith, Antonio Llombart-Cussac, Matthew P Goetz, Stephen Johnston
CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease...
2018: NPJ Breast Cancer
Mehmet Altan, Kelley M Kidwell, Vasiliki Pelekanou, Daniel E Carvajal-Hausdorf, Kurt A Schalper, Maria I Toki, Dafydd G Thomas, Michael S Sabel, Daniel F Hayes, David L Rimm
B7-H4 (VTCN1) is a member of the CD28/B7 family of immune co-inhibitory molecules. The relationship of tumor and stromal B7-H4 protein expression with PD-L1, tumor infiltrating lymphocytes (TILs) and its association with clinico-pathological variables are not well defined. Herein, we explore the expression level of B7-H4 protein in breast cancer and evaluate its association with TILs, levels of PD-L1 expression, and clinico-pathological characteristics in two independent populations. In this study, we used multiplexed automated quantitative immunofluorescence (QIF) to measure the levels of B7-H4 and PD-L1 protein and determined TILs through pathologist assessment of H&E-stained preparations in over a thousand breast cancer cases from two institutions represented in tissue microarray format...
2018: NPJ Breast Cancer
Sunil Kumar, Daniel Lindsay, Q Brent Chen, Amy L Garrett, Xianming M Tan, Carey K Anders, Lisa A Carey, Gaorav P Gupta
Serial monitoring of plasma DNA mutations in estrogen receptor positive metastatic breast cancer (ER + MBC) holds promise as an early predictor of therapeutic response. Here, we developed dPCR-SEQ, a customized assay that utilizes digital PCR-based target enrichment followed by next-generation sequencing to analyze plasma DNA mutations in ESR1 , PIK3CA , and TP53 . We validated dPCR-SEQ in a prospective cohort of 58 patients with ER + MBC and demonstrate excellent concordance with hotspot ESR1 mutation abundance measured by conventional digital PCR...
2018: NPJ Breast Cancer
Cristina Guarducci, Martina Bonechi, Matteo Benelli, Chiara Biagioni, Giulia Boccalini, Dario Romagnoli, Roberto Verardo, Rachel Schiff, C Kent Osborne, Carmine De Angelis, Angelo Di Leo, Luca Malorni, Ilenia Migliaccio
CDK4/6 inhibitors represent a new treatment standard for hormone receptor-positive (HR+), HER2-negative advanced breast cancer (BC) patients. Although efficacious, resistance to these agents is universal. Here, we profiled a large panel of HR+ BC cell lines with conditioned resistance to the CDK4/6 inhibitor palbociclib, and analyzed cell cycle-related markers by gene expression profiles (GEP) and western blot (WB). GEP showed high molecular heterogeneity among the models, with E2F targets being significantly enriched both during treatment and at the time of resistance...
2018: NPJ Breast Cancer
Charles E Geyer, Gong Tang, Eleftherios P Mamounas, Priya Rastogi, Soonmyung Paik, Steven Shak, Frederick L Baehner, Michael Crager, D Lawrence Wickerham, Joseph P Costantino, Norman Wolmark
The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score® test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded...
2018: NPJ Breast Cancer
Najme Faham, Ling Zhao, Alana L Welm
Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular mechanisms that govern how RON promotes metastasis, and how to block it, are still largely unknown. We sought to determine critical effectors of RON using a combination of mutational and pharmacologic strategies. High-throughput proteomic analysis of breast cancer cells upon activation of RON showed robust phosphorylation of ribosomal protein S6...
2018: NPJ Breast Cancer
Benlong Yang, Jeff Chou, Yaozhong Tao, Dengbin Wu, Xinhong Wu, Xueqing Li, Yan Li, Yiwei Chu, Feng Tang, Yanxia Shi, Linlin Ma, Tong Zhou, William Kaufmann, Lisa A Carey, Jiong Wu, Zhiyuan Hu
Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be significantly prognostic in breast cancer but have not yet been applied for calculation of risk of recurrence in clinical assays. A compact set of 17 immunity genes was derived herein from an Affymetrix-derived gene expression dataset including 1951 patients (AFFY1951). The 17 immunity genes demonstrated significant prognostic stratification of estrogen receptor (ER)-negative breast cancer patients with high proliferation gene expression...
2018: NPJ Breast Cancer
Kimberly S Keene, Tari King, E Shelley Hwang, Bo Peng, Kandace P McGuire, Coya Tapia, Hong Zhang, Sejong Bae, Faina Nakhlis, Nancy Klauber-Demore, Ingrid Meszoely, Michael S Sabel, Shawna C Willey, Agda Karina Eterovic, Cliff Hudis, Antonio C Wolff, Jennifer De Los Santos, Alastair Thompson, Gordon B Mills, Funda Meric-Bernstam
Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls...
2018: NPJ Breast Cancer
Kevin H Kensler, Francisco Beca, Gabrielle M Baker, Yujing J Heng, Andrew H Beck, Stuart J Schnitt, Aditi Hazra, Bernard A Rosner, A Heather Eliassen, Susan E Hankinson, Myles Brown, Rulla M Tamimi
Sex steroid hormone signaling is critical in the development of breast cancers, although the role of the androgen receptor remains unclear. This study evaluated androgen receptor (AR) expression in normal breast tissue as a potential marker of breast cancer risk. We conducted a nested case-control study of women with benign breast disease (BBD) within the Nurses' Health Studies. Epithelial AR expression was assessed by immunohistochemistry in normal tissue from the BBD biopsy and the percent of positive nuclei was estimated in ordinal categories of 10% for 78 breast cancer cases and 276 controls...
2018: NPJ Breast Cancer
Rishi R Rawat, Daniel Ruderman, Paul Macklin, David L Rimm, David B Agus
In this pilot study, we introduce a machine learning framework to identify relationships between cancer tissue morphology and hormone receptor pathway activation in breast cancer pathology hematoxylin and eosin (H&E)-stained samples. As a proof-of-concept, we focus on predicting clinical estrogen receptor (ER) status-defined as greater than one percent of cells positive for estrogen receptor by immunohistochemistry staining-from spatial arrangement of nuclear features. Our learning pipeline segments nuclei from H&E images, extracts their position, shape and orientation descriptors, and then passes them to a deep neural network to predict ER status...
2018: NPJ Breast Cancer
Mark Jesus M Magbanua, Hope S Rugo, Louai Hauranieh, Ritu Roy, Janet H Scott, Jen Chieh Lee, Feng Hsiao, Eduardo V Sosa, Laura Van't Veer, Laura J Esserman, John W Park
Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools ( n  = 45) appeared less aberrant than the corresponding primary tumors (PT, n  = 16). PIK3CA mutations were detected in 26% of DTC pools ( n  = 53), none of them were shared with matched PTs. Expression profiling of DTC pools ( n  = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e...
2018: NPJ Breast Cancer
Heather D Couture, Lindsay A Williams, Joseph Geradts, Sarah J Nyante, Ebonee N Butler, J S Marron, Charles M Perou, Melissa A Troester, Marc Niethammer
RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning...
2018: NPJ Breast Cancer
Patrick S Dischinger, Elizabeth A Tovar, Curt J Essenburg, Zachary B Madaj, Eve E Gardner, Megan E Callaghan, Ashley N Turner, Anil K Challa, Tristan Kempston, Bryn Eagleson, Robert A Kesterson, Roderick T Bronson, Megan J Bowman, Carrie R Graveel, Matthew R Steensma
The key negative regulatory gene of the RAS pathway, NF1 , is mutated or deleted in numerous cancer types and is associated with increased cancer risk and drug resistance. Even though women with neurofibromatosis (germline NF1 mutations) have a substantially increased breast cancer risk at a young age and NF1 is commonly mutated in sporadic breast cancers, we have a limited understanding of the role of NF1 in breast cancer. We utilized CRISPR-Cas9 gene editing to create Nf1 rat models to evaluate the effect of Nf1 deficiency on tumorigenesis...
2018: NPJ Breast Cancer
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