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Pd-l1 breast cancer

Sasha E Stanton, Mary L Disis
Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer. Triple negative breast cancers (TN) are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL. The majority of HER2(+) breast cancers have similar level of immune infiltrate as TN breast cancer yet the presence of TILs has not shown the same survival benefit...
2016: Journal for Immunotherapy of Cancer
Nadia F Nocera, M Catherine Lee, Lucy M De La Cruz, Cinthia Rosemblit, Brian J Czerniecki
The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy...
2016: Frontiers in Pharmacology
Honggeng Guan, Yuqiu Wan, Jing Lan, Qin Wang, Zhangyu Wang, Yecheng Li, Jiqing Zheng, Xueguang Zhang, Zemin Wang, Yueping Shen, Fang Xie
Regulatory T cells (Tregs), a key mediator in regulating anti-tumor immune suppression, tumor immune escape, metastasis and relapse, are considered an important therapeutic target in immunotherapy of human cancers. In the present investigation, elevated CD19(+) CD24(+) CD38(+) regulatory B cells (Bregs) were observed in PBMCs of invasive carcinoma of breast (IBCa) patients compared with that in patients with fibroadenoma (FIBma) or healthy individuals, and the positive correlation existed between Bregs and CD4(+) CD25(+) CD127(-) Tregs (r = 0...
October 20, 2016: Scientific Reports
Shaheenah Dawood, Hope S Rugo
PURPOSE OF REVIEW: This article describes the role of the PD-1 axis and reviews current data and future directions inhibiting PD-1 and PD-L1 in breast cancer. RECENT FINDINGS: Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Higher response rates are seen in triple negative breast cancer, compared with hormone receptor positive disease...
October 15, 2016: Current Opinion in Supportive and Palliative Care
Rin Ogiya, Naoki Niikura, Nobue Kumaki, Giampaolo Bianchini, Shigehisa Kitano, Takayuki Iwamoto, Naoki Hayashi, Kozue Yokoyama, Risa Oshitanai, Mayako Terao, Toru Morioka, Banri Tsuda, Takuho Okamura, Yuki Saito, Yasuhiro Suzuki, Yutaka Tokuda
The presence of tumour-infiltrating lymphocytes (TILs) is associated with favourable long-term outcome in breast cancer. However, little is known about changes in TILs during metastatic progression. To confirm our hypothesis that malignant tumours escape from the host immune system during metastasis, we evaluated the percentage of TILs in paired samples of primary and metastatic breast tumours. We retrospectively identified 25 patients with human epidermal growth factor receptor-2 (HER2)-positive (n = 14, HER2+) and triple negative (n = 11, TN) early breast cancer diagnosed during 1990-2009 at Tokai University Hospital and who subsequently experienced regional or distant recurrence confirmed by tumour biopsy/resection...
October 11, 2016: Cancer Science
Sang Byung Bae, Hyun Deuk Cho, Mee-Hye Oh, Ji-Hye Lee, Si-Hyong Jang, Soon Auck Hong, Junhun Cho, Sung Yong Kim, Sun Wook Han, Jong Eun Lee, Han Jo Kim, Hyun Ju Lee
PURPOSE: The interaction of programmed death receptor 1 (PD-1) and its ligand, programmed death receptor ligand 1 (PD-L1), negatively regulates immune responses. This study aimed to clarify PD-L1 expression levels in breast cancer through immunohistochemistry (IHC) and to evaluate associations between these findings and clinicopathologic variables, including prognosis. METHODS: PD-L1 expression was analyzed using IHC on tissue microarrays of 465 invasive breast carcinomas...
September 2016: Journal of Breast Cancer
Eileen E Parkes, Steven M Walker, Laura E Taggart, Nuala McCabe, Laura A Knight, Richard Wilkinson, Karen D McCloskey, Niamh E Buckley, Kienan I Savage, Manuel Salto-Tellez, Stephen McQuaid, Mary T Harte, Paul B Mullan, D Paul Harkin, Richard D Kennedy
BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype...
January 2017: Journal of the National Cancer Institute
Xiaoxian Li, Ceyda Sonmez Wetherilt, Uma Krishnamurti, Jing Yang, Yamin Ma, Toncred M Styblo, Jane L Meisel, Limin Peng, Momin T Siddiqui, Cynthia Cohen, Ritu Aneja
OBJECTIVES: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, and there is no approved targeted therapy. We studied the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) in TNBC. METHODS: Full-face sections from 136 TNBC cases without neoadjuvant therapy between 2004 and 2013 were stained and evaluated for immune cell PD-1 staining and stromal or tumoral PD-L1 staining using the H-score (staining percentage × intensity)...
October 2016: American Journal of Clinical Pathology
Florence T H Wu, Shan Man, Ping Xu, Annabelle Chow, Marta Paez-Ribes, Christina R Lee, Steven R Pirie-Shepherd, Urban Emmenegger, Robert S Kerbel
Antiangiogenic tyrosine kinase inhibitors (TKIs) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III trials. Angiopoietin-2 (Ang2) is a pro-angiogenic and pro-inflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models...
September 20, 2016: Cancer Research
Xin Wang, Feifei Teng, Li Kong, Jinming Yu
PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial...
2016: OncoTargets and Therapy
Chia-Wei Li, Seung-Oe Lim, Weiya Xia, Heng-Huan Lee, Li-Chuan Chan, Chu-Wei Kuo, Kay-Hooi Khoo, Shih-Shin Chang, Jong-Ho Cha, Taewan Kim, Jennifer L Hsu, Yun Wu, Jung-Mao Hsu, Hirohito Yamaguchi, Qingqing Ding, Yan Wang, Jun Yao, Cheng-Chung Lee, Hsing-Ju Wu, Aysegul A Sahin, James P Allison, Dihua Yu, Gabriel N Hortobagyi, Mien-Chie Hung
Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding...
August 30, 2016: Nature Communications
Upasana Joneja, Semir Vranic, Jeffrey Swensen, Rebecca Feldman, Wangjuh Chen, Jeffrey Kimbrough, Nianqing Xiao, Sandeep Reddy, Juan Palazzo, Zoran Gatalica
AIMS: Metaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions...
August 16, 2016: Journal of Clinical Pathology
I Zawlik, N Gablo, B Szymanska, Z Pawlowska, C Chudobinski, J Chalubinska-Fendler, Z Morawiec, H Zielinska-Blizniewska, A Morawiec-Sztandera, A Kolacinska
Immune checkpoints are molecules referred to inhibitory pathways in the immune system that play a pivotal role in prevention of autoimmunity and oncogenesis. The aim of the study was to evaluate expression levels of selected immune checkpoints- PD-1 (programmed cell death protein 1), and PD-L1 (programmed cell death 1 ligand 1) in breast cancer patients, suitable for breast conservation and sentinel node biopsy and determine their associations with clinicopathological factors.Expression of the genes coding for PD-1 and PD-L1 was analyzed in formalin-fixed paraffin-embedded specimens using real-time PCR...
2016: Neoplasma
Wojciech G Lesniak, Samit Chatterjee, Matthew Gabrielson, Ala Lisok, Bryan Wharram, Martin G Pomper, Sridhar Nimmagadda
The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pair is a major immune checkpoint pathway exploited by cancer cells to develop and maintain immune tolerance. With recent approvals of anti-PD-1 and anti-PD-L1 therapeutic antibodies, there is an urgent need for noninvasive detection methods to quantify dynamic PD-L1 expression in tumors and to evaluate the tumor response to immune modulation therapies. To address this need, we assessed [(64)Cu]atezolizumab for the detection of PD-L1 expression in tumors...
September 21, 2016: Bioconjugate Chemistry
Xue Li, Minghuan Li, Zhen Lian, Hui Zhu, Li Kong, Ping Wang, Jinming Yu
BACKGROUND: Cancer therapies that target the PD-1/PD-L1 pathway are in ongoing phase I/II clinical trials for several tumor types. However, the prognostic value of PD-L1 expression in breast cancer is unclear. OBJECTIVE: We assessed the prognostic role of PD-L1 expression in breast cancer. METHODS: We searched Medline/PubMed for eligible studies of the association between PD-L1 expression and patient survival in breast cancer published before 7 December 2015...
July 15, 2016: Targeted Oncology
Lei Guo, Wenbin Li, Xinxin Zhu, Yun Ling, Tian Qiu, Lin Dong, Yi Fang, Hongying Yang, Jianming Ying
PURPOSE: To estimate the therapeutic potential of PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression with a validated antibody and CD274 gene alternation in a large cohort of triple negative breast cancer (TNBC) and correlated with clinicopathological data and patients overall survival. METHODS: Immunohistochemistry and in situ mRNA hybridization was used to detect PD-L1 protein and mRNA expression in tumor tissues from 183 TNBC patients respectively...
2016: SpringerPlus
Melanie R Power Coombs, Megan E Harrison, David W Hoskin
Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells...
October 1, 2016: Cancer Letters
Xuefei Wang, Qiang Sun, Qiaofei Liu, Changjun Wang, Ru Yao, Yimin Wang
Breast cancer is the most common malignant tumor in women around the world. Most breast cancer-related deaths are from CTC (circulating tumor cells) metastasis. CTC is associated with the breast cancer patients' prognosis. But recently, circulating clusters were found and its metastasis and tumor formation ability is 23-50 times as CTC. However, its mechanism has not been clarified. These days, researchers have successfully completed CTC cluster separation, CTC cell culture, and PD-L1 was found to be related with histological grading of tumor...
August 2016: Medical Hypotheses
Carey K Anders, Vandana Abramson, Tira Tan, Rebecca Dent
Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as "immune-activated," consistently illustrating better disease outcome...
2016: American Society of Clinical Oncology Educational Book
Davide Bedognetti, Cristina Maccalli, Salha B J Al Bader, Francesco M Marincola, Barbara Seliger
Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs)...
April 2016: Breast Care
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