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Pd-l1 breast cancer

Hope S Rugo, Jean-Pierre Delord, Seock-Ah Im, Patrick A Ott, Sarina A Piha-Paul, Phillipe L Bedard, Jasgit Sachev, Christophe Le Tourneau, Emilie M J van Brummelen, Andreea Varga, Roberto Salgado, Sherene Loi, Sanatan Saraf, Dina Pietrangelo, Vassiliki Karantza, Antoinette R Tan
PURPOSE: We investigated the safety and antitumor activity of the anti-programmed death 1 monoclonal antibody pembrolizumab in patients with estrogen receptor‒positive (ER+)/human epidermal growth factor receptor 2-negative (HER2- ) advanced breast cancer with programmed death ligand 1‒positive (PD-L1‒positive) tumors in the phase Ib open-label, multicohort KEYNOTE-028 (NCT02054806) study. EXPERIMENTAL DESIGN: Patients with ER+/HER2- advanced breast cancer with PD-L1‒positive tumors (combined positive score ≥1) received pembrolizumab (10 mg/kg every 2 weeks) up to 2 years or until confirmed progression/intolerable toxicity...
March 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
David A Schaer, Richard P Beckmann, Jack A Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A Staschke, Linda A Chung, Lacey M Litchfield, Farhana F Merzoug, Xueqian Gong, Philip W Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D Novosiadly, Michael Kalos
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control...
March 13, 2018: Cell Reports
Yanchun Li, Mateusz Opyrchal, Song Yao, Xuan Peng, Li Yan, Hossam Jabbour, Thaer Khoury
PURPOSE: The purpose of the study is to investigate the prognostic significance of programmed death ligand-1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in HER2+ breast cancer (BC). METHODS: HER2+ BC cases (n  = 191) were collected between 1996 and 2013. Tissue microarray (TMA) slides were stained with two clones of PD-L1 antibodies (28-8 and 22C3) and the percentage of positive membranous staining was scored. TILs of the full sections were also scored using percentage scale...
March 9, 2018: Breast Cancer Research and Treatment
Fei Li, Yi Ren, Zhandong Wang
Objective: To evaluate the expression of programmed death 1 ligand 1 (PD-L1) in the cancer tissues and tumor-adjacent normal tissues of patients with invasive ductal carcinoma of the breast and to analyze the relationship between the expression of PD-L1 and the clinicopathological features of patients. Materials and Methods: This study included 112 cases of patients with invasive ductal carcinoma of breast who received surgical treatment from March 2012 to February 2016 in Xuzhou Cancer Hospital...
January 2018: Journal of Cancer Research and Therapeutics
Hongyan Yuan, Xiaoyi Wang, Jin Lu, Qiongsi Zhang, Irina Brandina, Ilya Alexandrov, Robert I Glazer
One of the central challenges in cancer prevention is the identification of factors in the tumor microenvironment (TME) that increase susceptibility to tumorigenesis. One such factor is stromal fibrosis, a histopathologic negative prognostic criterion for invasive breast cancer. Since the stromal composition of the breast is largely adipose and fibroblast tissue, it is important to understand how alterations in these tissues affect cancer progression. To address this question, a novel transgenic animal model was developed by crossing MMTV-NeuT mice containing a constitutively active ErbB2 gene into the FAT-ATTAC (fat apoptosis through targeted activation of caspase 8) background, which expresses an inducible caspase 8 fusion protein targeted to mammary adipose tissue...
January 30, 2018: Oncotarget
Dong Hoon Suh, Miseon Kim, Kyung Hun Lee, Keun Yong Eom, Maj Kamille Kjeldsen, Mansoor Raza Mirza, Jae Weon Kim
In 2017, 10 topics were selected as major clinical research advances in gynecologic oncology. For cervical cancer, efficacy and safety analysis results of a 9-valent human papillomavirus (HPV) vaccine and long-term impact of reduced dose of quadrivalent vaccine were updated. Brief introduction of KEYNOTE trials of pembrolizumab, a monoclonal antibody that blocks the interaction between programmed death (PD)-1 and its ligands, PD-L1 and PD-L2, followed. Tailored surveillance programs for gynecologic cancer related with Lynch syndrome and update on sentinel lymph node mapping were reviewed for uterine corpus cancer...
March 2018: Journal of Gynecologic Oncology
Gero Brockhoff, Stephan Seitz, Florian Weber, Florian Zeman, Monika Klinkhammer-Schalke, Olaf Ortmann, Anja Kathrin Wege
Triple negative breast cancer patients have a poor course of disease not least because of limited treatment options however immunotherapy by targeting the PD-1/PD-L1 checkpoint system is a promising strategy to improve the outcome. Here we systematically investigated the expression of PD-1 on tumor infiltrating lymphocytes and PD-L1 on both tumor and infiltrated immune cells. Moreover, the PD-L1 gene status in tumor cells was assessed. 103 tissue microarray samples derived from triple negative breast cancer specimens were immunohistochemically stained against PD-1 and PD-L1...
January 19, 2018: Oncotarget
Audrey Monneur, Anthony Gonçalves, François Bertucci
The development of immune checkpoints inhibitors represents one of the major recent advances in oncology. Monoclonal antibodies directed against the programmed cell death protein 1 (PD-1) or its ligand (PD-L1) provides durable disease control, particularly in melanoma, lung, kidney, bladder and head and neck cancers. The purpose of this review is to synthesize current data on the expression of PD-L1 in breast cancer and on the preliminary clinical results of PD-1/PD-L1 inhibitors in breast cancer patients. In breast cancer, PD-L1 expression is heterogeneous and is generally associated with the presence of tumor-infiltrating lymphocytes as well as the presence of poor-prognosis factors, such as young age, high grade, ER-negativity, PR-negativity, and HER-2 overexpression, high proliferative index, and aggressive molecular subtypes (triple negative, basal-like, HER-2-overexpressing)...
February 15, 2018: Bulletin du Cancer
Chia-Wei Li, Seung-Oe Lim, Ezra M Chung, Yong-Soo Kim, Andrew H Park, Jun Yao, Jong-Ho Cha, Weiya Xia, Li-Chuan Chan, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Chao-Kai Chou, Yen-Liang Liu, Hsin-Chih Yeh, Evan P Perillo, Andrew K Dunn, Chu-Wei Kuo, Kay-Hooi Khoo, Jennifer L Hsu, Yun Wu, Jung-Mao Hsu, Hirohito Yamaguchi, Tzu-Hsuan Huang, Aysegul A Sahin, Gabriel N Hortobagyi, Stephen S Yoo, Mien-Chie Hung
Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity...
February 12, 2018: Cancer Cell
Mariana Salatino, María Romina Girotti, Gabriel A Rabinovich
The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.
February 12, 2018: Cancer Cell
Eva-Maria Rom-Jurek, Nicole Kirchhammer, Peter Ugocsai, Olaf Ortmann, Anja K Wege, Gero Brockhoff
Programmed death ligand 1 (PD-L1) expression is an efficient strategy of tumor cells to escape immunological eradiation. However, only little is known about the factors that affect the cellular expression levels. Here we assessed the PD-L1 expression on different breast cancer cell lines under standard in vitro culture conditions and as a function of Epirubicin or Paclitaxel treatment. Moreover, we evaluated the expression in immunodeficient tumor mice as well as in humanized tumor mice (i.e., in the presence of a human immune system)...
February 13, 2018: International Journal of Molecular Sciences
Jing He, Lei Huo, Junsheng Ma, Jun Zhao, Roland L Bassett, Xiaoping Sun, Naoto T Ueno, Bora Lim, Yun Gong
Objectives: Inflammatory breast carcinoma (IBC) is rare but is the most lethal type of breast cancer. Programmed death ligand 1 (PD-L1) expression in IBCs has been understudied. Methods: In this study, tissue microarrays of 68 IBCs were immunostained with a PD-L1 antibody using an antibody clone (28-8) and detection system approved by the US Food and Drug Administration for selecting patients with non-small cell lung cancer and melanoma for anti-PD-L1 therapy. Results: Positive PD-L1 expression was found in 25 (36...
February 7, 2018: American Journal of Clinical Pathology
Maryann J Kwa, Sylvia Adams
Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple-negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor-infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway in maintaining immunosuppression in the tumor microenvironment...
February 9, 2018: Cancer
Seo Hee Choi, Jee Suk Chang, Ja Seung Koo, Jong Won Park, Joo Hyuk Sohn, Ki Chang Keum, Chang-Ok Suh, Yong Bae Kim
OBJECTIVES: Triple-negative breast cancers (TNBC) is an aggressive disease and often associated with early distant metastases, which negate the role of adjuvant radiotherapy. We studied the clinical utility of programmed death ligand-1 (PD-L1) and other available factors in predicting clinical outcome in TNBC. METHODS: Of the 539 patients with newly diagnosed TNBC between 2004 and 2011, we analyzed 117 patients who had both tumor samples which PD-L1 protein expression could be evaluated using immunohistochemistry and initial staging F-fluorodeoxyglucose (FDG) positron emission tomography (PET) data to find available immunologic or metabolic factors...
February 6, 2018: American Journal of Clinical Oncology
Catherine Terret, Chiara Russo
As its incidence increases with age, breast cancer in elderly patients takes on a growing importance in clinical oncology practice. Management decisions are challenging because there is a lack of high-quality evidence in this heterogeneous population. Epidemiological studies have shown that breast cancer mortality does not decrease substantially in the older population compared with younger adults. Recent data suggest a phenotype somewhat different from that of younger patients, also confirmed at the molecular level...
January 31, 2018: Drugs & Aging
Mai F Tolba, Hany A Omar
Immunotherapy comprises a promising new era in cancer therapy. Immune checkpoint inhibitors targeting either the programmed death (PD)-1 receptor or its ligand PD-L1 were first approved by the Food and Drug Administration (FDA) for the management of metastatic melanoma in 2011. The approval of this class is being extended to include other types of immunogenic tumors. Although breast cancer (BC) was first categorized as non-immunogenic tumor type, there are certain subsets of BC that showed a high level of tumor infiltrating lymphocytes (TILs)...
January 12, 2018: Critical Reviews in Oncology/hematology
Manuela Terranova-Barberio, Scott Thomas, Niwa Ali, Nela Pawlowska, Jeenah Park, Gregor Krings, Michael D Rosenblum, Alfredo Budillon, Pamela N Munster
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy...
December 26, 2017: Oncotarget
April Swoboda, Rita Nanda
An effective antitumor immune response requires interaction between cells of the adaptive and innate immune system. Three key elements are required: generation of activated tumor-directed T cells, infiltration of activated T cells into the tumor microenvironment, and killing of tumor cells by activated T cells. Tumor immune evasion can occur as a result of the disruption of each of these three key T cell activities, resulting in three distinct cancer-immune phenotypes. The immune inflamed phenotype, characterized by the presence of a robust tumor immune infiltrate, suggests impaired activated T cell killing of tumor cells related to the presence of inhibitory factors...
2018: Cancer Treatment and Research
Helena J Janse van Rensburg, Taha Azad, Min Ling, Yawei Hao, Brooke Snetsinger, Prem Khanal, Lori M Minassian, Charles H Graham, Michael J Rauh, Xiaolong Yang
The Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional co-activator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumour microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2) and large tumour suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines...
January 16, 2018: Cancer Research
Tamara Muliaditan, James W Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F Madden, Joy M Burchell, Shahram Kordasti, Sandra S Diebold, James Spicer, James N Arnold
PURPOSE: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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