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https://www.readbyqxmd.com/read/28338653/breast-ductal-carcinoma-in-situ-carry-mutational-driver-events-representative-of-invasive-breast-cancer
#1
Jia-Min B Pang, Peter Savas, Andrew P Fellowes, Gisela Mir Arnau, Tanjina Kader, Ravikiran Vedururu, Chelsee Hewitt, Elena A Takano, David J Byrne, David Yh Choong, Ewan Ka Millar, C Soon Lee, Sandra A O'Toole, Sunil R Lakhani, Margaret C Cummings, G Bruce Mann, Ian G Campbell, Alexander Dobrovic, Sherene Loi, Kylie L Gorringe, Stephen B Fox
The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30)...
March 24, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28165340/targeting-the-adenosine-2a-receptor-enhances-chimeric-antigen-receptor-t-cell-efficacy
#2
Paul A Beavis, Melissa A Henderson, Lauren Giuffrida, Jane K Mills, Kevin Sek, Ryan S Cross, Alexander J Davenport, Liza B John, Sherly Mardiana, Clare Y Slaney, Ricky W Johnstone, Joseph A Trapani, John Stagg, Sherene Loi, Lev Kats, David Gyorki, Michael H Kershaw, Phillip K Darcy
Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs)...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28049579/tumour-infiltrating-lymphocytes-and-the-emerging-role-of-immunotherapy-in-breast-cancer
#3
Stephen J Luen, Peter Savas, Stephen B Fox, Roberto Salgado, Sherene Loi
Breast cancer has not previously been considered a highly immunogenic cancer. Observations of tumour-infiltrating lymphocytes (TILs) in and around neoplastic cells in tumour samples, and associations with improved pathological complete response and clinical survival end points have changed our perspective on this. Lymphocytic infiltrates have long been observed in breast cancer; however, more recently, retrospective analysis of prospectively collected tissue samples from clinical trials has demonstrated the potential role of host immunosurveillance in influencing the biology of breast cancer...
February 2017: Pathology
https://www.readbyqxmd.com/read/28027521/correlation-between-severe-infection-and-breast-cancer-metastases-in-the-eortc-10994-big-1-00-trial-investigating-innate-immunity-as-a-tumour-suppressor-in%C3%A2-breast-cancer
#4
Nathan Touati, Konstantinos Tryfonidis, Franco Caramia, Hervé Bonnefoi, David Cameron, Leen Slaets, Belinda S Parker, Sherene Loi
BACKGROUND: Breast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti-tumour immune response. We investigated whether 'severe infection' can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones...
December 24, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/28027312/the-subclonal-architecture-of-metastatic-breast-cancer-results-from-a-prospective-community-based-rapid-autopsy-program-cascade
#5
Peter Savas, Zhi Ling Teo, Christophe Lefevre, Christoffer Flensburg, Franco Caramia, Kathryn Alsop, Mariam Mansour, Prudence A Francis, Heather A Thorne, Maria Joao Silva, Nnennaya Kanu, Michelle Dietzen, Andrew Rowan, Maik Kschischo, Stephen Fox, David D Bowtell, Sarah-Jane Dawson, Terence P Speed, Charles Swanton, Sherene Loi
BACKGROUND: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. However, evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. METHODS AND FINDINGS: Three patients with oestrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program (CASCADE)...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27964843/tumour-infiltrating-lymphocytes-in-advanced-her2-positive-breast-cancer-treated-with-pertuzumab-or-placebo-in-addition-to-trastuzumab-and-docetaxel-a-retrospective-analysis-of-the-cleopatra-study
#6
Stephen J Luen, Roberto Salgado, Stephen Fox, Peter Savas, Jennifer Eng-Wong, Emma Clark, Astrid Kiermaier, Sandra M Swain, Jose Baselga, Stefan Michiels, Sherene Loi
BACKGROUND: High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel. METHODS: CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer...
January 2017: Lancet Oncology
https://www.readbyqxmd.com/read/27912781/an-immune-stratification-reveals-a-subset-of-pd-1-lag-3-double-positive-triple-negative-breast-cancers
#7
Giulia Bottai, Carlotta Raschioni, Agnese Losurdo, Luca Di Tommaso, Corrado Tinterri, Rosalba Torrisi, Jorge S Reis-Filho, Massimo Roncalli, Christos Sotiriou, Armando Santoro, Alberto Mantovani, Sherene Loi, Libero Santarpia
BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. METHODS: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259)...
December 3, 2016: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/27684533/rna-sequencing-to-predict-response-to-neoadjuvant-anti-her2-therapy-a-secondary-analysis-of-the-neoaltto-randomized-clinical-trial
#8
Debora Fumagalli, David Venet, Michail Ignatiadis, Hatem A Azim, Marion Maetens, Françoise Rothé, Roberto Salgado, Ian Bradbury, Lajos Pusztai, Nadia Harbeck, Henry Gomez, Tsai-Wang Chang, Maria Antonia Coccia-Portugal, Serena Di Cosimo, Evandro de Azambuja, Lorena de la Peña, Paolo Nuciforo, Jan C Brase, Jens Huober, José Baselga, Martine Piccart, Sherene Loi, Christos Sotiriou
Importance: In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents. Objective: To investigate the ability of clinically and biologically relevant genes and gene signatures (GSs) measured by RNA sequencing to predict the efficacy of anti-HER2 agents...
September 29, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27617737/a-community-based-model-of-rapid-autopsy-in-end-stage-cancer-patients
#9
Kathryn Alsop, Heather Thorne, Shahneen Sandhu, Anne Hamilton, Christopher Mintoff, Elizabeth Christie, Odette Spruyt, Scott Williams, Orla McNally, Linda Mileshkin, Sumitra Ananda, Julene Hallo, Sherene Loi, Clare Scott, Peter Savas, Lisa Devereux, Patricia O'Brien, Sameera Gunawardena, Clare Hampson, Kate Strachan, Rufaro Diana Jaravaza, Victoria Francis, Gregory Young, David Ranson, Ravindra Samaranayake, David Stevens, Samantha Boyle, Clare Fedele, Monique Topp, Gwo Ho, Zhi Ling Teo, Renea A Taylor, Melissa M Papargiris, Mitchell G Lawrence, Hong Wang, Gail P Risbridger, Nicole M Haynes, Mikolaj Medon, Ricky W Johnstone, Eva Vidacs, Gisela Mir Arnau, Ismael A Vergara, Anthony T Papenfuss, Grant McArthur, Paul Waring, Shirley Carvosso, Christopher Angel, David Gyorki, Benjamin Solomon, Gillian Mitchell, Sue Shanley, Prudence A Francis, Sarah-Jane Dawson, Amy Haffenden, Erin Tidball, Mila Volchek, Jan Pyman, Mohammed Madadin, Jodie Leditschke, Stephen Cordner, Mark Shackleton, David D Bowtell
No abstract text is available yet for this article.
October 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27611952/role-of-tp53-mutations-in-triple-negative-and-her2-positive-breast-cancer-treated-with-neoadjuvant-anthracycline-taxane-based-chemotherapy
#10
Silvia Darb-Esfahani, Carsten Denkert, Albrecht Stenzinger, Christoph Salat, Bruno Sinn, Christian Schem, Volker Endris, Peter Klare, Wolfgang Schmitt, Jens-Uwe Blohmer, Wilko Weichert, Markus Möbs, Hans Tesch, Sherko Kümmel, Peter Sinn, Christian Jackisch, Manfred Dietel, Toralf Reimer, Sherene Loi, Michael Untch, Gunter von Minckwitz, Valentina Nekljudova, Sibylle Loibl
BACKGROUND: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. METHODS: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27368881/palbociclib-in-combination-with-fulvestrant-in-women-with-hormone-receptor-positive-her2-negative-advanced-metastatic-breast-cancer-detailed-safety-analysis-from-a-multicenter-randomized-placebo-controlled-phase-iii-study-paloma-3
#11
Sunil Verma, Cynthia Huang Bartlett, Patrick Schnell, Angela M DeMichele, Sherene Loi, Jungsil Ro, Marco Colleoni, Hiroji Iwata, Nadia Harbeck, Massimo Cristofanilli, Ke Zhang, Alexandra Thiele, Nicholas C Turner, Hope S Rugo
BACKGROUND: Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. MATERIALS AND METHODS: Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo...
October 2016: Oncologist
https://www.readbyqxmd.com/read/27363491/standardized-evaluation-of-tumor-infiltrating-lymphocytes-in-breast-cancer-results-of-the-ring-studies-of-the-international-immuno-oncology-biomarker-working-group
#12
Carsten Denkert, Stephan Wienert, Audrey Poterie, Sibylle Loibl, Jan Budczies, Sunil Badve, Zsuzsanna Bago-Horvath, Anita Bane, Shahinaz Bedri, Jane Brock, Ewa Chmielik, Matthias Christgen, Cecile Colpaert, Sandra Demaria, Gert Van den Eynden, Giuseppe Floris, Stephen B Fox, Dongxia Gao, Barbara Ingold Heppner, S Rim Kim, Zuzana Kos, Hans H Kreipe, Sunil R Lakhani, Frederique Penault-Llorca, Giancarlo Pruneri, Nina Radosevic-Robin, David L Rimm, Stuart J Schnitt, Bruno V Sinn, Peter Sinn, Nicolas Sirtaine, Sandra A O'Toole, Giuseppe Viale, Koen Van de Vijver, Roland de Wind, Gunter von Minckwitz, Frederick Klauschen, Michael Untch, Peter A Fasching, Toralf Reimer, Karen Willard-Gallo, Stefan Michiels, Sherene Loi, Roberto Salgado
Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists...
October 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27269946/plasma-esr1-mutations-and-the-treatment-of-estrogen-receptor-positive-advanced-breast-cancer
#13
Charlotte Fribbens, Ben O'Leary, Lucy Kilburn, Sarah Hrebien, Isaac Garcia-Murillas, Matthew Beaney, Massimo Cristofanilli, Fabrice Andre, Sherene Loi, Sibylle Loibl, John Jiang, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith M Bliss, Stephen R D Johnston, Nicholas C Turner
PURPOSE: ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer. MATERIALS AND METHODS: In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy...
September 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27231202/the-e3-ligase-e6ap-represses-breast-cancer-metastasis-via-regulation-of-ect2-rho-signaling
#14
Mariam Mansour, Sue Haupt, Ai-Leen Chan, Nathan Godde, Alexandra Rizzitelli, Sherene Loi, Franco Caramia, Siddhartha Deb, Elena A Takano, Mark Bishton, Cameron Johnstone, Brendon Monahan, Yarra Levav-Cohen, Yong-Hui Jiang, Alpha S Yap, Stephen Fox, Ora Bernard, Robin Anderson, Ygal Haupt
Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors...
July 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27221704/adenosine-2b-receptor-expression-on-cancer-cells-promotes-metastasis
#15
Deepak Mittal, Debottam Sinha, Deborah Barkauskas, Arabella Young, Murugan Kalimutho, Kimberley Stannard, Franco Caramia, Benjamin Haibe-Kains, John Stagg, Kum Kum Khanna, Sherene Loi, Mark J Smyth
Adenosine plays an important role in inflammation and tumor development, progression, and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony-forming ability, while transiently delaying cell-cycle arrest in vitro The prometastatic activity of adenosine is partly tumor A2BR dependent and independent of host A2BR expression...
August 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27117582/immune-response-in-breast-cancer-brain-metastases-and-their-microenvironment-the-role-of-the-pd-1-pd-l-axis
#16
Renata Duchnowska, Rafał Pęksa, Barbara Radecka, Tomasz Mandat, Tomasz Trojanowski, Bożena Jarosz, Bogumiła Czartoryska-Arłukowicz, Wojciech P Olszewski, Waldemar Och, Ewa Kalinka-Warzocha, Wojciech Kozłowski, Anna Kowalczyk, Sherene Loi, Wojciech Biernat, Jacek Jassem
BACKGROUND: A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies. METHODS: Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment...
April 27, 2016: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/27100299/effects-of-estrogen-receptor-and-human-epidermal-growth-factor-receptor-2-levels-on-the-efficacy-of-trastuzumab-a-secondary-analysis-of-the-hera-trial
#17
Sherene Loi, Urania Dafni, Dimitris Karlis, Varvara Polydoropoulou, Brandon M Young, Scooter Willis, Bradley Long, Evandro de Azambuja, Christos Sotiriou, Giuseppe Viale, Josef Rüschoff, Martine J Piccart, Mitch Dowsett, Stefan Michiels, Brian Leyland-Jones
IMPORTANCE: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy...
August 1, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27001208/hormone-receptor-positive-her2-negative-metastatic-breast-cancer-a-systematic-review-of-the-current-treatment-landscape
#18
REVIEW
Jane Beith, Katie Burslem, Richard Bell, Natasha Woodward, Nicole McCarthy, Richard De Boer, Sherene Loi, Andrew Redfern
Endocrine therapy for the treatment of hormone receptor positive, HER2 negative, metastatic breast cancer is continually evolving. We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) of agents used in this setting to assess the effectiveness and safety of these agents for postmenopausal women. Across the 32 studies in more than 10,000 patients, the greatest improvement in progression-free survival (PFS) was seen with the addition of a cyclin-dependent kinase (CDK)4/6 inhibitor to standard endocrine therapy...
March 2016: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/26947331/fulvestrant-plus-palbociclib-versus-fulvestrant-plus-placebo-for-treatment-of-hormone-receptor-positive-her2-negative-metastatic-breast-cancer-that-progressed-on-previous-endocrine-therapy-paloma-3-final-analysis-of-the-multicentre-double-blind-phase-3-randomised
#19
Massimo Cristofanilli, Nicholas C Turner, Igor Bondarenko, Jungsil Ro, Seock-Ah Im, Norikazu Masuda, Marco Colleoni, Angela DeMichele, Sherene Loi, Sunil Verma, Hiroji Iwata, Nadia Harbeck, Ke Zhang, Kathy Puyana Theall, Yuqiu Jiang, Cynthia Huang Bartlett, Maria Koehler, Dennis Slamon
BACKGROUND: In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses...
April 2016: Lancet Oncology
https://www.readbyqxmd.com/read/26922998/mouse-models-of-tumor-immunotherapy
#20
REVIEW
Shin Foong Ngiow, Sherene Loi, David Thomas, Mark J Smyth
Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials...
2016: Advances in Immunology
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