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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
#1
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/27672107/somatic-mutation-copy-number-and-transcriptomic-profiles-of-primary-and-matched-metastatic-estrogen-receptor-positive-breast-cancers
#2
D Fumagalli, T R Wilson, R Salgado, X Lu, J Yu, C O'Brien, K Walter, L Y Huw, C Criscitiello, I Laios, V Jose, D N Brown, F Rothé, M Maetens, D Zardavas, P Savas, D Larsimont, M J Piccart-Gebhart, S Michiels, M R Lackner, C Sotiriou, S Loi
BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material...
October 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27172896/loss-of-arid1a-activates-anxa1-which-serves-as-a-predictive-biomarker-for-trastuzumab-resistance
#3
Katrien Berns, Amir Sonnenblick, Annemiek Gennissen, Sylvain Brohée, E Marielle Hijmans, Bastiaan Evers, Debora Fumagalli, Christine Desmedt, Sibylle Loibl, Carsten Denkert, Patrick Neven, Wei Guo, Fan Zhang, Theo A Knijnenburg, Tjalling Bosse, Michiel S van der Heijden, Sanne Hindriksen, Wouter Nijkamp, Lodewyk F A Wessels, Heikki Joensuu, Gordon B Mills, Roderick L Beijersbergen, Christos Sotiriou, René Bernards
PURPOSE: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment. EXPERIMENTAL DESIGN: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2(+) breast cancer cell lines...
November 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26926684/genomic-characterization-of-primary-invasive-lobular-breast-cancer
#4
Christine Desmedt, Gabriele Zoppoli, Gunes Gundem, Giancarlo Pruneri, Denis Larsimont, Marco Fornili, Debora Fumagalli, David Brown, Françoise Rothé, Delphine Vincent, Naima Kheddoumi, Ghizlane Rouas, Samira Majjaj, Sylvain Brohée, Peter Van Loo, Patrick Maisonneuve, Roberto Salgado, Thomas Van Brussel, Diether Lambrechts, Ron Bose, Otto Metzger, Christine Galant, François Bertucci, Martine Piccart-Gebhart, Giuseppe Viale, Elia Biganzoli, Peter J Campbell, Christos Sotiriou
PURPOSE: Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. METHODS: From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features...
June 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/26440892/principles-governing-a-to-i-rna-editing-in-the-breast-cancer-transcriptome
#5
Debora Fumagalli, David Gacquer, Françoise Rothé, Anne Lefort, Frederick Libert, David Brown, Naima Kheddoumi, Adam Shlien, Tomasz Konopka, Roberto Salgado, Denis Larsimont, Kornelia Polyak, Karen Willard-Gallo, Christine Desmedt, Martine Piccart, Marc Abramowicz, Peter J Campbell, Christos Sotiriou, Vincent Detours
Little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific "editabilities," i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls...
October 13, 2015: Cell Reports
https://www.readbyqxmd.com/read/26358523/integrative-proteomic-and-gene-expression-analysis-identify-potential-biomarkers-for-adjuvant-trastuzumab-resistance-analysis-from-the-fin-her-phase-iii-randomized-trial
#6
RANDOMIZED CONTROLLED TRIAL
Amir Sonnenblick, Sylvain Brohée, Debora Fumagalli, Françoise Rothé, Delphine Vincent, Michael Ignatiadis, Christine Desmedt, Roberto Salgado, Nicolas Sirtaine, Sherene Loi, Patrick Neven, Sibylle Loibl, Carsten Denkert, Heikki Joensuu, Martine Piccart, Christos Sotiriou
Trastuzumab is a remarkably effective therapy for patients with human epidermal growth factor receptor 2 (HER2)--positive breast cancer (BC). However, not all women with high levels of HER2 benefit from trastuzumab. By integrating mRNA and protein expression data from Reverse-Phase Protein Array Analysis (RPPA) in HER2-positive BC, we developed gene expression metagenes that reflect pathway activation levels. Next we assessed the ability of these metagenes to predict resistance to adjuvant trastuzumab using gene expression data from two independent datasets...
October 6, 2015: Oncotarget
https://www.readbyqxmd.com/read/26234940/constitutive-phosphorylated-stat3-associated-gene-signature-is-predictive-for-trastuzumab-resistance-in-primary-her2-positive-breast-cancer
#7
Amir Sonnenblick, Sylvain Brohée, Debora Fumagalli, Delphine Vincent, David Venet, Michail Ignatiadis, Roberto Salgado, Gert Van den Eynden, Françoise Rothé, Christine Desmedt, Patrick Neven, Sibylle Loibl, Carsten Denkert, Heikki Joensuu, Sherene Loi, Nicolas Sirtaine, Pirkko-Liisa Kellokumpu-Lehtinen, Martine Piccart, Christos Sotiriou
BACKGROUND: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance...
2015: BMC Medicine
https://www.readbyqxmd.com/read/25884932/no-significant-viral-transcription-detected-in-whole-breast-cancer-transcriptomes
#8
Danai Fimereli, David Gacquer, Debora Fumagalli, Roberto Salgado, Françoise Rothé, Denis Larsimont, Christos Sotiriou, Vincent Detours
BACKGROUND: Studies evaluating the presence of viral sequences in breast cancer (BC), including various strains of human papillomavirus and human herpes virus, have yielded conflicting results. Most were based on RT-PCR and in situ hybridization. METHODS: In this report we searched for expressed viral sequences in 58 BC transcriptomes using five distinct in silico methods. In addition, we complemented our RNA sequencing results with exome sequencing, PCR and immunohistochemistry (IHC) analyses...
2015: BMC Cancer
https://www.readbyqxmd.com/read/25850943/uncovering-the-genomic-heterogeneity-of-multifocal-breast-cancer
#9
Christine Desmedt, Debora Fumagalli, Elisabetta Pietri, Gabriele Zoppoli, David Brown, Serena Nik-Zainal, Gunes Gundem, Françoise Rothé, Samira Majjaj, Anna Garuti, Enrico Carminati, Sherene Loi, Thomas Van Brussel, Bram Boeckx, Marion Maetens, Laura Mudie, Delphine Vincent, Naima Kheddoumi, Luigi Serra, Ilaria Massa, Alberto Ballestrero, Dino Amadori, Roberto Salgado, Alexandre de Wind, Diether Lambrechts, Martine Piccart, Denis Larsimont, Peter J Campbell, Christos Sotiriou
Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples)...
August 2015: Journal of Pathology
https://www.readbyqxmd.com/read/25559818/pik3ca-mutations-are-associated-with-decreased-benefit-to-neoadjuvant-human-epidermal-growth-factor-receptor-2-targeted-therapies-in-breast-cancer
#10
RANDOMIZED CONTROLLED TRIAL
Ian J Majewski, Paolo Nuciforo, Lorenza Mittempergher, Astrid J Bosma, Holger Eidtmann, Eileen Holmes, Christos Sotiriou, Debora Fumagalli, Jose Jimenez, Claudia Aura, Ludmila Prudkin, Maria Carmen Díaz-Delgado, Lorena de la Peña, Sherene Loi, Catherine Ellis, Nikolaus Schultz, Evandro de Azambuja, Nadia Harbeck, Martine Piccart-Gebhart, René Bernards, José Baselga
PURPOSE: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer. PATIENTS AND METHODS: Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO)...
April 20, 2015: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/25412710/transfer-of-clinically-relevant-gene-expression-signatures-in-breast-cancer-from-affymetrix-microarray-to-illumina-rna-sequencing-technology
#11
Debora Fumagalli, Alexis Blanchet-Cohen, David Brown, Christine Desmedt, David Gacquer, Stefan Michiels, Françoise Rothé, Samira Majjaj, Roberto Salgado, Denis Larsimont, Michail Ignatiadis, Marion Maetens, Martine Piccart, Vincent Detours, Christos Sotiriou, Benjamin Haibe-Kains
BACKGROUND: Microarrays have revolutionized breast cancer (BC) research by enabling studies of gene expression on a transcriptome-wide scale. Recently, RNA-Sequencing (RNA-Seq) has emerged as an alternative for precise readouts of the transcriptome. To date, no study has compared the ability of the two technologies to quantify clinically relevant individual genes and microarray-derived gene expression signatures (GES) in a set of BC samples encompassing the known molecular BC's subtypes...
2014: BMC Genomics
https://www.readbyqxmd.com/read/25336696/new-strategies-in-breast-cancer-the-significance-of-molecular-subtypes-in-systemic-adjuvant-treatment-for-small-t1a-bn0m0-tumors
#12
REVIEW
Amir Sonnenblick, Debora Fumagalli, Hatem A Azim, Christos Sotiriou, Martine Piccart
Awareness of breast cancer heterogeneity has strikingly increased in the past decade in parallel with the development of high-throughput molecular tests. Beyond the clear usefulness of antiestrogen treatment in luminal tumors and trastuzumab in HER2-positive tumors, breast cancer subtypes may have additional clinical and predictive roles that can be relevant to clinical practice. In this article, we discuss the significance of molecular subtypes in the systemic treatment of early-stage breast tumors smaller than 1 cm (T1a,bN0M0) and suggest new strategies for future treatment recommendations for these patients...
December 15, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/25270265/deciphering-clonality-in-aneuploid-breast-tumors-using-snp-array-and-sequencing-data
#13
Ingrid M Lönnstedt, Franco Caramia, Jason Li, Debora Fumagalli, Roberto Salgado, Andrew Rowan, Max Salm, Nnennaya Kanu, Peter Savas, Stuart Horswell, Stephan Gade, Sibylle Loibl, Patrick Neven, Christos Sotiriou, Charles Swanton, Sherene Loi, Terence P Speed
Intra-tumor heterogeneity concerns the existence of genetically different subclones within the same tumor. Single sample quantification of heterogeneity relies on precise determination of chromosomal copy numbers throughout the genome, and an assessment of whether identified mutation variant allele fractions match clonal or subclonal copy numbers. We discuss these issues using data from SNP arrays, whole exome sequencing and pathologist purity estimates on several breast cancers characterized by ERBB2 amplification...
2014: Genome Biology
https://www.readbyqxmd.com/read/25225904/the-aurora-initiative-for-metastatic-breast-cancer
#14
REVIEW
D Zardavas, M Maetens, A Irrthum, T Goulioti, K Engelen, D Fumagalli, R Salgado, P Aftimos, K S Saini, C Sotiriou, P Campbell, P Dinh, G von Minckwitz, R D Gelber, M Dowsett, A Di Leo, D Cameron, J Baselga, M Gnant, A Goldhirsch, L Norton, M Piccart
Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme...
November 11, 2014: British Journal of Cancer
https://www.readbyqxmd.com/read/25185240/plasma-circulating-tumor-dna-as-an-alternative-to-metastatic-biopsies-for-mutational-analysis-in-breast-cancer
#15
F Rothé, J-F Laes, D Lambrechts, D Smeets, D Vincent, M Maetens, D Fumagalli, S Michiels, S Drisis, C Moerman, J-P Detiffe, D Larsimont, A Awada, M Piccart, C Sotiriou, M Ignatiadis
BACKGROUND: Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. PATIENTS AND METHODS: The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients...
October 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/25151406/is-the-differentiation-into-molecular-subtypes-of-breast-cancer-important-for-staging-local-and-systemic-therapy-and-follow-up
#16
REVIEW
Amir Sonnenblick, Debora Fumagalli, Christos Sotiriou, Martine Piccart
Breast cancer complexity has long been known and investigated. After a first classification of the disease based on histology features, starting from the 1980s breast cancers have been distinguished on the basis of oestrogen receptor expression and later according to HER2. By 2000 the "microarray revolution" had shown that the phenotypic differences between breast cancers were a reflection of their mRNA expression profiles, while the more recent "genomic revolution" is revealing the genomic bases of breast cancer heterogeneity...
October 2014: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/25049332/luminal-b-breast-cancer-molecular-characterization-clinical-management-and-future-perspectives
#17
REVIEW
Felipe Ades, Dimitrios Zardavas, Ivana Bozovic-Spasojevic, Lina Pugliano, Debora Fumagalli, Evandro de Azambuja, Giuseppe Viale, Christos Sotiriou, Martine Piccart
Gene expression profiling has reshaped our understanding of breast cancer by defining and characterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor 2-enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has been reported to have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has a distinct profile of response to hormone therapy and chemotherapy...
September 1, 2014: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/24608200/tumor-infiltrating-lymphocytes-are-prognostic-in-triple-negative-breast-cancer-and-predictive-for-trastuzumab-benefit-in-early-breast-cancer-results-from-the-finher-trial
#18
RANDOMIZED CONTROLLED TRIAL
S Loi, S Michiels, R Salgado, N Sirtaine, V Jose, D Fumagalli, P-L Kellokumpu-Lehtinen, P Bono, V Kataja, C Desmedt, M J Piccart, S Loibl, C Denkert, M J Smyth, H Joensuu, C Sotiriou
BACKGROUND: We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+). PATIENTS AND METHODS: A prospective-retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified...
August 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/23739063/somatic-mutation-profiling-and-associations-with-prognosis-and-trastuzumab-benefit-in-early-breast-cancer
#19
RANDOMIZED CONTROLLED TRIAL
Sherene Loi, Stefan Michiels, Diether Lambrechts, Debora Fumagalli, Bart Claes, Pirkko-Liisa Kellokumpu-Lehtinen, Petri Bono, Vesa Kataja, Martine J Piccart, Heikki Joensuu, Christos Sotiriou
BACKGROUND: Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset. METHODS: The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab...
July 3, 2013: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/23638089/association-between-sparc-mrna-expression-prognosis-and-response-to-neoadjuvant-chemotherapy-in-early-breast-cancer-a-pooled-in-silico-analysis
#20
Hatem A Azim, Sandeep Singhal, Michail Ignatiadis, Christine Desmedt, Debora Fumagalli, Isabelle Veys, Denis Larsimont, Martine Piccart, Stefan Michiels, Christos Sotiriou
INTRODUCTION: SPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics. However, little is known regarding its role in breast cancer (BC). METHODS: We conducted a pooled analysis of publically available datasets, in which BC patients who received no systemic therapy or received neoadjuvant chemotherapy were eligible. Patients were assigned to molecular subtypes using PAM-50. We computed a SPARC module (SPARC7), composed of genes with an absolute correlation with SPARC >0...
2013: PloS One
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