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Gene expression Neoadjuvant Breast Proliferation

Takayuki Iwamoto, Toyomasa Katagiri, Naoki Niikura, Yuichiro Miyoshi, Mariko Kochi, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Masako Omori, Yutaka Tokuda, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Balazs Gyorffy, Junji Matsuoka
BACKGROUND: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers. RESULTS: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). Post-Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66...
February 16, 2017: Oncotarget
Cynthia X Ma, Feng Gao, Jingqin Luo, Donald W Northfelt, Matthew P Goetz, Andres Forero, Jeremy Hoog, Michael J Naughton, Foluso Ademuyiwa, Rama Suresh, Karen S Anderson, Julie Margenthaler, Rebecca Aft, Timothy J Hobday, Timothy Moynihan, William Gillanders, Amy Cyr, Timothy J Eberlein, Tina Hieken, Helen Krontiras, Zhanfang Guo, Michelle Lee, Nicholas C Spies, Zachary L Skidmore, Obi L Griffith, Malachi Griffith, Shana Thomas, Caroline Bumb, Kiran Vij, Cynthia Huang Bartlett, Maria Koehler, Hussam Al-Kateb, Souzan Sanati, Matthew J Ellis
PURPOSE: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the anti-proliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. EXPERIMENTAL DESIGN: Eligible patients with clinical stage II/III ER+/HER2- breast cancer received anastrozole 1mg daily for 4 weeks (cycle 0) (with goserelin if premenopausal), followed by adding palbociclib (125mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67>10%, in which case patients went off study due to inadequately response...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hans-Peter Sinn, Andreas Schneeweiss, Marius Keller, Kornelia Schlombs, Mark Laible, Julia Seitz, Sotirios Lakis, Elke Veltrup, Peter Altevogt, Sebastian Eidt, Ralph M Wirtz, Frederik Marmé
BACKGROUND: Proliferation may predict response to neoadjuvant therapy of breast cancer and is commonly assessed by manual scoring of slides stained by immunohistochemistry (IHC) for Ki-67 similar to ER and PgR. This method carries significant intra- and inter-observer variability. Automatic scoring of Ki-67 with digital image analysis (qIHC) or assessment of MKI67 gene expression with RT-qPCR may improve diagnostic accuracy. METHODS: Ki-67 IHC visual assessment was compared to the IHC nuclear tool (AperioTM) on core biopsies from a randomized neoadjuvant clinical trial...
February 13, 2017: BMC Cancer
Michal Jarzab, Monika Kowal, Wieslaw Bal, Malgorzata Oczko-Wojciechowska, Justyna Rembak-Szynkiewicz, Malgorzata Kowalska, Ewa Stobiecka, Ewa Chmielik, Tomasz Tyszkiewicz, Malgorzata Kaszuba, Elzbieta Nowicka, Barbara Lange, Agnieszka Czarniecka, Jolanta Krajewska, Alicja Dyla, Miroslaw Dobrut, Dariusz Lange, Barbara Jarzab, Barbara Bobek-Billewicz, Rafal Tarnawski
INTRODUCTION: Prediction of response to preoperative breast cancer chemotherapy may offer a substantial optimization of medical management of this disease. The most efficient prediction would be done a priori, before the start of chemotherapy and based on the biological features of patient and tumor. Numerous markers have been proposed but none of them has been applied as a routine. The role of MKI67 and HSP90 expression has been recently suggested to predict treatment sensitivity in HER2-positive breast cancer...
2016: Folia Histochemica et Cytobiologica
Anne-Sophie Hamy, Hélène Bonsang-Kitzis, Marick Lae, Matahi Moarii, Benjamin Sadacca, Alice Pinheiro, Marion Galliot, Judith Abecassis, Cecile Laurent, Fabien Reyal
INTRODUCTION: HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions. METHODS: We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC...
2016: PloS One
Yue Wang, Kenneth M K Mark, Matthew H Ung, Arminja Kettenbach, Todd Miller, Wei Xu, Wenqing Cheng, Tian Xia, Chao Cheng
Homologous recombination (HR) is the primary pathway for repairing double-strand DNA breaks implicating in the development of cancer. RNAi-based knockdowns of BRCA1 and RAD51 in this pathway have been performed to investigate the resulting transcriptomic profiles. Here we propose a computational framework to utilize these profiles to calculate a score, named RNA-Interference derived Proliferation Score (RIPS), which reflects cell proliferation ability in individual breast tumors. RIPS is predictive of breast cancer classes, prognosis, genome instability, and neoadjuvant chemosensitivity...
October 27, 2016: Genome Medicine
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
Andriy Marusyk, Doris P Tabassum, Michalina Janiszewska, Andrew E Place, Anne Trinh, Andrii I Rozhok, Saumyadipta Pyne, Jennifer L Guerriero, Shaokun Shu, Muhammad Ekram, Alexander Ishkin, Daniel P Cahill, Yuri Nikolsky, Timothy A Chan, Mothaffar F Rimawi, Susan Hilsenbeck, Rachel Schiff, Kent C Osborne, Antony Letai, Kornelia Polyak
Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold...
November 15, 2016: Cancer Research
Hemantika Dasgupta, Nupur Mukherjee, Saimul Islam, Rittwika Bhattacharya, Neyaz Alam, Anup Roy, Susanta Roychoudhury, Jaydip Biswas, Chinmay Kumar Panda
AIM: To understand the importance of homologous recombination repair pathway in development of breast carcinoma (BC), alterations of some key regulatory genes like BRCA1, BRCA2, FANCC and FANCD2 were analyzed in pretherapeutic/neoadjuvant chemotherapy (NACT)-treated BC samples. MATERIALS & METHODS: Alterations (deletion/methylation/expression) of the genes were analyzed in 118 pretherapeutic and 41 NACT-treated BC samples. RESULTS: High deletion/methylation (29-68%) and 64-78% overall alterations of the genes were found in the samples...
January 2017: Future Oncology
A S Hamy, I Bieche, J Lehmann-Che, V Scott, Ph Bertheau, J M Guinebretière, M C Matthieu, B Sigal-Zafrani, O Tembo, M Marty, B Asselain, F Spyratos, P de Cremoux
PURPOSE: Neoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment. METHODS: We used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years)...
October 2016: Breast Cancer Research and Treatment
Albina Stocker, Marie-Luise Hilbers, Claire Gauthier, Josias Grogg, Gerd A Kullak-Ublick, Burkhardt Seifert, Zsuzsanna Varga, Andreas Trojan
BACKGROUND: Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds...
2016: PloS One
Daniel G Stover, Jonathan L Coloff, William T Barry, Joan S Brugge, Eric P Winer, Laura M Selfors
PURPOSE: To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer. EXPERIMENTAL DESIGN: Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected...
December 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tarek M A Abdel-Fatah, Devika Agarwal, Dong-Xu Liu, Roslin Russell, Oscar M Rueda, Karen Liu, Bing Xu, Paul M Moseley, Andrew R Green, Alan G Pockley, Robert C Rees, Carlos Caldas, Ian O Ellis, Graham R Ball, Stephen Y T Chan
BACKGROUND: Proliferation markers and profiles have been recommended for guiding the choice of systemic treatments for breast cancer. However, the best molecular marker or test to use has not yet been identified. We did this study to identify factors that drive proliferation and its associated features in breast cancer and assess their association with clinical outcomes and response to chemotherapy. METHODS: We applied an artificial neural network-based integrative data mining approach to data from three cohorts of patients with breast cancer (the Nottingham discovery cohort (n=171), Uppsala cohort (n=249), and Molecular Taxonomy of Breast Cancer International Consortium [METABRIC] cohort; n=1980)...
July 2016: Lancet Oncology
Nikiana Simigdala, Qiong Gao, Sunil Pancholi, Hanne Roberg-Larsen, Marketa Zvelebil, Ricardo Ribas, Elizabeth Folkerd, Andrew Thompson, Amandeep Bhamra, Mitch Dowsett, Lesley-Ann Martin
BACKGROUND: Therapies targeting estrogenic stimulation in estrogen receptor-positive (ER+) breast cancer (BC) reduce mortality, but resistance remains a major clinical problem. Molecular studies have shown few high-frequency mutations to be associated with endocrine resistance. In contrast, expression profiling of primary ER+ BC samples has identified several promising signatures/networks for targeting. METHODS: To identify common adaptive mechanisms associated with resistance to aromatase inhibitors (AIs), we assessed changes in global gene expression during adaptation to long-term estrogen deprivation (LTED) in a panel of ER+ BC cell lines cultured in 2D on plastic (MCF7, T47D, HCC1428, SUM44 and ZR75...
2016: Breast Cancer Research: BCR
Marie Klintman, Richard Buus, Maggie Chon U Cheang, Amna Sheri, Ian E Smith, Mitch Dowsett
PURPOSE: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. EXPERIMENTAL DESIGN: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies...
May 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tesa M Severson, Ekaterina Nevedomskaya, Justine Peeters, Thomas Kuilman, Oscar Krijgsman, Annelot van Rossum, Marjolein Droog, Yongsoo Kim, Rutger Koornstra, Inès Beumer, Annuska M Glas, Daniel Peeper, Jelle Wesseling, Iris M Simon, Lodewyk Wessels, Sabine C Linn, Wilbert Zwart
Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment...
June 7, 2016: Oncotarget
Soumi Saha, Pranab Mandal, Suvro Ganguly, Debarshi Jana, Asif Ayaz, Abhirup Banerjee, Rahul Chouhan, Diptendra Kumar Sarkar
Human tumor suppressor BRCA2 has been known to function in the repair of DNA double strand break. Germ line mutation in BRCA genes predisposes individuals to familial breast and ovarian cancer. The aim of present study was to characterize the implication of BRCA2 expression in cases of non - hereditary (sporadic) breast cancer. Female breast cancer patients aged between 20 and 75 years who underwent surgery were randomly selected. Patients with Stage IV disease at time of primary diagnosis or previous history of any other malignancy other than breast carcinoma or undergoing neoadjuvant chemotherapy were excluded from the study...
December 2015: Indian Journal of Surgical Oncology
Stefanie de Groot, Ayoub Charehbili, Hanneke W M van Laarhoven, Antien L Mooyaart, N Geeske Dekker-Ensink, Saskia van de Ven, Laura G M Janssen, Jesse J Swen, Vincent T H B M Smit, Joan B Heijns, Lonneke W Kessels, Tahar van der Straaten, Stefan Böhringer, Hans Gelderblom, Jacobus J M van der Hoeven, Henk-Jan Guchelaar, Hanno Pijl, Judith R Kroep
BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR...
January 6, 2016: Breast Cancer Research: BCR
Aleix Prat, Cheng Fan, Aranzazu Fernández, Katherine A Hoadley, Rossella Martinello, Maria Vidal, Margarita Viladot, Estela Pineda, Ana Arance, Montserrat Muñoz, Laia Paré, Maggie C U Cheang, Barbara Adamo, Charles M Perou
BACKGROUND: Predicting treatment benefit and/or outcome before any therapeutic intervention has taken place would be clinically very useful. Herein, we evaluate the ability of the intrinsic subtypes and the risk of relapse score at diagnosis to predict survival and response following neoadjuvant chemotherapy. In addition, we evaluated the ability of the Claudin-low and 7-TNBCtype classifications to predict response within triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in a combined dataset of 957 breast cancer patients, including 350 with TNBC, treated with sequential anthracycline and anti-microtubule-based neoadjuvant regimens...
2015: BMC Medicine
Maurizio Callari, Vera Cappelletti, Francesca D'Aiuto, Valeria Musella, Antonio Lembo, Fabien Petel, Thomas Karn, Takayuki Iwamoto, Paolo Provero, Maria Grazia Daidone, Luca Gianni, Giampaolo Bianchini
PURPOSE: In spite of improvements of average benefit from adjuvant/neoadjuvant treatments, there are still individual patients with early breast cancer at high risk of relapse. We explored the association with outcome of robust gene cluster-based metagenes linked to proliferation, ER-related genes, and immune response to identify those high-risk patients. EXPERIMENTAL DESIGN: A total of 3,847 publicly available gene-expression profiles were analyzed (untreated, N = 826; tamoxifen-treated, N = 685; chemotherapy-treated, N = 1,150)...
January 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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