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breast cancer, tamoxifen metabolism, prognosis

Kwang-Pil Ko, Seung Hyun Ma, Jae-Jeong Yang, Yunji Hwang, Choonghyun Ahn, Young-Min Cho, Dong-Young Noh, Byung-Joo Park, Wonshik Han, Sue K Park
Previous observational studies have suggested that metformin in diabetes patients may reduce breast cancer risk more than the reductions from other anti-diabetes medications. This randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of metformin for controlling physical and metabolic profiles related to prognosis and adverse events in non-diabetic breast cancer patients. Female breast cancer patients (N = 105), at least 6 months post-mastectomy, with obesity (≥25 kg/m(2)) and/or pre-diabetes (fasting blood sugar levels ≥100 mg/dL), were randomly assigned to three groups (placebo, metformin 500 mg, and metformin 1000 mg) stratified by tamoxifen use...
September 2015: Breast Cancer Research and Treatment
Keith Sacco, Godfrey Grech
Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome...
2015: EPMA Journal
D M F Martins, F C B Vidal, R D M Souza, S A Brusaca, L M O Brito
The CYP2D6 enzyme is crucial for the metabolism of tamoxifen. The CYP2D6 gene is highly polymorphic, and individuals can be extensive, intermediate, or poor tamoxifen metabolizers. The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival. We observed a high frequency of CYP2D6 *10, with an allelic frequency of 0.14 (14...
November 2014: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Nagireddy Putluri, Suman Maity, Ramakrishna Kommagani, Ramakrishna Kommangani, Chad J Creighton, Vasanta Putluri, Fengju Chen, Sarmishta Nanda, Salil Kumar Bhowmik, Atsushi Terunuma, Tiffany Dorsey, Agostina Nardone, Xiaoyong Fu, Chad Shaw, Tapasree Roy Sarkar, Rachel Schiff, John P Lydon, Bert W O'Malley, Stefan Ambs, Gokul M Das, George Michailidis, Arun Sreekumar
Breast cancer (BCa) molecular subtypes include luminal A, luminal B, normal-like, HER-2-enriched, and basal-like tumors, among which luminal B and basal-like cancers are highly aggressive. Biochemical pathways associated with patient survival or treatment response in these more aggressive subtypes are not well understood. With the limited availability of pathologically verified clinical specimens, cell line models are routinely used for pathway-centric studies. We measured the metabolome of luminal and basal-like BCa cell lines using mass spectrometry, linked metabolites to biochemical pathways using Gene Set Analysis, and developed a novel rank-based method to select pathways on the basis of their enrichment in patient-derived omics data sets and prognostic relevance...
May 2014: Neoplasia: An International Journal for Oncology Research
N T Brewer, J T Defrank, W K Chiu, J G Ibrahim, C M Walko, P Rubin, O A Olajide, S G Moore, R E Raab, D R Carrizosa, S W Corso, G Schwartz, J M Peppercorn, H L McLeod, L A Carey, W J Irvin
BACKGROUND: CYP2D6 is a critical enzyme in the metabolism of tamoxifen and potentially a key determinant in breast cancer outcomes. Our study examined patients' beliefs about how the CYP2D6 genotype would affect their prognoses. METHODS: Women enrolled in a pharmacogenomic clinical trial and on tamoxifen for prevention or treatment of breast cancer underwent CYP2D6 genotyping (EM = extensive, IM = intermediate, PM = poor metabolizing alleles). The informed consent said that the purpose of the trial was to examine effects of dose adjustment based on genotype, but that clinical benefits were uncertain...
2014: Public Health Genomics
Jingmei Li, Kamila Czene, Hiltrud Brauch, Werner Schroth, Pilar Saladores, Yi Li, Keith Humphreys, Per Hall
INTRODUCTION: Not all breast cancer patients respond to tamoxifen treatment, possibly due to genetic predisposition. As tamoxifen-induced reductions in percent mammographic density (PMD) have been linked to the risk and prognosis of breast cancer, we conducted a candidate gene study to investigate the association between germline CYP2D6 polymorphisms and PMD change. METHODS: Baseline and follow-up mammograms were retrieved for 278 tamoxifen-treated subjects with CYP2D6 metabolizer status (extensive (EM), heterozygous extensive/intermediate (hetEM/IM) or poor metabolizer (PM))...
2013: Breast Cancer Research: BCR
Aleksandra Markiewicz, Marzena Wełnicka-Jaśkiewicz, Jarosław Skokowski, Janusz Jaśkiewicz, Jolanta Szade, Jacek Jassem, Anna J Zaczek
INTRODUCTION: Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, however its prognostic impact in breast cancer patients has not been thoroughly investigated. Other factors that could contribute to responsiveness to tamoxifen treatment are polymorphisms in ESR1 gene and genes involved in tamoxifen metabolism. The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors...
2013: PloS One
Jeffrey Peppercorn, Erika Hamilton, Paul Kelly Marcom, Laura Beskow, Gary H Lyman
BACKGROUND: This study evaluated self-reported knowledge, practice, and attitudes toward commercially available cytochrome P450 2D6 (CYP2D6) pharmacogenomic testing for patients on tamoxifen for breast cancer (CYPT) among US oncologists while evidence for the use of the test was evolving. METHODS: A self-administered survey of medical oncology breast cancer specialists at National Comprehensive Cancer Network (NCCNO) centers and a random sample of community-based oncologists (CBOs) was undertaken...
October 15, 2013: Cancer
Cassio Cardoso-Filho, Luis Otavio Sarian, Camila Borges Martins de Oliveira, Leonardo da Silveira Bossi, Gustavo Jacob Lourenço, Carmen Silvia Passos Lima, Maria Salete Costa Gurgel
PURPOSE: Individual differences in cytochrome P-450 efficiency partly explain their variations in resistance to tamoxifen and estrogen metabolism. Two polymorphisms of the CYP1A1 gene-A4889G and T6235C-are known to affect activation of estrone and estradiol and to deregulate concentration of highly active tamoxifen metabolites. However, the clinicopathologic implications of these findings have not yet been evaluated. OBJECTIVE: The objective of this study is to evaluate whether T6235C and A4889G gene polymorphisms are related to pathological presentations and clinical outcomes of ER+/PR+ breast cancer (BC) in women using tamoxifen...
September 2013: Cancer Chemotherapy and Pharmacology
F Farabegoli, M Vettraino, M Manerba, L Fiume, M Roberti, G Di Stefano
Galloflavin (GF), a recently identified lactate dehydrogenase inhibitor, hinders the proliferation of cancer cells by blocking glycolysis and ATP production. The aim of the present experiments was to study the effect of this compound on breast cancer cell lines reproducing different pathological subtypes of this tumor: MCF-7 (the well differentiated form), MDA-MB-231 (the aggressive triple negative tumor) and MCF-Tam (a sub-line of MCF-7 with acquired tamoxifen resistance). We observed marked differences in the energetic metabolism of these cell lines...
November 20, 2012: European Journal of Pharmaceutical Sciences
V Craig Jordan, Ifeyinwa Obiorah, Ping Fan, Helen R Kim, Eric Ariazi, Heather Cunliffe, Hiltrud Brauch
The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5 years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-saving medicine for the pre-menopausal patient...
October 2011: Breast: Official Journal of the European Society of Mastology
Lance D Miller, Lan G Coffman, Jeff W Chou, Michael A Black, Jonas Bergh, Ralph D'Agostino, Suzy V Torti, Frank M Torti
Changes in iron regulation characterize the malignant state. However, the pathways that effect these changes and their specific impact on prognosis remain poorly understood. We capitalized on publicly available microarray datasets comprising 674 breast cancer cases to systematically investigate how expression of genes related to iron metabolism is linked to breast cancer prognosis. Of 61 genes involved in iron regulation, 49% were statistically significantly associated with distant metastasis-free survival...
November 1, 2011: Cancer Research
Ron H N van Schaik, Marleen Kok, Fred C G J Sweep, Martin van Vliet, Marianne van Fessem, Marion E Meijer-van Gelder, Caroline Seynaeve, Jan Lindemans, Jelle Wesseling, Laura J Van 't Veer, Paul N Span, Hanneke van Laarhoven, Stefan Sleijfer, John A Foekens, Sabine C Linn, Els M J J Berns
AIMS: Tamoxifen is metabolized by cytochrome P450s, with an important role for CYP2D6. Recently, we demonstrated in 80 patients that CYP2C19*2 is associated with increased survival in breast cancer patients using tamoxifen. Here, we aimed to confirm this in a large group of 499 patients. MATERIALS & METHODS: A total of 499 estrogen receptor-positive primary breast tumor specimens of advanced disease patients treated with first-line tamoxifen were genotyped for CYP2C19*2 and *17 variant alleles, with primary end point time-to-treatment failure (TTF)...
August 2011: Pharmacogenomics
Song Yao, William E Barlow, Kathy S Albain, Ji-Yeob Choi, Hua Zhao, Robert B Livingston, Warren Davis, James M Rae, I-Tien Yeh, Laura F Hutchins, Peter M Ravdin, Silvana Martino, Alan P Lyss, C Kent Osborne, Martin Abeloff, Gabriel N Hortobagyi, Daniel F Hayes, Christine B Ambrosone
PURPOSE: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). EXPERIMENTAL DESIGN: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy...
December 15, 2010: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Gizeh Pérez-Tenorio, Elin Karlsson, Marie Ahnström Waltersson, Birgit Olsson, Birgitta Holmlund, Bo Nordenskjöld, Tommy Fornander, Lambert Skoog, Olle Stål
The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer...
August 2011: Breast Cancer Research and Treatment
Ubaldo E Martinez-Outschoorn, Renee M Balliet, Dayana B Rivadeneira, Barbara Chiavarina, Stephanos Pavlides, Chenguang Wang, Diana Whitaker-Menezes, Kristin M Daumer, Zhao Lin, Agnieszka K Witkiewicz, Neal Flomenberg, Anthony Howell, Richard G Pestell, Erik S Knudsen, Federica Sotgia, Michael P Lisanti
Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells...
August 15, 2010: Cell Cycle
Werner Schroth, Ute Hamann, Peter A Fasching, Silke Dauser, Stefan Winter, Michel Eichelbaum, Matthias Schwab, Hiltrud Brauch
PURPOSE: This study aimed to validate matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS)/Taqman copy number assay (CNA) CYP2D6 genotyping by AmpliChip CYP450 Test for the prediction of tamoxifen metabolizer phenotypes in breast cancer, and to investigate the influence of CYP2D6 variant coverage on genotype-phenotype relationships and tamoxifen outcome. EXPERIMENTAL DESIGN: Hormone receptor-positive postmenopausal breast cancer patients (n = 492) treated with adjuvant tamoxifen, previously analyzed by MALDI-TOF MS/CNA, were reanalyzed by AmpliChip CYP450 Test and validated by independent methods...
September 1, 2010: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Raffaele Longo, Mario D'Andrea, Roberta Sarmiento, Giampietro Gasparini
Breast cancer is the most common female cancer, with more than one million new patients diagnosed annually worldwide. The great heterogeneity, in terms of prognosis and outcome, within patients with the same clinical and pathological characteristics may limit the potential for personalized therapy. Most of the cytotoxic agents and new targeted agents have a narrow therapeutic index and the administration of an equal dose may result in a wide range of toxicities as well as to different antitumor efficacy. Inter-subject variability in drug toxicity and response is common during treatment, so that individualization of treatments is an important issue...
April 2010: Expert Opinion on Investigational Drugs
Kazuma Kiyotani, Taisei Mushiroda, Chiyo K Imamura, Naoya Hosono, Tatsuhiko Tsunoda, Michiaki Kubo, Yusuke Tanigawara, David A Flockhart, Zeruesenay Desta, Todd C Skaar, Fuminori Aki, Koichi Hirata, Yuichi Takatsuka, Minoru Okazaki, Shozo Ohsumi, Takashi Yamakawa, Mitsunori Sasa, Yusuke Nakamura, Hitoshi Zembutsu
PURPOSE: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. PATIENTS AND METHODS: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported...
March 10, 2010: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
H Jernström, E Bågeman, C Rose, P-E Jönsson, C Ingvar
BACKGROUND: CYP2C8/9 polymorphisms may influence breast cancer-free survival after diagnosis due to their role in the metabolism of tamoxifen, paclitaxel, and other chemotherapy. cytochrome P450 (CYP)2C8/9 metabolise arachidonic acid to epoxyeicosatrienoic acids, which enhance migration and invasion in vitro and promote angiogenesis in vivo. We aimed to investigate the frequency of CYP2C8/9 polymorphisms in relation to breast tumour characteristics and disease-free survival. METHODS: A prospective series of 652 breast cancer patients from southern Sweden was genotyped for CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3...
December 1, 2009: British Journal of Cancer
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