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Esr1 mutation

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https://www.readbyqxmd.com/read/29045530/tracking-evolution-of-aromatase-inhibitor-resistance-with-circulating-tumour-dna-analysis-in-metastatic-breast-cancer
#1
Charlotte Fribbens, Isaac Garcia Murillas, Matthew Beaney, Sarah Hrebien, Ben O'Leary, Lucy Kilburn, Karen Howarth, Michael Epstein, Emma Green, Nitzan Rosenfeld, Alistair Ring, Stephen Johnston, Nicholas Turner
Background: Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to first line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Patients and Methods: 83 patients on first line AI therapy for metastatic breast cancer were enrolled in a prospective study...
October 4, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29032804/-clinical-relevance-of-esr1-circulating-mutations-detection-in-hormone-receptor-positive-metastatic-breast-cancer
#2
REVIEW
Florian Clatot, Anne Perdrix, David Sefrioui, Nasrin Sarafan-Vasseur, Frédéric Di Fiore
If hormone therapy is a key treatment for hormone receptor positive advanced breast cancers, secondary resistance occurs as a rule. Recently, acquired alterations of the ESR1 gene have been identified as a mechanism of resistance on aromatase inhibitor (AI) treatment. The selective pressure by AI exposure during the metastatic setting triggers the emergence of ESR1 activating mutations. In that context, the "liquid biopsy" concept has been used to detect this molecular resistance before progression. Thus, the ESR1 circulating mutation detection will soon be used in daily practice to help monitoring patients on AI treatment and provide an early change for specific therapies that still have to be determined in prospective clinical trials...
October 9, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29029116/upregulation-of-irs1-enhances-igf1-response-in-y537s-and-d538g-esr1-mutant-breast-cancer-cells
#3
Zheqi Li, Kevin M Levine, Amir Bahreini, Peilu Wang, David Chu, Ben Ho Park, Steffi Oesterreich, Adrian V Lee
Increased evidence suggests that somatic mutations in the ligand binding domain of estrogen receptor (ERα/ESR1) are critical mediators of endocrine-resistant breast cancer progression. Insulin-like growth factor-1 (IGF1) is an essential regulator of breast development and tumorigenesis, and also has a role in endocrine resistance. A recent study showed enhanced crosstalk between IGF1 and ERα in ESR1 mutant cells, but detailed mechanisms are incompletely understood. Using genome-edited MCF-7 and T47D cell lines harboring Y537S and D538G ESR1 mutations, we characterized altered IGF1 signaling...
September 27, 2017: Endocrinology
https://www.readbyqxmd.com/read/28978004/detection-of-esr1-mutations-in-circulating-cell-free-dna-from-patients-with-metastatic-breast-cancer-treated-with-palbociclib-and-letrozole
#4
Rekha Gyanchandani, Karthik J Kota, Amruth R Jonnalagadda, Tanya Minteer, Beth A Knapick, Steffi Oesterreich, Adam M Brufsky, Adrian V Lee, Shannon L Puhalla
ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28945887/hybrid-capture-based-genomic-profiling-of-circulating-tumor-dna-from-patients-with-estrogen-receptor-positive-metastatic-breast-cancer
#5
J H Chung, D Pavlick, R Hartmaier, A B Schrock, L Young, B Forcier, P Ye, M K Levin, H Burris, L M Gay, A D Hoffman, P J Stephens, G M Frampton, D M Lipson, D M Nguyen, S Ganesan, B H Park, L T Vahdat, B Leyland-Jones, T I Mughal, L Pusztai, J O'Shaughnessy, V A Miller, J S Ross, S M Ali
Background: Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative...
August 31, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28905136/highly-sensitive-detection-of-esr1-mutations-in-cell-free-dna-from-patients-with-metastatic-breast-cancer-using-molecular-barcode-sequencing
#6
Nanae Masunaga, Naofumi Kagara, Daisuke Motooka, Shota Nakamura, Tomohiro Miyake, Tomonori Tanei, Yasuto Naoi, Masafumi Shimoda, Kenzo Shimazu, Seung Jin Kim, Shinzaburo Noguchi
PURPOSE: We aimed to develop a highly sensitive method to detect ESR1 mutations in cell-free DNA (cfDNA) using next-generation sequencing with molecular barcode (MB-NGS) targeting the hotspot segment (c.1600-1713). METHODS: The sensitivity of MB-NGS was tested using serially diluted ESR1 mutant DNA and then cfDNA samples from 34 patients with metastatic breast cancer were analyzed with MB-NGS. The results of MB-NGS were validated in comparison with conventional NGS and droplet digital PCR (ddPCR)...
September 13, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28882552/prognostic-and-predictive-biomarkers-in-breast-cancer-past-present-and-future
#7
REVIEW
Andrea Nicolini, Paola Ferrari, Michael J Duffy
Following a diagnosis of breast cancer, the most immediate challenges in patient management are the determination of prognosis and identification of the most appropriate adjuvant systemic therapy. Determining prognosis can best be addressed with a combination of traditional clinicopathological prognostic factors, biomarkers such as HER2/neu and specific multigene genes tests. Amongst the best validated prognostic multigene tests are uPA/PAI1, Oncotype DX and MammaPrint. Oncotype DX and MammaPrint, may be used for predicting outcome and aiding adjunct therapy decision making in patients with ER-positive, HER2-negative breast cancers that are either lymph node-negative or node positive (1-3 metastatic nodes), while uPA/PAI-1 may be similarly used in ER-positive, lymph node-negative patients...
September 4, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28881720/analysis-of-esr1-and-pik3ca-mutations-in-plasma-cell-free-dna-from-er-positive-breast-cancer-patients
#8
Takashi Takeshita, Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Mai Tomiguchi, Aiko Sueta, Keiichi Murakami, Yoko Omoto, Hirotaka Iwase
BACKGROUND: The measurement of ESR1 and PIK3CA mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive method to quickly assess and monitor endocrine therapy (ET) resistant metastatic breast cancer (MBC) patients. METHODS: The subjects of this retrospective study were a total of 185 plasma samples from 86 estrogen receptor-positive BC patients, of which 151 plasma samples were from 69 MBC patients and 34 plasma samples were from 17 primary BC (PBC) patients...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28874413/a-phase-ii-trial-of-neoadjuvant-mk2206-an-akt-inhibitor-with-anastrozole-in-clinical-stage-2-or-3-pik3ca-mutant-er%C3%A2-positive-and-her2-negative-breast-cancer
#9
Cynthia X Ma, Vera Suman, Matthew P Goetz, Donald W Northfelt, Mark E Burkard, Foluso Ademuyiwa, Michael J Naughton, Julie Margenthaler, Rebecca Aft, Richard J Gray, Amye J Tevaarwerk, Lee G Wilke, Tufia C Haddad, Timothy Moynihan, Charles Loprenzi, Tina Hieken, Erica K Barnell, Zachary L Skidmore, Yan-Yang Feng, Kilannin Krysiak, Jeremy Hoog, Zhanfang Guo, Leslie Nehring, Kari B Wisinski, Elaine R Mardis, Ian S Hagemann, Kiran Vij, Souzan Sanati, Hussam Al-Kateb, Obi L Griffith, Malachi Griffith, Austin Doyle, Charles Erlichman, Matthew J Ellis
PURPOSE: Hyper-activation of AKT is common and associated with endocrine resistance in estrogen receptor positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. EXPERIMENTAL DESIGN: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were pre-registered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing...
September 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28854070/first-in-human-phase-i-study-of-the-tamoxifen-metabolite-z-endoxifen-in-women-with-endocrine-refractory-metastatic-breast-cancer
#10
Matthew P Goetz, Vera J Suman, Joel M Reid, Don W Northfelt, Michael A Mahr, Andrew T Ralya, Mary Kuffel, Sarah A Buhrow, Stephanie L Safgren, Renee M McGovern, John Black, Travis Dockter, Tufia Haddad, Charles Erlichman, Alex A Adjei, Dan Visscher, Zachary R Chalmers, Garrett Frampton, Benjamin R Kipp, Minetta C Liu, John R Hawse, James H Doroshow, Jerry M Collins, Howard Streicher, Matthew M Ames, James N Ingle
Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor-positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day...
October 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28815558/sequence-variants-in-esr1-and-oxtr-are-associated-with-mayer-rokitansky-k%C3%A3-ster-hauser-syndrome
#11
Sara Yvonne Brucker, Liliane Frank, Simone Eisenbeis, Melanie Henes, Diethelm Wallwiener, Olaf Riess, Barbara van Eijck, Dorit Schöller, Michael Bonin, Kristin Katharina Rall
INTRODUCTION: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus and the upper two-thirds of the vagina in otherwise phenotypically normal females. It is found isolated or associated with renal, skeletal and other malformations. Despite ongoing research, the etiology is mainly unknown. For a long time, the hypothesis of deficient hormone receptors as the cause for MRKHS has existed, supported by previous findings of our group. The aim of the present study was to identify unknown genetic causes for MRKHS and to compare them with data banks including a review of the literature...
August 16, 2017: Acta Obstetricia et Gynecologica Scandinavica
https://www.readbyqxmd.com/read/28799536/estrogen-receptor-esr1-mutation-in-bone-metastases-from-breast-cancer
#12
Stephan Bartels, Matthias Christgen, Angelina Luft, Sascha Persing, Kai Jödecke, Ulrich Lehmann, Hans Kreipe
Activating mutations of estrogen receptor α gene (ESR1) in breast cancer can cause endocrine resistance of metastatic tumor cells. The skeleton belongs to the metastatic sides frequently affected by breast cancer. The prevalence of ESR1 mutation in bone metastasis and the corresponding phenotype are not known. In this study bone metastases from breast cancer (n=231) were analyzed for ESR1 mutation. In 27 patients (12%) (median age 73 years, range: 55-82 years) activating mutations of ESR1 were detected. The most frequent mutation was p...
August 11, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28778025/comparison-of-esr1-mutations-in-tumor-tissue-and-matched-plasma-samples-from-metastatic-breast-cancer-patients
#13
Takashi Takeshita, Yutaka Yamamoto, Mutsuko Yamamoto-Ibusuki, Mai Tomiguchi, Aiko Sueta, Keiichi Murakami, Yoko Omoto, Hirotaka Iwase
BACKGROUND: ESR1 mutation in circulating cell-free DNA (cfDNA) is emerging as a noninvasive biomarker of acquired resistance to endocrine therapy, but there is a paucity of data comparing the status of ESR1 gene in cfDNA with that in its corresponding tumor tissue. The objective of this study is to validate the degree of concordance of ESR1 mutations between plasma and tumor tissue. METHODS: ESR1 ligand-binding domain mutations Y537S, Y537N, Y537C, and D538G were analyzed using droplet digital PCR in 35 patients with metastatic breast cancer (MBC) (35 tumor tissue samples and 67 plasma samples)...
October 2017: Translational Oncology
https://www.readbyqxmd.com/read/28775043/oestrogen-inhibition-reverses-pulmonary-arterial-hypertension-and-associated-metabolic-defects
#14
Xinping Chen, Eric D Austin, Megha Talati, Joshua P Fessel, Eric H Farber-Eger, Evan L Brittain, Anna R Hemnes, James E Loyd, James West
Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment...
August 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28743985/loss-of-er%C3%AE-partially-reverses-the-effects-of-maternal-high-fat-diet-on-energy-homeostasis-in-female-mice
#15
Troy A Roepke, Ali Yasrebi, Alejandra Villalobos, Elizabeth A Krumm, Jennifer A Yang, Kyle J Mamounis
Maternal high-fat diet (HFD) alters hypothalamic developmental programming and disrupts offspring energy homeostasis in rodents. 17β-estradiol (E2) also influences hypothalamic programming through estrogen receptor (ER) α. Therefore, we hypothesized that females lacking ERα would be more susceptible to maternal HFD. To address this question, heterozygous ERα knockout (WT/KO) dams were fed a control breeder chow diet (25% fat) or a semi-purified HFD (45% fat) 4 weeks prior to mating with WT/KO males or heterozygous males with an ERα DNA-binding domain mutation knocked in (WT/KI) to produce WT, ERα KO, or ERα KIKO females lacking ERE-dependent ERα signaling...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729136/heparinase-enables-reliable-quantification-of-circulating-tumor-dna-from-heparinized-plasma-samples-by-droplet-digital-pcr
#16
David Sefrioui, Ludivine Beaussire, Florian Clatot, Julien Delacour, Anne Perdrix, Thierry Frebourg, Pierre Michel, Frédéric Di Fiore, Nasrin Sarafan-Vasseur
BACKGROUND: Heparin is often used as a blood anticoagulant for tumor marker analysis but results in the inhibition of PCR detection of circulating tumor DNA (ctDNA), which has been deemed a potential "liquid biopsy". We aimed to evaluate the impact of heparinase addition on heparinized plasma samples to allow ctDNA analysis. METHODS: Plasma samples were collected in heparinized (n=194) and EDTA (n=8) tubes from hormone receptor-positive metastatic breast cancer (HR+MBC) (n=144) and pancreatic adenocarcinoma (PA) patients (n=50)...
July 17, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28704214/bile-acids-upregulate-brca1-and-downregulate-estrogen-receptor-1-gene-expression-in-ovarian-cancer-cells
#17
Qunyan Jin, Olivier Noel, Mai Nguyen, Lionel Sam, Glenn S Gerhard
Two major risk factors for ovarian cancer include loss-of-function mutations in the BRCA1 (breast cancer 1, early onset) gene and aspects of estrogen metabolism. Modulation of the levels of the normal BRCA1 allele and estrogen receptor expression may therefore be a preventive strategy. Consensus binding motifs for the bile acid-responsive transcription factor farnesoid X receptor were identified in the BRCA1 and estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) genes, supported by chromatin immunoprecipitation sequencing data...
July 12, 2017: European Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28694015/predicting-treatment-resistance-and-relapse-through-circulating-dna
#18
Emma Beddowes, Stephen J Sammut, Meiling Gao, Carlos Caldas
The use of circulating DNA(ctDNA) to provide a non-invasive, personalised genomic snapshot of a patients' tumour has huge potential. Over the past five years this area of research has gained huge momentum. A number of studies in metastatic breast cancer have shown the potential of ctDNA to predict prognosis and treatment response using ctDNA. Further developments have included deeper sequencing using whole exome and shallow whole genome approaches which has the potential to identify new mutations and chromosomal copy number changes which appear upon resistance to treatment...
August 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28687497/the-protein-encoded-by-the-ccdc170-breast-cancer-gene-functions-to-organize-the-golgi-microtubule-network
#19
Pengtao Jiang, Yueran Li, Andrey Poleshko, Valentina Medvedeva, Natalia Baulina, Yongchao Zhang, Yan Zhou, Carolyn M Slater, Trinity Pellegrin, Jason Wasserman, Michael Lindy, Andrey Efimov, Mary Daly, Richard A Katz, Xiaowei Chen
Genome-Wide Association Studies (GWAS) and subsequent fine-mapping studies (>50) have implicated single nucleotide polymorphisms (SNPs) located at the CCDC170/C6ORF97-ESR1 locus (6q25.1) as being associated with the risk of breast cancer. Surprisingly, our analysis using genome-wide differential allele-specific expression (DASE), an indicator for breast cancer susceptibility, suggested that the genetic alterations of CCDC170, but not ESR1, account for GWAS-associated breast cancer risk at this locus. Breast cancer-associated CCDC170 nonsense mutations and rearrangements have also been detected, with the latter being specifically implicated in driving breast cancer...
August 2017: EBioMedicine
https://www.readbyqxmd.com/read/28680952/a-review-of-fulvestrant-in-breast-cancer
#20
REVIEW
Mark R Nathan, Peter Schmid
Fulvestrant is a selective estrogen receptor degrader that binds, blocks and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. This review article further explains the mechanism of action of the drug and goes on to review the trials carried out to optimize its dosing. Multiple trials have been undertaken to compare fulvestrant with other endocrine treatments, and results have shown it to have similar efficacy to anastrozole, tamoxifen and exemestane at 250 mg every 28 days...
2017: Oncology and Therapy
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