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Esr1 mutation

A Harrod, J Fulton, V T M Nguyen, M Periyasamy, L Ramos-Garcia, C-F Lai, G Metodieva, A de Giorgio, R L Williams, D B Santos, P J Gomez, M-L Lin, M V Metodiev, J Stebbing, L Castellano, L Magnani, R C Coombes, L Buluwela, S Ali
Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations...
October 17, 2016: Oncogene
Zhaomei Mu, Naoual Benali-Furet, Georges Uzan, Anaëlle Znaty, Zhong Ye, Carmela Paolillo, Chun Wang, Laura Austin, Giovanna Rossi, Paolo Fortina, Hushan Yang, Massimo Cristofanilli
The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs...
September 30, 2016: International Journal of Molecular Sciences
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
(no author information available yet)
ESR1 expression is enhanced by noncoding somatic mutations and inherited SNVs in regulatory elements.
September 16, 2016: Cancer Discovery
John McIntyre, Peter F Rambau, Angela Chan, Sidney Yap, Don Morris, S Nelson Gregg, Martin Köbel
AIMS: The clinical course of patients with low-grade serous carcinoma (LGSC) can be substantially different. The purpose of this study was to explore whether molecular or pathological features could identify patients that follow a more aggressive course. METHODS AND RESULTS: 26 primary LGSCs (11 with aggressive and 15 with indolent clinical course) and 5 paired recurrences were assessed for non-synonymous somatic mutations in 18 MAP kinase pathway genes as well as 42 other classic cancer "hot spot" genes using a custom designed AmpliSeq panel based on the AmpliSeq Cancer hotspot panel v2...
August 30, 2016: Histopathology
Swneke D Bailey, Kinjal Desai, Ken J Kron, Parisa Mazrooei, Nicholas A Sinnott-Armstrong, Aislinn E Treloar, Mark Dowar, Kelsie L Thu, David W Cescon, Jennifer Silvester, S Y Cindy Yang, Xue Wu, Rossanna C Pezo, Benjamin Haibe-Kains, Tak W Mak, Philippe L Bedard, Trevor J Pugh, Richard C Sallari, Mathieu Lupien
Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers...
October 2016: Nature Genetics
Polly Niravath, Burcu Cakar, Matthew Ellis
Importance: The application of next-generation sequencing (NGS) genomic testing for somatic mutations in breast oncology has been slower than anticipated due to issues with clinical applicability and natural heterogeneity of breast cancer. This review summarizes the state of the field and considers approaches for more effective implementation. Observations: While there is an emerging role for germline genetic testing potentially predicting sensitivity to platinum salts and PARP inhibitors, the data regarding somatic mutation for prediction of drug sensitivity remains controversial...
August 25, 2016: JAMA Oncology
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...
August 19, 2016: Oncotarget
Guanglong Jiang, Shijun Zhang, Aida Yazdanparast, Meng Li, Aniruddha Vikram Pawar, Yunlong Liu, Sai Mounika Inavolu, Lijun Cheng
BACKGROUND: Proper cell models for breast cancer primary tumors have long been the focal point in the cancer's research. The genomic comparison between cell lines and tumors can investigate the similarity and dissimilarity and help to select right cell model to mimic tumor tissues to properly evaluate the drug reaction in vitro. In this paper, a comprehensive comparison in copy number variation (CNV), mutation, mRNA expression and protein expression between 68 breast cancer cell lines and 1375 primary breast tumors is conducted and presented...
2016: BMC Genomics
Aditya Bardia, John A Iafrate, Tilak Sundaresan, Jerry Younger, Valentina Nardi
UNLABELLED: : The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the "right drug" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues...
September 2016: Oncologist
Suzanne A W Fuqua, Yassine Rechoum, Guowei Gu
No abstract text is available yet for this article.
October 1, 2016: JAMA Oncology
Sarat Chandarlapaty, David Chen, Wei He, Patricia Sung, Aliaksandra Samoila, Daoqi You, Trusha Bhatt, Parul Patel, Maurizio Voi, Michael Gnant, Gabriel Hortobagyi, José Baselga, Mary Ellen Moynahan
Importance: Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established. Objective: To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes...
October 1, 2016: JAMA Oncology
Christopher A Miller, Yevgeniy Gindin, Charles Lu, Obi L Griffith, Malachi Griffith, Dong Shen, Jeremy Hoog, Tiandao Li, David E Larson, Mark Watson, Sherri R Davies, Kelly Hunt, Vera J Suman, Jacqueline Snider, Thomas Walsh, Graham A Colditz, Katherine DeSchryver, Richard K Wilson, Elaine R Mardis, Matthew J Ellis
Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI...
August 9, 2016: Nature Communications
Josh Lauring, Antonio C Wolff
No abstract text is available yet for this article.
September 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Jacqueline A Shaw, David S Guttery, Allison Hills, Daniel Fernandez-Garcia, Karen Page, Brenda M Rosales, Kate S Goddard, Robert K Hastings, Jinli Luo, Olivia Ogle, Laura Woodley, Simak Ali, Justin Stebbing, R Charles Coombes
PURPOSE: The purpose of this study was to directly compare mutation profiles in multiple single CTCs and cfDNA isolated from the same blood samples taken from patients with metastaic breast cancer (MBC). We aimed to determine whether cell-free DNA would reflect the heterogeneity observed in 40 single CTCs. EXPERIMENTAL DESIGN: CTCs were enumerated by Cellsearch. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with metastatic breast cancer...
June 22, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
Ming Zhang, Yi Pan, Xueling Qi, Yan Liu, Rongfang Dong, Danfeng Zheng, Qing Chang, Jing Zhang, Weigang Fang, Yanfeng Zhong
BACKGROUND: Isocitrate dehydrogenase (IDH) mutations have been reported as biomarkers associated with tumorigenesis and prognosis in gliomas. However, genes affected by these mutations are still under investigation. The purpose of this study is to identify new molecular biomarkers associated with IDH mutation and prognosis in astrocytic tumors, which account for the largest proportion of gliomas. MATERIALS AND METHODS: NanoString analysis was conducted on 40 astrocytic tumors...
June 2, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Hope S Rugo, Neelima Vidula, Cynthia Ma
The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of resistance mechanisms leading to estrogen-independent growth of hormone receptor-positive (HR+) breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets...
2016: American Society of Clinical Oncology Educational Book
Luca Gelsomino, Guowei Gu, Yassine Rechoum, Amanda R Beyer, Sasha M Pejerrey, Anna Tsimelzon, Tao Wang, Kenneth Huffman, Andrew Ludlow, Sebastiano Andò, Suzanne A W Fuqua
The purpose of this study was to address the role of ESR1 hormone-binding mutations in breast cancer. Soft agar anchorage-independent growth assay, Western blot, ERE reporter transactivation assay, proximity ligation assay (PLA), coimmunoprecipitation assay, silencing assay, digital droplet PCR (ddPCR), Kaplan-Meier analysis, and statistical analysis. It is now generally accepted that estrogen receptor (ESR1) mutations occur frequently in metastatic breast cancers; however, we do not yet know how to best treat these patients...
June 2016: Breast Cancer Research and Treatment
Costanza Paoletti, Jose M Larios, Maria C Muñiz, Kimberly Aung, Emily M Cannell, Elizabeth P Darga, Kelley M Kidwell, Dafydd G Thomas, Nahomi Tokudome, Martha E Brown, Mark C Connelly, David A Chianese, Anne F Schott, N Lynn Henry, James M Rae, Daniel F Hayes
Fulvestrant is a dose dependent selective estrogen receptor (ER) down-regulator (SERD) used in ER-positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch(®) system. Clinical data are limited to a subset of patients with ER-positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10)...
August 2016: Molecular Oncology
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