Activating ESR1 mutations in hormone-resistant metastatic breast cancer
Dan R. Robinson,Yi-Mi Wu,Pankaj Vats,Fengyun Su,Robert J. Lonigro,Xuhong Cao,Shanker Kalyana-Sundaram,Rui Wang,Yu Ning,Lynda Hodges,Amy Gursky,Javed Siddiqui,Scott A. Tomlins,Sameek Roychowdhury,Kenneth J. Pienta,Scott Y. H. Kim,J. Scott Roberts,James M. Rae,Catherine Van Poznak,Daniel F. Hayes,Rashmi Chugh,Lakshmi P. Kunju,Moshe Talpaz,Anne F. Schott,Arul M. Chinnaiyan +24 more
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TLDR
Five new LBD-localized ESR1 mutations identified here were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro, suggesting that activating mutations in E SR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.Abstract:
Arul Chinnaiyan and colleagues report the results of prospective clinical sequencing of 11 estrogen receptor–positive metastatic breast cancers. They identify ESR1 mutations affecting the ligand-binding domain in six hormone-resistant metastatic breast cancers and show that the mutant estrogen receptors are constitutively active and continue to be responsive to anti-estrogen therapies in vitro. Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.read more
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Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients
Ahmet Zehir,Ryma Benayed,Ronak Shah,Aijazuddin Syed,Sumit Middha,Hyunjae R. Kim,Preethi Srinivasan,Jianjiong Gao,Debyani Chakravarty,Sean M. Devlin,Matthew D. Hellmann,David Barron,Alison M. Schram,Meera Hameed,Snjezana Dogan,Dara S. Ross,Jaclyn F. Hechtman,Deborah DeLair,Jinjuan Yao,Diana Mandelker,Donavan T. Cheng,Raghu Chandramohan,Abhinita Mohanty,Ryan Ptashkin,Gowtham Jayakumaran,Meera Prasad,Mustafa H Syed,Anoop Balakrishnan Rema,Zhen Y Liu,Khedoudja Nafa,Laetitia Borsu,Justyna Sadowska,Jacklyn Casanova,Ruben Bacares,Iwona Kiecka,Anna Razumova,Julie B Son,Lisa Stewart,Tessara Baldi,Kerry Mullaney,Hikmat Al-Ahmadie,Efsevia Vakiani,Adam Abeshouse,Alexander V Penson,Philip Jonsson,Niedzica Camacho,Matthew T. Chang,Helen Won,Benjamin Gross,Ritika Kundra,Zachary J. Heins,Hsiao-Wei Chen,Sarah Phillips,Hongxin Zhang,Jiaojiao Wang,Angelica Ochoa,Jonathan Wills,Michael H. Eubank,Stacy B. Thomas,Stuart Gardos,Dalicia N. Reales,Jesse Galle,Robert Durany,Roy Cambria,Wassim Abida,Andrea Cercek,Darren R. Feldman,Mrinal M. Gounder,A. Ari Hakimi,James J. Harding,Gopa Iyer,Yelena Y. Janjigian,Emmet Jordan,Ciara Marie Kelly,Maeve A. Lowery,Luc G. T. Morris,Antonio Omuro,Nitya Raj,Pedram Razavi,Alexander N. Shoushtari,Neerav Shukla,Tara Soumerai,Anna M. Varghese,Rona Yaeger,Jonathan A. Coleman,Bernard H. Bochner,Gregory J. Riely,Leonard B. Saltz,Howard I. Scher,Paul Sabbatini,Mark E. Robson,David S. Klimstra,Barry S. Taylor,José Baselga,Nikolaus Schultz,David M. Hyman,Maria E. Arcila,David B. Solit,Marc Ladanyi,Michael F. Berger +99 more
TL;DR: A large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer are compiled and identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types.
Journal ArticleDOI
Patient-derived xenograft models: an emerging platform for translational cancer research.
Manuel Hidalgo,Frédéric Amant,Andrew V. Biankin,Eva Budinská,Annette T. Byrne,Carlos Caldas,Robert Clarke,Steven de Jong,Jos Jonkers,Gunhild Mari Mælandsmo,Sergio Roman-Roman,Joan Seoane,Livio Trusolino,Alberto Villanueva +13 more
TL;DR: The current state of the art in this field is summarized, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and a European consortium of PDX models is introduced.
Journal ArticleDOI
Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer
Nicholas C. Turner,Jungsil Ro,Fabrice Andre,Sherene Loi,Sunil Verma,Hiroji Iwata,Nadia Harbeck,Sibylle Loibl,Cynthia Huang Bartlett,Ke Zhang,Carla Giorgetti,Sophia Randolph,Maria Koehler,Massimo Cristofanilli,Massimo Cristofanilli +14 more
TL;DR: Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrants alone.
Journal ArticleDOI
Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility
Min Yu,Min Yu,Aditya Bardia,Nicola Aceto,Francesca Bersani,Marissa W. Madden,Maria C. Donaldson,Rushil Desai,Huili Zhu,Valentine Comaills,Zongli Zheng,Zongli Zheng,Ben S. Wittner,Petar Stojanov,Elena F. Brachtel,Dennis C. Sgroi,Ravi Kapur,Toshihiro Shioda,David T. Ting,Sridhar Ramaswamy,Gad Getz,Gad Getz,A. John Iafrate,Cyril H. Benes,Mehmet Toner,Shyamala Maheswaran,Daniel A. Haber,Daniel A. Haber +27 more
TL;DR: It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations.
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Treating cancer with selective CDK4/6 inhibitors
TL;DR: Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile.
References
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Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer
Sarah-Jane Dawson,Dana W.Y. Tsui,Muhammed Murtaza,Heather Biggs,Oscar M. Rueda,Suet-Feung Chin,Mark J Dunning,Davina Gale,Tim Forshew,Betania Mahler-Araujo,Sabrina Rajan,Sean Humphray,Jennifer Becq,David Halsall,Matthew G. Wallis,David Bentley,Carlos Caldas,Nitzan Rosenfeld +17 more
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Mutational Processes Molding the Genomes of 21 Breast Cancers
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TL;DR: Risk of endometrial cancer increases following tamoxifen therapy for invasive breast cancer; however, net benefit greatly outweighs risk, and tamoxIFen treatment for breast cancer should continue.
Journal ArticleDOI
Advances in understanding cancer genomes through second-generation sequencing
TL;DR: This Review focuses on the methodological considerations for characterizing somatic genome alterations in cancer and the future prospects for these approaches.
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