ESR1 ligand-binding domain mutations in hormone-resistant breast cancer
Weiyi Toy,Yang Shen,Helen Won,Bradley Green,Rita A. Sakr,Marie Will,Zhiqiang Li,Kinisha Gala,Sean W. Fanning,Tari A. King,Clifford A. Hudis,Clifford A. Hudis,David Chen,Tetiana Taran,Gabriel N. Hortobagyi,Geoffrey L. Greene,Michael F. Berger,José Baselga,José Baselga,Sarat Chandarlapaty,Sarat Chandarlapaty +20 more
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TLDR
A comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases that implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.Abstract:
Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies. Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.read more
Citations
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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.
Integrative Genomics Viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
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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.
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Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial
Massimo Cristofanilli,Nicholas C. Turner,Igor Bondarenko,Jungsil Ro,Seock-Ah Im,Norikazu Masuda,Marco Colleoni,Angela DeMichele,Sherene Loi,Sunil Verma,Hiroji Iwata,Nadia Harbeck,Ke Zhang,Kathy Puyana Theall,Yuqiu Jiang,Cynthia Huang Bartlett,Maria Koehler,Dennis J. Slamon +17 more
TL;DR: This study aimed to confirm the earlier findings with this extended follow-up and show the results for subgroup and biomarker analyses, and assesses endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline.
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A view on drug resistance in cancer
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