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author Hyman, David M.
Piha-Paul, Sarina A.
Won, Helen
Rodon, Jordi
Saura, Cristina
Shapiro, Geoffrey I.
Juric, Dejan
Quinn, David I.
Moreno, Victor
Doger, Bernard
Mayer, Ingrid A.
Boni, Valentina
Calvo, Emiliano
Loi, Sherene
Lockhart, Albert C.
Erinjeri, Joseph P.
Scaltriti, Maurizio
Ulaner, Gary A.
Patel, Juber
Tang, Jiabin
Beer, Hannah
Selcuklu, S. Duygu
Hanrahan, Aphrothiti J.
Bouvier, Nancy
Melcer, Myra
Murali, Rajmohan
Schram, Alison M.
Smyth, Lillian M.
Jhaveri, Komal
Li, Bob T.
Drilon, Alexander
Harding, James J.
Iyer, Gopa
Taylor, Barry S.
Berger, Michael F.
Cutler, Richard E.
Xu, Feng
Butturini, Anna
Eli, Lisa D.
Mann, Grace
Farrell, Cynthia
Lalani, Alshad S.
Bryce, Richard P.
Arteaga, Carlos L.
Meric-Bernstam, Funda
Baselga, José
Solit, David B.
author_facet Hyman, David M.
Piha-Paul, Sarina A.
Won, Helen
Rodon, Jordi
Saura, Cristina
Shapiro, Geoffrey I.
Juric, Dejan
Quinn, David I.
Moreno, Victor
Doger, Bernard
Mayer, Ingrid A.
Boni, Valentina
Calvo, Emiliano
Loi, Sherene
Lockhart, Albert C.
Erinjeri, Joseph P.
Scaltriti, Maurizio
Ulaner, Gary A.
Patel, Juber
Tang, Jiabin
Beer, Hannah
Selcuklu, S. Duygu
Hanrahan, Aphrothiti J.
Bouvier, Nancy
Melcer, Myra
Murali, Rajmohan
Schram, Alison M.
Smyth, Lillian M.
Jhaveri, Komal
Li, Bob T.
Drilon, Alexander
Harding, James J.
Iyer, Gopa
Taylor, Barry S.
Berger, Michael F.
Cutler, Richard E.
Xu, Feng
Butturini, Anna
Eli, Lisa D.
Mann, Grace
Farrell, Cynthia
Lalani, Alshad S.
Bryce, Richard P.
Arteaga, Carlos L.
Meric-Bernstam, Funda
Baselga, José
Solit, David B.
author_sort Hyman, David M.
collection PubMed
description Somatic mutations of ERBB2 (HER2) and ERBB3 (HER3) are found in a wide range of cancers. Preclinical modelling suggests that a subset lead to constitutive HER2 activation, but most remain biologically uncharacterized. We sought to prospectively define the biologic and therapeutic significance of known oncogenic HER2 and HER3 mutations and variants of unknown biological significance by conducting a multi-histology, genomically selected, ‘basket’ study utilizing the pan-HER kinase inhibitor neratinib (SUMMIT; Clinicaltrials.gov NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours harbouring kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to further refine our biological understanding of both characterized and novel genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
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spelling pubmed-58085812018-07-31 HER kinase inhibition in patients with HER2- and HER3-mutant cancers Hyman, David M. Piha-Paul, Sarina A. Won, Helen Rodon, Jordi Saura, Cristina Shapiro, Geoffrey I. Juric, Dejan Quinn, David I. Moreno, Victor Doger, Bernard Mayer, Ingrid A. Boni, Valentina Calvo, Emiliano Loi, Sherene Lockhart, Albert C. Erinjeri, Joseph P. Scaltriti, Maurizio Ulaner, Gary A. Patel, Juber Tang, Jiabin Beer, Hannah Selcuklu, S. Duygu Hanrahan, Aphrothiti J. Bouvier, Nancy Melcer, Myra Murali, Rajmohan Schram, Alison M. Smyth, Lillian M. Jhaveri, Komal Li, Bob T. Drilon, Alexander Harding, James J. Iyer, Gopa Taylor, Barry S. Berger, Michael F. Cutler, Richard E. Xu, Feng Butturini, Anna Eli, Lisa D. Mann, Grace Farrell, Cynthia Lalani, Alshad S. Bryce, Richard P. Arteaga, Carlos L. Meric-Bernstam, Funda Baselga, José Solit, David B. Nature Article Somatic mutations of ERBB2 (HER2) and ERBB3 (HER3) are found in a wide range of cancers. Preclinical modelling suggests that a subset lead to constitutive HER2 activation, but most remain biologically uncharacterized. We sought to prospectively define the biologic and therapeutic significance of known oncogenic HER2 and HER3 mutations and variants of unknown biological significance by conducting a multi-histology, genomically selected, ‘basket’ study utilizing the pan-HER kinase inhibitor neratinib (SUMMIT; Clinicaltrials.gov NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours harbouring kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to further refine our biological understanding of both characterized and novel genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology. 2018-01-31 2018-02-08 /pmc/articles/PMC5808581/ /pubmed/29420467 http://dx.doi.org/10.1038/nature25475 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Reprints and permissions information is available at www.nature.com/reprints
spellingShingle Article
Hyman, David M.
Piha-Paul, Sarina A.
Won, Helen
Rodon, Jordi
Saura, Cristina
Shapiro, Geoffrey I.
Juric, Dejan
Quinn, David I.
Moreno, Victor
Doger, Bernard
Mayer, Ingrid A.
Boni, Valentina
Calvo, Emiliano
Loi, Sherene
Lockhart, Albert C.
Erinjeri, Joseph P.
Scaltriti, Maurizio
Ulaner, Gary A.
Patel, Juber
Tang, Jiabin
Beer, Hannah
Selcuklu, S. Duygu
Hanrahan, Aphrothiti J.
Bouvier, Nancy
Melcer, Myra
Murali, Rajmohan
Schram, Alison M.
Smyth, Lillian M.
Jhaveri, Komal
Li, Bob T.
Drilon, Alexander
Harding, James J.
Iyer, Gopa
Taylor, Barry S.
Berger, Michael F.
Cutler, Richard E.
Xu, Feng
Butturini, Anna
Eli, Lisa D.
Mann, Grace
Farrell, Cynthia
Lalani, Alshad S.
Bryce, Richard P.
Arteaga, Carlos L.
Meric-Bernstam, Funda
Baselga, José
Solit, David B.
HER kinase inhibition in patients with HER2- and HER3-mutant cancers
title HER kinase inhibition in patients with HER2- and HER3-mutant cancers
title_full HER kinase inhibition in patients with HER2- and HER3-mutant cancers
title_fullStr HER kinase inhibition in patients with HER2- and HER3-mutant cancers
title_full_unstemmed HER kinase inhibition in patients with HER2- and HER3-mutant cancers
title_short HER kinase inhibition in patients with HER2- and HER3-mutant cancers
title_sort her kinase inhibition in patients with her2- and her3-mutant cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808581/
https://www.ncbi.nlm.nih.gov/pubmed/29420467
http://dx.doi.org/10.1038/nature25475
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