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Article: Integrating molecular mechanisms and clinical evidence in the management of Trastuzumab resistant or refractory Her-2 + metastatic breast cancer
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TitleIntegrating molecular mechanisms and clinical evidence in the management of Trastuzumab resistant or refractory Her-2 + metastatic breast cancer
 
AuthorsWong, H2
Leung, R2
Kwong, A2
Chiu, J2
Liang, R2
Swanton, C1 3
Yau, T2
 
KeywordsAKT
Breast cancer
ErbB-2
mTOR
PI3 kinase
Trastuzumab
 
Issue Date2011
 
PublisherAlphaMed Press, Inc. The Journal's web site is located at http://www.theoncologist.org/
 
CitationOncologist, 2011, v. 16 n. 11, p. 1535-1546 [How to Cite?]
DOI: http://dx.doi.org/10.1634/theoncologist.2011-0165
 
AbstractHuman epidermal growth factor receptor (HER)-2 + breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to Trastuzumab is observed in >50% of patients with HER-2 + advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of Trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies. © AlphaMed Press.
 
ISSN1083-7159
2013 Impact Factor: 4.540
 
DOIhttp://dx.doi.org/10.1634/theoncologist.2011-0165
 
PubMed Central IDPMC3233287
 
ISI Accession Number IDWOS:000297860900008
Funding AgencyGrant Number
Raymond Liang
Funding Information:

Raymond Liang

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorWong, H
 
dc.contributor.authorLeung, R
 
dc.contributor.authorKwong, A
 
dc.contributor.authorChiu, J
 
dc.contributor.authorLiang, R
 
dc.contributor.authorSwanton, C
 
dc.contributor.authorYau, T
 
dc.date.accessioned2012-09-05T05:31:13Z
 
dc.date.available2012-09-05T05:31:13Z
 
dc.date.issued2011
 
dc.description.abstractHuman epidermal growth factor receptor (HER)-2 + breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to Trastuzumab is observed in >50% of patients with HER-2 + advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of Trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies. © AlphaMed Press.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationOncologist, 2011, v. 16 n. 11, p. 1535-1546 [How to Cite?]
DOI: http://dx.doi.org/10.1634/theoncologist.2011-0165
 
dc.identifier.doihttp://dx.doi.org/10.1634/theoncologist.2011-0165
 
dc.identifier.epage1546
 
dc.identifier.hkuros198374
 
dc.identifier.isiWOS:000297860900008
Funding AgencyGrant Number
Raymond Liang
Funding Information:

Raymond Liang

 
dc.identifier.issn1083-7159
2013 Impact Factor: 4.540
 
dc.identifier.issue11
 
dc.identifier.pmcidPMC3233287
 
dc.identifier.pmid22020213
 
dc.identifier.scopuseid_2-s2.0-82355164794
 
dc.identifier.spage1535
 
dc.identifier.urihttp://hdl.handle.net/10722/163425
 
dc.identifier.volume16
 
dc.languageeng
 
dc.publisherAlphaMed Press, Inc. The Journal's web site is located at http://www.theoncologist.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofOncologist
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntibodies, Monoclonal, Humanized - Pharmacology
 
dc.subject.meshAntineoplastic Agents - Pharmacology
 
dc.subject.meshBreast Neoplasms - Drug Therapy - Enzymology - Genetics - Pathology
 
dc.subject.meshDrug Resistance, Neoplasm
 
dc.subject.meshFemale
 
dc.subject.meshHumans
 
dc.subject.meshNeoplasm Metastasis
 
dc.subject.meshProspective Studies
 
dc.subject.meshReceptor, Erbb-2 - Antagonists & Inhibitors - Biosynthesis - Genetics - Metabolism
 
dc.subjectAKT
 
dc.subjectBreast cancer
 
dc.subjectErbB-2
 
dc.subjectmTOR
 
dc.subjectPI3 kinase
 
dc.subjectTrastuzumab
 
dc.titleIntegrating molecular mechanisms and clinical evidence in the management of Trastuzumab resistant or refractory Her-2 + metastatic breast cancer
 
dc.typeArticle
 
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Author Affiliations
  1. CR-UK London Research Institute
  2. The University of Hong Kong
  3. Royal Marsden Hospital, Sutton