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Article: Integrating molecular mechanisms and clinical evidence in the management of Trastuzumab resistant or refractory Her-2 + metastatic breast cancer

TitleIntegrating molecular mechanisms and clinical evidence in the management of Trastuzumab resistant or refractory Her-2 + metastatic breast cancer
Authors
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/
Citation
Oncologist, 2011, v. 16 n. 11, p. 1535-1546 How to Cite?
Abstract
Human 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.
Persistent Identifierhttp://hdl.handle.net/10722/163425
ISSN
2013 Impact Factor: 4.540
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Raymond Liang
Funding Information:

Raymond Liang

References

 

Author Affiliations
  1. CR-UK London Research Institute
  2. The University of Hong Kong
  3. Royal Marsden Hospital, Sutton
DC FieldValueLanguage
dc.contributor.authorWong, Hen_HK
dc.contributor.authorLeung, Ren_HK
dc.contributor.authorKwong, Aen_HK
dc.contributor.authorChiu, Jen_HK
dc.contributor.authorLiang, Ren_HK
dc.contributor.authorSwanton, Cen_HK
dc.contributor.authorYau, Ten_HK
dc.date.accessioned2012-09-05T05:31:13Z-
dc.date.available2012-09-05T05:31:13Z-
dc.date.issued2011en_HK
dc.identifier.citationOncologist, 2011, v. 16 n. 11, p. 1535-1546en_HK
dc.identifier.issn1083-7159en_HK
dc.identifier.urihttp://hdl.handle.net/10722/163425-
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.en_HK
dc.languageengen_US
dc.publisherAlphaMed Press, Inc. The Journal's web site is located at http://www.theoncologist.org/en_HK
dc.relation.ispartofOncologisten_HK
dc.subjectAKTen_HK
dc.subjectBreast canceren_HK
dc.subjectErbB-2en_HK
dc.subjectmTORen_HK
dc.subjectPI3 kinaseen_HK
dc.subjectTrastuzumaben_HK
dc.subject.meshAntibodies, Monoclonal, Humanized - Pharmacologyen_US
dc.subject.meshAntineoplastic Agents - Pharmacologyen_US
dc.subject.meshBreast Neoplasms - Drug Therapy - Enzymology - Genetics - Pathologyen_US
dc.subject.meshDrug Resistance, Neoplasmen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshNeoplasm Metastasisen_US
dc.subject.meshProspective Studiesen_US
dc.subject.meshReceptor, Erbb-2 - Antagonists & Inhibitors - Biosynthesis - Genetics - Metabolismen_US
dc.titleIntegrating molecular mechanisms and clinical evidence in the management of Trastuzumab resistant or refractory Her-2 + metastatic breast canceren_HK
dc.typeArticleen_HK
dc.identifier.emailKwong, A: avakwong@hkucc.hku.hken_HK
dc.identifier.emailLiang, R: rliang@hku.hken_HK
dc.identifier.emailYau, T: tyaucc@hku.hken_HK
dc.identifier.authorityKwong, A=rp01734en_HK
dc.identifier.authorityLiang, R=rp00345en_HK
dc.identifier.authorityYau, T=rp01466en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1634/theoncologist.2011-0165en_HK
dc.identifier.pmid22020213en_HK
dc.identifier.pmcidPMC3233287-
dc.identifier.scopuseid_2-s2.0-82355164794en_HK
dc.identifier.hkuros198374-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-82355164794&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume16en_HK
dc.identifier.issue11en_HK
dc.identifier.spage1535en_HK
dc.identifier.epage1546en_HK
dc.identifier.isiWOS:000297860900008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridWong, H=23089414000en_HK
dc.identifier.scopusauthoridLeung, R=52364352500en_HK
dc.identifier.scopusauthoridKwong, A=8913654300en_HK
dc.identifier.scopusauthoridChiu, J=36887309300en_HK
dc.identifier.scopusauthoridLiang, R=26643224900en_HK
dc.identifier.scopusauthoridSwanton, C=7005912775en_HK
dc.identifier.scopusauthoridYau, T=23391533100en_HK

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