Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab
Identifieur interne : 001D51 ( Pmc/Curation ); précédent : 001D50; suivant : 001D52Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab
Auteurs : Roberto Salgado ; Carsten Denkert ; Christine Campbell ; Peter Savas ; Paolo Nuciforo ; Claudia Aura ; Evandro De Azambuja ; Holger Eidtmann ; Catherine E. Ellis ; Jose Baselga ; Martine J. Piccart-Gebhart ; Stefan Michiels ; Ian Bradbury ; Christos Sotiriou ; Sherene LoiSource :
- JAMA oncology [ 2374-2437 ] ; 2015.
Abstract
The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown.
To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination.
The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin–stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis.
Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including
Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor–positive (10.0% [5.0%-22.5%]) vs hormone receptor–negative (12.5% [3.0%-35.0%]) samples (
The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points.
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DOI: 10.1001/jamaoncol.2015.0830
PubMed: 26181252
PubMed Central: 5551492
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab</title><author><name sortKey="Salgado, Roberto" sort="Salgado, Roberto" uniqKey="Salgado R" first="Roberto" last="Salgado">Roberto Salgado</name></author><author><name sortKey="Denkert, Carsten" sort="Denkert, Carsten" uniqKey="Denkert C" first="Carsten" last="Denkert">Carsten Denkert</name></author><author><name sortKey="Campbell, Christine" sort="Campbell, Christine" uniqKey="Campbell C" first="Christine" last="Campbell">Christine Campbell</name></author><author><name sortKey="Savas, Peter" sort="Savas, Peter" uniqKey="Savas P" first="Peter" last="Savas">Peter Savas</name></author><author><name sortKey="Nuciforo, Paolo" sort="Nuciforo, Paolo" uniqKey="Nuciforo P" first="Paolo" last="Nuciforo">Paolo Nuciforo</name></author><author><name sortKey="Aura, Claudia" sort="Aura, Claudia" uniqKey="Aura C" first="Claudia" last="Aura">Claudia Aura</name></author><author><name sortKey="De Azambuja, Evandro" sort="De Azambuja, Evandro" uniqKey="De Azambuja E" first="Evandro" last="De Azambuja">Evandro De Azambuja</name></author><author><name sortKey="Eidtmann, Holger" sort="Eidtmann, Holger" uniqKey="Eidtmann H" first="Holger" last="Eidtmann">Holger Eidtmann</name></author><author><name sortKey="Ellis, Catherine E" sort="Ellis, Catherine E" uniqKey="Ellis C" first="Catherine E." last="Ellis">Catherine E. Ellis</name></author><author><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="Jose" last="Baselga">Jose Baselga</name></author><author><name sortKey="Piccart Gebhart, Martine J" sort="Piccart Gebhart, Martine J" uniqKey="Piccart Gebhart M" first="Martine J." last="Piccart-Gebhart">Martine J. Piccart-Gebhart</name></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name></author><author><name sortKey="Bradbury, Ian" sort="Bradbury, Ian" uniqKey="Bradbury I" first="Ian" last="Bradbury">Ian Bradbury</name></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name></author><author><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26181252</idno><idno type="pmc">5551492</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551492</idno><idno type="RBID">PMC:5551492</idno><idno type="doi">10.1001/jamaoncol.2015.0830</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">001E95</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001E95</idno><idno type="wicri:Area/Pmc/Curation">001D51</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001D51</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab</title><author><name sortKey="Salgado, Roberto" sort="Salgado, Roberto" uniqKey="Salgado R" first="Roberto" last="Salgado">Roberto Salgado</name></author><author><name sortKey="Denkert, Carsten" sort="Denkert, Carsten" uniqKey="Denkert C" first="Carsten" last="Denkert">Carsten Denkert</name></author><author><name sortKey="Campbell, Christine" sort="Campbell, Christine" uniqKey="Campbell C" first="Christine" last="Campbell">Christine Campbell</name></author><author><name sortKey="Savas, Peter" sort="Savas, Peter" uniqKey="Savas P" first="Peter" last="Savas">Peter Savas</name></author><author><name sortKey="Nuciforo, Paolo" sort="Nuciforo, Paolo" uniqKey="Nuciforo P" first="Paolo" last="Nuciforo">Paolo Nuciforo</name></author><author><name sortKey="Aura, Claudia" sort="Aura, Claudia" uniqKey="Aura C" first="Claudia" last="Aura">Claudia Aura</name></author><author><name sortKey="De Azambuja, Evandro" sort="De Azambuja, Evandro" uniqKey="De Azambuja E" first="Evandro" last="De Azambuja">Evandro De Azambuja</name></author><author><name sortKey="Eidtmann, Holger" sort="Eidtmann, Holger" uniqKey="Eidtmann H" first="Holger" last="Eidtmann">Holger Eidtmann</name></author><author><name sortKey="Ellis, Catherine E" sort="Ellis, Catherine E" uniqKey="Ellis C" first="Catherine E." last="Ellis">Catherine E. Ellis</name></author><author><name sortKey="Baselga, Jose" sort="Baselga, Jose" uniqKey="Baselga J" first="Jose" last="Baselga">Jose Baselga</name></author><author><name sortKey="Piccart Gebhart, Martine J" sort="Piccart Gebhart, Martine J" uniqKey="Piccart Gebhart M" first="Martine J." last="Piccart-Gebhart">Martine J. Piccart-Gebhart</name></author><author><name sortKey="Michiels, Stefan" sort="Michiels, Stefan" uniqKey="Michiels S" first="Stefan" last="Michiels">Stefan Michiels</name></author><author><name sortKey="Bradbury, Ian" sort="Bradbury, Ian" uniqKey="Bradbury I" first="Ian" last="Bradbury">Ian Bradbury</name></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name></author><author><name sortKey="Loi, Sherene" sort="Loi, Sherene" uniqKey="Loi S" first="Sherene" last="Loi">Sherene Loi</name></author></analytic><series><title level="j">JAMA oncology</title><idno type="ISSN">2374-2437</idno><idno type="eISSN">2374-2445</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Importance</title><p id="P1">The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown.</p></sec><sec id="S2"><title>Objective</title><p id="P2">To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination.</p></sec><sec id="S3"><title>Design, Setting, and Participants</title><p id="P3">The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin–stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis.</p></sec><sec id="S4"><title>Main Outcomes and Measures</title><p id="P4">Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including <italic>PIK3CA</italic> genotype.</p></sec><sec id="S5"><title>Results</title><p id="P5">Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor–positive (10.0% [5.0%-22.5%]) vs hormone receptor–negative (12.5% [3.0%-35.0%]) samples (<italic>P</italic> = .02). For the pCR end point, levels of TILs greater than 5% were associated with higher pCR rates independent of treatment group (adjusted odds ratio, 2.60 [95% CI, 1.26-5.39]; <italic>P</italic> = .01). With a median (IQR) follow-up time of 3.77 (3.50-4.22) years, every 1% increase in TILs was associated with a 3% decrease in the rate of an event (adjusted hazard ratio, 0.97 [95% CI, 0.95-0.99]; <italic>P</italic> = .002) across all treatment groups.</p></sec><sec id="S6"><title>Conclusions and Relevance</title><p id="P6">The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points.</p></sec><sec id="S7"><title>Trial Registration</title><p id="P7"><ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov</ext-link> Identifier: NCT00553358</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101652861</journal-id><journal-id journal-id-type="pubmed-jr-id">43608</journal-id><journal-id journal-id-type="nlm-ta">JAMA Oncol</journal-id><journal-id journal-id-type="iso-abbrev">JAMA Oncol</journal-id><journal-title-group><journal-title>JAMA oncology</journal-title></journal-title-group><issn pub-type="ppub">2374-2437</issn><issn pub-type="epub">2374-2445</issn></journal-meta><article-meta><article-id pub-id-type="pmid">26181252</article-id><article-id pub-id-type="pmc">5551492</article-id><article-id pub-id-type="doi">10.1001/jamaoncol.2015.0830</article-id><article-id pub-id-type="manuscript">NIHMS886582</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab</article-title><subtitle>A Secondary Analysis of the NeoALTTO Trial</subtitle></title-group><contrib-group><contrib contrib-type="author"><name><surname>Salgado</surname><given-names>Roberto</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Denkert</surname><given-names>Carsten</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Campbell</surname><given-names>Christine</given-names></name><degrees>MSc</degrees></contrib><contrib contrib-type="author"><name><surname>Savas</surname><given-names>Peter</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Nuciforo</surname><given-names>Paolo</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Aura</surname><given-names>Claudia</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>de Azambuja</surname><given-names>Evandro</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Eidtmann</surname><given-names>Holger</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Ellis</surname><given-names>Catherine E.</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Baselga</surname><given-names>Jose</given-names></name><degrees>MD</degrees></contrib><contrib contrib-type="author"><name><surname>Piccart-Gebhart</surname><given-names>Martine J.</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Michiels</surname><given-names>Stefan</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Bradbury</surname><given-names>Ian</given-names></name><degrees>PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Sotiriou</surname><given-names>Christos</given-names></name><degrees>MD, PhD</degrees></contrib><contrib contrib-type="author"><name><surname>Loi</surname><given-names>Sherene</given-names></name><degrees>MD, PhD</degrees></contrib><aff id="A1">Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium (Salgado, Sotiriou); Department of Pathology, Gasthuis Zusters Antwerpen Hospitals, Antwerp, Belgium (Salgado); Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany (Denkert); German Cancer Consortium, Berlin, Germany (Denkert); Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, United Kingdom (Campbell, Bradbury); Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia (Savas, Loi); Val d'Hebron Institute of Oncology, Barcelona, Spain (Nuciforo, Aura); Breast European Adjuvant Study Team, Institut Jules Bordet, Brussels, Belgium (de Azambuja); Department of Obstetrics and Gynecology, Campus Kiel, University Hospital Kiel, Kiel, Germany (Eidtmann); GlaxoSmithKline Oncology, Collegeville, Pennsylvania (Ellis); Memorial Sloan-Kettering Cancer Center, New York, New York (Baselga); Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium (Piccart-Gebhart); Centre de Recherche en Epidémiologie et Santé des Populations, INSERM U1018, Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Sud, Villejuif, France (Michiels)</aff></contrib-group><author-notes><corresp id="FN1">Corresponding Author: Sherene Loi, MD, PhD, Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia (<email>sherene.loi@petermac.org</email>)</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>29</day><month>6</month><year>2017</year></pub-date><pub-date pub-type="ppub"><month>7</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>10</day><month>8</month><year>2017</year></pub-date><volume>1</volume><issue>4</issue><fpage>448</fpage><lpage>454</lpage><pmc-comment>elocation-id from pubmed: 10.1001/jamaoncol.2015.0830</pmc-comment>
<abstract><sec id="S1"><title>Importance</title><p id="P1">The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown.</p></sec><sec id="S2"><title>Objective</title><p id="P2">To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination.</p></sec><sec id="S3"><title>Design, Setting, and Participants</title><p id="P3">The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin–stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis.</p></sec><sec id="S4"><title>Main Outcomes and Measures</title><p id="P4">Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including <italic>PIK3CA</italic> genotype.</p></sec><sec id="S5"><title>Results</title><p id="P5">Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor–positive (10.0% [5.0%-22.5%]) vs hormone receptor–negative (12.5% [3.0%-35.0%]) samples (<italic>P</italic> = .02). For the pCR end point, levels of TILs greater than 5% were associated with higher pCR rates independent of treatment group (adjusted odds ratio, 2.60 [95% CI, 1.26-5.39]; <italic>P</italic> = .01). With a median (IQR) follow-up time of 3.77 (3.50-4.22) years, every 1% increase in TILs was associated with a 3% decrease in the rate of an event (adjusted hazard ratio, 0.97 [95% CI, 0.95-0.99]; <italic>P</italic> = .002) across all treatment groups.</p></sec><sec id="S6"><title>Conclusions and Relevance</title><p id="P6">The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points.</p></sec><sec id="S7"><title>Trial Registration</title><p id="P7"><ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov</ext-link> Identifier: NCT00553358</p></sec></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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