Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer
Denis M. Collins,Stephen F. Madden,N. Gaynor,Dalal Alsultan,Dalal Alsultan,Marion Le Gal,Alex J Eustace,Kathy Gately,Clare Hughes,Anthony Davies,Thamir Mahgoub,Jo Ballot,Sinead Toomey,Darran P. O'Connor,William M. Gallagher,Frankie A. Holmes,Virginia Espina,Lance A. Liotta,Bryan T. Hennessy,Bryan T. Hennessy,Kenneth J. O'Byrne,Max Hasmann,Birgit Bossenmaier,Norma O'Donovan,John Crown +24 more
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TKIs differentially alter tumor cell phenotype which can impact NK cell–mediated response to coadministered antibody therapies, and mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.Abstract:
Purpose: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC. Experimental Design: Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array–determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry–based protocols. Results: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell–mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone. Conclusions: TKIs differentially alter tumor cell phenotype which can impact NK cell–mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.read more
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Apoptosis-inducing anti-HER2 agents operate through oligomerization-induced receptor immobilization.
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Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2
Dennis J. Slamon,Brian Leyland-Jones,Steven Shak,Hank Fuchs,Virginia E. Paton,Alex Bajamonde,Thomas Fleming,Wolfgang Eiermann,Janet M. Wolter,Mark D. Pegram,José Baselga,Larry Norton +11 more
TL;DR: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression, a higher rate of objective response, a longer duration of response, and a lower rate of death at 1 year.
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Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies
Brian D. Lehmann,Joshua A. Bauer,Xi Chen,Melinda E. Sanders,A. Bapsi Chakravarthy,Yu Shyr,Jennifer A. Pietenpol +6 more
TL;DR: Gen expression profiles from 21 breast cancer data sets and identified 587 TNBC cases may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
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Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer
Charles E. Geyer,John K. Forster,Deborah Lindquist,Stephen Chan,C. Gilles Romieu,Tadeusz Pienkowski,Agnieszka Jagiełło-Gruszfeld,John Crown,Arlene Chan,Bella Kaufman,Dimosthenis Skarlos,Mario Campone,Neville Davidson,Mark S. Berger,Cristina Oliva,Stephen D. Rubin,S. Stein,David Cameron +17 more
TL;DR: Lapatinib plus capecitabine is superior to cape citabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.
Journal ArticleDOI
A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes
Richard M. Neve,Richard M. Neve,Koei Chin,Jane Fridlyand,Jennifer Yeh,Frederick L. Baehner,Tea Fevr,Laura Clark,Nora Bayani,Jean-Philippe Coppe,Frances Tong,Terence P. Speed,Paul T. Spellman,Sandy DeVries,Anna Lapuk,Nicholas J. Wang,Wen-Lin Kuo,Jackie L. Stilwell,Daniel Pinkel,Donna G. Albertson,F. M. Waldman,Frank McCormick,Robert B. Dickson,Michael D. Johnson,Marc E. Lippman,Stephen P. Ethier,Adi F. Gazdar,Joe W. Gray,Joe W. Gray +28 more
TL;DR: It is shown, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.
Journal ArticleDOI
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.
Antonio C. Wolff,M. Elizabeth H. Hammond,David G. Hicks,Mitch Dowsett,Lisa M. McShane,Kimberly H. Allison,D. C. Allred,John M. S. Bartlett,Michael Bilous,Patrick L. Fitzgibbons,Wedad Hanna,Robert B. Jenkins,Pamela B. Mangu,Soonmyung Paik,Edith A. Perez,Michael F. Press,Patricia A. Spears,Gail H. Vance,Giuseppe Viale,Daniel F. Hayes +19 more
TL;DR: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive).
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