Grant Number:	5R01CA229409-05 Interpret this number
Primary Investigator:	Carey, Lisa
Organization:	Univ Of North Carolina Chapel Hill
Project Title:	Optimizing Her2-Targeting Using Rna and DNA-Based Predictive Algorithms
Fiscal Year:	2023

ABSTRACT HER2-positive disease, which comprises 20% of all breast cancers, is among the most aggressive but treatable forms. Outcomes for HER2-positive patients have been transformed by the development of several highly effective HER2-targeting agents that are given broadly for stages I-IV HER2+ breast cancer either as single agents or as dual HER2-targeting. These drugs have reduced death rates from this disease by nearly 40%, however come at a high financial cost – all HER2-targeted drugs individually cost at least $100,000 per year. We also clearly overtreat many of the approximately 40,000 non-metastatic patients diagnosed with HER2-positive breast cancers in the U.S. each year. Most of the treatment regimens used in stages I-III HER2- positive breast cancer include polychemotherapy with 2-3 cytotoxic drugs plus 1-2 HER2-targeted drugs given for 1 year. Genomic studies from large randomized trials provide opportunities for improvement. Several studies have found that tumor and microenvironmental influences are major contributors to variability in response and outcome. RNA- and DNA-based studies from CALGB 40601 and other neoadjuvant trials of HER2-targeting agents suggest that tumor intrinsic molecular subtype and immune cell activation are at least as important as treatment type in determining outcome and can identify tumors that respond best to single or dual HER2- targeting. These studies suggest a way to more thoughtfully and rationally treat HER2-positive breast cancer patients, but we must do this collaboratively and comprehensively. We propose to collectively integrate and analyze the clinical, gene expression, gene aberration, response to therapy, and outcomes data from more than 1500 women participating in multiple randomized neoadjuvant clinical trials of HER2-targeted therapy. We will examine the role of tumor and microenvironmental factors in determining response to HER2-targeting, relationship of pathologic complete response to outcome, and the biology of residual disease after dual or single HER2-targeting in HER2-positive breast cancer.




Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials.
Authors: Fernandez-Martinez A. , Rediti M. , Tang G. , Pascual T. , Hoadley K.A. , Venet D. , Rashid N.U. , Spears P.A. , Islam M.N. , El-Abed S. , et al. .
Source: Jama Oncology, 2024-03-28 00:00:00.0; , .
EPub date: 2024-03-28 00:00:00.0.
PMID: 38546612
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Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials.
Authors: Rediti M. , Fernandez-Martinez A. , Venet D. , Rothé F. , Hoadley K.A. , Parker J.S. , Singh B. , Campbell J.D. , Ballman K.V. , Hillman D.W. , et al. .
Source: Nature Communications, 2023-11-03 00:00:00.0; 14(1), p. 7053.
EPub date: 2023-11-03 00:00:00.0.
PMID: 37923752
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Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials.
Authors: Fernandez-Martinez A. , Pascual T. , Singh B. , Nuciforo P. , Rashid N.U. , Ballman K.V. , Campbell J.D. , Hoadley K.A. , Spears P.A. , Pare L. , et al. .
Source: Jama Oncology, 2023-01-05 00:00:00.0; , .
EPub date: 2023-01-05 00:00:00.0.
PMID: 36602784
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Independent Validation of the PAM50-Based Chemo-Endocrine Score (CES) in Hormone Receptor-Positive HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2-Based Therapy.
Authors: Pascual T. , Fernandez-Martinez A. , Tanioka M. , Dieci M.V. , Pernas S. , Gavila J. , Guarnieri V. , Cortes J. , Villagrasa P. , Chic N. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2021-06-01 00:00:00.0; 27(11), p. 3116-3125.
EPub date: 2021-02-25 00:00:00.0.
PMID: 33632929
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Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.
Authors: Fernandez-Martinez A. , Krop I.E. , Hillman D.W. , Polley M.Y. , Parker J.S. , Huebner L. , Hoadley K.A. , Shepherd J. , Tolaney S. , Henry N.L. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2020-12-10 00:00:00.0; 38(35), p. 4184-4193.
EPub date: 2020-10-23 00:00:00.0.
PMID: 33095682
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A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.
Authors: Prat A. , Guarneri V. , Paré L. , Griguolo G. , Pascual T. , Dieci M.V. , Chic N. , González-Farré B. , Frassoldati A. , Sanfeliu E. , et al. .
Source: The Lancet. Oncology, 2020 11; 21(11), p. 1455-1464.
PMID: 33152285
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What Is the Real Impact of Estrogen Receptor Status on the Prognosis and Treatment of HER2-Positive Early Breast Cancer?
Authors: Brandão M. , Caparica R. , Malorni L. , Prat A. , Carey L.A. , Piccart M. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2020-06-15 00:00:00.0; 26(12), p. 2783-2788.
EPub date: 2020-02-11 00:00:00.0.
PMID: 32046997
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HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis.
Authors: Schettini F. , Pascual T. , Conte B. , Chic N. , Brasó-Maristany F. , Galván P. , Martínez O. , Adamo B. , Vidal M. , Muñoz M. , et al. .
Source: Cancer Treatment Reviews, 2020 Mar; 84, p. 101965.
EPub date: 2020-01-17 00:00:00.0.
PMID: 32000054
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