||5R01CA229409-03 Interpret this number
||Univ Of North Carolina Chapel Hill
||Optimizing Her2-Targeting Using Rna and DNA-Based Predictive Algorithms
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.
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.
, Fernandez-Martinez A.
, Tanioka M.
, Dieci M.V.
, Pernas S.
, Gavila J.
, Guarnieri V.
, Cortes J.
, Villagrasa P.
, Chic N.
, et al.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021-06-01; 27(11), p. 3116-3125.
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.
, 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.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2020-12-10; 38(35), p. 4184-4193.
A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation.
, Guarneri V.
, Paré L.
, Griguolo G.
, Pascual T.
, Dieci M.V.
, Chic N.
, González-Farré B.
, Frassoldati A.
, Sanfeliu E.
, et al.
The Lancet. Oncology, 2020 11; 21(11), p. 1455-1464.
What Is the Real Impact of Estrogen Receptor Status on the Prognosis and Treatment of HER2-Positive Early Breast Cancer?
, Caparica R.
, Malorni L.
, Prat A.
, Carey L.A.
, Piccart M.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020-06-15; 26(12), p. 2783-2788.