@article{59c5364109954a058a01a7c194803bc1,
title = "A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer",
abstract = "Background: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-Targeted treatments without chemotherapy. Patients and methods: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). Results: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-Type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). Conclusions: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-Targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-Targeted therapy without chemotherapy.",
keywords = "ErbB2 receptor tyrosine kinase, PIK3CA mutations, PTEN protein, breast cancer, fluorescent in situ hybridization, precision medicine",
author = "J. Veeraraghavan and {De Angelis}, C. and R. Mao and T. Wang and S. Herrera and Pavlick, {A. C.} and A. Contreras and P. Nuciforo and Mayer, {I. A.} and A. Forero and R. Nanda and Goetz, {M. P.} and Chang, {Jenny C.} and Wolff, {A. C.} and Krop, {I. E.} and Fuqua, {S. A.W.} and A. Prat and Hilsenbeck, {S. G.} and B. Weigelt and Reis-Filho, {J. S.} and C. Gutierrez and Osborne, {C. K.} and Rimawi, {M. F.} and R. Schiff",
note = "Funding Information: This work was supported in part by the NIH: SPORE Grants (P50 CA058183 and CA186784 to RS, CKO and MFR); Cancer Center Grants (P30 CA125123, P30 CA008748); the Breast Cancer Research Foundation (to RS, CKO and JSR-F; no grant number applies); research grant from the Breast Cancer Research Foundation BCRF-17-143 (to RS and CKO); the Cancer Prevention & Research Institute of Texas CPRIT RP 140102 and the Conquer Cancer Foundation—Gianni Bonadonna Breast Cancer Research Fellowship (to CDA); Department of Defense grants W81XWH-17-1-0579 (to MFR) and W81XWH-17-1-0580 (to RS), and the Translational Breast Cancer Research Consortium (TBCRC). We are grateful for the funding support to the TBCRC from The AVON Foundation, the Breast Cancer Research Foundation and Susan G. Komen. Funding Information: AF: research funding from Genentech (to Institution). RN: research funding from Celgene, Corcept, and Merck. Advisory boards for AstraZeneca, Celgene, Genentech, Merck, Daiichi, Macrogenics, Syndax, and PUMA biotechnology. MPG: research funding from Lilly and Pfizer. Consulting/Advisory boards for Lilly, Biovica, Novartis, Sermonix, and Genomic Health. JCC: Research funding from Novartis, Celgene, AstraZeneca, Merck, and Takeda; Advisory boards for Genentech, and Celgene. AP: research funding from Nanostring Technologies, Advisory boards for Nanostring Technologies, Novartis, and Roche. JSR-F: consultance fees from Goldman Sachs, Scientific Advisory Boards of Volition Rx and Paige.AI, Ad hoc Scientific Advisory Boards of Ventana, Genentech and Roche. CG: research grant from Ventana. CKO: research funding from AstraZeneca and GlaxoSmithKline, Advisory boards for Tolmar Pharmaceuticals, Genentech, and AstraZeneca, DMC for Eli Lilly, stockholder of GeneTex. MFR: Research funding from GlaxoSmithKline and Genentech. RS: Research funding from AstraZeneca, GlaxoSmithKline, Gilead Sciences, and PUMA Biotechnology; Consulting/advisory committee member for Macrogenics, and Eli Lilly. All remaining authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2019",
month = jun,
day = "1",
doi = "10.1093/annonc/mdz076",
language = "English (US)",
volume = "30",
pages = "927--933",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "6",
}