TY - JOUR
T1 - Erbb2 mrna expression and response to ado-trastuzumab emtansine (T-dm1) in her2-positive breast cancer
AU - Griguolo, Gaia
AU - Brasó-Maristany, Fara
AU - González-Farré, Blanca
AU - Pascual, Tomás
AU - Chic, Núria
AU - Saurí, Tamara
AU - Kates, Ronald
AU - Gluz, Oleg
AU - Martínez, Débora
AU - Paré, Laia
AU - Tsvetkova, Vassilena
AU - Pesantez, David
AU - Vidal, Maria
AU - Adamo, Barbara
AU - Muñoz, Montserrat
AU - Galván, Patricia
AU - Barberá, Laura
AU - Cuatrecasas, Miriam
AU - Christgen, Mathias
AU - Kreipe, Hans
AU - Monge-Escartín, Inés
AU - Villagrasa, Patricia
AU - Soy, Dolors
AU - Giarratano, Tommaso
AU - Dieci, Maria Vittoria
AU - Conte, Pierfranco
AU - Harbeck, Nadia
AU - Guarneri, Valentina
AU - Prat, Aleix
N1 - Funding Information:
Funding: This study has received funding from Instituto de Salud Carlos III—PI16/00904 and PI19/01846 (to A.P.), Breast Cancer Now—2018NOVPCC1294 (to A.P.), Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-PRAT (to A.P.), Fundació La Marató TV3 201935-30 (to A.P.), the European Union’s Horizon 2020 research and innovation programme H2020-SC1-BHC-2018-2020 (to A.P.), Pas a Pas (to A.P.), Save the Mama (to A.P.), Fundación Científica Asociación Española Contra el Cáncer AECC_Postdoctoral17-1062 (to F. B-M), Generalitat de Catalunya Peris PhD4MD 2019 SLT008/18/00122 (to N.C.), DiSCOG—University of Padova DOR 1721185/17 and DOR 1830512/18 (to MV.D.), Conquer Cancer Foundation/Shanken Family Foundation -YIA in Breast Cancer 2019 (to G.G.).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/14
Y1 - 2020/7/14
N2 - Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.
AB - Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.
KW - Antibody-drug conjugates
KW - ERBB2 mRNA
KW - HER2-positive breast cancer
KW - T-DM1
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U2 - 10.3390/cancers12071902
DO - 10.3390/cancers12071902
M3 - Article
AN - SCOPUS:85087926715
VL - 12
SP - 1
EP - 15
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 7
M1 - 1902
ER -