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ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer

Division of Medical Oncology 2, Istituto Oncologico Veneto IOV—IRCCS, 35128 Padova, Italy
Department of Surgery, Oncology and Gastroenterology, University of Padova, 35124 Padova, Italy
Department of Medical Oncology, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
Department of Pathology, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
SOLTI breast cancer cooperative group, 08008 Barcelona, Spain
The West German Study Group, 41061 Mönchengladbach, Germany
Ev. Hospital Bethesda, Breast Center Niederrhein, 41061 Mönchengladbach, Germany
University Clinics Cologne, 50937 Cologne, Germany
Medical School Hannover, Institute of Pathology, 30625 Hannover, Germany
Pharmacy Department, Division of Medicines, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
Breast Center, Department of Gynecology and Obstetrics, University of Munich (LMU) and CCCLMU, 80337 Munich, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(7), 1902;
Received: 13 June 2020 / Revised: 6 July 2020 / Accepted: 8 July 2020 / Published: 14 July 2020
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. View Full-Text
Keywords: ERBB2 mRNA; HER2-positive breast cancer; T-DM1; antibody-drug conjugates ERBB2 mRNA; HER2-positive breast cancer; T-DM1; antibody-drug conjugates
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Griguolo, G.; Brasó-Maristany, F.; González-Farré, B.; Pascual, T.; Chic, N.; Saurí, T.; Kates, R.; Gluz, O.; Martínez, D.; Paré, L.; Tsvetkova, V.; Pesantez, D.; Vidal, M.; Adamo, B.; Muñoz, M.; Galván, P.; Barberá, L.; Cuatrecasas, M.; Christgen, M.; Kreipe, H.; Monge-Escartín, I.; Villagrasa, P.; Soy, D.; Giarratano, T.; Dieci, M.V.; Conte, P.; Harbeck, N.; Guarneri, V.; Prat, A. ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer. Cancers 2020, 12, 1902.

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