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Griguolo, Gaia; Braso-Maristany, Fara; Gonzalez-Farre, Blanca; Pascual, Tomas; Chic, Nuria; Sauri, Tamara; Kates, Ronald; Gluz, Oleg; Martinez, Debora; Pare, Laia; Tsvetkova, Vassilena; Pesantez, David; Vidal, Maria; Adamo, Barbara; Munoz, Montserrat; Galvan, Patricia; Barbera, Laura; Cuatrecasas, Miriam; Christgen, Mathias; Kreipe, Hans; Monge-Escartin, Ines; Villagrasa, Patricia; Soy, Dolors; Giarratano, Tommaso; Dieci, Maria Vittoria; Conte, Pierfranco; Harbeck, Nadia; Guarneri, Valentina; Prat, Aleix (2020): ERBB2mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer. In: Cancers, Vol. 12, No. 7, 1902
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Abstract

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 analyzedERBB2expression 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 ofERBB2levels 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,ERBB2expression 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. HighERBB2mRNA 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.ERBB2expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20-8.41% of tumors across 15 cancer types asERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified highERBB2mRNA 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 byERBB2levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.