Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

• DOI: 10.1126/scisignal.aat9773
• Publication Date: 2018-10-09T18:19:56Z
• Authors: Emiliano Cocco; F. Javier Carmona; Pedram Razavi; Helen H. Won; Yanyan Cai; Valentina Rossi; Carmen Chan; James Cownie; Joanne Soong; Eneda Toska; Sophie G. Shifman; Ivana Sarotto; Peter Savas; Michael J. Wick; Kyriakos P. Papad...; Alyssa Moriarty; Richard E. Cutler; Francesca Avogadr...; Alshad S. Lalani; Richard P. Bryce; Sarat Chandarlapaty; David M. Hyman; David B. Solit; Valentina Boni; Sherene Loi; José Baselga; Michael F. Berger; Filippo Montemurro; Maurizio Scaltriti
• Keywords: Neratinib

Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common and drive of "HER2-negative" (not ERBB2 amplified) tumors but rare "HER2-positive" (ERBB2 breast cancer. We analyzed DNA-sequencing data from HER2-positive patients used cell lines a patient-derived xenograft model to test consequence HER2 mutations on efficacy anti-HER2 agents such as trastuzumab, lapatinib, neratinib, an irreversible pan-EGFR inhibitor. were present ~7% tumors, all which metastatic not previously treated. Compared amplification alone, both cultured lines, co-occurrence mutation was associated with poor response trastuzumab standard-of-care agents. In mice, xenografts established patient whose tumor acquired D769Y after progression trastuzumab-based therapy resistant or lapatinib sensitive neratinib. Clinical revealed that six heavily pretreated bearing coincident subsequently exhibited statistically significant neratinib monotherapy. Thus, these findings indicate reduces therapies commonly treat cancer, particularly inhibitor-treated patients, well potentially scheduled for first-line treatment. Therefore, we propose clinical studies testing warranted selectively cancer carry ERBB2/HER2.