RT Journal Article SR Electronic T1 Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2) JF Science Signaling JO Sci. Signal. FD American Association for the Advancement of Science SP eaat9773 DO 10.1126/scisignal.aat9773 VO 11 IS 551 A1 Cocco, Emiliano A1 Javier Carmona, F. A1 Razavi, Pedram A1 Won, Helen H. A1 Cai, Yanyan A1 Rossi, Valentina A1 Chan, Carmen A1 Cownie, James A1 Soong, Joanne A1 Toska, Eneda A1 Shifman, Sophie G. A1 Sarotto, Ivana A1 Savas, Peter A1 Wick, Michael J. A1 Papadopoulos, Kyriakos P. A1 Moriarty, Alyssa A1 Cutler, Richard E. A1 Avogadri-Connors, Francesca A1 Lalani, Alshad S. A1 Bryce, Richard P. A1 Chandarlapaty, Sarat A1 Hyman, David M. A1 Solit, David B. A1 Boni, Valentina A1 Loi, Sherene A1 Baselga, José A1 Berger, Michael F. A1 Montemurro, Filippo A1 Scaltriti, Maurizio YR 2018 UL http://stke.sciencemag.org/content/11/551/eaat9773.abstract AB Breast cancers with amplification or mutation in the epidermal growth factor receptor (EGFR) family member HER2 are usually treated with targeted inhibitors, but resistance is common. Amplification and mutation of HER2 are generally considered mutually exclusive occurrences in treatment-naïve patients. However, Cocco et al. discovered a small proportion of treatment-naïve and, more often, previously treated patients with metastatic breast cancer in which HER2 amplification and mutation were coincident. It is not yet clear why, but these co-amplified/mutant cells were resistant to currently approved HER2-specific and HER2/EGFR-specific inhibitors but were sensitive to the new pan-EGFR inhibitor neratinib. Neratinib, which inhibits EGFR and HER2, as well as HER3 and HER4, was more effective at blocking the activity of the EGFR pathway and other receptor tyrosine kinases, common modes of resistance in HER2-driven tumors. Patients and mice bearing their tumor cells showed improved survival and even tumor regression on neratinib, suggesting that this may be a treatment option for certain breast cancer patients.Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.