Abstract
Abstract
Overexpression/amplification of HER2/ERBB2 occurs in 20% of breast cancers. Thanks to specific anti-HER2 agents, the prognosis of HER2-positive breast cancer has improved considerably. However, acquired resistance inevitably emerges over time and tumors escape pharmacologic pressure. In this work, we propose that acquisition of activating somatic mutations in HER2 upon anti-HER2 therapy may be more frequent than commonly reported and can reduce sensitivity to these agents. Moreover, we tested whether neratinib, an irreversible pan-HER inhibitor, is effective in tumors bearing both amplification and mutations of ERBB2. By targeted exome sequencing, we found that samples from metastatic breast cancer (MBC) patients relapsing to multiple lines of anti-HER2 therapy presented the acquisition of HER2 mutations. These mutations spanned from the extracellular domain (L313I, R456C) to the kinase domain (L755S, D769Y) of the receptor. To investigate the role of these mutations in drug resistance, we conducted functional studies by stably transducing the L755S HER2 mutation (the most frequent HER2 mutation in breast cancer) in two ERBB2-amplified breast cancer cell lines intrinsically sensitive to HER2 inhibition. In both models, we found that expression of L755S mutant-HER2 was sufficient to limit sensitivity to trastuzumab, lapatinib, or the combination of both agents. Consistently, neither trastuzumab nor lapatinib was effective in inhibiting tumor growth of patient-derived xenografts established from a patient with ERBB2-amplified/mutant (D769Y) breast cancer. However, neratinib treatment demonstrated marked sensitivity in this tumor model, resulting in significant tumor growth inhibition. The antitumor activity of neratinib was also explored in breast cancer patients with coexisting ERBB2 amplification and mutation, either by compassionate use after failure of standard-of-care therapy or as part of a “basket” trial (NCT01953926) enrolling ERBB2-mutant patients. In both settings, we observed durable clinical response to neratinib. MBC case #HER2 co-mutationResponse to neratinibDurability of response (mo)1D769YSD62L313ISD93Y772_A775dupSD44L755SSD55V777LPR6
Our findings indicate that acquired HER2 mutations may reduce the effectiveness of therapeutic agents commonly used for the management of ERBB2-amplified MBC. Moreover, we propose neratinib as an effective treatment option for patients whose tumors harbor both ERBB2 amplifications and mutations.
Citation Format: Emiliano Cocco, F. Javier Carmona, Helen H. Won, Michael F. Berger, David M. Hyman, Valentina Rossi, Carmen Chan, Alyssa Moriarty, Kyriakos P. Papadopoulos, Michael J. Wick, James Cownie, Ivana Sarotto, Richard E. Cutler, Francesca Avogadri-Connors, Peter Savas, Alshad S. Lalani, Valentina Boni, Sherene Loi, Jose Baselga, Filippo Montemurro, Maurizio Scaltriti. Neratinib has clinical activity in HER2-amplified breast cancer patients with tumors that have acquired activating mutations in HER2 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B169.
