Abstract 2173: Testing neratinib-containing drug combination regimens on HER2 mutated non-amplified, ER+ breast cancer patient-derived xenografts
Authors: Li Shunqiang , Primeau Tina M. , Pratt Stephanie L. , Harrill Katherine R. , Avogadri-Connors Francesca , Lalani Alshad S. , Ma Cynthia X. , Bose Ron 
Published: August 2018

Abstract
Introduction: HER2 activating mutations are a novel, druggable genomic alteration in metastatic breast cancer (MBC). These HER2 mutations are predominantly found in HER2 gene amplification negative, hormone receptor positive breast cancers. We have previously demonstrated that HER2 mutations can be potently inhibited by the second generation, irreversible pan-HER tyrosine kinase inhibitor, neratinib (Bose et al., Cancer Discovery 2013). Further, we performed a phase II clinical trial to treat HER2 mutated MBC and we found that neratinib monotherapy produced a clinical benefit rate of 31% and progression free survival of 16 weeks in a heavily pre-treated patient population (Ma et al., Clinical Cancer Research 2017). The objective of the current pre-clinical study is to develop combination strategies to improve the anti-tumor activity of neratinib in HER2 mutated breast cancer. As ER and CDK4/6 signaling activation are known resistance mechanisms to HER2 targeted agents in HER2 positive breast cancer, we hypothesized that neratinib in combination with agents that target ER (fulvestrant) or CDK4/6 (palbociclib) will induce synergistic anti-tumor effect in HER2 mutated MBC. In addition, we hypothesized that dual HER2 targeting (with trastuzumab) or in combination with chemotherapy agents (vinorelbine), may be more effective than neratinib alone. Since these partnering agents are well established in the treatment of breast cancer and are without overlapping toxicities with neratinib, rapid clinical translation is possible for the treatment of patients with HER2 mutated, ER+ MBC.
Description of our Human-in-Mouse Patient Derived Xenografts (PDX): We developed two HER2 mutated breast cancer PDX lines. Both lines come from HER2 mutation positive, HER2 gene amplification negative, ER+ MBC patients. PDX-51 has a HER2 exon 20 insertion mutation (ERBB2 G776insYVMA), a PIK3CA H1047R mutation and is wild-type for TP53. PDX-64 has a HER2 kinase domain missense mutation (ERBB2 L869R) and is wild-type for both PIK3CA and TP53. Both PDX lines are grown in female NSG strain mice without any exogenous estrogen supplementation.
Results: We tested combinations of neratinib with fulvestrant, palbociclib, trastuzumab, or vinorelbine for their anti-tumor activity and effects on cell proliferation and survival pathway signaling activities, including ER, CDK4/6 and HER2 pathways, in vivo. We will present data on the efficacy of these drug combinations. Tumor size measurements and reverse phase protein array (RPPA) data on the treated PDX lines will be shown.
Citation Format: Shunqiang Li, Tina M. Primeau, Stephanie L. Pratt, Katherine R. Harrill, Francesca Avogadri-Connors, Alshad S. Lalani, Cynthia X. Ma, Ron Bose. Testing neratinib-containing drug combination regimens on HER2 mutated non-amplified, ER+ breast cancer patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2173.