Abstract 3971: Combination of neratinib and enzalutamide is an effective treatment for HER2-positive breast cancer metastasis to the brain
Authors: Harshil D. Dhruv, Lauren Hartman, Chris Gooden, George Reid, Christophe Legendre, George Snipes, Cynthia Osborne, Joyce O'Shaughnessy, Bodour Salhia
Journal: Cancer Research (2018)

Abstract An estimated 10% to 30% of all breast cancer patients eventually develop brain metastases. Up to half of the patients with epidermal growth factor receptor 2 (HER2)-positive breast cancer will develop brain metastasis. Treatment options for patients with breast cancer brain metastases are limited to surgical resection and radiotherapy with dismal median survivals of 2 to 24 months. Efforts to identify clinically relevant targeted therapeutics have been limited by the lack of molecularly characterized model systems. We have developed a patient derived xenograft (PDX) model of a HER2-positive breast cancer brain metastasis and have genomically characterized the PDX and its -matched tumor. Whole exome and RNA sequencing data revealed high fidelity of the PDX tumor with its corresponding patient-matched tumor and confirmed retention of driver gene alterations such as the amplification and overexpression of HER2. Additionally, immunohistochemistry of the patient tumor revealed overexpression of the Androgen receptor (AR) (IHC Score 2+), which was also confirmed in the PDX. Given the importance of both HER2 and AR in aggressive tumor behavior, we developed a preclinical study to inhibit both targets. Neratinib and enzalutamide were selected because of their known blood brain barrier penetration properties. As proof of concept we first tested the combination strategy in the flank of NOG mice (n = 10 animals/group). Tumors were allowed to grow to ~250 mm3 in size and animals were subsequently treated with either vehicle control, neratinib (40 mg/Kg) alone, enzalutamide (30 mg/Kg) alone, or combination for 2 weeks. Neratinib alone and thecombination with enzalutamide demonstrated exceptional efficacy in suppressing tumor growth as compared to either the vehicle control or Enzalutamide alone (5 fold reduction in tumor size, p &amp;lt; 0.001). Interestingly, when the treatments were stopped, tumors treated with Neratinib alone grew significantly faster compared to tumor growth with the combination treatment (p &amp;lt; 0.05), suggesting more effective and sustained tumor suppression by the addition of Enzalutamide. Studies in an orthotopic setting and molecular profiling of treated and non-treated tumors are ongoing. In summary, our results demonstrated that Neratinib in combination with Enzalutamide could potentially be developed for patients with HER2 and AR-positive breast cancer metastasis to the brain and warrants further preclinical testing. Citation Format: Harshil D. Dhruv, Lauren Hartman, Chris Gooden, George Reid, Christophe Legendre, George Snipes, Cynthia Osborne, Joyce O'Shaughnessy, Bodour Salhia. Combination of neratinib and enzalutamide is an effective treatment for HER2-positive breast cancer metastasis to the brain [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 3971.