Abstract 4818: Neratinib/fulvestrant but not fulvestrant alone maintain complete responses after treatment with trastuzumab/paclitaxel of mice bearing ER+/HER2+ xenografts
Authors: Schwarz Luis J. , Croessmann Sarah E. , Avogadri-Connors Francesca , Cutler Richard E. , Lalani Alshad S. , Arteaga Carlos L. 
Published: July 2017

Background: Neratinib is a potent, irreversible pan-HER tyrosine kinase inhibitor. The phase III trial ExteNET showed improved disease-free survival of neratinib vs placebo in early-stage HER2+ breast cancer patients (pts) after trastuzumab-based adjuvant therapy. This benefit from neratinib was greater in pts with hormone receptor (HR)+ tumors. Based on these findings, we sought to establish a human-in-mouse model that would simulate this clinical trial and outcome, thus providing a platform for mechanistic investigation.

Methods: ER+/HER2-amplified MDA-361 cells were injected subcutaneously (SC) into 5-week-old female athymic mice without estradiol supplementation. Mice with tumors ≥250 mm3 were treated with trastuzumab (tz) 20 mg/kg + paclitaxel (pac) 15 mg/kg IP twice weekly for 4 weeks, and then randomized to fulvestrant (fulv) SC 5 mg/week ± neratinib 20 mg/kg/day by orogastric gavage for 4 weeks.

Results: Xenografts in all 20 mice showed a prompt and marked reduction in volume after tz/pac treatment; 10 mice achieved a complete response (CR) before receiving ‘extended adjuvant’ therapy with fulv (n=5) or neratinib/fulv (n=5). A CR was maintained with neratinib/fulv following tz/pac, whereas tumors rapidly recurred in mice treated with fulv alone (p&lt;0.05 at week 8; Table). Immunoblot analysis of MDA-361 tumors recurring on fulv showed almost complete downregulation of ER levels.

TimepointTreatmentMean (± SD) tumor volume, mm3 (% change from baseline)Trastuzumab + paclitaxel →fulvestrant(n=5)Trastuzumab + paclitaxel →fulvestrant + neratinib(n=5)BaselineTreatment start163.4 ± 52.9 (–)187.1 ± 73.1 (–)Week 4Trastuzumab + paclitaxel8.6 ± 12.0 (–96.1)9.8 ± 10.5 (–93.9)Week 8Fulvestrant ± neratinib814.0 ± 435.1 (+401.5)2.0 ± 4.5 (–98.8)**p&lt;0.05 between groups (Student’s t-test). SD, standard deviation.

Conclusions: Neratinib/fulvestrant but not fulvestrant alone maintained complete tumor responses following initial treatment with tz/pac; recapitulating the design and outcomes observed in the HR+ subgroup of the ExteNET trial. The experimental model used herein provides a platform for investigation of the underlying mechanisms for the findings in ExteNET. Experiments evaluating ER gene signatures and expression levels, as well as the effects of neratinib ± fulvestrant following initial adjuvant pertuzumab/trastuzumab/paclitaxel are underway.

Citation Format: Luis J. Schwarz, Sarah E. Croessmann, Francesca Avogadri-Connors, Richard E. Cutler, Alshad S. Lalani, Carlos L. Arteaga. Neratinib/fulvestrant but not fulvestrant alone maintain complete responses after treatment with trastuzumab/paclitaxel of mice bearing ER+/HER2+ xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4818. doi:10.1158/1538-7445.AM2017-4818