Abstract 2994: A new ER+Her2- Palbociclib resistant breast cancer PDX model

Abstract

Abstract One out of eight women will get breast cancer during their lifetime with over 250000 new cases of invasive breast cancer diagnosed yearly. The majority of breast cancer medicines (94%) were initially approved in the metastatic setting for patients that have been heavily pre-treated and resistant to the standard of care1. Thus, it is crucial that pre-clinical models are representative of this patient population in order for results to be translational. One recently approved class of drugs are the CDK4/6i which increase progression free survival for many patients. However, some tumors are intrinsically resistant, and others develop resistance over time. Hence, there is a need for new pre-clinical models that mimic these resistance features to test new therapies. WHIM81 and WHIM84 are two new ER+Her2- breast cancer PDX models from the Washington University Human in Mouse collection derived from heavily pretreated tumors. WHIM81 was derived from a patient with liver metastasis consistent with breast primary after she received treatment with Palbociclib, first as a monotherapy for 20 days and later in combination with letrozole for 2 months. During treatment, the patient developed the liver metastasis, whereas the WHIM84 model was grafted from a second patient with a bone metastasis prior to the patient seeing Palbociclib, but once she did, the tumor was unresponsive. In this PDX study, athymic nude mice bearing either WHIM81 or WHIM84 tumors were treated with 3 different concentrations of Palbociclib (10 mg/kg, 25 mg/kg and 75 mg/kg) administered daily for the duration of the experiment and also included an arm with Fulvestrant administered once weekly through a subcutaneous injection of 3 mg/dose. Our results showed that although WHIM81 tumors were responsive to a very high dose of Palbociclib (75 mg/kg), those tumors showed resistance to Palbociclib doses of 10 mg/kg and Palbociclib 25 mg/kg group as well as Fulvestrant, consistent with what was seen in the clinic for the tumor from which this PDX is derived. On the contrary WHIM84, while still showing resistance at the 10 mg/kg dose, was sensitive to treatment with Palbociclib at a dose of 25 mg/kg. Loss of pRb is an unlikely driver of resistance as WHIM81 retains pRb expression based on the presence of both pRb and phospo-pRb in the tumor. Thus, we believe that WHIM81 will provide a valuable new model to test novel therapies aimed to treat patients with CDK4/6i resistant cancers. 1. Leo and Szucs. (2020). Nature Reviews Drug Discovery. 19, 10. Citation Format: Michele Melton, Emma M. Hyddmark, Hongmei Jiang, Athena Bast, Nicole Semanik, Stacy Deeds, Andrew Brown. A new ER+Her2- Palbociclib resistant breast cancer PDX model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2994.