Abstract 1814: RAD1901, an orally available SERD, as an effective combination partner in ER+ breast cancer
Authors: Bihani Teeru , Brown Jeffrey L. , Purandare Dinesh M. , Hattersley Gary , Garner Fiona 
Published: July 2016

Breast cancer is subdivided into categories based on a patient's estrogen receptor (ER), progesterone receptor (PR) or Her2 expression status. Estrogen receptor positive (ER+) breast cancer makes up approximately 70% of all breast cancers diagnosed and given the dependence on ER signaling in this disease segment, most treatment modalities focus on inhibiting some aspect of this pathway. Indeed, preventing estrogen synthesis (e.g. with aromatase inhibitors) and modulating ER pathway activity (e.g. with tamoxifen) continue to be mainstays in the standard of care for ER+ breast cancer patients. While patients typically respond well to these agents, a majority of patients will relapse, emphasizing the need to understand the specific mechanisms that can contribute to clinical resistance. One such mechanism is the activation of compensatory or concurrent signaling pathways that can stimulate growth (eg. Her2, CDK4/6) and/or confer survival (eg. PI3K, AKT, mTOR). The recent approval of palbociclib (CDK4/6i) or everolimus (mTORi) in combination with an aromatase inhibitor for the treatment of advanced ER+ disease demonstrates the effectiveness of combining anti-hormonals with targeted agents. While these combinations have superior efficacy compared to the use of aromatase inhibitors alone, alterations in ER itself, such as amplification and mutations, have been described as a second mechanism that can drive resistance to aromatase inhibitors in patients. These findings highlight the need for a selective estrogen receptor downregulator (SERD) that can degrade both wild-type and aberrant forms of ER in order to more effectively treat this patient population. We have recently demonstrated that treatment with RAD1901, an orally bioavailable SERD, results in consistent and robust tumor growth inhibition of patient derived xenograft (PDx) models, regardless of ER status. We hypothesized that combining RAD1901 with agents that inhibit compensatory signaling pathways would mitigate both mechanisms of resistance in ER+ breast cancer patients, leading to greater efficacy. We performed an efficacy screen with RAD1901 in patient derived xenograft (PDx) models with varied genetic backgrounds, allowing us to mimic clinical phenotypes and to better represent the heterogeneity within the ER+ breast cancer patient population. These models harbored a wide range of ER expression levels, in addition to other genetic alterations, which accurately represented the patients’ diverse treatment history profiles. Based on results from the screen, models were selected for additional studies to determine which targeted agent, if any, can be combined with RAD1901 to achieve maximal efficacy. By doing this, we were able to correlate response with genetic background in clinically relevant models, potentially allowing us to predict treatment strategies that have a higher likelihood of success for specific patients.

Citation Format: Teeru Bihani, Jeffrey L. Brown, Dinesh M. Purandare, Gary Hattersley, Fiona Garner. RAD1901, an orally available SERD, as an effective combination partner in ER+ breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1814.