FFNP-PET as a predictive biomarker of response to endocrine therapy approaches in advanced breast cancer

ABSTRACT Approximately 70% of breast cancers (BCs) are estrogen receptor (ER) positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-). Endocrine therapy (ET) reduces recurrence risk and improves survival for many in this group. However, despite standard of care and adjuvant ET, over 20% of patients with ER+/HER2- BC experience metastatic recurrence in the years to come, and virtually all patients with metastatic disease eventually experience disease progression on ET due to intrinsic or acquired resistance mechanisms. Progression on ET, however, does not preclude continued responsiveness to alternate forms of ET, including those that combine therapies directed at ER and key signaling pathways that drive ET resistance. However, there are currently no biomarkers that can reliably identify which patients will benefit from ET-based approaches so that chemotherapy could be avoided or delayed. The PgR gene is highly regulated by ER at the RNA and protein level, and thus expression of PgR in ER+ BC would be indicative of the functional status of ER and associated predictive benefit from ET. We propose to evaluate the utility of positron emission tomography (PET) imaging with the PgR radiotracer, [18F]fluoro-furanyl-norprogesterone (FFNP) to predict response to ET-based therapies. In a recent phase II single-arm clinical trial, we demonstrated that FFNP-PET imaging, before and after a one-day estradiol (E2) challenge (ΔFFNP-PET), predicted response to ET with 100% sensitivity and 100% specificity in women with advanced ER+ BC. In this proposal, we will dissect the functional relationship between PgR and ER and its implications for ΔFFNP-PET as a predictive imaging biomarker of ER function for the full range of current and emerging ET-based approaches using patient-derived tumor xenografts (PDX) and genetically engineered models, interfacing with a clinical trial. We propose three Aims. In Aim 1, we will examine the impact of ESR1 gene mutations on ER-PgR crosstalk, PgR expression, and ΔFFNP-PET as an imaging biomarker of ER function in preclinical models. In Aim 2, we will evaluate the utility of ΔFFNP-PET in predicting response to single agent ET agents alone and in combination with targeted therapies in PDX models of ER+/HER2- BC. In Aim 3, we will interface with a clinical trial to examine the impact of tumor genomics on ΔFFNP-PET and its accuracy in predicting response to therapy in patients with metastatic ER+ HER2- breast cancer enrolled in a phase II trial of endocrine therapy in combination with the CDK4/6 inhibitor abemaciclib. Overall, this study aims to have a far-reaching and high impact on the implementation of precision medicine in identifying, stratifying, and predicting response to clinically available and novel SERDs alone and in combination with other targeted therapies in patients with advanced ER+/HER2- BC.