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

摘要 大约70%的乳腺癌（BC）是雌激素受体（ER）阳性（ER+）和人表皮生长因子受体阳性（ER+）。 生长因子受体2阴性（HER2-）。内分泌治疗（ET）可降低复发风险， 这个群体中的许多人的生存。然而，尽管有标准治疗和辅助ET，超过20%的患者 ER +/HER2-BC在未来几年内会经历转移性复发，并且几乎所有转移性患者 由于内在或获得性抗性机制，疾病最终在ET上经历疾病进展。 然而，ET的进展并不排除对其他形式的ET的持续反应，包括 那些结合针对ER和驱动ET抗性的关键信号通路的联合收割机疗法的药物。然而，在这方面， 目前还没有生物标志物可以可靠地识别哪些患者将从基于ET的方法中获益 这样就可以避免或推迟化疗。PgR基因在RNA上受到ER的高度调节， 蛋白水平，因此ER + BC中PgR的表达将指示ER的功能状态， 与ET相关的预测获益。我们建议评估正电子发射断层扫描（PET）的效用 用PgR放射性示踪剂[18F]氟-呋喃基-去甲孕酮（FFNP）进行成像，以预测对基于ET的 治疗在最近的一项II期单组临床试验中，我们证明了FFNP-PET成像， 在一天雌二醇（E2）激发（Δ FFNP-PET）后，预测对ET的反应具有100%的灵敏度和100%的特异性。 晚期ER + BC女性的特异性。在本提案中，我们将剖析 PgR和ER及其对Δ FFNP-PET作为全身ER功能的预测性成像生物标志物的意义 一系列使用患者源性肿瘤异种移植物（PDX）的当前和新兴ET方法， 基因工程模型，与临床试验相结合。我们提出三个目标。在目标1中，我们将研究 ESR1基因突变对ER-PgR串扰、PgR表达和Δ FFNP-PET成像的影响 在临床前模型中ER功能的生物标志物。在目标2中，我们将评估Δ FFNP-PET在预测 在PDX模型中单独和与靶向疗法组合的对单一药剂ET药剂的响应 ER +/HER2-BC。在目标3中，我们将结合临床试验，研究肿瘤基因组学对 Δ FFNP-PET及其预测转移性ER + HER2-乳腺癌患者治疗应答的准确性 参与内分泌治疗与CDK4/6抑制剂abemaciclib联合治疗的II期试验的癌症。 总的来说，这项研究旨在对精准医疗的实施产生深远的影响， 识别、分层和预测对临床可用和新型SERD单独和联合治疗的反应 晚期ER +/HER2-BC患者的其他靶向治疗。

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.