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+)和人类表皮 生长因子受体2阴性(HER2-)。内分泌治疗(ET)降低复发风险并改善 对于这群人中的许多人来说。然而，尽管有标准的护理和辅助ET，超过20%的患者 ER+/HER2-BC在未来几年会经历转移复发，几乎所有转移的患者 由于固有或获得性耐药机制，疾病最终在ET上经历疾病进展。 然而，ET的进展并不排除对替代形式的ET的持续反应性，包括 这些药物结合了针对ER的治疗和驱动ET耐药的关键信号通路。然而， 目前还没有生物标志物可以可靠地确定哪些患者将从基于ET的方法中受益 这样就可以避免或推迟化疗。PGR基因在RNA和DNA中受ER的高度调控 ER+BC中的蛋白水平和PGR的表达可反映ER和BC的功能状态 ET带来的相关预测性益处。我们建议评估正电子发射断层扫描(PET)的实用性。 用PGR放射性示踪剂[18F]氟呋喃去甲孕酮(FFNP)显像预测ET的疗效 治疗。在最近的II期单臂临床试验中，我们展示了FFNP-PET成像，在此之前和 在一天的雌二醇(E2)激发(ΔFFNPPET)后，预测对ET的反应具有100%的敏感性和100%的敏感性 ER+BC晚期患者的特异性。在本提案中，我们将剖析 PgR和ER及其对ΔFFNP-PET作为全身性ER功能预测影像标志物的意义 目前和新兴的基于ET的方法使用患者来源的肿瘤异种移植(PDX)和 基因工程模型，与临床试验对接。我们提出了三个目标。在目标1中，我们将研究 雌激素受体1基因突变对ER-PgR串扰、PgR表达及ΔFFNP-PET显像的影响 临床前模型中内质网功能的生物标志物。在目标2中，我们将评估ΔFFNP-PET在预测中的应用 在PDX模型中单独和联合靶向治疗对单一药物和ET药物的反应 ER+/HER2-BC。在目标3中，我们将与一项临床试验对接，以检查肿瘤基因组学对 Δ-FFNP-PET及其预测ER+HER2转移性乳腺患者治疗反应的准确性 癌症患者参加了内分泌治疗联合CDK4/6抑制剂阿贝西利的II期试验。 总体而言，这项研究旨在对精准医疗在中国的实施产生深远的影响 识别、分层和预测对临床可用的和新的SERD单独和组合的反应 与其他靶向治疗联合治疗ER+/HER2-BC晚期患者。

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.