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

FFNP-PET 作为晚期乳腺癌内分泌治疗方法反应的预测生物标志物

• 批准号: 10504739
• 负责人: FARROKH DEHDASHTI
• 金额: $ 64.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504739
• 关键词: Address; Agonist; Aromatase Inhibitors; Biological Markers; Biopsy; Breast Cancer Patient; Breast Cancer cell line; CDK4 gene; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; DNA Sequence Alteration; Data; Disease; Disease Progression; ERBB2 gene; ESR1 gene; Enrollment; Epidermal Growth Factor Receptor; Estradiol; Estrogen Receptor Status; Estrogen Receptors; Estrogen receptor positive; Estrogens; FPS-FES Oncogene; Fulvestrant; GNRH1 gene; Gene Expression Profile; Gene Mutation; Genetic Engineering; Genetically Engineered Mouse; Genomics; Goals; Human; Image; Metastatic breast cancer; Modeling; Mutate; Mutation; PIK3CA gene; Patients; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Pre-Clinical Model; Prediction of Response to Therapy; Progesterone Receptors; Proteins; RNA; Receptor Gene; Receptor Signaling; Recurrence; Resistance; Risk; Selective Estrogen Receptor Modulators; Signal Pathway; Specificity; Tamoxifen; Tumor-Derived; Woman; Xenograft Model; adjuvant endocrine therapy; advanced breast cancer; arm; base; chemotherapy; clinical development; exome sequencing; experience; functional genomics; functional status; genetic signature; genomic signature; hormone therapy; imaging biomarker; improved; indexing; inhibitor; mTOR Inhibitor; malignant breast neoplasm; novel; phase II trial; precision medicine; preclinical study; predicting response; predictive marker; public health relevance; radiotracer; receptor expression; receptor function; resistance mechanism; response; response biomarker; standard of care; targeted treatment; transcriptome sequencing; treatment choice; treatment response; tumor; tumor xenograft; virtual

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.

抽象的 大约 70% 的乳腺癌 (BC) 为雌激素受体 (ER) 阳性 (ER+)，且人类表皮 生长因子受体 2 阴性 (HER2-)。内分泌治疗（ET）可降低复发风险并改善 这个群体中许多人的生存。然而，尽管有标准护理和辅助 ET，仍有超过 20% 的患者患有 ER+/HER2- BC 在未来几年内会经历转移性复发，并且几乎所有患有转移性乳腺癌的患者 由于内在或获得性耐药机制，疾病最终在 ET 上经历疾病进展。 然而，ET 的进展并不排除对其他形式 ET 的持续反应，包括 那些将针对 ER 的疗法与驱动 ET 耐药的关键信号通路相结合的疗法。然而， 目前没有生物标志物可以可靠地识别哪些患者将从基于 ET 的方法中受益 从而避免或延迟化疗。 PgR 基因在 RNA 上受到 ER 的高度调控， 蛋白水平，因此 ER+ BC 中 PgR 的表达将指示 ER 和 BC 的功能状态 ET 的相关预测效益。我们建议评估正电子发射断层扫描 (PET) 的实用性 使用 PgR 放射性示踪剂 [18F] 氟呋喃去甲孕酮 (FFNP) 进行成像，以预测基于 ET 的反应 疗法。在最近的一项 II 期单臂临床试验中，我们证明了 FFNP-PET 成像在之前和 经过一天雌二醇 (E2) 激发 (ΔFFNP-PET) 后，预测 ET 反应的灵敏度为 100%，灵敏度为 100% 晚期 ER+ BC 女性的特异性。在这个提案中，我们将剖析之间的功能关系 PgR 和 ER 及其对 ΔFFNP-PET 作为 ER 功能的预测成像生物标志物的影响 一系列当前和新兴的基于 ET 的方法，使用患者来源的肿瘤异种移植物 (PDX) 和 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，我们将检查 ESR1 基因突变对 ER-PgR 串扰、PgR 表达和 ΔFFNP-PET 成像的影响 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 ΔFFNP-PET 在预测中的效用 PDX 模型中对单药 ET 药物的单独反应以及与靶向治疗组合的反应 ER+/HER2- BC。在目标 3 中，我们将进行一项临床试验，以检查肿瘤基因组学对 ΔFFNP-PET 及其预测转移性 ER+ HER2- 乳腺患者治疗反应的准确性 癌症登记参加了内分泌治疗与 CDK4/6 抑制剂 abemaciclib 联合治疗的 II 期试验。 总体而言，本研究旨在对精准医疗的实施产生深远而高的影响。 单独或组合识别、分层和预测对临床可用和新型 SERD 的反应 与其他靶向治疗一起治疗晚期 ER+/HER2- BC 患者。