A feasibility trial of functional precision cancer medicine to inform treatment selection in metastatic breast cancer

标题：一项功能性精准癌症药物的可行性试验，以告知治疗选择， 转移性乳腺癌 在转移性乳腺癌中，除了HER 2范例的显著例外，基因组治疗的前景是， “精确医学”，其中患者肿瘤中的突变驱动基因被识别，编码的蛋白质 被治疗性抑制剂靶向，尚未完全实现。突变本身，特别是那些 在基因组中鉴定的，不足以提供指导治疗选择的信息。肿瘤尤其 转移，在复杂的生态系统中生长，并表现出惊人的异质性和可塑性，使它们能够 在一系列压力下动态地发展。 为了克服这一限制，我们现在已经建立了一个功能性精准肿瘤学（FPO）平台， 其中患者来源的异种移植物（PDX）和类器官（PDO）从获自 乳腺癌患者。这些模型忠实地保留了复杂的分子和生物学特征 因此，可以更可靠地预测临床反应。类器官 适合于中等通量药物筛选和药物“命中”已经在PDX中得到验证， 构成临床前药物评价的金标准。我们将药物分析结果与基因组 深入了解治疗反应或耐药性的决定因素，并创建基因型药物 响应相关性。我们在一项正在进行的早期乳腺癌临床试验中利用这个平台， 癌症，不仅要生成患者衍生的模型，而且还要识别转移性肿瘤高风险的患者。 复发 在本文提出的试验中（FORESEE：转移性乳腺癌的功能性精确肿瘤学： 可行性试验，NCT 04450706），我们的目标是系统地分析该平台的性能，并获得 对转移性乳腺癌拟议治疗的临床活性的见解。我们建立PDO 直接从转移部位的活组织检查中获得，并在转移性乳腺癌患者中进行基于PDO的药物筛选。 乳腺癌，无论是新诊断的三阴性或激素受体阳性和Her 2阴性， 已经用尽了内分泌单一疗法和联合疗法。在目标1中，我们将评估我们的PDO- 集中FPO管道导致治疗建议在12周内。在目标2中，我们将评估如何 通常我们的FPO管道和并行商业（黄金标准）测试会导致治疗建议 以及这些建议重叠的频率。我们的治疗选择的临床疗效 将捕获FPO测定（目标3）。总的来说，这些研究将调查我们基于PDO的FPO是否 管道可以有意义地纳入研究性临床实践，并提供初步的见解 可以为更大规模研究的设计提供信息。

Title: A feasibility trial of functional precision cancer medicine to inform treatment selection in metastatic breast cancer. In metastatic breast cancer, with the notable exception of the HER2 paradigm, the promise of the genomic “precision medicine” in which mutant driver genes in a patient’s tumor are identified and the encoded proteins are targeted with therapeutic inhibitors, has not been fully realized. Mutations alone, particularly those identified in gene panels, are insufficiently informative to guide treatment selection. Tumors, especially metastases, grow in complex ecosystems and exhibit striking heterogeneity and plasticity that allow them to evolve dynamically under a series of pressures. To overcome this limitation, we have now established a Functional Precision Oncology (FPO) platform, whereby patient derived xenografts (PDX) and organoids (PDO) are established from tumors obtained from patients with breast cancer. These models retain faithfully the complex molecular and biologic characteristics of the originating tumors and, to that end, can predict clinical responses more reliably. Organoids are amenable to medium-throughput drug screening and drug “hits” have been validated in PDXs, which currently constitute the gold standard for preclinical drug evaluation. We integrate drug profiling results with genomic studies to gain insights into determinants of treatment response or resistance and create genotype – drug response correlations. We leverage this platform in the context of an ongoing clinical trial in early-stage breast cancer, not only to generate patient-derived models, but also identify patients at high risk of metastatic recurrence. In the trial proposed herein (FORESEE: Functional precision oncology for metastatic breast cancer: a feasibility trial, NCT04450706), we aim to systematically analyze the performance of this platform and gain insights on the clinical activity of the proposed treatments in metastatic breast cancer. We establish PDOs directly from biopsies of metastatic sites and perform PDO-based drug screens in women with metastatic breast cancer, either newly diagnosed triple negative or hormone receptor-positive and Her2-negative who have exhausted endocrine mono- and combinatorial therapies. With Aim 1, we will assess how often our PDO- focused FPO pipeline leads to a treatment recommendation within 12 weeks. With Aim 2, we will assess how often our FPO pipeline and concurrent commercial (gold standard) testing lead to treatment recommendations and how often these recommendations overlap. The clinical efficacy of treatment selection informed by our FPO assays will be captured (Aim 3). Collectively, these studies will investigate whether our PDO-based FPO pipeline can be meaningfully incorporated in an investigational clinical practice and provide preliminary insights of impact that can inform the design of a larger study.