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

标题：功能精准癌症药物的可行性试验，为治疗选择提供信息 转移性乳腺癌。 在转移性乳腺癌中，除了HER2范例之外，基因组的前景 识别患者肿瘤中突变的驱动基因和编码的蛋白质的“精确医学” 是以治疗抑制剂为靶点的，尚未完全实现。仅仅是突变，特别是那些 在基因小组中确定的基因不足以提供足够的信息指导治疗选择。肿瘤，尤其是 转移，生长在复杂的生态系统中，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演变。 为了克服这一限制，我们现在建立了一个功能精确肿瘤学(FPO)平台， 其中患者来源的异种移植物(PDX)和有机类化合物(PDO)是从来自于 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性。 因此，它可以更可靠地预测临床反应。有机化合物是 对中通量药物的筛选和药物“命中”已在PDX中得到验证，目前 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学相结合 深入了解治疗反应或耐药性的决定因素并创造基因-药物的研究 响应相关性。我们在正在进行的乳房早期临床试验中利用这一平台 癌症，不仅可以产生患者衍生的模型，还可以识别高转移风险的患者 复发。 在这里提出的试验中(预见：转移性乳腺癌的功能精确肿瘤学：A 可行性试验，NCT04450706)，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方法的临床活性的见解。我们建立PDO 直接从转移部位的活检组织中提取，并对患有转移的女性进行基于PDO的药物筛选 乳腺癌，要么是新诊断的三阴性，要么是激素受体阳性和Her2阴性 已经用尽了内分泌单一疗法和联合疗法。对于目标1，我们将评估我们的PDO- 聚焦的FPO管道导致12周内的治疗建议。对于目标2，我们将评估如何 通常，我们的FPO管道和同时进行的商业(黄金标准)测试会导致治疗建议 以及这些建议重叠的频率。从我们的经验教训选择治疗方法的临床效果 将捕获FPO检测(目标3)。总的来说，这些研究将调查我们基于PDO的FPO 管道可以有意义地结合到研究临床实践中，并提供初步见解 可以为设计一项更大规模的研究提供参考。

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.