Integrated radiomic and liquid biopsy monitoring in SWOG S1802: A phase 3 therapeutic trial for metastatic prostate cancer

摘要 前列腺癌（PC）在美国比任何其他恶性肿瘤折磨更多的男性，并且是第二大原因 癌症死亡率的一半。最近，新的治疗方法提高了一些男性的生存率， 对别人没有什么好处。组织分析已经确定了与抗性相关的基因和途径， 进展为晚期疾病，但对何时以及如何发生这种变化的动力学知之甚少 在治疗期间。只有通过微创监测才能获得这种见解， 随着时间的推移，疾病特征分析。我们的多学科团队已经开发并测试了两种这样的微创 监测能力：首先是多参数液体活检：血液样本的简化分析， 同时测量来自单个循环肿瘤细胞的PC相关细胞和分子特征， 匹配的血浆无细胞核酸第二个是放射组学分析：高通量提取 定量度量以识别PC相关的表型成像特征。通过将两者的优势结合起来 方法，我们的目标是测试假设，液体活检和放射组学技术可以联合应用， 随着时间的推移，无创监测转移性PC，最终形成新的预后和预测工具， 疗法为了最大限度地发挥我们的研究结果的影响，将整合液体活检分析和放射组学分析 西南肿瘤学（SWOG）S1802，一项针对1200多名新发 仅接受标准全身治疗的确诊转移性去势敏感性前列腺癌（mCSPC） 或与原发性肿瘤的确定性治疗组合。值得注意的是，SWOG和其他参与 合作团体已经审查并批准了这一建议（见支持信），以及所需的血液 作为现行方案的一部分，已经收集了样本和CT扫描。在这个独特的环境中，我们将 追求三个具体目标。我们将：1.使用多参数液体活检来监测不断变化的细胞和 S1802治疗期间mCSPC的分子景观; 2.使用CT扫描的放射组学分析来监测 S1802治疗期间mCSPC的影像学表现演变;和3.整合细胞、分子和 放射组学数据开发预测PFS和OS的复合疾病监测模型。 活检和CT图像将在患者体内进行匹配，并在治疗过程中的关键拐点进行分析。 试验：诊断时、开始全身治疗后、确定性治疗后和疾病进展时。在 这样，所提出的工作将阐明在治疗过程中PC相关表型何时以及如何出现，以及如何 它们与临床结果有关。特别是，我们将更好地了解液体活检的哪些成分- 循环细胞，血浆，或两者-最准确地反映了肿瘤的演变分子概况， 指标与这些分子特征最密切相关，可以作为早期的成本效益指标， 新出现的耐药性，以及结合液体活检和放射组学特征的复合模型最能预测 PFS和OS，可作为监测和调整治疗的强大微创工具。

Abstract Prostate cancer (PC) afflicts more men in the U.S. than any other malignancy and is the second leading cause of cancer death in this population. Recently, new therapies have improved survival in some men but have offered little benefit to others. Tissue profiling has identified genes and pathways associated with resistance and progression to advanced disease, but little is known about the dynamics of when and how such changes arise during therapy. Such insights can only be gained through minimally invasive monitoring that allows repeated disease profiling over time. Our multidisciplinary team has developed and tested two such minimally invasive monitoring capabilities: The first is multi-parametric liquid biopsy: streamlined analysis of blood samples that simultaneously measures PC-relevant cellular and molecular features from single circulating tumor cells and matched plasma cell-free nucleic acids. The second is radiomic analysis: high-throughput extraction of quantitative metrics to identify PC-relevant phenomic imaging features. By synergizing the strengths of the two methods, our goal is to test the hypothesis that liquid biopsy and radiomic techniques can be applied jointly to monitor metastatic PC noninvasively over time, culminating in new prognostic and predictive tools to guide therapy. To maximize the impact of our findings, liquid biopsy profiling and radiomic analysis will be integrated into Southwest Oncology (SWOG) S1802, a phase 3 prospective therapeutic trial for over 1200 men with newly diagnosed metastatic castrate sensitive prostate cancer (mCSPC) treated with standard systemic therapy alone or in combination with definitive treatment of the primary tumor. Notably, SWOG and the other participating cooperative groups have reviewed and approved this proposal (see Letters of Support), and the requisite blood samples and CT scans already are being collected as part of the active protocol. In this unique setting, we will pursue three Specific Aims. We will: 1. Use multi-parametric liquid biopsies to monitor the evolving cellular and molecular landscape of mCSPC during treatment in S1802; 2. Use radiomic analysis of CT scans to monitor the evolving radiographic landscape of mCSPC during treatment in S1802; and 3. Integrate cellular, molecular, and radiomic data to develop composite disease monitoring models predictive of PFS and OS. Importantly, liquid biopsies and CT images will be matched within patients and analyzed at key inflection points over the course of the trial: at diagnosis, after initiation of systemic therapy, after definitive therapy, and at disease progression. In this way, the proposed work will illuminate when and how PC-relevant phenotypes arise during therapy, and how they relate to clinical outcomes. In particular, we will better understand which components of the liquid biopsy – circulating cells, plasma, or both – most accurately reflect the tumor's evolving molecular profile, which radiomic metrics most closely correlate with these molecular features and can serve as early cost-effective indicators of emerging resistance, and which composite models combining liquid biopsy and radiomic features best predict PFS and OS and can serve as powerful minimally-invasive tools to monitor and adjust therapy.