Optimizing Pancreatic Cancer Management with Next Generation Imaging and Liquid Biopsy

项目总结： 胰腺导管腺癌(PDA)将成为全球第二大癌症死亡原因。 到2030年美国。大多数PDA患者存在不可切除/转移性疾病，且全身 化疗是这些患者的主要治疗方法。手术是少数患者的选择(约30%) 他们表现为局部疾病，尽管大多数人在高度病态的手术后早期复发，原因是 隐匿性转移瘤。因此，新辅助治疗(NAT)是一种新兴的标准方法，但仅限于 如果所选的系统治疗有效，则有益。事实上，对于所有的PDA患者，无论是转移性的还是其他的， 有效的系统治疗的持续时间是他们生存的最重要因素。有一个严重的未满足的问题 需要准确和及时地评估治疗反应，以便1)使患者接受有效的全身治疗 尽快治疗，并尽可能长时间地让他们继续治疗，2)迅速停止有毒的、昂贵的 和无效的治疗，以及3)促进基于证据的个性化临床决策，关于治愈- 意向手术。目前PDA的治疗主要依靠CT和肿瘤标志物 (CA19-9)。然而，这些工具不够敏感，而且速度太慢，无法判断患者的益处。 快速致命的转移性疾病，并寻找最有可能从手术中受益的合适的候选人 在NAT之后。我们现在有了尖端的工具，可以在分子水平上更精确地量化疾病负担 和新陈代谢水平。我们先前已经证明突变的kras循环肿瘤(Ct)dna可以被检测到。 对PDA的敏感性高，经有效治疗后往往迅速下降，可能是一个更动态的预测指标。 治疗效果优于CA19-9。我们还表明，利用混合集成的18-氟-1，4-二氟化碳的代谢成像技术， 脱氧葡萄糖(FDG)正电子发射断层扫描/磁共振成像(PET/MRI)可改善 CT上隐匿的微小转移的检测，早期反应评估 不能切除/转移性动脉导管未闭患者对NAT病理反应的预测 切除手术。基于这些有希望的结果，我们假设KRAS ctDNA的适当组合 而PET/MRI生物标记物将使及时评估PDA患者治疗的临床效用。在AIM 1，我们将定义不能切除/转移性PDA的早期化疗切换阈值 KRAS ctDNA和FDG PET/MRI生物标记物的定量变化，用于未来的前瞻性试验。在AIM 2、我们将构建、测试和验证潜在可切除肿瘤患者的手术益处或无效性模型。 PDA使用动态KRAS ctDNA和FDG PET/MRI响应数据。我们的首要目标是集成可靠的 能够准确指导治疗并使精准医学能够改善患者预后的生物标志物 带着这种致命的疾病。

PROJECT SUMMARY: Pancreatic ductal adenocarcinoma (PDA) will become the 2nd leading cause of cancer deaths in the United States by 2030. Most patients with PDA present with nonresectable/metastatic disease, and systemic chemotherapy is the anchoring treatment in these patients. Surgery is an option in the minority of patients (~30%) who present with localized disease, though most develop early recurrence after a highly morbid surgery due to occult metastases. Therefore, neoadjuvant therapy (NAT) is an emerging standard approach, but is only beneficial if the selected systemic therapy is effective. Indeed, for all patients with PDA, metastatic or otherwise, the duration of effective systemic therapy is the most important factor in their survival. There is a critical unmet need for accurate and timely assessment of treatment response in order to 1) get patients on effective systemic therapy as soon as possible and keep them on it as long as possible, 2) expeditiously discontinue toxic, costly and ineffective therapies, and 3) facilitate evidence-based personalized clinical decisions regarding curative- intent surgery. Current management of PDA relies principally on computed tomography (CT) and tumor markers (CA19-9). However, these tools are not sensitive enough and are too slow for adjudicating benefit in patients with rapidly lethal metastatic disease, and for identifying suitable candidates most likely to benefit from surgery after NAT. We now have cutting-edge tools for more precise quantification of disease burden at the molecular and metabolic levels. We have previously shown that mutant KRAS circulating tumor (ct)DNA can be detected with high sensitivity in PDA, tends to drop rapidly with effective therapy, and may be a more dynamic predictor of therapy response than CA19-9. We have also shown that metabolic imaging with hybrid integrated 18-fluoro- deoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) improves the detection of subtle metastases that are occult on CT, early response assessment in patients with nonresectable/metastatic PDA, and prediction of pathological response to NAT in patients who undergo resection. Building on these promising results, we hypothesize that the appropriate combination of KRAS ctDNA and PET/MRI biomarkers will enable timely assessment of the clinical utility of therapy in PDA patients. In Aim 1, we will define thresholds for early chemotherapy switch in unresectable/metastatic PDA using dynamic and quantitative changes in KRAS ctDNA and FDG PET/MRI biomarkers for use in future prospective trials. In Aim 2, we will construct, test and validate a model of surgical benefit or futility for patients with potentially resectable PDA using dynamic KRAS ctDNA and FDG PET/MRI response data. Our overarching goal is to integrate reliable biomarkers that can accurately guide therapy and enable precision medicine to improve outcomes of patients with this deadly disease.