FNA3 Precision Medicine Program - An integrated multi-layered approach to improve management of patients with Salivary Gland Malignancies

由于其临床和经济相关性，原发性癌症、复发和进展的快速准确诊断是肿瘤学的关键焦点。由于涎腺病变的组织学多样性，涎腺恶性肿瘤（SGM）的诊断尤其具有挑战性。细针穿刺（FNA）细胞学检查通常是唾液腺病变的第一个可用标本。SGM的不同组织型的广谱性对细胞病理学识别提出了重大挑战，并且“不确定”唾液腺FNA的诊断澄清通常导致临床不确定性。值得注意的是，常规的下一代测序（NGS）测试尚未实施到FNA的诊断途径中，并且目前尚未在SGM中进行分子信息手术。我们假设，我们可以通过将NGS添加到FNA中来增加已经建立的快速诊断工具的灵敏度，并识别不同SGM子集中的肿瘤特异性改变。因此，我们认为通过补充NGS来优化FNA可以显著缩短确诊时间，并且我们可以评估开始适当和分子信息治疗的时间。此外，我们建议我们的小组将促进肿瘤相关的一步手术，一个独立的结局指标可能是减少额外的手术和费用。此外，将侧重于临床验证最近建立的NGS面板检测和分析的无细胞DNA。SGM患者血浆中cfDNA的基于NGS的分析将有望提供一种微创方法来鉴定不同SGM亚型中已经建立的生物标志物并随时间推移对其进行测量，最终旨在真实的时间监测肿瘤演变和耐药性。此外，我们希望通过测量突变格局的变化来捕获SGM的分子和遗传异质性，并可能识别用于外周血样本靶向治疗的新遗传改变。 目前，除了根治性肿瘤切除术外，SGM患者还没有有效的局部或全身治疗选择用于治愈性和一线治疗。因此，SGM患者通常基于显示高治疗失败率的治疗方式进行治疗。我们的目标是确定治疗靶点，并授权测试候选药物，当SGM复发。因此，我们建立了不同头颈部恶性肿瘤（包括SGM）的三维器官型共培养（OTC）模型。在治疗失败的情况下，复发性SGM的临床前测试平台将直接整合OTC衍生的敏感性数据，以确定对二线治疗的个体反应。通过这个多流项目，我们建议利用几种创新技术来简化综合项目的进度。

Rapid and accurate diagnosis of primary cancer, recurrence, and progression is a key focus in oncology because of its clinical and economic relevance. The diagnosis of salivary gland malignancies (SGM) is especially challenging due to the histological diversity of salivary gland lesions. Fine needle aspiration (FNA) cytology is often the first available specimen from salivary gland lesions. The broad spectrum of different histotypes of SGM poses significant challenges for cytopathologic recognition and the diagnostic clarification of “indeterminate” salivary gland FNAs often results in clinical uncertainty. Notably, routine next-generation sequencing (NGS)-testing has not been implemented into the diagnostic pathway of FNA and molecularly-informed surgery in SGM is currently not being performed. We hypothesize, that we can increase the sensitivity of an already established, rapid diagnostic tool by adding NGS to FNA and identify tumor-specific alterations in different SGM subsets. Therefore, we believe that optimizing FNA by supplementing NGS can significantly shorten time to definitive diagnosis and we can possibly assess time to initiation of appropriate and molecularly informed treatment. Moreover, we propose that our panel will facilitate an oncological relevant one step surgical procedure and an independent outcome measure might be a reduction of additional surgical procedures and costs. Furthermore, will focus on the clinical validation of a recently established NGS-panel for the detection and analysis of cell-free DNA. NGS-based analysis of cfDNA in plasma from SGM patients will hopefully provide a minimally invasive method to identify already established biomarkers in different SGM subtypes and measure them over time, ultimately aiming to monitor tumor evolution and resistance in real time. In addition, we are hoping to capture molecular and genetic heterogeneity in SGM by measuring changes in the mutational landscape and to possibly identify new genetic alterations for targeted therapy in peripheral blood samples. At present, no effective local or systemic treatment option for curative and first-line therapy is available for SGM patients beside radical tumor excision. Hence, SGM patients often are treated based on therapeutic modalities that show high rates of treatment failure. Our aim is to identify therapeutic targets and empower testing of candidate pharmacologic drugs, when SGMs recur. Therefore, we established a 3D-organotypic co-culture (OTC) model of different head and neck malignancies, including SGM. In case of treatment failure, the preclinical testing platform for recurrent SGM will directly integrate OTC-derived sensitivity data in the setting of individual response to second-line treatment. With this multi-stream project, we propose to leverage several innovative technologies to streamline progress in an integrated program.