CTCclinUT - clinical utility of CTCs in metastasized breast cancer patients enabled by diagnostic leukapheresis

在过去的几十年里，靶向治疗已经成为治疗乳腺癌（BC）的首选方法。然而，原发肿瘤选择治疗的预测效用是有限的，获得转移性病变的连续活检是具有挑战性的。因此，为了管理BC，通过分析循环肿瘤细胞（ctc）等液体活检来获得其分子致命弱点的信息的想法非常有趣。ctc通过肿瘤组织进入血液，通常被认为是转移形成的前体细胞。CTC计数是一个强有力的预后因素，可用于监测治疗效果，但由于缺乏证据证明CTC在预测个体化、特异性和成功的治疗策略方面的临床效用，因此尚未将其应用于临床实践。造成这种困境的主要原因是血液中检测和分离的ctc非常罕见，这阻碍了ctc的比较基础分析和分析前研究，以揭示ctc的不同生物学特性。然而，为了制定未来的个体化和基于ctc的治疗决策，这是绝对需要的。通过CTCclinUt项目，我们计划通过对转移性BC指数患者进行纵向ctc分析来克服这些挑战，这些患者患有高ctc数，并且接受了额外的诊断性白细胞分离(DLA) -杜塞尔多夫首创的一种方法，从患者的总血容量中分离肿瘤细胞。结合最新的平行高通量分子分析技术，这将使我们能够在单细胞水平上研究复杂的CTC群体的基因组突变、基因拷贝数变异和基因表达谱。通过这种方式，CTCclinUt将使我们深入了解CTCs的异质性生物学及其在疾病和治疗干预期间的克隆进化，并将帮助我们了解在治疗史中激活的耐药机制。最终目标是将ctc的分子特征转化为优化的治疗方案。

Over the last decades targeted therapy has become the preferred approach to treat breast cancer (BC). However, the predictive utility of the primary tumor to select a therapy is limited and obtaining serial biopsies of metastatic lesions is challenging. Thus, in order to manage BC the idea of deriving information on its molecular Achilles heel from liquid biopsies by analyzing e.g. circulating tumor cells (CTCs) is very intriguing. CTCs are shed into the blood by tumor tissue and are commonly considered as precursor cells for metastasis formation. The CTC count is a strong prognostic factor, which can be used to monitor treatment efficacy, but CTCs have not been implemented into clinical practice due to missing proof of their clinical utility to predict individualized, specific and successful treatment strategies. The main cause for this dilemma is the rarity of CTCs detected and isolated from blood, which is preventing both comparative basic analytic and pre-analytic CTC-research in order to uncover the different biology of CTCs. This, however, is absolutely needed in order to develop future individualized and CTC-based therapy decision. With the project presented here - CTCclinUt - we plan to overcome these challenges by performing longitudinal CTC-analyses of metastasized BC index patients who suffer from high CTC-numbers and who have undergone additional diagnostic leukapheresis (DLA) – a method pioneered in Duesseldorf to isolate tumor cells from a patient’s total blood volume. In combination with latest technologies for parallel high throughput molecular analyses this will enable us to investigate complex CTC populations for genomic mutations, gene copy number variations, and gene expression profiles on single cell level. In this way CTCclinUt will give us insights into the CTCs’ heterogeneous biology and their clonal evolution during disease and therapeutic intervention and will help us to understand resistance mechanisms activated during treatment history. The final aim will be to translate the CTCs’ molecular characteristics into optimized therapy regimen.