Detection of somatic mutations in circulating tumor DNA of patients with operable lung cancer
Final Report Abstract
Lung cancer is one of the deadliest cancers worldwide. More than two thirds of patients with an initial diagnosis of lung cancer are no longer operable. After curative therapy with surgical resection, surgical patients have a recurrence rate of almost 20% within two years postoperatively. After the initial diagnosis, staging is carried out using PET computed tomography of the thorax and abdomen as well as cranial magnetic resonance imaging (MRI). Liquid biopsies are not routinely obtained from blood in operable patients, compared to patients with advanced metastatic carcinoma (stage IV according to UICC). If molecular genetic changes are detected in the tumor and also in the blood, tumor growth can be observed as part of targeted cancer therapy using liquid biopsy. The extent to which liquid biopsy can be used in surgical patients to stratify the risk of postoperative recurrence remains to be clarified. After surgical resection, the tumor can be examined for genetic changes using deep sequencing. In this prospective study, blood samples are collected at the time of surgery and examined for genetic changes after genetic processing of the tumor tissue. There are two methods: digital droplet PCR, which previously specifically examined a gene mutation personalized to the tumor, and deep sequencing (next-generation sequencing NGS), which can now identify more than 100 genes with high sensitivity. Due to the technical progress and complex preparation of the limited blood samples, A) the genetic changes in the blood were examined with those in the tumor sample in a subgroup of 9 patients using deep sequencing for validation. For this purpose, a 100-gene panel was developed based on the genome databases for lung cancer. 87% (48/55 mutations) of the mutations detected in plasma matched the mutations in tumor tissue. In the next step B), a further 74 blood samples from patients with operable-stage lung cancer were examined for genetic variations using 100-gene panel deep sequencing. The genomic DNA was compared with cell-free DNA in the same patient. In total, circulating tumor DNA (ctDNA) was detected in 63 cases (76%) of 83 patients. For prognostic assessment C), the positive detection of genetic changes in the blood was correlated with the postoperative recurrence rate within 24 months. Of the 83 patients examined, 56 patients were followed up. A significant difference between the group of patients with positive ctDNA (n=41) and negative ctDNA (n=15) in terms of postoperative recurrence rate was not found. The tumor tissue is heterogeneous, which is also reflected in the circulating tumor DNA. Personalized monitoring in aftercare in addition to image morphological follow-up should be discussed in practice.
Publications
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Detection of circulating tumor DNA by digital droplet PCR in resectable lung cancer as a predictive tool for recurrence. Lung Cancer, 151, 91-96.
Gassa, Asmae; Fassunke, Jana; Schueten, Sarah; Kuhlmann, Luca; Scherer, Marie; Qien, Jie; Zhao, Yue; Michel, Max; Loeser, Heike; Wolf, Juergen; Buettner, Reinhard; Doerr, Fabian; Heldwein, Matthias; Hagmeyer, Lars; Frank, Konrad; Merkelbach-Bruse, Sabine; Quaas, Alexander; Bruns, Christiane; Hekmat, Khosro ... & Alakus, Hakan
