Lung cancer is the most commonly occurring type of cancer worldwide and also has the highest mortality rate. Although targeted therapy of non-small cell lung carcinoma (NSCLC) has become common, the majority of patients receiving first-line epithelial growth factor receptor (EGFR)-TKI treatment develop drug resistance. The EGFR T790M (NM_005228.4(EGFR):c.2369C>T (p.Thr790Met)) mutation accounts for half of all reported resistance cases; however, the molecular mechanism resulting in the drug resistance remains to be characterized. Circulating tumor DNA (ctDNA) isolated from plasma has great potential for identification of gene mutations in NSCLC. Collection of ctDNA is relatively non-invasive and can avoid the inherent disadvantages of tissue biopsy. In the present study, next-generation sequencing technology was used to detect the variation of ctDNA in the peripheral blood of patients administered with EGFR-TKI. The patients were monitored serially to establish a dynamic resistance gene detection system, with the rationale being to alter the treatment strategy as soon as the emergence of drug resistance gene mutations. A mutation spectrum of the group of patients was constructed. A driver gene mutation was identified in the ctDNA of each patient, and certain patients had clinically targetable gene mutations like EGFR, ROS proto-oncogene receptor tyrosine kinase and B-Raf proto-oncogene serine/threonine kinase. The dynamic monitoring of EGFR status indicated that the EGFR mutation rate was consistent with the tumor burden of patients. Overall, ctDNA detection is a useful method for the molecular genotyping of patients with cancer. The dynamic resistance gene detection system described in the present study is a sensitive and useful tool for the monitoring of gene status, which has potential to be used for direction of treatment strategy by detecting the emergence of drug resistance gene mutations.
45 Background: Despite the increase of our knowledge about carcinogenesis and recent successful development of innovative cancer drugs, cancer mortality has only slightly decreased in the past decades. Cancer early detection is probably the most cost-effective means to reduce cancer mortality as prognosis is much better when cancer is detected and treated at the early stage. Recently studies have demonstrated that blood-based mutation detection approaches may be effective to identify asymptomatic cancer patients from general population. Methods: Here we reported a novel multivariate cancer risk score (MCRS) model that interrogates shallow whole genome sequencing (WGS) data from cell-free DNA (cfDNA) and protein markers results in a single blood draw. Results: In a prospective clinical study consisting of 76 stage I-IV cancer patients and 152 normal individuals, the MCRS model demonstrated 60% sensitivity at 98.5% specificity. In order to validate clinical utility of the MCRS model in detection of cancer patients, we collated the data from a previous study of occult maternal malignancies from 1.93 million pregnant women undergoing NIPT test between 2016 and 2017. 466 out of the 639 pregnant women who tested positive for multiple chromosomal aneuploidies (MCAs) in the initial NIPTs (i.e. 0.06 - 0.1x WGS), have also underwent the protein markers test. Out of the 466 subjects, 39 maternal malignant cancer cases were diagnosed with a median follow-up of 399 days (IR, 303 - 487 days) by imaging and histology. The cancer patients presented a wide spectrum of cancer types, the most frequent being breast cancer (10 cases), liver cancer (8) and lymphoma (8), at stage II to IV. This subgroup of 466 subjects was selected as an independent validation cohort for our study. Through our new method, we analyzed shallow WGS and proteins data. The MCRS model allowed 28 of the 39 (71.8%) cancer cases to be identified with a positive predictive value of 73.7% and specificity of 97.7%. Conclusions: Taken together, these data demonstrate the MCRS model holds promise for detecting cancer in asymptomatic individuals, particularly in the populations at high risk of cancer.
e15054 Background: Several studies have shown the clinical value of using circulating tumor DNA (ctDNA) for minimal residual disease (MRD) detection, which is more sensitive than traditional imaging methods. However, most MRD detection technologies focus on identifying mutations and require cancer tissue samples. These methods often have limitations, such as high cost, inaccessible cancer tissue, or inability to overcome tumor heterogeneity. SeekInCure is a cost-effective multi-dimensional MRD test that does not require cancer tissue analysis. The purpose of this prospective study was to evaluate the potential broad clinical utility of SeekInCure for detecting MRD in patients with hepatocellular carcinoma (HCC). Methods: 34 HCC patients undergoing radical surgery were prospectively enrolled in this study from Peking University Shenzhen Hospital. Peripheral blood samples of 8 mL were collected before and after surgery and analyzed using the SeekInCure assay, which integrates the protein tumor marker (AFP) and cancer genomic hallmarks: copy number aberrations and fragment size from ctDNA. Patients with positive results for AFP and/or ctDNA in the preoperative/postoperative samples were defined as MRD-positive (MRD+), while negative results were defined as MRD-negative (MRD-). Results: Of the 34 patients, 73.5% (25/34) were in early stages (stages I/II: 61.8%/11.8%), and 61.8% (21/34) received adjuvant therapies. The median follow-up was 279.5 days, ranging from 90 to 1,253 days. 82% (28/34) of the patients had MRD+ results in the preoperative samples, which showed remarkable sensitivity in a cohort with more than 70% of early-stage patients. Our previous findings were confirmed, with preoperative MRD+ patients having worse survival than MRD- patients1. After radical surgery, 26.5% (9/34) were MRD+. MRD+ patients had worse survival than MRD- patients, with a median overall survival (OS) time of 298 days for MRD+ patients, while the OS time for MRD- patients was not reached (P < 0.01). 6 patients with MRD- in both pre- and post-operative samples had a very favorable outcome (100% OS). Conversely, 9 patients with both positive results had the worst outcome. We also found that MRD- patients receiving adjuvant therapies did not have a survival benefit compared to those without adjuvant therapies, but MRD+ patients receiving adjuvant therapies had better OS than those without adjuvant therapies (P = 0.026). Conclusions: This study confirms the excellent performance of our SeekInCure assay, which does not require cancer tissue analysis, in detecting MRD and the prognostic value of MRD in HCC patients. Adjuvant has no influence on survival, especially in MRD- patients, which indicates that amost one-third of HCC patients do not need additional adjuvant therapy.
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