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The performance of next generation sequencing in profiling somatic mutations from plasma samples, especially in early‐stage cancer, is limited by its sensitivity due to the extremely low amount of cell‐free DNA (cfDNA). Polymerase‐chain reaction amplification of limited amounts of DNA often results in product redundancy and the amplification of contaminant DNA. Numerous methods have been developed to detect and quantify ultralow frequency mutations. In this study, the potential of tagging each DNA molecule with a unique molecular identifier (UMI) is explored to detect ultralow frequency mutations in early‐stage lung cancer patients. Paired tissue and blood samples from 32 patients with early‐stage (stage IA‐IIB) nonsmall cell lung cancer are sequenced using a panel consisting of 168 cancer‐related genes. Collectively, 93.8% of tissue samples and 59.4% of plasma samples have mutations detected. The concordance rates are acceptable for all patients except for stage IA. Notably, mutations at an alleleic frequency as low as 0.1% are detected in UMI‐tagged cfDNA samples. Moreover, patients with nonadenocarcinoma histology have a significantly higher detection rate than patients with adenocarcinoma (92.9% vs 33.3%, P = 0.002). The study demonstrates the potential of UMI in early detection of lung cancer from plasma samples. [ABSTRACT FROM AUTHOR]

Background: Detection of circulating tumor DNA (ctDNA) is a promising method for postoperative surveillance of lung cancer. However, relatively low positive rate in early stage patients restricts its application. Aberrant methylation of ctDNA can be detected in blood samples, and may provide a more sensitive method. This study is designed to systematically evaluate and compare the detection of aberrant methylation and mutations in ctDNA among surgical non-small cell lung cancer (NSCLC) patients, aiming to investigate the feasibility of ctDNA detection as a means of lung cancer surveillance.Methods: This is a prospective observational study. Consecutive surgical NSCLC patients will be recruited. Blood samples will be collected both before and after surgery (during the follow-up period), while matching tumor tissues and tumor-adjacent normal tissues will be collected during surgery. Quantitative analysis of aberrant methylation and mutations of ctDNA will be conducted in combination with a three-year follow-up data.Discussion: This is the first registered prospective study designed to investigate the feasibility of ctDNA methylation detection as a means of postoperative lung cancer surveillance. We will systematically evaluate and compare the quantitative detection of ctDNA mutations and ctDNA methylation in surgical NSCLC patients, combining with the follow-up information. By integrating genetic and epigenetic information of ctDNA, more effective strategies for postoperative surveillance may be defined.Trial Registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826; Pre-results). [ABSTRACT FROM AUTHOR]

We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays in prognostic analysis and demonstrates a median lead-time of 299 days to radiologically confirmed recurrence. Personalized non-canonical variants account for 98.2% with prognostic effects similar to canonical variants. The proposed tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for prognostic prediction at the decision point of adjuvant treatment. PROPHET shows potential to evaluate the effect of adjuvant therapy and serve as an arbiter of the equivocal radiological diagnosis. These findings highlight the potential advantages of personalized cancer techniques in MRD detection. [Display omitted] • PROPHET outperforms fixed-panel MRD assays in head-to-head comparison in NSCLC • TNMB stage, integrating landmark ctDNA MRD and TNM, improves prognosis prediction • PROPHET illustrates a median lead time of 299 days to radiological recurrence • Post-relapse ctDNA status facilitates decision on later lines of treatment Chen et al. introduce personalized Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) for detecting molecular residual disease (MRD) in NSCLC, featuring a notably low limit of detection (LOD). It exhibits elevated sensitivity and extended lead time than radiologically confirmed recurrence. It also facilitates prognostic accuracy and postoperative treatment evaluation. [ABSTRACT FROM AUTHOR]

Highlights • De novo T790 M is significantly more likely to coexist with EGFR L858R than with 19del in NSCLC. • The relative allele frequency of T790 M mutation may serve as a predictive biomarker for treatment response to EGFR-TKIs. • Osimertinib is potentially an effective drug for the treatment of advanced NSCLC with de novo T790 M. Abstract Introduction De novo T790 M mutation in EGFR has been reported in various studies. However, its genetic characteristics and association with EGFR tyrosine kinase inhibitors (TKIs) treatment response remain poorly studied. Methods We retrospectively screened 1228 consecutive non-small cell lung cancer (NSCLC) patients and identified 29 de novo T790 M carriers. Capture-based targeted deep sequencing was conducted on 21 eligible samples as well as a 20-sample cohort with acquired T790 M mutation after EGFR-TKIs treatment. We characterized and compared their mutational profiles using a panel consisting of 168 lung cancer-related genes. Results De novo T790 M mutation was found in 5.8% of the TKI-naive patients harboring EGFR activating mutations. Among the de novo T790 M samples, T790 M was significantly more likely to coexist with L858R than with 19del (76.2% vs. 23.8%) compared to the acquired T790 M cohort (30.0% vs. 70.0%) (p = 0.003). These two groups harbored different concurrent gene mutations as well. Notably, the ratio of allele frequency (AF) of the T790 M mutation to the EGFR activating mutation in each patient, defined as the T790 M relative AF (RAF), differed significantly between the de novo and acquired T790 M cohorts (86.1% vs. 22.3%, p < 0.0001). Among the 10 patients with de novo T790 M who received the 1st-generation EGFR-TKIs treatment, interestingly, the only one who achieved partial response (PR) had the lowest T790 M RAF of 19.7%. The other 9 patients with an average T790 M RAF of 85.9% (±22.6%) achieved stable disease or progressive disease as the best response. One patient, treated with osimertinib after erlotinib failure, achieved PR and the therapeutic response sustained for more than 14.5 months. Conclusion The molecular characteristics of de novo T790 M carriers differ distinctly from acquired T790 M carriers. The RAF of EGFR T790 M mutation may serve as a predictive biomarker for treatment response to EGFR-TKIs. Osimertinib is potentially an effective drug for the treatment of NSCLC with de novo T790 M. [ABSTRACT FROM AUTHOR]

Introduction Anaplastic lymphoma kinase ( ALK ) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK -rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Methods Among 96 ALK -rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. Results The median Progression-free survival (PFS) of the 96 ALK -rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4 - ALK variants and non EML4 - ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4 - ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4 - ALK variants. Conclusions Our results indicate prolonged PFS in patients with EML4 - ALK variant 2. [ABSTRACT FROM AUTHOR]