Latest Research in Lung Cancer Genomics: Analysis of Circulating Tumor DNA Detection in Non-Small Cell Lung Cancer

Background and Motivation

In recent years, the treatment of non-small cell lung cancer (NSCLC) has seen significant changes due to the success of targeted therapies. The National Comprehensive Cancer Network guidelines recommend extensive molecular testing for lung cancer to identify patients who may benefit from targeted treatments. However, obtaining sufficient tissue biopsy samples from NSCLC patients has become increasingly difficult. The increasing number of biomarkers leads to inadequate samples for comprehensive molecular analysis. Furthermore, the location of tumors and the clinical condition of patients make tissue collection highly challenging. Therefore, next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in the blood holds promise to overcome these limitations of tissue testing.

Study Origin

This study was jointly conducted by medical doctors and postdoctoral researchers Hsin-Yi Wang, Chao-Chi Ho, Yen-Ting Lin, among others. They are from the National Taiwan University Hospital, and the study was published in January 2024 in the journal JCO Precision Oncology. The DOI is: https://doi.org/10.1200/po.23.00314.

Study Design and Methods

Study Design

The BFAST (Blood First Assay Screening Trial) is a prospective study using NGS methods to detect ctDNA, screening patients with newly treated advanced or metastatic NSCLC. This study was conducted at National Taiwan University Hospital, with a total of 269 patients undergoing FoundationOne Liquid Companion Diagnostic (F1LCDx) testing, among which 264 patients also underwent tissue genetic testing.

Study Subjects and Sample Processing

All patients signed informed consent for blood screening, and the study was approved by the hospital ethics committee. Patients were 18 years and older, and diagnosed with unresectable stage IIIB or IV NSCLC. The study period was from February 2019 to March 2022. Genomic profiling was performed using a hybrid capture NGS detection device, F1LCDx, detecting gene mutations in over 300 cancer-related genes.

Tissue genetic testing included analysis of EGFR, ALK, ROS1, and BRAF mutations, as well as optional tissue NGS, depending on the decisions of clinicians and patients. Each patient’s clinical relevant actionable mutations were determined through comprehensive genetic analysis, defined as tier 1 mutations (according to ESMO-ESCAT and AMP/ASCO/CAP joint guidelines).

Experimental Results and Data Analysis Methods

The primary data of the study included the sensitivity and consistency of each detection method. The consistency between different diagnostic methods was evaluated using the Kappa test. Additionally, progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and Cox proportional hazards regression analysis was used to adjust factors related to PFS and OS.

Study Results and Analysis

Patient Characteristics and Mutation Conditions

Among the total 269 patients, 76.2% showed actionable mutations. Standard tissue testing failed to detect known driver mutations in about 22.7% of patients, while liquid NGS detected additional mutations in 14% of patients, including RET, KRAS, MET, and ERBB2 mutations.

Comparison of Detection Methods

The sensitivity of single-gene testing was inferior to that of liquid NGS, which had a sensitivity of 83.41%. The number of clinically relevant actionable mutations detected in patients increased by 42% with the supplementary use of ctDNA NGS testing. Furthermore, comprehensive genetic testing found that approximately 54.3% of patients had common co-mutations in TP53, DNMT3A, TET2, and PIK3CA.

Among NSCLC patients with EGFR mutations, TET2 co-mutations were associated with shorter PFS in EGFR-TKI treatment. Multivariate PFS analysis showed significant correlation between TET2 and EGFR-TKI treatment trials.

Study and Clinical Significance

Scientific Value

This study is the first systematic analysis of circulating tumor DNA in patients with non-small cell lung cancer in Taiwan, compared with tissue genetic testing. It provides important data support for selecting more appropriate genetic testing methods in clinical practice.

Application Value

By improving the accuracy and sensitivity of liquid biopsy testing, the proportion of detected actionable mutations can be significantly increased, thus screening more patients who may benefit from targeted therapies. For patients where tissue biopsy is not feasible or difficult, liquid biopsy provides a non-invasive and efficient alternative.

Study Highlights

• High Detection Rate: The number of clinically relevant actionable mutations detected in patients increased by 42% after supplementary ctDNA NGS testing.
• Correlation of EGFR and TET2 Mutations: The significant correlation between TET2 co-mutations and shorter PFS in EGFR-TKI treatment is a key finding.
• New Detection Methods: Compared to traditional tissue genetic testing, liquid NGS demonstrated higher sensitivity and broader detection coverage.

Conclusion

This study, through systematic genomic sequencing methods, especially the analysis of circulating tumor DNA, offers more possibilities for precise treatment for patients with non-small cell lung cancer. The study indicates that liquid NGS testing is not only convenient but also superior in detection coverage and sensitivity compared to traditional tissue genetic testing, especially for high-frequency mutations in Asian populations. Additionally, the analysis of co-mutations allows clinicians to consider more factors when formulating treatment plans, further advancing precision medicine.

Predicting from this study, liquid biopsy is likely to gain wider application in the field of cancer treatment in the future, especially for patients who cannot obtain sufficient tissue samples. This represents a significant clinical advancement for patients with non-small cell lung cancer.