Challenges in implementing circulating tumor DNA analyses in lung cancer research

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, including Norway. This study focused on non-small cell lung cancer (NSCLC), the most common subtype, and aimed to enhance the classification of NSCLC patients using circulating tumor DNA (ctDNA)as a biomarker. Despite ad vancements in treatment, the prognosis for NSCLC remains highly variable, with some patients experiencing positive responses, while others face relapse or no response at all. The thesis investigated the potential of ctDNA, which carries tumor-specific mutations, to improve prognostic accuracy and promote more individualized and thereby improved cancer management. The theoretical utility is high, but ctDNA analyses pose challenges due to its low levels in the blood, particularly in early-stage patients. Therefore, a key objective of this project was to develop an approach for ctDNA analysis that could be implemented in routine diagnostic laboratories. To address these challenges, a 'tumor-informed' ctDNA analysis approach was tested and validated. This involved analyzing the patient's tumor DNA and customizing the analysis to individual patients. By incorporating quality assessment of the tumor DNA, the analysis could be tailored to improve data quality and reliability. The results demonstrated that ctDNA detection using this customized approach served as a negative prognostic factor in our NSCLC patient cohort. However, it was found that the benefit of ctDNA detection was limited to a minority of patients who had detectable ctDNA. Furthermore, the study explored the relationship between ctDNA levels and tumor metabolic activity. Preliminary findings indicated a correlation between these two characteristics, suggesting the potential involvement of tumor metabolism in ctDNA release. However, further research is necessary to confirm these results and elucidate the underlying mechanisms. The findings of this project contribute to the ongoing efforts to improve personalized treatment strategies and outcomes for NSCLC patients.