A team of DZL scientists from the German Cancer Research Center (DKFZ, Department of Cancer Genome Research), the Heidelberg University Hospital, and the Thoraxklinik Heidelberg (Department of Thoracic Oncology) has made significant progress towards a reliable, minimally invasive prediction of therapy success in patients with advanced non-small cell lung cancer (NSCLC). The innovative approach uses a combination of biomarkers from the patient's blood.
Immunotherapy - especially anti-PD-(L)1 therapy - has significantly improved the treatment of lung cancer, but it does not work equally well for all patients. While some patients respond to the therapy for years, others benefit little or not at all. Currently, there are no reliable methods for oncologists to predict which patients will respond to immunotherapy.
The determination of circulating tumor DNA (ctDNA) in the blood of patients has shown that a reduction in ctDNA during treatment correlates with a favourable prognosis. However, especially in patients with advanced lung cancer, sufficient tumor material is not always available to perform the required personalized ctDNA analysis. The research therefore focused on the determination of DNA fragmentation patterns and genetic changes (copy number variations, CNVs) from plasma cell-free DNA (cfDNA). This was done with the help of low-coverage whole genome sequencing of cfDNA. This method offers a cost-effective alternative to personalized ctDNA analysis, which does not require prior information from tumor tissue.
The study analyzed CNVs and fragmentation features in cfDNA from 49 patients with advanced NSCLC. Samples were analyzed before and after four cycles of anti-PD-(L)1 therapy to assess the potential clinical benefit of these biomarkers. The pre-treatment cfDNA analyses showed which patients were likely to benefit from immunotherapy. In addition, the determination of cfDNA changes during the course of therapy helped to assess the effectiveness of the treatment - patients in whom cfDNA abnormalities disappeared survived significantly longer.
"The integration of CNVs and fragmentation features represents an innovative approach that increases the sensitivity of ctDNA diagnostics and enables a more accurate prediction of treatment response to PD-(L)1 inhibitors," says Dr. Florian Janke, first author of the study. A next goal is to confirm the results in a larger cohort and to further improve the sensitivity for the detection of residual disease.
The groundbreaking study is the result of a collaboration between researchers from the German Cancer Research Center (DKFZ), Heidelberg University Hospital and the Thoraxklinik in Heidelberg. Prof. Petros Christopoulos, oncologist at the Thoraxklinik and co-author of the study, summarizes: "Our research once again underlines the importance of molecular tumor profiling for the current treatment of NSCLC. In addition to identifying therapeutic targets, novel, more sensitive ctDNA tests can improve the monitoring of metastatic disease, as the present study shows, or identify patients with a higher risk of relapse in the curative setting"
Original Publication: Janke F, Gasser M, Angeles AK, Riediger AL, Görtz M, Appenheimer L, Laut AK, Ogrodnik S, Gerhardt S, Stenzinger A, Schneider MA, Thomas M, Christopoulos P, Sültmann H. J. Low-coverage whole genome sequencing of cell-free DNA to predict and track immunotherapy response in advanced non-small cell lung cancer. Exp Clin Cancer Res. 2025 Mar 8;44(1):87. doi: 10.1186/s13046-025-03348-0. PMID: 40055810; PMCID: PMC11889826.
