ddPCR-based ctDNA monitoring detects resistance and predicts progression months before imaging in metastatic NSCLC and breast cancer
Investigators evaluated serial circulating tumor DNA monitoring using digital droplet PCR in a real-world cohort of 48 metastatic patients with EGFR-mutant NSCLC and HR+/HER2-negative breast cancer at a Brazilian oncology center. The study found that early mutation clearance preceded radiological response, while rising ctDNA fractional abundance anticipated disease progression by approximately five months in NSCLC and up to nine months in breast cancer. Acquired resistance mechanisms were clearly mapped, with EGFR C797S dominating third-generation TKI resistance in NSCLC and ESR1 hotspot mutations appearing in half of the breast cancer cohort. These findings support liquid biopsy as a minimally invasive tool for early resistance detection and therapeutic guidance, though the authors note the small sample size and call for larger prospective validation.
The original study
Serial ctDNA Analysis for Monitoring Molecular Response and Acquired Resistance in Metastatic NSCLC and HR+/HER2-Negative Breast Cancer: A Real-World Study.
- Authors
- Knebel FH, Ribeiro MFSA, Linck RDM, Ferreira IF, Masotti C, Saddi R, et al.
- Journal
- Cancer medicine
- Type
- Journal Article
- PMID
- 42817873
Original abstract
Circulating tumor DNA (ctDNA) is a promising biomarker for disease monitoring, yet evidence of its clinical utility in routine care remains limited. We evaluated the utility of serial ctDNA monitoring using digital PCR (ddPCR) for detecting acquired resistance (AR) and monitoring response in metastatic non-small cell lung cancer (NSCLC) and breast cancer (MBC). This real-world, longitudinal study included 48 metastatic patients (42 with EGFR-mutant NSCLC; 6 with HR+/HER2-negative MBC) treated at a Brazilian oncology reference center. Serial plasma samples were analyzed by ddPCR for activating and resistance mutations at specific time points. In the NSCLC cohort, EGFR T790M was detected in 48.4% of patients who progressed on 1st/2nd-generation TKIs. For patients on 3rd-generation TKIs, EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications. Longitudinal analysis anticipated radiological progression by approximately 5 months. Early molecular response, characterized by mutation clearance, preceded radiological response. In the MBC cohort, hotspot ESR1 mutations (D538G, L536R, Y537S) were identified in 50% of patients. Variations in ctDNA fractional abundance predicted disease progression up to 9 months before radiological confirmation. This study provides real-world evidence that ddPCR-based ctDNA monitoring enables early detection of resistance and predicts disease progression significantly earlier than standard imaging in both NSCLC and MBC. Despite the limited sample size, particularly in the MBC cohort, these real-world findings support liquid biopsy as a minimally invasive tool with the potential to guide therapeutic decisions and inform personalized management in precision oncology. Larger prospective studies are needed to confirm these observations.