Circulating Tumor DNA Monitoring Reveals Molecular Progression before Radiologic Progression in a Real-life Cohort of Patients with Advanced Non–small Cell Lung Cancer

Abstract

Purpose The clinical potential of liquid biopsy in advanced cancer patients is real-time monitoring for early detection of treatment failure. Our study aimed to investigate the clinical validity of circulating tumor DNA (ctDNA) treatment monitoring in a real-life cohort of advanced Non-Small Cell Lung Cancer (NSCLC) patients. Patients and Methods Advanced or non-curative locally advanced NSCLC patients were prospectively included in an exploratory study (NCT03512847). Selected cancer-specific mutations were measured in plasma by standard or uniquely designed digital droplet PCR (ddPCR) assays before every treatment-cycle during first line treatment until progressive disease (PD). Correlation between an increase in ctDNA (=molecular progression) and radiologic PD was investigated, defined as lead time, and the corresponding numbers of likely futile treatment cycles were determined. Utility of ctDNA measurements in clarifying the results of non-conclusive radiologic evaluation scans was evaluated. Results Cancer-specific mutations and longitudinal plasma sampling were present in 132 of 150 patients. CtDNA was detectable in 88 (67%) of 132 patients treated by respectively chemotherapy (n=41), immunotherapy (n=43), or combination-treatment (n=4). In 66 (90%) of 73 patients experiencing PD, a ctDNA increase was observed with a median lead time of 1.5 months before radiologic PD. Overall, 119 (33%) of 365 treatment-cycles were administered after molecular progression. Additionally, ctDNA measurements could clarify the results in 38 (79%) of 48 non-conclusive radiologic evaluations. Conclusions ctDNA monitoring leads to earlier detection of treatment failure, and clarifies the majority of non-conclusive radiologic evaluations, giving the potential of sparing patients from likely futile treatments and needless adverse events.

Utilizing Plasma Circulating Tumor DNA Sequencing for Precision Medicine in the Management of Solid Cancers

“…In patients with metastatic CRC treated with an anti-EGFR monoclonal antibody, treatment-emergent, subclonal alterations in KRAS, MET, and EGFR extracellular domain (ECD) causing acquired resistance to anti-EGFR were detectable in plasma as early as 10 months prior to the clinical tumor progression [22,44,45]. In CRC, breast cancer, and NSCLC treated with chemotherapy, longitudinal monitoring of ctDNA was able to detect molecular progression with a median molecular lead time of 1.3-3.3 months [36,46,47]. Whether "molecular progression" revealed by ctDNA monitoring has a true clinical significance, however, can only be determined by demonstrating that early treatment modification based on ctDNA results (e.g., early introduction of a subsequent line of treatment or therapy targeting somatic alterations identified by ctDNA) improves long-term survival or quality of life.…”

Circulating Tumor DNA Is a Variant of Liquid Biopsy with Predictive and Prognostic Clinical Value in Breast Cancer Patients

“…The analysis of ctDNA allows for monitoring the response to treatment in realtime regimens, including the detection of molecular residual disease, which has been described for lung cancer [101,[111][112][113], colorectal cancer [114], ovarian cancer [115], and others [87,116,117]. It was found that the use of the methylation markers for a number of genes allows not only for the identification of patients with colorectal cancer, but also for monitoring recurrence [95].…”