Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer

Area of Science:

• Oncology
• Molecular Diagnostics
• Genomics

Background:

• Physicians use prognosis for patient counseling and clinical trial eligibility.
• Cell-free circulating tumor DNA (cfDNA) sequencing is increasingly used for clinical decisions.

Purpose of the Study:

• To investigate the association between cfDNA variant allele frequency (VAF) and prognosis in patients with metastatic disease.

Main Methods:

• Retrospective analysis of 298 patients with metastatic disease undergoing cfDNA sequencing.
• Assessment of the correlation between cfDNA VAF and overall survival (OS).

Main Results:

• cfDNA mutations were detected in 80.5% of patients.
• More than one nonsynonymous mutation (NSM) was linked to significantly worse OS (HR=2.3, P<0.0001).
• Higher cfDNA VAF quartiles (Q3, Q4) were significantly associated with worse OS (Q3 HR=2.3, P=0.0069; Q4 HR=3.8, P<0.0001).
• Multivariate analysis identified VAF Q4, male sex, low albumin, extensive metastases, and prior therapies as independent predictors of worse OS.

Conclusions:

• Elevated cfDNA VAF and increased NSM are associated with poorer OS in metastatic cancer.
• Further research is needed to establish cfDNA VAF thresholds for clinical use and its prognostic value across tumor types.