Application of an Ultrasensitive NGS-Based Blood Test for the Diagnosis of Early-Stage Lung Cancer: Sensitivity, a Hurdle Still Difficult to Overcome

SIMPLE SUMMARY: Currently, an accurate diagnosis of lung cancer relies on the microscopic examination of tissue biopsies. These samples can, however, only be obtained by invasive procedures. The aim of our study was to evaluate the use of a liquid biopsy for early-stage lung cancer detection in patients with a lung lesion on imaging. This approach would be particularly relevant for suspected lung lesions that are difficult to reach for a tissue-based diagnosis. Despite technical improvements for the use of liquid biopsy-based cell-free DNA analysis, its application for the detection of early-stage lung cancer is currently limited by sensitivity and a biological background of somatic variants. ABSTRACT: Diagnosis of lung cancer requires histological examination of a tissue sample, which in turn requires an invasive procedure that cannot always be obtained. Circulating tumor DNA can be reliably detected in blood samples of advanced-stage lung cancer patients and might also be a minimally invasive alternative for early-stage lung cancer detection. We wanted to explore the potential of targeted deep sequencing as a test for the diagnosis of early-stage lung cancer in combination with imaging. Mutation detection on cell-free DNA from pretreatment plasma samples of 51 patients with operable non-small cell lung cancer was performed and results were compared with 12 control patients undergoing surgery for a non-malignant lung lesion. By using a variant allele frequency threshold of 1%, somatic variants were detected in 23.5% of patients with a median variant allele fraction of 3.65%. By using this threshold, we could almost perfectly discriminate early-stage lung cancer patients from controls. Our study results are discussed in the light of those from other studies. Notwithstanding the potential of today’s techniques for the use of liquid biopsy-based cell-free DNA analysis, sensitivity of this application for early-stage lung cancer detection is currently limited by a biological background of somatic variants with low variant allele fraction.