“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.
They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.
A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.
Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.
Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.
In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).
In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.
Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.
“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.
The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.
SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.
