Number of Plasma Variants Associated With Lung Cancer Survival, Says Liquid Biopsy Analysis

Researchers have found that the number of variants a patient had in their plasma had prognosis implications, with circulating cell-free DNA mutational load having a significant association with overall survival.

A new study is adding to the mounting evidence supporting use of liquid biopsy to further personalized treatment in lung cancer, finding that the blood analysis offers reliable information on variants in the majority of patients with advanced lung cancer and has implications for survival.

Findings appeared in a recent issue of Molecular Medicine.

Analyzing the circulating cell-free DNA (cfDNA) in plasma among 60 patients with lung cancer and 16 patients with benign lung disease, the researchers of the study showed that liquid biopsy identified significantly more variants in the patients with lung cancer compared with controls (median, 3 vs 6) and among patients with more severe disease. There was a median of 7 variants detected among patients with stage IIIB-IV disease, compared with a median of 4 variants among patients with stage I-IIIA disease.

“An increased likelihood of detecting a variant in an advanced-stage disease is related to its elevated ability to shed DNA into the bloodstream,” wrote the researchers. “Apart from stage, the shedding ability has been associated to tumor size, metastatic location, and genomic subtype (Lam et al 2020; Cho et al 2020). This adds further information for concordant and discordant variants while, unfortunately, this cohort did not have enough sample size to evaluate this further.”

The researchers also found that the number of variants a patient had in their plasma had prognosis implications, with cfDNA mutational load being significantly associated with overall survival. Patients were divided into 3 groups: those with 0 to 3 variants, 4 to 9 variants, and at least 10 mutations.

In multivariate analysis, adjusted for disease stage and Eastern Cooperative Oncology Group performance status, this association with survival remained among patients with 0 to 3 mutations and patients with 10 to 22 variants.

“Mutational load in tissue, measured by TMB [tumor mutational burden], has been associated to prognosis of lung cancer previously, but international consensus guidelines concerning choice of sequencing method and cutoff values have not been reached,” explained the researchers. “TMB has not been as thoroughly investigated in cfDNA, and, as previously mentioned, several studies have reported a varying agreement in TMB between tissue and cfDNA.”

The researchers noted that agreement between tumor and plasma samples varied significantly based on disease stage. For example, patients with advanced disease (stage IIIB-V) had a high rate of agreement (88.2%) in their cases with clinically relevant variants, while patients with earlier stage disease (stage I-IIIA) had no agreement in any of their cases.

Plasma samples also detected 1 variant in EGFR, 2 variants in KRAS, and 1 variant in BRAF that was undetected in tumor samples.

“This study concludes that in the vast majority of advanced [non–small cell lung cancer] patients, a reliable variant analysis can be performed using liquid biopsy from plasma,” the authors wrote. “Furthermore, we found that the number of variants in plasma is associated with prognosis, possibly indicating a strategy for closer follow up on this crucial patient group.”


Qvick A, Stenmark B, Carlsson J, Isaksson J, Karlsson C, Helenius G. Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer. Mol Med. Published online July 3, 2021. doi:10.1186/s10020-021-00331-1

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