Results of a new study indicate that blood tumor mutational burden — as measured by a novel cancer gene panel (NCC-GP150) with an optimized gene panel size and algorithm — may serve as a potential biomarker to identify patients with non small-cell lung cancer (NSCLC) who can benefit from anti-PD-1 and anti-PD-L1 therapy.

Reporting online in JAMA Oncology, the multi-center team of Chinese scientists noted that tumor mutational burden (TMB) has previously been associated with immunotherapy responses. “However,” the authors wrote, “whether TMB estimated by circulating tumor DNA in blood is associated with clinical outcomes of immunotherapy remains to be explored.”

Tumor mutational burden blood test. Source: Getty

As such, the study had three primary objectives: 1) explore the optimal gene panel size and algorithm to design a cancer gene panel for TMB; 2) evaluate the panel reliability, and 3) further validate the feasibility of blood TMB as a clinical actionable biomarker for immunotherapy.

To help achieve these goals, the researchers used The Cancer Genome Atlas database to design and validate a cancer gene panel called NCC-GP150. They then used matched blood and tissue samples from 48 advanced NSCLC patients (mean age, 60±13 years; 15 female) to determine the correlation between blood TMB (as estimated by NCC-GP150) and tissue TMB (as measured by whole-exome sequencing).

Once this was complete, a second independent cohort of 50 patients (mean age, 58±8 years; 15 females) with advanced NSCLC was used to identify the utility of blood TMB estimated by NCC-GP150 to distinguish patients who might benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. 

The trial found that a cancer gene panel of 150 genes demonstrated stable correlations with whole exome sequencing for estimating TMB (median r² = 0.91), particularly when synonymous mutations were included (median r² = 0.92; interquartile range, 0.91-0.93). On the other hand, TMB estimated by the NCC-GP150 panel found higher correlations when estimated by whole exome sequencing than most of the randomly sampled 150-gene panels. 

The study also found that blood TMB estimated by NCC-GP150 correlated well with the matched tissue TMB calculated by whole exome sequencing (Spearman correlation=0.62). 

In the anti-PD-1 and anti-PD-L1 treatment cohort, a blood TMB ≥6 was associated with superior progression-free survival (HR = 0.39; 95% CI, 0.18-0.84) and objective response rate (39.3%; 95% CI: 23.9-56.5) than when blood TMB was <6 (objective response rate 9.1%; 95% CI: 1.6-25.9).

The researchers concluded that NCC-GP150 can be used for blood TMB estimation as a surrogate for whole exome sequencing-based TMB. 

“We present the first study, to our knowledge, to systematically explore the optimal gene panel size and algorithm of a cancer gene panel design for TMB (especially blood TMB) estimation,” the researchers wrote. “With whole exome sequencing data from The Cancer Genome Atlas, we found that a minimum gene panel size of 150 was sufficient for TMB estimation.”

The study also validated the satisfactory correlation of NCC-GP150-based blood TMB with whole exome sequencing-based tissue TMB. “Taken together,” they concluded, “NCC-GP150 with a smaller panel size and satisfactory performance may be more accessible for clinic use with superior cost-effectiveness.”