Longitudinal circulating tumor DNA (ctDNA) analysis can predict disease recurrence and guide adjuvant treatment in patients with resected non-small cell lung cancer (NSCLC), according to a study published in Nature Communications.
ctDNA positivity — both after surgery and after adjuvant therapy — was significantly associated with worse recurrence-free survival (RFS), researchers found.
The researchers prospectively evaluated 103 patients with NSCLC who underwent surgical resection, with or without adjuvant therapy, between 2018 and 2020.
There were 71 patients (68.9%) who received adjuvant chemotherapy (ACT), including 69 who received chemotherapy alone and 2 who received chemoradiotherapy. The median duration of ACT was 73 days (range, 5-153 days). There were 7 EGFR-positive patients who received either adjuvant targeted therapy or chemotherapy plus targeted therapy, and 25 patients did not receive any adjuvant treatment after surgery.
Next-generation sequencing was performed on resected tumor and plasma samples from all 103 patients, and somatic mutations were detected in 91 patients. The median number of mutations per patient was 2 (range, 1-8 mutations). TP53 mutations were most frequent, identified in 73.6% of patients (67/91).
ctDNA analysis after surgery showed significantly reduced RFS in patients who were ctDNA positive compared with those who were ctDNA negative (hazard ratio [HR], 4.0; 95% CI, 2.0-8.0; P <.001). ctDNA positivity after adjuvant therapy was also significantly associated with worse RFS (HR, 3.2; 95% CI, 1.3–8.2; P <.05).
In a multivariate analysis that included postsurgical ctDNA status, histology, baseline TP53 status, and T stage, postsurgical ctDNA status had the strongest independent association with RFS (P <.001).
Longitudinal ctDNA analysis during post-treatment surveillance showed significantly lower RFS in patients with detectable ctDNA at any time point compared with those who were always ctDNA negative after surgery (HR, 8.5; 95% CI, 3.7-20; P <.001).
ctDNA positivity preceded radiological recurrence, with a median lead time from ctDNA-positive detection to recurrence of 88 days (P <.001). Using joint modeling of longitudinal ctDNA analysis and time to recurrence, researchers accurately predicted patients’ recurrence status at 12 months after surgery (P <.001; AUROC, 0.89) and at 15 months after surgery (P <.001; AUROC, 0.83).
“[W]e demonstrated that ctDNA serves as a robust biomarker for postsurgical and post-ACT risk stratification and early detection of recurrence in NSCLC,” the researchers wrote. “Moreover, our data suggest that postsurgical ctDNA analysis could guide ACT treatment decisions and avoid overtreatment in patients who were less likely to benefit from ACT.”
Qiu B, Guo W, Zhang F, et al. Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC. Nat Commun. Published online November 19, 2021. doi:10.1038/s41467-021-27022-z