Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non–small cell lung cancer

Abstract

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for dynamically monitoring tumors. However, published data on perioperative ctDNA in patients with operable non-small cell lung cancer (NSCLC) are currently limited. METHODS: This prospective study recruited 123 patients with resectable stage I to IIIA NSCLC. Preoperative and postoperative plasma samples and tumor tissue samples were subjected to next-generation sequencing with a panel of 425 cancer-related genes. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3 to 6 months for up to 3 years. RESULTS: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 29 of 117 patients (24.8%) and was associated with inferior recurrence-free survival (RFS; hazard ratio [HR], 2.42; 95% CI, 1.11-5.27; P = .022) and inferior overall survival (OS; HR, 5.54; 95% CI, 1.01-30.35; P = .026). Similarly, ctDNA was detected in 12 of 116 first postsurgical samples (10.3%) and was associated with shorter RFS (HR, 3.04; 95% CI, 1.22-7.58; P = .012). During surveillance after surgery, longitudinal ctDNA-positive patients (37 of 119; 31.1%) had significantly shorter RFS (HR, 3.46; 95% CI, 1.59-7.55; P < .001) and significantly shorter OS (HR, 9.99; 95% CI, 1.17-85.78; P = .010) in comparison with longitudinal ctDNA-negative patients. Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 8.71 months. CONCLUSIONS: These results suggest that perioperative ctDNA analyses can predict recurrence and survival, and serial ctDNA analyses can identify disease recurrence/metastasis earlier than routine radiologic imaging in patients with resectable NSCLC.

Analysis of Molecular Biomarkers in Resected Early-Stage Non-Small Cells Lung Cancer: A Narrative Review

“…Regarding the prognostic role of the ctDNA, the results in the literature are still unclear. However, some evidence suggests that perioperative ctDNA could be associated with oncological outcomes [51].…”

Role of ctDNA for the detection of minimal residual disease in resected non-small cell lung cancer: a systematic review

“…The characteristics of the 13 identified studies which evaluated MRD by ctDNA in radically-resected NSCLC (stage I-III) patients are listed in Table 1. Pre-operative plasma samples (baseline timepoint) were collected immediately before surgery in two studies (31,35), within 7 days in four studies (32)(33)(34)36) or within 13 days in one study (28). Post-operative plasma samples (landmark timepoint) were collected within 10 days from surgery in three studies (28,31,35), within 10-15 days from surgery in five studies (32)(33)(34)37,38), between 15 and 30 days in five studies (29,31,36,38,39) and within 120 days from surgery in one study (30).…”

“…Pre-operative plasma samples (baseline timepoint) were collected immediately before surgery in two studies (31,35), within 7 days in four studies (32)(33)(34)36) or within 13 days in one study (28). Post-operative plasma samples (landmark timepoint) were collected within 10 days from surgery in three studies (28,31,35), within 10-15 days from surgery in five studies (32)(33)(34)37,38), between 15 and 30 days in five studies (29,31,36,38,39) and within 120 days from surgery in one study (30). A schematic representation of the plasma samples timing across the studies is depicted in Figure 3.…”

“…Tumor tissue was collected intra-operatively in all the studies except for one in which tissue specimen was not provided (30). In addition, 8 out of 13 studies longitudinally collected blood samples during follow-up period, up to four years from surgery, in order to perform the surveillance analysis (30)(31)(32)34,36,37,39,40). The analytical methods used to assess MRD were predominantly based on Next-Generation Sequencing (NGS) (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), while Polymerase Chain Reaction (PCR)-based methods were applied in one study (40).…”

Circulating CD45+EpCAM+ cells as a diagnostic marker for early-stage primary lung cancer

“…As tumor cells die, ctDNA is released into the bloodstream in small amounts, which represents a promising strategy for cancer surveillance ( 15 ). The detection of ctDNA is also associated with the risk of recurrence and long-term prognosis of patients with lung cancer after surgery ( 15 , 16 ). Other blood circulation markers, such as proteins, antibodies, miRNAs, and exosomes, are also under investigation ( 17 – 19 ).…”