Deep sequencing of circulating tumor DNA detects molecular residual disease and predicts recurrence in gastric cancer

Abstract

Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I–III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity (p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991–61.29, p < 0.0001 and HR = 7.664, 95% CI, 2.916–21.06, p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.

The Emerging Role of Liquid Biopsy in Gastric Cancer

“…Postoperative ctDNA detection was associated with disease recurrence in all patients in this study. The ctDNA positivity preceded radiological recurrence by a median of 6 months, and its positivity at any time postoperatively associated with worse disease-free and overall survival [ 48 ]. Another study analyzed the personalized cancer-specific rearrangements of 25 gastric cancer patients in the postoperative period for one year.…”

Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas

“…Despite the small number of patients and events, we found that detectable ctDNA after chemoradiation (p=0.004) and postoperatively (p=0.045) were associated with disease recurrence. Analysis of ctDNA after completion of de nitive therapy has been shown to be promising in detection of minimal residual disease in several disease sites to date [37][38][39][40][41][42] . Recent retrospective data from MDACC has emerged that suggest that post-chemoradiation ctDNA may identify patients with localized esophageal cancers at increased risk of recurrence and death and may potentially help in the determination of which patients are most likely to bene t from surgery.…”

Clinical Applications of Liquid Biopsy in Gastric Cancer

“…Usually, ctDNA can be detected before therapy and disappears after complete surgical resection. Its presence after or its reappearance at follow-up indicates minimal residual disease (MRD), which is a cause of recurrence ( 41 , 42 , 46 , 47 , 49 , 50 ).…”