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.
Highlights
Gastric cancer is one of the most common malignancies in the world and is the third leading cause of cancer-related death[1,2]
Almost all patients were treated with adjuvant chemotherapy (45/46, 98%) and two patients had neoadjuvant chemotherapy
No functional clustering were seen in these 16 new mutations, though they did include known driver genes such as TP53, RB1, PIK3CA, ATR. These results suggest the importance of broadly tracking cell-free tumor DNA (ctDNA) changes using a large gene panel instead of tumorinformed approach that focuses only on select tumorderived mutations. This prospective cohort study evaluated the clinical utility of ctDNA for detection of molecular residual disease (MRD) and longitudinal disease monitoring in locoregional gastric cancer treated with curative intent
Summary
Gastric cancer is one of the most common malignancies in the world (especially in East Asia) and is the third leading cause of cancer-related death[1,2]. Even with current adjuvant chemotherapy regimens such as oral S-1 and CAPOX4,5, Routine clinical imaging and biomarker modalities cannot reliably detect post-operative molecular residual disease (MRD) or micrometastatic recurrence. Circulating cell-free tumor DNA (ctDNA) is a promising biomarker for non-invasive molecular profiling, monitoring and predicting response to systemic treatment[11,12,13], and more recently, cancer detection as Official journal of the Cell Death Differentiation Association. Recent studies have demonstrated the potential of using ctDNA for monitoring clinical response to immunotherapy[20] and tracking anti-HER2 resistance[21] in the metastatic setting. We sought to evaluate the utility of longitudinal ctDNA targeted deep sequencing for detecting MRD and micrometastatic recurrence in resected, locoregional gastric cancer
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