Postoperative ctDNA in indicating the recurrence risk and monitoring the effect of adjuvant therapy in surgical non–small cell lung cancers.
Authors: Tian Xiaoru , Wang Ruotian , Qian Kun , Li Yuanbo , Wang Tengteng , Liu Lei , Liu Baodong , Su Lei , Zhang Peilong , Zhao Xin , Wang Kai , Xiong Yuanyuan , Zhang Yi 
Published: June 2022

8533

Background: Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residue disease in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC) patients. Methods: Forty-one surgical NSCLC patients were enrolled. Tumor tissues were collected at surgery and subjected to targeted NGS of 1021 cancer-related genes. The serial peripheral blood samples were collected at postoperative one month and then at every third or sixth month and subjected to ultra-deep targeted NGS covering 338 genes. Results: From 41 eligible patients including 18 patients with stage Ⅰ disease, 2 with stage Ⅱ and 21 with stage Ⅲ, 41 tumor tissues and 137 plasma samples were enrolled and successfully tested. In tissue samples, 323 somatic variations were identified, with a median of 8 (range, 1-21) gene variations detected in each patient. TP53 was the most common mutation (63.41%), followed by EGFR (58.53%), LRP1B (17.07%) and KRAS (14.63%). The first-postoperative ctDNA positive was found in 13 of 41 patients (31.71%), 9 stage Ⅲ, 2 stage Ⅱ and 2 stage Ⅰ. During a median 9.47 months follow-up, 38.46% (5/13) patients with detectable ctDNA in the first postoperative blood sample experienced recurrence, while 3.57% (1/28) patients with undetectable ctDNA ultimately recurred. The DFS can be stratified by the first-postoperative ctDNA status, with ctDNA-positive groups having significantly reduced DFS (p < 0.05). We detected ctDNA in at least one time point after surgery in 17 patients (41.46%), 5 of them (29.41%) experienced recurrence. Twenty-four patients without ctDNA detection during postoperative surveillance, one (4.17%) of them ultimately recurred. Serial ctDNA detection revealed disease recurrence ahead of radiologic imaging by a median of 5.25 months (range, 0.98-14.19). Among the 41 patients, 6 patients had surgery alone, 35 patients received adjuvant therapy. For these 35 patients, ctDNA analysis can stratify patients before and after adjuvant therapy. Recurrence ratio was 33.33% (4/12) in patients with detectable and 4.34% (1/23) in patients with undetectable ctDNA before adjuvant therapy. For ctDNA analysis after adjuvant therapy, no patients (11/11) with negative ctDNA had disease-recurrence while 33.33% (1/3) patients with positive ctDNA experienced recurrence. All four patients with clearance ctDNA by adjuvant therapy remained disease free. Conclusions: For NSCLC patients, postoperative ctDNA is a prognostic marker, which reveals disease recurrence ahead of radiographic examination. Importantly, ctDNA-detecting may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.