Abstract 1991: Chromosomal instability of circulating tumor DNA predicts response to neoadjuvant chemotherapy in gastric cancer
Authors: Jia Yongning , Zhu Honglin , Pang Fei , Shan Fei , Li Shuangxi , Wang Danhua , Li Lin , Ma Tonghui , Li Ziyu 
Published: September 2020

Background: Neoadjuvant chemotherapy (NAC) was increasingly used for early-stage gastric cancer (GC) treatment to reduce the recurrence and mortality. However, clinical practices demonstrated that not all the patients underwent NAC prior to surgery could benefit from it. Current available methods for assessing the response to NAC, such as Tumor Regression Grading (TRG), CT, or serum tumor markers, can only evaluated after NAC or surgery. Novel markers for predicting the effect of neoadjuvant chemotherapy on prognosis before NAC is in urgent need. Gastric Cancer is featured by frequent somatic copy number alterations (SCNA) and high chromosomal instability. In addition, chromosomal instability has been demonstrated to effectively predict the therapeutic response to radiotherapy, chemotherapy, and targeted therapy. In this work, we investigated the chromosomal instability in GC patients undergoing NAC as a prognosis predictor.

Methods: From Jan 2016 to Jun 2017, a cohort of 25 patients with Stage II/III gastric adenocarcinoma after surgical treatment at Department of Gastrointestinal Oncology, Peking University Cancer Hospital were enrolled in our study. ctDNA was collected before (pre-NAC) and after NAC (post-NAC). We analyzed the mutation profiles of 50 plasma samples collected from 25 patients using a 179 cancer-related gene panel (GenetronHealth; Beijing, China). Copy number instability (CNI) scores of ctDNA were calculated to reflect chromosome instability in ctDNA.

Results: Based on the clinical evaluation of a combination of TRG, CT and serum tumor markers, 60% (15/25) patients were responsive to NAC. The pre-NAC CNI scores of ctDNA were significantly higher than that of post-NAC (median 127 vs. 113, Paired t test P=0.0403), which correlated well with the response rates and prognosis in the GC patients treated with NAC. 73.7% (14/19) patients with higher pre-NAC CNI score (CNI score &gt;90) were responsive to NAC, while the response rate of the lower pre-NAC CNI score (CNI score &lt;90) was only 16.7%(1/6). And the pre-NAC CNI scores of response group were much higher than that of the non-Response. (median 129 vs 86.5). Furthermore, comparing with the patients with lower pre-NAC CNI (CNI score &gt;90), the higher ones had obviously better prognosis after NAC treatment (P=0.037, HR=9.358).

Conclusions: To our knowledge, this is the first time demonstrating that the chromosomal instability quantification measured by CNI score of pre-NAC ctDNA may become a novel promising markers of response and prognosis to NAC in gastric cancer patients before NAC treatment. Additional larger cohort study aimed at understanding relationship between response to therapy and ctDNA instability are further required.

Citation Format: Yongning Jia, Honglin Zhu, Fei Pang, Fei Shan, Shuangxi Li, Danhua Wang, Lin Li, Tonghui Ma, Ziyu Li. Chromosomal instability of circulating tumor DNA predicts response to neoadjuvant chemotherapy in gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1991.