Abstract 1489P
Background
As one of the most prevalent and deadly malignancy around the world, gastric cancer (GC) is confronted with limited options for therapy. HER2-targeted regimen (represented by Trastuzumab) is currently the first option for targeted therapy against GC, yet the evolution of cancer during HER2-targeted treatment is largely unknown, and proper biomarkers for response/resistance prediction remain unveiled. In this study, in order to dynamically monitor therapeutic responses against GC, we explored the longitudinal changes of ctDNA (circulating tumor DNA) in GC patients receiving HER2-targeted regimen.
Methods
40 advanced GC patients receiving HER2-targeted therapy were recruited, and an overall number of 327 plasma samples along with the treatment were collected from peripheral blood plasma. We performed targeted exome sequencing for each sample's ctDNA and analyzed related clinical parameters. A 37-case GC cohort receiving immune checkpoint inhibitor (ICI) therapy was also cited for further analysis.
Results
ctDNA ERBB2 amplification shared a high concordance (94.4%) with paired tissue HER2 positivity. Compared with baseline, ERBB2-CNV, TMB and tumor CNV load (TCL) were reduced at PR/SD and elevated at PD. The continuous elevation of either ERBB2-CNV, TMB or TCL hinted a disease progression ahead of image diagnosis in 1/3 cases for 25.9 days in average. ERBB2-CNV was a favorable, while TMB was an adverse prognostic factor in predicting PFS of HER2-targeted therapy. Specifically, ERBB2-high-TMB-high patients didn't respond to HER2-targeted therapy as vigorously as ERBB2-high-TMB-low patients (ORR=45.5% vs 70.6%, DCR=63.6% vs 100%, mPFS=7.13 vs 3.07 month). In contrast, ERBB2-high-TMB-high patients displayed a better response to ICI therapy than ERBB2-high-TMB-low patients (ORR=50% vs 16.7%, DCR=75% vs 50%, mPFS=13.57 vs 2.53 month).
Conclusions
Our work suggested that dynamic surveillance of ctDNA provides helpful insight in forecasting disease progression and predicting prognosis for HER2-targeted therapy. We also pointed out that ctDNA TMB deserved further attention in order to improve the outcome for a specific population of HER2-positive GC patients with immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Major Program of National Natural Science Foundation of China (No. 91959205) National Key Research and Development Program of China (No. 2017YFC1308900) National Natural Science Foundation of China (No. 81802327).
Disclosure
All authors have declared no conflicts of interest.