Yonsei Med J.  2023 Sep;64(9):531-540. 10.3349/ymj.2023.0096.

Monitoring the Outcomes of Systemic Chemotherapy Including Immune Checkpoint Inhibitor for HER2-Positive Metastatic Gastric Cancer by Liquid Biopsy

• Jung SH
• Lee Ck
• Kwon WS
• Yun S
• Jung M
• Kim HS
• Chung HC
• Chung YJ
• Rha SY

• KMID: 2545516
• DOI: http://doi.org/10.3349/ymj.2023.0096

Abstract

Purpose
For precision medicine, exploration and monitoring of molecular biomarkers are essential. However, in advanced gastric cancer (GC) with visceral lesions, an invasive procedure cannot be performed repeatedly for the follow-up of molecular biomarkers.
Materials and Methods
To verify the clinical implication of serial liquid biopsies targeting circulating tumor DNA (ctDNA) on treatment response, we conducted targeted deep sequencing for serially collected ctDNA of 15 HER2-positive metastatic GC patients treated with anti-PD-1 inhibitor in combination with standard systemic treatment.
Results
In the baseline ctDNAs, 14 patients (93%) harbored more than one genetic alteration. A number of mutations in wellknown cancer-related genes, such as KRAS and PIK3CA, were identified. Copy number alterations were identified in eight GCs (53.3%), and amplification of the ERBB2 gene (6/15, 40.0%) was the most recurrent. When we calculated the mean variant allele frequency (VAF) of mutations in each ctDNA as the molecular tumor burden index (mTBI), the mTBI trend was largely consistent with the VAF profiles in both responder and non-responder groups. Notably, in the longitudinal analysis of ctDNA, mTBI provided 2–42 weeks (mean 13.4 weeks) lead time in the detection of disease progression compared to conventional follow-up with CT imaging.
Conclusion
Our data indicate that the serial genetic alteration profiling of ctDNA is feasible to predict treatment response in HER2-positive GC patients in a minimally invasive manner. Practically, ctDNA profiles are useful not only for the molecular diagnosis of GC but also for the selection of GC patients with poor prognosis for systemic treatment (ClinicalTrials.gov identifier: NCT02901301).

Keyword

Gastric cancer; liquid biopsy; circulating tumor DNA; immune checkpoint inhibitor; molecular tumor burden index