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EBioMedicine
Circulating tumor DNA analyses predict progressive disease and indicate trastuzumab-resistant mechanism in advanced gastric cancer
a Department of GI Oncology, The Fifth Medical Center, General Hospital of PLA, Beijing 100071, China
b Geneplus-Beijing Institute, Beijing 102206, China
c University of California San Diego, San Diego, La Jolla, CA 92093, USA
Article history:
Keywords:
Advanced gastric cancer
Circulating tumor DNA (ctDNA)
Trastuzumab
Resistance mechanism
Monitoring 
Background: Circulating tumor DNA (ctDNA) isolated from plasma contains genetic mutations that can be repre-sentative of those found in primary tumor tissue DNA. These samples can provide insights into tumoral hetero-geneity in patients with advanced gastric cancer (AGC). Although trastuzumab has been shown to be effective in first-line therapy for patients with metastatic gastric cancer with overexpression of human epidermal growth factor receptor 2 (HER2), the mechanism of AGC resistance is incompletely understood.
Methods: In this prospective study, we used targeted capture sequencing to analyze 173 serial ctDNA samples from 39 AGC patients. We analyzed cancer cell fractions with PyClone to understand the clonal population struc-ture in cancer, and monitored serial samples during therapy. Serial monitoring of ctDNA using the molecular tumor burden index (mTBI), identified progressive disease before imaging results (mean: 18 weeks).
Findings: We reconstructed the clonal structure of ctDNA during anti-HER2 treatment, and identified 32 expanding mutations potentially related to trastuzumab resistance. Multiple pathways activating in the same pa-tients revealed heterogeneity in trastuzumab resistance mechanisms in AGC. In patients who received chemo-therapy, mTBI was validated for the prediction of progressive disease, with a sensitivity of 94% (15/16). A higher mTBI (≥1%) in pretreatment ctDNA was also a risk factor for progression-free survival.
Conclusions: Analysis of ctDNA clones based on sequencing is a promising approach to clinical management, and may lead to improved therapeutic strategies for AGC patients.
Fund: This work was supported by grants from the National International Cooperation Grant (to J.X.; Project No.
© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).