Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer

Merel J. M. van Velzen*, Aafke Creemers, Tom van den Ende, Sandor Schokker, Sarah Krausz, Roy J. Reinten, Frederike Dijk, Carel J. M. van Noesel, Hans Halfwerk, Sybren L. Meijer, Banafsche Mearadji, Sarah Derks, Maarten F. Bijlsma, Hanneke W. M. van Laarhoven

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel. Methods: Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses. Results: ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson’s R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10–4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28–5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53–16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31–12.75; p = 0.016). Conclusion: Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.

Original languageEnglish
Pages (from-to)906-915
Number of pages10
JournalGastric Cancer
Issue number5
Early online date2022
Publication statusPublished - Sept 2022

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