Monitoring gastric cancer progression with circulating tumour DNA

Abstract

Background: Circulating tumour DNA (ctDNA) is an emerging candidate biomarker for malignancies and may be useful for monitoring the disease status of gastric cancer.

Methods: We performed targeted deep sequencing of plasma cell-free DNA (cfDNA) by massively parallel sequencing in patients with tumours harbouring TP53 mutations. The quantitative values of TP53-ctDNA during the clinical course were compared with the tumour status.

Results: Three out of ten patients with TP53 mutations in primary tumours showed detectable TP53 mutation levels in preoperative cfDNA. Although the cfDNA concentrations were not always reflective of the disease course, the ctDNA fraction correlated with the disease status.

Conclusions: ctDNA may serve as a useful biomarker to monitor gastric cancer progression and residual disease.

Figures

Figure 1

Comparison of cell-free DNA and ctDNA with regard to treatment response. The levels of cell-free DNA (cfDNA; grey bar) and ctDNA (line graph) at various time points in patients 4 (A), 5 (B), and 8 (C) are displayed. The vertical axis on the left represents the concentration of cfDNA, and the vertical axis on the right represents the TP53-mutant fraction in cfDNA. The horizontal axis labels represent the time points of plasma sampling and tumour status (in parenthesis). The presence or absence of tumour after surgery is described by the R status (R0: no residual tumour, R1: microscopic residual tumour, R2: macroscopic residual tumour). Abbreviations: POD: postoperative day; PD: progressive disease.

Figure 2

The relationship between ctDNA and clinical observations during the treatment course. ctDNA values during the clinical course are depicted in comparison with serum tumour markers, treatment, response, and tumour burden (specimen photos and radiological images). The horizontal arrows indicate the time scale for each case. The day of gastrectomy is represented by the vertical line. The presence or absence of tumour after surgery is described by the R status (R0: no residual tumour, R1: microscopic residual tumour, R2: macroscopic residual tumour). The intervals from surgery are indicated inside the arrows. Chemotherapy is depicted by colour bars under the time scale. The specimen photos depict the resected stomach, representing the tumour burden before surgery. CT (A, B, and C) and positron emission tomography (PET)-CT (A) images display the status of metastatic liver tumours at each assessment point, indicated by triangle markers. In each case, ctDNA is expressed as the percent relative to the ctDNA values before surgery. POD: postoperative day, PD: progressive disease, XP: capecitabine+cisplatin, Her: trastuzumab, CPT-11: irinotecan, w-PTX: weekly administration of paclitaxel. (A) The ctDNA fraction was measured for both TP53 (c.103delT) and PIK3CA (c.1633G>A). (B) The ctDNA fraction was measured for both TP53 (c.747G>C) and PIK3CA (c.1633G>A). (C) The ctDNA fraction was measured for both TP53 (c.155G>T) and FBXW7 (c.1177C>T).