Circulating tumor DNA and circumferential resection margin as key prognostic indicators for survival in rectal cancer.

Abstract

3579 Background: Recurrence of colorectal cancer has been linked to the presence of epigenetic circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA prior to treatment remains unknown. This study investigated the correlation between pre-treatment ctDNA and current radiological (MRI) prognostic markers in patients with rectal cancer. Methods: Forty-two patients with rectal cancer were enrolled, with all having staging MRI prior to treatment. Plasma was taken for ctDNA at diagnosis. The presence of either methylated branched-chain amino acid transaminase 1 (BCAT1) or Ikaros family zinc finger (IKZF1) in cell-free DNA from plasma was deemed a positive ctDNA result. Correlation of MRI prognostic indicators and ctDNA results was assessed with chi-square tests. Univariable and multivariable cox regression analyses were performed to determine variables associated with overall survival (OS). Results: Mean age was 64.4 years (SD 12.5) and majority were male (30/42, 71.4%). 11, 13, 9 & 9 patients had stages I, II, III, IV respectively. Patients had a minimum follow-up of 36 months. Thirty-three (78.6%) patients received neoadjuvant chemoradiotherapy. 29 (69.0%) patients underwent surgical resection. 3-year survival rate was 64% in the overall group. 67% (n=28/42) of patients were positive for the methylated ctDNA at diagnosis. 11 out of 12 patients with a positive circumferential resection margin (CRM +) were ctDNA positive (p=0.03). Univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion (EMVI) (HR 3.0, 95% CI 1.1-8.4), CRM+ (HR 12.2, 95%CI 3.9-37.6), metastatic disease (HR 7.32, 95% CI 2.63-20.37) and ctDNA% methylation (HR 1.1, 95% CI 1.04-1.13) (Table 1). The presence of CRM+ and a positive ctDNA had a HR of 20.5 (95% CI 5.1-82.3). With multivariable analysis, including adjustment for age and EMVI, only CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 20.2, 95% CI 4.5-90.9). Conclusions: In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment pre and post treatment could potentially inform prognosis and help tailor patients’ treatment.[Table: see text]

Clinical Characteristics of Metastatic Colorectal Cancer Combined with Gastrointestinal Perforation and Prognostic Value of Circulating Tumor DNA

“…Clinically, it is generally believed that primary tumor, metastases, and circulating tumor cells are the main sources of ctDNA [18,19]. Some studies have also found that the infiltration and metastasis of cancer cells can lead to an increase in the level of ctDNA in the body [20,21], suggesting that it may be related to the prognosis of patients.…”

“…Clinically, it is generally believed that primary tumor, metastases, and circulating tumor cells are the main sources of ctDNA [ 18 , 19 ]. Some studies have also found that the infiltration and metastasis of cancer cells can lead to an increase in the level of ctDNA in the body [ 20 , 21 ], suggesting that it may be related to the prognosis of patients. The results of this study showed that the plasma ctDNA level of the death group was higher than that of the survival group, and the survival rate of the high (ctDNA) expression group was lower than that of the low expression group, indicating that the higher the plasma ctDNA level was, the higher the risk of poor prognosis would be.…”

Minimal Residual Disease in Colorectal Cancer: Are We Finding the Needle in a Haystack?

“…Correlative studies evaluating patients with LARC have been concordant in showing association between ctDNA levels and clinical response to either chemoradiotherapy (CRT) or surgery [ 37 , 38 , 39 , 40 , 41 , 42 ]. Additionally, four studies demonstrated correlation between ctDNA levels and tumor regression grade (TRG) score in MRI after CRT [ 38 , 39 , 42 , 43 ], and another one showed association between involvement of circumferential resection margin and detection of ctDNA by a methylation-based assay [ 44 ]. However, studies have showed discordant results in demonstrating the value of ctDNA for predicting pCR [ 40 , 41 , 45 , 46 ].…”