High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib

Abstract

Background: Regorafenib improves progression free survival (PFS) in a subset of metastatic colorectal cancer (mCRC) patients, although no biomarkers of efficacy are available. Circulating methylated DNA (cmDNA) assessed by a five-gene panel was previously associated with outcome in chemotherapy treated mCRC patients. We hypothesized that cmDNA could be used to identify cases most likely to benefit from regorafenib (i.e., patients with PFS longer than 4 months). Methods: Plasma samples from mCRC patients were collected prior to (baseline samples N = 60) and/or during regorafenib treatment ( N = 62) for the assessment of cmDNA and total amount of cell free DNA (cfDNA). Results: In almost all patients, treatment with regorafenib increased the total cfDNA, but decreased cmDNA warranting the normalization of cmDNA to the total amount of circulating DNA (i.e., cmDNA/ml). We report that cmDNA/ml dynamics reflects clinical response with an increase in cmDNA/ml associated with higher risk of progression (HR for progression = 1.78 [95%CI: 1.01–3.13], p = 0.028). Taken individually, high baseline cmDNA/ml (above median) was associated with worst prognosis (HR for death = 3.471 [95%CI: 1.83–6.57], p < 0.0001) and also predicted shorter PFS (<16 weeks with PPV 86%). In addition, high cmDNA/ml values during regorafenib treatment predicted with higher accuracy shorter PFS (<16 weeks with a PPV of 96%), therefore associated with increased risk of progression (HR for progression = 2.985; [95%CI: 1.63–5.46; p < 0.0001). Conclusions: Our data highlight the predictive and prognostic value of cmDNA/ml in mCRC patients treated with regorafenib.

Integrated epigenetic biomarkers in circulating cell-free DNA as a robust classifier for pancreatic cancer

“…Liquid biopsies, a well-known noninvasive method, have aroused public attention as diagnostic materials for cancer, particularly circulating tumor DNA (ctDNA) in plasma. Taking advantage of technical advances, both genetic and epigenetic aberrations of cell-free DNA (cfDNA) can be detected [2] and have shown promising performance in clinical practice, including diagnosis [3][4][5][6][7][8], prognosis [9][10][11][12], and drug resistance [13,14].…”

Hypermethylation and decreased expression of TMEM240 are potential early-onset biomarkers for colorectal cancer detection, poor prognosis, and early recurrence prediction

“…In a Taiwanese CRC cohort, a quantitative polymerase chain reaction (qPCR) revealed that 86.1% of CRC patients exhibited hypermethylated BEND5 [15], suggesting that more sensitive biomarkers were worth investigating in Asian cohorts. In addition, assays of circulating methylated DNA (cmDNA) could be used as outcome predictors in chemotherapy and multikinase inhibitor-treated metastatic CRC patients [16]. These findings encouraged us to identify additional potential CRC-specific methylation markers, and combining multiple biomarkers in the early stage of CRC screening may provide more sensitive CRC early diagnoses [6,9].…”

DNA Methylation-Based Testing in Liquid Biopsies as Detection and Prognostic Biomarkers for the Four Major Cancer Types

“…Recently, Barault et al also suggested that plasmatic methylation changes of EYA4 me , GRIA4 me , ITGA4 me , MAP3K14-AS1 me and MSC me panel over time correlate with tumor response in metastatic CRC patients treated with chemoor targeted therapy [160]. Interestingly, using the same panel, Amatu et al reported that circulating methylated DNA normalized to the total amount of circulating DNA dynamics can reflect clinical response to treatment with regorafenib [161].…”