Methylated free‐circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer

Abstract

Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.

TMEFF2 Promoter Hypermethylation Is an Unfavorable Prognostic Marker in Gliomas

“…We noticed that O-methylguanine-DNA methyltransferase (MGMT) is an important biomarker for the chemosensitivity of gliomas, and methylation detection (not IHC) is more precise for the clinical testing of MGMT in glioma patients [1,33,34]. Andreas Herbst et al and Su Man Lee et al detected methylated free-circulating DNA (ctDNA) for TMEFF2 in the blood of metastatic colorectal cancers and non-small cell lung cancer, respectively [35,36]. It has also been reported that sequencing ctDNA in cerebrospinal uid (CSF) can provide a landscape of the tumor genome for glioma patients and is associated with disease outcome [37].…”

Correlation Between Tumor-Specific Mutated and Methylated DNA in Colorectal Cancer

“…Recently, presence of ctDNA was confirmed in WT patients using epigenetic modifications such as hypermethylation. [17][18][19] Meth-ctDNA seems to represent tumor-specific DNA and is found in nearly all colorectal adenocarcinomas, 10 as opposed to ctDNA based on RAS/RAF mutations. It may be a major step forward, if mut-ctDNA can be replaced by meth-ctDNA in several clinical settings.…”

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

“…In patients curatively resected for CRC, pre-therapeutic serum HLTF me levels were associated with increased relative risk of disease recurrence [158]. In a clinical trial including 467 metastatic CRC patients treated with a combination therapy containing fluoropyrimidine, oxaliplatin and bevacizumab, patients with detectable plasmatic HPP1 me before the start of treatment showed a significantly poorer OS [159]. Moreover, patients in which it reduced to undetectable levels 2-3 weeks after treatment, showed a better OS compared to patients that maintained detectable plasma HPP1 me levels [159], suggesting the usefulness of HPP1 me as a prognostic and early response biomarker.…”

“…In a clinical trial including 467 metastatic CRC patients treated with a combination therapy containing fluoropyrimidine, oxaliplatin and bevacizumab, patients with detectable plasmatic HPP1 me before the start of treatment showed a significantly poorer OS [159]. Moreover, patients in which it reduced to undetectable levels 2-3 weeks after treatment, showed a better OS compared to patients that maintained detectable plasma HPP1 me levels [159], suggesting the usefulness of HPP1 me as a prognostic and early response biomarker. 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].…”