title: 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.
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.|Institute of Laboratory Medicine, University of Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herbst
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Vdovin
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany.
authors.forename: Sanja
authors.initials: S
authors.lastname: Gacesa
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ofner
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.
authors.forename: Alexander
authors.identifier: 0000-0002-0215-9977
authors.initials: A
authors.lastname: Philipp
authors.affiliation: Institute of Laboratory Medicine, University of Munich, Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nagel
authors.affiliation: Institute of Laboratory Medicine, University of Munich, Munich, Germany.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Op den Winkel
authors.affiliation: Department of Medicine III and The Comprehensive Cancer Center, University of Munich, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Institute of Laboratory Medicine, University of Munich, Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Stieber
authors.affiliation: Medizinische Klinik I, Kliniken Maria-Hilf GmbH, Mönchengladbach, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Graeven
authors.affiliation: Department of Hematology and Oncology, Ruhr-University of Bochum, St. Josef Hospital, Bochum, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Reinacher-Schick
authors.affiliation: Instituto CUF de Oncologia (I.C.O.), Lisbon, Portugal.
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ricard
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.affiliation: HOPE - Practice for Oncology, Hamburg, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Hegewisch-Becker
authors.affiliation: Department of Medicine II, University of Munich, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|HELIOS Klinikum Berlin-Buch, Berlin, Germany.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
mesh_terms: D000328:Adult; D000368:Aged; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C423567:TMEFF2 protein, human; D000068258:Bevacizumab
keywords: HPP1; colorectal cancer; free-circulating DNA; prognosis; response