1. High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib
- Author
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Alessio Amatu, Marta Schirripa, Federica Tosi, Sara Lonardi, Katia Bencardino, Erica Bonazzina, Laura Palmeri, Damiano Alfio Patanè, Elio Gregory Pizzutilo, Benedetta Mussolin, Francesca Bergamo, Giulia Alberti, Rossana Intini, Letizia Procaccio, Marco Arese, Silvia Marsoni, Michele Nichelatti, Vittorina Zagonel, Salvatore Siena, Alberto Bardelli, Fotios Loupakis, Federica Di Nicolantonio, Andrea Sartore-Bianchi, and Ludovic Barault
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,lcsh:RC254-282 ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Regorafenib ,Internal medicine ,Medicine ,Progression-free survival ,Liquid biopsy ,Original Research ,Chemotherapy ,DNA methylation ,liquid biopsy ,Plasma samples ,Metastatic colorectal cancer ,digital PCR ,business.industry ,Regorafenib, DNA methylation, Metastatic colorectal cancer, cell free circulating DNA, Methylated DNA, liquid biopsy, digital PCR, treatment monitoring, biomarkers, prognosis ,biomarkers ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,3. Good health ,treatment monitoring ,030104 developmental biology ,Increased risk ,Oncology ,chemistry ,Cell-free fetal DNA ,Methylated DNA ,030220 oncology & carcinogenesis ,cell free circulating DNA ,prognosis ,business - 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 (
- Published
- 2019
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