High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib
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 trea...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00622/full |
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| author | 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 Giulia Alberti Rossana Intini Letizia Procaccio Letizia Procaccio Marco Arese Marco Arese Silvia Marsoni Silvia Marsoni Michele Nichelatti Vittorina Zagonel Salvatore Siena Salvatore Siena Alberto Bardelli Alberto Bardelli Fotios Loupakis Federica Di Nicolantonio Federica Di Nicolantonio Andrea Sartore-Bianchi Andrea Sartore-Bianchi Ludovic Barault Ludovic Barault |
| author_facet | 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 Giulia Alberti Rossana Intini Letizia Procaccio Letizia Procaccio Marco Arese Marco Arese Silvia Marsoni Silvia Marsoni Michele Nichelatti Vittorina Zagonel Salvatore Siena Salvatore Siena Alberto Bardelli Alberto Bardelli Fotios Loupakis Federica Di Nicolantonio Federica Di Nicolantonio Andrea Sartore-Bianchi Andrea Sartore-Bianchi Ludovic Barault Ludovic Barault |
| author_sort | Alessio Amatu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T12:29:22Z |
| format | Article |
| id | doaj.art-03adbb2e3faf4c54b1f03312367d97e5 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T12:29:22Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-03adbb2e3faf4c54b1f03312367d97e52022-12-21T23:01:14ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-07-01910.3389/fonc.2019.00622437599High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With RegorafenibAlessio Amatu0Marta Schirripa1Federica Tosi2Sara Lonardi3Katia Bencardino4Erica Bonazzina5Laura Palmeri6Damiano Alfio Patanè7Elio Gregory Pizzutilo8Benedetta Mussolin9Francesca Bergamo10Giulia Alberti11Giulia Alberti12Rossana Intini13Letizia Procaccio14Letizia Procaccio15Marco Arese16Marco Arese17Silvia Marsoni18Silvia Marsoni19Michele Nichelatti20Vittorina Zagonel21Salvatore Siena22Salvatore Siena23Alberto Bardelli24Alberto Bardelli25Fotios Loupakis26Federica Di Nicolantonio27Federica Di Nicolantonio28Andrea Sartore-Bianchi29Andrea Sartore-Bianchi30Ludovic Barault31Ludovic Barault32Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyCandiolo Cancer Institute, FPO–IRCCS, Candiolo, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyDepartment of Surgery, Oncology and Gastroenterology, University of Padua, Padua, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyDepartment of Surgery, Oncology and Gastroenterology, University of Padua, Padua, ItalyCandiolo Cancer Institute, FPO–IRCCS, Candiolo, ItalyDepartment of Oncology, University of Turin, Candiolo, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyDepartment of Precision Oncology, FIRC Institute of Molecular Oncology (IFOM), Milan, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyDipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, ItalyCandiolo Cancer Institute, FPO–IRCCS, Candiolo, ItalyDepartment of Oncology, University of Turin, Candiolo, ItalyMedical Oncology 1, Veneto Institute of Oncology, IRCCS, Padua, ItalyCandiolo Cancer Institute, FPO–IRCCS, Candiolo, ItalyDepartment of Oncology, University of Turin, Candiolo, ItalyNiguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, ItalyDipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, ItalyCandiolo Cancer Institute, FPO–IRCCS, Candiolo, ItalyDepartment of Oncology, University of Turin, Candiolo, ItalyBackground: 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.https://www.frontiersin.org/article/10.3389/fonc.2019.00622/fullregorafenibDNA methylationmetastatic colorectal cancercell free circulating DNAliquid biopsydigital PCR |
| spellingShingle | 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 Giulia Alberti Rossana Intini Letizia Procaccio Letizia Procaccio Marco Arese Marco Arese Silvia Marsoni Silvia Marsoni Michele Nichelatti Vittorina Zagonel Salvatore Siena Salvatore Siena Alberto Bardelli Alberto Bardelli Fotios Loupakis Federica Di Nicolantonio Federica Di Nicolantonio Andrea Sartore-Bianchi Andrea Sartore-Bianchi Ludovic Barault Ludovic Barault High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib Frontiers in Oncology regorafenib DNA methylation metastatic colorectal cancer cell free circulating DNA liquid biopsy digital PCR |
| title | High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib |
| title_full | High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib |
| title_fullStr | High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib |
| title_full_unstemmed | High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib |
| title_short | High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib |
| title_sort | high circulating methylated dna is a negative predictive and prognostic marker in metastatic colorectal cancer patients treated with regorafenib |
| topic | regorafenib DNA methylation metastatic colorectal cancer cell free circulating DNA liquid biopsy digital PCR |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.00622/full |
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