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NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer

There is a need for biomarkers to improve the clinical benefit from systemic treatment of colorectal cancer. We designed a prospective, clinical study where patients receiving regorafenib as last-line treatment had sequential blood samples drawn. Effect and toxicity was monitored. The primary clinic...

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Autores principales: Jensen, Lars Henrik, Olesen, René, Petersen, Lone Noergaard, Boysen, Anders Kindberg, Andersen, Rikke Fredslund, Lindebjerg, Jan, Nottelmann, Lise, Thomsen, Caroline Emilie Brenner, Havelund, Birgitte Mayland, Jakobsen, Anders, Hansen, Torben Frøstrup
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896074/
https://www.ncbi.nlm.nih.gov/pubmed/31731482
http://dx.doi.org/10.3390/cancers11111649
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author Jensen, Lars Henrik
Olesen, René
Petersen, Lone Noergaard
Boysen, Anders Kindberg
Andersen, Rikke Fredslund
Lindebjerg, Jan
Nottelmann, Lise
Thomsen, Caroline Emilie Brenner
Havelund, Birgitte Mayland
Jakobsen, Anders
Hansen, Torben Frøstrup
author_facet Jensen, Lars Henrik
Olesen, René
Petersen, Lone Noergaard
Boysen, Anders Kindberg
Andersen, Rikke Fredslund
Lindebjerg, Jan
Nottelmann, Lise
Thomsen, Caroline Emilie Brenner
Havelund, Birgitte Mayland
Jakobsen, Anders
Hansen, Torben Frøstrup
author_sort Jensen, Lars Henrik
collection PubMed
description There is a need for biomarkers to improve the clinical benefit from systemic treatment of colorectal cancer. We designed a prospective, clinical study where patients receiving regorafenib as last-line treatment had sequential blood samples drawn. Effect and toxicity was monitored. The primary clinical endpoint was progression free survival (PFS). Cell-free circulating tumor (ct) DNA was measured as either the fraction with Neuropeptide Y (NPY) methylated DNA or KRAS/NRAS/BRAF mutated ctDNA. One hundred patients were included from three Danish centers. Among 95 patients who received regorafenib for at least two weeks, the median PFS was 2.1 months (95% confidence interval (CI) 1.8–3.3) and the median overall survival (OS) was 5.2 months (95% CI 4.3–6.5). Grade 3–4 toxicities were reported 51 times, most frequently hypertension, hand-food syndrome, and skin rash. In the biomarker population of 91 patients, 49 could be monitored using mutated DNA and 90 using methylated DNA. There was a strong correlation between mutated and methylated DNA. The median survival for patients with a level of methylated ctDNA above the median was 4.3 months compared to 7.6 months with ctDNA below the median, p < 0.001. The median time from increasing methylated ctDNA to disease progression was 1.64 months (range 0.46–8.38 months). In conclusion, NPY methylated ctDNA was a universal liquid biopsy marker in colorectal cancer patients treated with regorafenib. High baseline levels correlated with short survival and changes during treatment may predict early effect and later progression. We suggest plasma NPY methylation analysis as an easy and universally applicable method for longitudinal monitoring of ctDNA in metastatic colorectal cancer patients.
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spelling pubmed-68960742019-12-23 NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer Jensen, Lars Henrik Olesen, René Petersen, Lone Noergaard Boysen, Anders Kindberg Andersen, Rikke Fredslund Lindebjerg, Jan Nottelmann, Lise Thomsen, Caroline Emilie Brenner Havelund, Birgitte Mayland Jakobsen, Anders Hansen, Torben Frøstrup Cancers (Basel) Article There is a need for biomarkers to improve the clinical benefit from systemic treatment of colorectal cancer. We designed a prospective, clinical study where patients receiving regorafenib as last-line treatment had sequential blood samples drawn. Effect and toxicity was monitored. The primary clinical endpoint was progression free survival (PFS). Cell-free circulating tumor (ct) DNA was measured as either the fraction with Neuropeptide Y (NPY) methylated DNA or KRAS/NRAS/BRAF mutated ctDNA. One hundred patients were included from three Danish centers. Among 95 patients who received regorafenib for at least two weeks, the median PFS was 2.1 months (95% confidence interval (CI) 1.8–3.3) and the median overall survival (OS) was 5.2 months (95% CI 4.3–6.5). Grade 3–4 toxicities were reported 51 times, most frequently hypertension, hand-food syndrome, and skin rash. In the biomarker population of 91 patients, 49 could be monitored using mutated DNA and 90 using methylated DNA. There was a strong correlation between mutated and methylated DNA. The median survival for patients with a level of methylated ctDNA above the median was 4.3 months compared to 7.6 months with ctDNA below the median, p < 0.001. The median time from increasing methylated ctDNA to disease progression was 1.64 months (range 0.46–8.38 months). In conclusion, NPY methylated ctDNA was a universal liquid biopsy marker in colorectal cancer patients treated with regorafenib. High baseline levels correlated with short survival and changes during treatment may predict early effect and later progression. We suggest plasma NPY methylation analysis as an easy and universally applicable method for longitudinal monitoring of ctDNA in metastatic colorectal cancer patients. MDPI 2019-10-25 /pmc/articles/PMC6896074/ /pubmed/31731482 http://dx.doi.org/10.3390/cancers11111649 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jensen, Lars Henrik
Olesen, René
Petersen, Lone Noergaard
Boysen, Anders Kindberg
Andersen, Rikke Fredslund
Lindebjerg, Jan
Nottelmann, Lise
Thomsen, Caroline Emilie Brenner
Havelund, Birgitte Mayland
Jakobsen, Anders
Hansen, Torben Frøstrup
NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer
title NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer
title_full NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer
title_fullStr NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer
title_full_unstemmed NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer
title_short NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer
title_sort npy gene methylation as a universal, longitudinal plasma marker for evaluating the clinical benefit from last-line treatment with regorafenib in metastatic colorectal cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896074/
https://www.ncbi.nlm.nih.gov/pubmed/31731482
http://dx.doi.org/10.3390/cancers11111649
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