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

Lars Henrik Jensen, René Olesen, Lone Noergaard Petersen, Anders Kindberg Boysen, Rikke Fredslund Andersen, Jan Lindebjerg, Lise Nottelmann, Caroline Emilie Brenner Thomsen, Birgitte Mayland Havelund, Anders Jakobsen, Torben Frøstrup Hansen

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Resumé

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.

OriginalsprogEngelsk
Artikelnummer1649
TidsskriftCancers
Vol/bind11
Udgave nummer11
Antal sider13
ISSN2072-6694
DOI
StatusUdgivet - 25. okt. 2019

Fingeraftryk

Neuropeptide Y
Colorectal Neoplasms
DNA
Disease-Free Survival
Confidence Intervals
Circulating Neoplastic Cells
Exanthema
Prospective Studies
Food
Population

Citer dette

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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",
abstract = "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.",
author = "Jensen, {Lars Henrik} and Ren{\'e} Olesen and Petersen, {Lone Noergaard} and Boysen, {Anders Kindberg} and Andersen, {Rikke Fredslund} and Jan Lindebjerg and Lise Nottelmann and Thomsen, {Caroline Emilie Brenner} and Havelund, {Birgitte Mayland} and Anders Jakobsen and Hansen, {Torben Fr{\o}strup}",
year = "2019",
month = "10",
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doi = "10.3390/cancers11111649",
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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. / 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.

I: Cancers , Bind 11, Nr. 11, 1649, 25.10.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - NPY Gene Methylation as a Universal, Longitudinal Plasma Marker for Evaluating the Clinical Benefit from Last-Line Treatment with Regorafenib in Metastatic Colorectal Cancer

AU - Jensen, Lars Henrik

AU - Olesen, René

AU - Petersen, Lone Noergaard

AU - Boysen, Anders Kindberg

AU - Andersen, Rikke Fredslund

AU - Lindebjerg, Jan

AU - Nottelmann, Lise

AU - Thomsen, Caroline Emilie Brenner

AU - Havelund, Birgitte Mayland

AU - Jakobsen, Anders

AU - Hansen, Torben Frøstrup

PY - 2019/10/25

Y1 - 2019/10/25

N2 - 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.

AB - 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.

U2 - 10.3390/cancers11111649

DO - 10.3390/cancers11111649

M3 - Journal article

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 11

M1 - 1649

ER -