Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab

Erik van Dijk, Hedde D Biesma, Martijn Cordes, Dominiek Smeets, Maarten Neerincx, Sudipto Das, Paul P Eijk, Verena Murphy, Anna Barat, Orna Bacon, Jochen H M Prehn, Johannes Betge, Timo Gaiser, Bozena Fender, Gerrit A Meijer, Deborah A McNamara, Rut Klinger, Miriam Koopman, Matthias P A Ebert, Elaine W KayBryan T Hennessey, Henk M W Verheul, William M Gallagher, Darran P O'Connor, Cornelis J A Punt, Fotios Loupakis, Diether Lambrechts, Annette T Byrne, Nicole C T van Grieken, Bauke Ylstra

Research output: Contribution to journalArticle

Abstract

Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.

Original languageEnglish
Pages (from-to)2052-2060
Number of pages9
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume36
Issue number20
DOIs
Publication statusPublished - Jul 10 2018

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Colorectal Neoplasms
Chromosomes
Disease-Free Survival
Survival
Multicenter Studies
Bevacizumab
Biomarkers
Clinical Trials
Genome
Biopsy
Drug Therapy
Neoplasms

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Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab. / van Dijk, Erik; Biesma, Hedde D; Cordes, Martijn; Smeets, Dominiek; Neerincx, Maarten; Das, Sudipto; Eijk, Paul P; Murphy, Verena; Barat, Anna; Bacon, Orna; Prehn, Jochen H M; Betge, Johannes; Gaiser, Timo; Fender, Bozena; Meijer, Gerrit A; McNamara, Deborah A; Klinger, Rut; Koopman, Miriam; Ebert, Matthias P A; Kay, Elaine W; Hennessey, Bryan T; Verheul, Henk M W; Gallagher, William M; O'Connor, Darran P; Punt, Cornelis J A; Loupakis, Fotios; Lambrechts, Diether; Byrne, Annette T; van Grieken, Nicole C T; Ylstra, Bauke.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 36, No. 20, 10.07.2018, p. 2052-2060.

Research output: Contribution to journalArticle

van Dijk, E, Biesma, HD, Cordes, M, Smeets, D, Neerincx, M, Das, S, Eijk, PP, Murphy, V, Barat, A, Bacon, O, Prehn, JHM, Betge, J, Gaiser, T, Fender, B, Meijer, GA, McNamara, DA, Klinger, R, Koopman, M, Ebert, MPA, Kay, EW, Hennessey, BT, Verheul, HMW, Gallagher, WM, O'Connor, DP, Punt, CJA, Loupakis, F, Lambrechts, D, Byrne, AT, van Grieken, NCT & Ylstra, B 2018, 'Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 36, no. 20, pp. 2052-2060. https://doi.org/10.1200/JCO.2017.77.1782
van Dijk, Erik ; Biesma, Hedde D ; Cordes, Martijn ; Smeets, Dominiek ; Neerincx, Maarten ; Das, Sudipto ; Eijk, Paul P ; Murphy, Verena ; Barat, Anna ; Bacon, Orna ; Prehn, Jochen H M ; Betge, Johannes ; Gaiser, Timo ; Fender, Bozena ; Meijer, Gerrit A ; McNamara, Deborah A ; Klinger, Rut ; Koopman, Miriam ; Ebert, Matthias P A ; Kay, Elaine W ; Hennessey, Bryan T ; Verheul, Henk M W ; Gallagher, William M ; O'Connor, Darran P ; Punt, Cornelis J A ; Loupakis, Fotios ; Lambrechts, Diether ; Byrne, Annette T ; van Grieken, Nicole C T ; Ylstra, Bauke. / Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018 ; Vol. 36, No. 20. pp. 2052-2060.
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title = "Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab",
abstract = "Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.",
author = "{van Dijk}, Erik and Biesma, {Hedde D} and Martijn Cordes and Dominiek Smeets and Maarten Neerincx and Sudipto Das and Eijk, {Paul P} and Verena Murphy and Anna Barat and Orna Bacon and Prehn, {Jochen H M} and Johannes Betge and Timo Gaiser and Bozena Fender and Meijer, {Gerrit A} and McNamara, {Deborah A} and Rut Klinger and Miriam Koopman and Ebert, {Matthias P A} and Kay, {Elaine W} and Hennessey, {Bryan T} and Verheul, {Henk M W} and Gallagher, {William M} and O'Connor, {Darran P} and Punt, {Cornelis J A} and Fotios Loupakis and Diether Lambrechts and Byrne, {Annette T} and {van Grieken}, {Nicole C T} and Bauke Ylstra",
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TY - JOUR

T1 - Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab

AU - van Dijk, Erik

AU - Biesma, Hedde D

AU - Cordes, Martijn

AU - Smeets, Dominiek

AU - Neerincx, Maarten

AU - Das, Sudipto

AU - Eijk, Paul P

AU - Murphy, Verena

AU - Barat, Anna

AU - Bacon, Orna

AU - Prehn, Jochen H M

AU - Betge, Johannes

AU - Gaiser, Timo

AU - Fender, Bozena

AU - Meijer, Gerrit A

AU - McNamara, Deborah A

AU - Klinger, Rut

AU - Koopman, Miriam

AU - Ebert, Matthias P A

AU - Kay, Elaine W

AU - Hennessey, Bryan T

AU - Verheul, Henk M W

AU - Gallagher, William M

AU - O'Connor, Darran P

AU - Punt, Cornelis J A

AU - Loupakis, Fotios

AU - Lambrechts, Diether

AU - Byrne, Annette T

AU - van Grieken, Nicole C T

AU - Ylstra, Bauke

PY - 2018/7/10

Y1 - 2018/7/10

N2 - Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.

AB - Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.

U2 - 10.1200/JCO.2017.77.1782

DO - 10.1200/JCO.2017.77.1782

M3 - Article

C2 - 29792754

VL - 36

SP - 2052

EP - 2060

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 20

ER -