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
AU - O'Connor, Darran P
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85049562166&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29792754
U2 - https://doi.org/10.1200/JCO.2017.77.1782
DO - https://doi.org/10.1200/JCO.2017.77.1782
M3 - Article
C2 - 29792754
SN - 0732-183X
VL - 36
SP - 2052
EP - 2060
JO - Journal of clinical oncology
JF - Journal of clinical oncology
IS - 20
M1 - 36(20)
ER -