TY - JOUR
T1 - Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy
AU - Smeets, Dominiek
AU - Miller, Ian S.
AU - O’Connor, Darran P.
AU - Das, Sudipto
AU - Moran, Bruce
AU - Boeckx, Bram
AU - Gaiser, Timo
AU - Betge, Johannes
AU - Barat, Ana
AU - Klinger, Rut
AU - van Grieken, Nicole C. T.
AU - Cremolini, Chiara
AU - Prenen, Hans
AU - Mazzone, Massimiliano
AU - Depreeuw, Jeroen
AU - Bacon, Orna
AU - Fender, Bozena
AU - Brady, Joseph
AU - Hennessy, Bryan T.
AU - McNamara, Deborah A.
AU - Kay, Elaine
AU - Verheul, Henk M.
AU - Maarten, Neerincx
AU - Gallagher, William M.
AU - Murphy, Verena
AU - Prehn, Jochen H. M.
AU - Koopman, Miriam
AU - Punt, Cornelis J. A.
AU - Loupakis, Fotios
AU - Ebert, Matthias P. A.
AU - Ylstra, Bauke
AU - Lambrechts, Diether
AU - Byrne, Annette T.
AU - O'Connor, Darran P.
PY - 2018/10/5
Y1 - 2018/10/5
N2 - Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 xenografts match with low instability clusters and fail to respond. Overall, we identify copy number load as a novel potential predictive biomarker of BVZ combination therapy.
AB - Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 xenografts match with low instability clusters and fail to respond. Overall, we identify copy number load as a novel potential predictive biomarker of BVZ combination therapy.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85054450821&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30291241
U2 - https://doi.org/10.1038/s41467-018-06567-6
DO - https://doi.org/10.1038/s41467-018-06567-6
M3 - Article
C2 - 30291241
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4112
ER -