Metastatic Colorectal Cancer, Chromosomal Instability, Copy Number Alterations, Bevacizumab Combination Therapy.
The ANGIOPREDICT project was funded by the European Commission Framework Programme Seven (FP7) initiative under contract No. 278981 ‘ANGIOPREDICT’ Science Foundation Ireland under grant 13/CDA/2183. Irish Cancer Society Fellowship award CRF13DAS. Flemish Research Foundation ‘Kom op tegen kanker’ (grant 419.052.173). FWO-F (grant G070615N). State of Baden-Württemberg for “Center of Geriatric Biology and Oncology (ZOBEL)—Perspektivförderung” and “Biology of Frailty —Sonderlinie Medizin”.
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.
Physics | Physiology
Smeets D, Miller IS, O'Connor DP, Das S, Moran B, Boeckx B, Gaiser T, Betge J, Barat A, Klinger R, van Grieken NCT, Cremolini C, Prenen H, Mazzone M, Depreeuw J, Bacon O, Fender B, Brady J, Hennessy BT, McNamara DA, Kay E, Verheul HM, Maarten N, Gallagher WM, Murphy V, Prehn JHM, Koopman M, Punt CJA, Loupakis F, Ebert MPA, Ylstra B, Lambrechts D, Byrne AT. Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy. Nature Communications. 2018;9(1):4112.
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