Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy

• DOI: 10.1038/s41467-018-06567-6
• Publication Date: 2018-10-01T14:27:20Z
• Authors: Dominiek Smeets; Ian S. Miller; Darran P. O’Connor; Sudipto Das; Bruce Moran; Bram Boeckx; Timo Gaiser; Johannes Betge; Ana Barat; Rut Klinger; Nicole C. T. van ...; Chiara Cremolini; Hans Prenen; Massimiliano Mazzone; Jeroen Depreeuw; Orna Bacon; Bozena Fender; Joseph Brady; Bryan T. Hennessy; Deborah A. McNamara; Elaine Kay; Henk M. Verheul; Neerincx Maarten; William M. Gallagher; Verena Murphy; Jochen H. M. Prehn; Miriam Koopman; Cornelis J. A. Punt; Fotios Loupakis; Matthias P. A. Ebert; Bauke Ylstra; Diether Lambrechts; Annette T. Byrne
• Keywords: Male; Adenocarcinoma; Aged; Animals; Antineoplastic Agents, Immunological; Bevacizumab; Chromosomal Instability; Colorectal Neoplasms; Female; Humans; Male; Mice; Middle Aged; Retrospective Studies; Xenograft Model Antitumor Assays; DNA Copy Number Variations; DNA Copy Number Variations; MICROSATELLITE INSTABILITY; Science; CHROMOSOMAL INSTABILITY; Adenocarcinoma; Article; Mice; 03 medical and health sciences; Antineoplastic Agents, Immunological; 0302 clinical medicine; BURROWS-WHEELER TRANSFORM; Chromosomal Instability; Animals; Humans; Aged; Retrospective Studies; Science & Technology; COLON-CANCER; Q; RANDOMIZED PHASE-III; Middle Aged; Xenograft Model Antitumor Assays; READ ALIGNMENT; 3. Good health; Multidisciplinary Sciences; Bevacizumab; ENDOTHELIAL GROWTH-FACTOR; Science & Technology - Other Topics; CONSENSUS MOLECULAR SUBTYPES; Female; 1ST-LINE THERAPY; Colorectal Neoplasms; Engineering sciences. Technology; PLUS BEVACIZUMAB

Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers bevacizumab (BVZ) response in metastatic colorectal (mCRC). We cluster 409 mCRCs three subclusters characterized by different degrees CIN. Tumors belonging to intermediate-to-high clusters improved outcome following chemotherapy plus BVZ versus alone. In contrast, low tumors, which amongst others consist POLE-mutated and microsatellite-instable derive no further benefit from BVZ. This is confirmed 81 mCRC tumors the phase 2 MoMa involving CNA overlap CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond respond FOLFOX mouse avastin (B20), while CMS1/3 match fail respond. Overall, identify load a novel predictive biomarker combination therapy.