Abstract
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.
Highlights
When classifying tumors as CIN-high or CIN-low based on the 25% threshold, we observed a significantly improved progression-free survial (PFS) for CIN-high tumors treated (P = 1.99 × 10−3; hazard ratios (HRs) = 0.28; CI 0.12–0.63, Cox regression) (Fig. 7b)
We assessed the relevance of copy number aberrations (CNAs) in predicting outcome of BVZ combination therapy in mCRC
Our analysis revealed an overlap between consensus molecular subtypes (CMS) subtypes and CNA clusters, with an enrichment of CMS1/3 in CNA cluster 1 and CMS2/4 in CNA clusters 2 and 3
Summary
Patients with advanced (locally irresectable or metastatic) CRC commencing combination chemotherapy involving BVZ between July 2004 and April 2012 were included in this study. The follow-up period for the UHEI, VUMC and RSCI cohorts started on July 28, 2004, September 7, 2004, and August 18, 2004, respectively. Most tumor tissues selected were collected at diagnosis of a metastatic CRC (n = 166), but a minority was collected before metastatic disease relapse, i.e., at the time of resection of an early stage CRC (for which they developed a metastatic relapse; n = 108) For the latter patients, we considered tumor characteristics collected at the time of resection, while treatment data (involving BVZ plus chemotherapy) and outcome were considered for metastatic disease relapse
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