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

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.

Therapeutic Targeting of the Colorectal Tumor Stroma

“…There have been many studies of gene copy number changes in colorectal tumors; 68 these have also been used to create a CRC classification system, based on chromosome instability. 69 . Copy number load was initially studied as a potential biomarker of response to bevacizumab in patients with metastatic CRC.…”

“…Resistance of tumor cells to drugs (initial or acquired during treatment) poses an constant challenge 156 , and strategies are needed to determine which tumors are most likely to respond to which therapies. Genomic 50,69,[157][158][159][160][161][162][163] and other classes of biomarkers of response have been proposed, 164 but there are no markers that can be used to predict response to anti-angiogenic agents.…”

“…Chromosome instability was reported to be a biomarker of response to bevacizumab in patients with metastatic CRC 69 . Tumors with intermediate to high levels of chromosome instability (clusters 2 and 3) had better responses to chemotherapy with bevacizumab than to chemotherapy alone (prolonging PFS by 149 days for cluster 2 and 85 days for cluster 3).…”

Two immune-enhanced molecular subtypes differ in inflammation, immune checkpoints, mutations and outcome in Stage I-II colonic carcinoma.

“…The C3 subtype is closely related to the CMS4 type (mesenchymal type). For the characteristics of the CMS4 type, tumor matrix infiltrating epithelial cells, tumor-associated fibroblasts (CAFs) and innate immune cells produce more inflammatory factors [24], which may be the reason for the strong immune activity of the C3 subtype. Most of the 13 types of immune metagene are highly expressed in the C3 subtype.…”

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

“…Accordingly, these data suggest that CIN, or more likely, the level of CIN, may confer sensitivity or resistance to specific anti-neoplastic drugs. Researchers have also shown that CIN can predict which patients are most likely to benefit from specific treatments, such as bevacizumab (an anti-angiogenic monoclonal antibody targeting vascular endothelial growth factor A [VEGF-A]), a key drug used in the treatment of colorectal and lung cancers [125]. Based on these collective observations, the authors suggest that the presence and level of CIN may be a useful tool that could assist oncologists in stratifying patient cohorts to distinguish those who will benefit from a given treatment from those who will not.…”