Biomarker Signatures Correlate with Clinical Outcome in Refractory Metastatic Colorectal Cancer Patients Receiving Bevacizumab and Everolimus

Abstract

A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-a, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFb-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P ¼ 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-a, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFb-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology.

Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody, TRC105

“…In the current trial, we detected a significant increase of PlGF (P < 0.0001) at C1D8 after the BEV monotherapy lead-in (Supplementary Table S2). This increase aligns with PlGF increases after BEV monotherapy treatment for 1 month, shown in Table 2 and in previous reports (7,12). After addition of TRC105 to BEV, PlGF levels at C2D1 remained significantly higher than baseline levels.…”

“…Identification of soluble biomarkers that predict benefit from the combination would allow enrichment of more responsive patients. To assess many of the key regulators of tumor angiogenesis, inflammation, and matrix remodeling, we developed a multiplex protein array, termed the Angiome (12)(13)(14)(15). We have taken a systematic approach to the development of this array, developing high-quality assays that have excellent sensitivity and yield reproducible results.…”

Insulin growth factor binding protein 2 mediates the progression of lymphangioleiomyomatosis

“…IGFBP2 also acts independently of IGF1 or IGF2 to modulate cell proliferation, invasion and survival through interaction with integrins, integrin-linked kinase and NF-κB [14]. Recently, IGFBP2 has been identified as a potential and valuable biomarker in malignancies including breast cancer [15], ovarian cancer [16], colorectal cancer [17, 18], glioblastoma [19], lung cancer [20, 21], prostate cancer [22], and gastric cancer [25]. Studies have shown that IGFBP2 plays pivotal roles in the pathogenesis of smooth muscle cell tumors [23–25].…”

Correlation Between IGFs-Related Proteins Expression and Incidence of Colorectal Cancer in Diabetic Patients and Related Mechanisms

“…Nearly 1.5 million people are diagnosed with colorectal carcinoma each year, making it the second most common cancer in industrial countries [ 2 ]. The incidence of colorectal cancer in China is higher in urban than non-urban areas [ 3 ], possibly due to lifestyle transitions [ 4 ]. In urban areas, the incidence and mortality of colorectal cancer stay at relatively high levels, affecting human health [ 5 ].…”