From CENTRAL to SENTRAL (SErum aNgiogenesis cenTRAL): Circulating Predictive Biomarkers to Anti-VEGFR Therapy

Abstract

Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio—HR: 0.73, 95% Confidence Interval—CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46–1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels’ early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.

Circulating PTGS2, JAG1, GUCY2C and PGF mRNA in Peripheral Blood and Serum as Potential Biomarkers for Patients with Metastatic Colon Cancer

“…Furthermore, a positive regulation of PGF in the serum of CRC patients was detected (but not in blood). Our results support the hypothesis of the overactivation of angiogenesis in metastatic CRC disease through several positively regulated pro-angiogenic factors (Figure 5) that can be detected as circulating mRNA [51].…”

“…Furthermore, a positive regulation of PGF in the serum of CRC patients was detected (but not in blood). Our results support the hypothesis of the overactivation of angiogenesis in metastatic CRC disease through several positively regulated pro-angiogenic factors (Figure 5) that can be detected as circulating mRNA [51]. (also termed PGF) may promote angiogenesis in vascular endothelial cells by binding to the VEGF receptor (VEGFR1), thereby increasing the availability of VEGF A for activation of VEGFR2, which exhibits higher kinase activity to induce angiogenesis-promoting signaling and other processes that favor tumor growth.…”

“…Regarding the prediction of treatment response, the expression of the GUCY2C gene in serum was the best marker, being useful in predicting patient response both in those treated with antiangiogenic and without antiangiogenic agents. This approach has also been studied in a prospective analysis of first-line therapy with antiangiogenics by Giampieri et al (2020) [51], who proposed early increase in circulating FGF-2 levels as a biomarker for patients most likely to benefit from this treatment [51]. Previously, also in metastatic colon cancer, increased serum levels of sTRAIL (serum-soluble TNF-related apoptosis-inducing ligand) were proposed as a useful biomarker for early evaluation of patients treated with antiangiogenic agents [64].…”

Serum Lactate Dehydrogenase Before Nivolumab Treatment Could Be a Therapeutic Prognostic Biomarker for Patients With Metastatic Clear Cell Renal Cell Carcinoma

“…McDermott et al studied the gene signature related to angiogenesis, immune and antigen presentation, and myeloid inflammation in RCC tumors, and found that highly angiogenic tumors were more responsive to antiangiogenic therapy, but not ICIs (12). High LDH serum levels as an angiogenic biomarker, indicating the overexpression of vascular endothelial growth factor (VEGF) and VEGF receptor (13), could be related to better outcomes in patients undergoing antiangiogenic treatment (14). Recently, the cancer immunogram has been investigated as a framework for personalized immunotherapy, suggesting that LDH levels could be a biomarker of inhibitory tumor metabolism (e.g.…”

Recent Research on Gastrointestinal Carcinoma

“…Although further studies are needed, variations in FGF2 levels might represent a potential biomarker in patients who are more likely to gain benefit from bevacizumab and other anti-VEGF (vascular endothelial growth factor) drugs. Notably, FGF2 levels seem to reach their highest value just before disease progression during bevacizumab treatment, possibly leading to studies focused on FGF2 inhibition in second-line therapy or subsequent lines of treatment [ 7 ]. Shifting the concept of personalized therapy and the need for predictive biomarkers to the setting of advanced neuroendocrine tumors (NETs), activation of the mTOR pathway and, in particular, the expressions of phosphorylated (p)-mTOR and p70S6-kinase (S6K), a downstream effector of mTOR, can predict better outcomes in patients with NETs of various origins treated with everolimus [ 8 ].…”