| VEGF |
At least 10 studies correlate VEGF plasma or urine levels with clinical outcome, yielding controversial results. Higher baseline levels correlate positively with PFS1,2 or response3 and negatively with PD,4,5 but also lower VEGF baseline levels correlate with longer PFS6 or TTP.7 Larger increase of VEGF levels under treatment was observed in patients with PR versus patients with SD/PD,8 opposed by another study showing that >50% reduction in VEGF levels under treatment correlates with higher response rate and longer OS.9 Higher baseline urine VEGF levels can correlate with PR/SD10 or shorter survival in another study.11 Seven studies show no correlation of changes in VEGF plasma levels with clinical outcome or tumor response.3,12-17 |
| sVEGFR-2 |
Larger increase of sVEGFR-2 plasma levels under treatment correlate with PD13 but also conversely with tumor size reduction.18 Larger decrease of sVEGFR-2 plasma levels was found in patients with PR versus SD/PD.8 Changes in sVEGFR-2 correlate to tumor shrinkage.19 In 3 trials, sVEGFR-2 levels were not correlated with clinical outcome.2,12,16 |
| sVEGFR-3 |
Lower baseline levels of VEGFR-3 and a greater reduction of sVEGFR-3 plasma levels under treatment were found in patients with PR or longer PFS.8,14,20
|
| bFGF |
Significant increase in plasma bFGF levels in patients correlates with PD or shorter OS under treatment.13,15 Five studies show no correlation of bFGF plasma or urine levels with clinical outcome.3,5,10,11,18 |
| PlGF |
Significant decrease in plasma PlGF correlates with PD13 and increase in serum PlGF with tumor size reduction.18 Baseline PlGF correlates with tumor reduction upon treatment.19 In 1 study, no correlation of PlGF plasma levels with PFS or OS14 was found. |
| Others |
Initial correlations for IL-8, SDF1α, VEGF-C, and PDGF-bb with clinical outcome were established, which still need confirmation.1,13,14,20
|
| Circulating Cells |
|---|
| CECs |
Six trials showed clinical correlations for CECs as biomarkers.12,13,21-24 Some of the results remain controversial. In 2 trials, an increase of CECs under treatment correlates with shorted PFS22 or PD,13 and 1 trial conversely correlated this with clinical benefit (PFS >6 months).12 Higher baseline CECs correlate with clinical benefit and longer PFS,23 and change in CECs under treatment correlates with response.24 More activated CECs are found in patients with PD and more resting CECs in patients with PR at then end of treatment.21 One trial showed no correlation of CEPs (CD133+) with clinical outcome.21 |
| CTC |
In 1 trial, the magnitude of change of CTCs under treatment correlates with response to treatment.24 One trial found no correlation of CTCs with PFS.22 |
| Functional Imaging |
|---|
| DCE-MRI |
Four trials correlate greater reduction in vascularity, vascular permeability, or tumor blood flow at different time points with better clinical response,25 longer PFS,26 or SD.27,28 Two studies showed no correlation of changes in vascular permeability with TTP, PFS, or OS upon treatment.29,30 |
| PET |
A decrease in FDG (18F-fluoro-2-deoxyglucose) uptake (18FDG-PET) and a reduced tumor perfusion is correlated with a longer TTP under treatment.30 Response in FLT-PET (18F-fluorothymidine-PET) at different time points correlates significantly with OS in treated patients.31
|
| Others |
|---|
| SNPs |
Superior median OS with the VEGF -2578 AA genotype or the VEGF -1154 A allele.32 Higher response rate in patients with IL-8 -251 TT genotype.33
|
| BP |
Longer OS in patients with grade 3 or 4 hypertension32 or dBP >90 mm Hg34 upon treatment. |
| Conclusions |
|---|
Currently, there is no biomarker available to predict clinical outcome consistently. Almost all candidate biomarkers were evaluated in rather small single-arm studies, and thus it is difficult to distinguish between predictive and prognostic biomarkers. Consequently, large randomized studies and independent validation of the candidate markers are warranted. Functional imaging seems promising as direct treatment effects can be observed in vivo, whereas circulating proteins and cells might not directly represent tumor response. More standardization is needed to enhance the pace of discovery of valid biomarkers (treatment, tumor entities, time points, biomarker definition sample source, etc.). |
