Abstract
Bevacizumab was the first molecular-targeted antiangiogenic therapy approved for the treatment of metastatic colorectal cancer. Until now, there are no predictive biomarkers available to decide the prescription of bevacizumab in patients with colorectal cancer. The purposes of this review were to provide a critical appraisal of the evidence and to identify possible predictive genetic biomarkers. A literature search was performed to identify studies that determine different levels of treatment response between patients stratified according to defined biomarkers. Interesting findings were reported between patients stratified according to rs3025039 and rs833061 polymorphisms of the gene VEGFA, with statistically and clinically significant differences for progression-free survival and overall survival. However, another study conducted in a larger sample does not confirm these previous findings, suggesting that well-designed prospective studies are still needed to achieve conclusive results. FLT1 (or VEGFR1) rs9513070 seems to be an interesting candidate as a predictive biomarker, with differences of more than 10 months in OS between different patients groups. In our opinion, possible interesting biomarker candidates for future research could be the polymorphisms rs833061 and rs3025039 of VEGF-A, rs9513070 or haplotype analysis of FLT1, rs2661280 of RGS5, rs444903 and rs6220 of EGF and Ang-2 or LDH plasma levels.
Introduction
Colorectal cancer represents the third most common cancer in men (746,000 cases, 10.0% of the total diagnosed cancer cases) and the second in women (614,000 cases, 9.2% of the total) worldwide, with 694,000 deaths every year [1]. Over the last years, new biological therapies were approved for the treatment of patients with metastatic disease.
Bevacizumab was the first molecular-targeted antiangiogenic therapy approved by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). This monoclonal antibody binds specifically to the circulating vascular endothelial growth factor A (VEGFA), which inhibits tumor angiogenesis [2, 3]. The increased expression of VEGFA has been found in most human cancers examined, including colon cancer [4, 5].
In metastatic colorectal cancer (mCRC), bevacizumab has been shown to increase the overall survival (OS), the progression-free survival (PFS) and the response rate (RR) in a first-line treatment associated with 5-fluorouracil/leucovorin/irinotecan and in combination with 5-fluorouracil/leucovorin, or capecitabine alone [6–9]. Bevacizumab has also been shown to improve the PFS in combination with fluoropyrimidines plus oxaliplatin in the first-line treatment of mCRC [10]. The combination of oxaliplatin/irinotecan/calcium folinate/fluoruracil (FOLFOXIRI) plus bevacizumab has shown better PFS and RR than irinotecan/folinate/fluoruracil (FOLFIRI) plus bevacizumab. Furthermore, the combined therapy with FOLFOXIRI plus bevacizumab produces one of the longest survivals reported up to date [11]. Therefore, bevacizumab added to standard chemotherapy is recommended as a first-line treatment for patients with potentially resectable and unresectable metastatic disease [12, 13].
According to clinical practice guidelines [12, 13] and the European public assessment report from the EMA [14], there are no predictive biomarkers currently available to decide the prescription of bevacizumab in patients with colorectal cancer. Concordantly, prescribing information approved by the FDA does not indicate the use of predictive biomarkers in clinical practice [15]. The purposes of this review were to provide a critical appraisal of the current evidence and to identify potential predictive genetic biomarkers, which can be considered as adequate candidates for future research.
Methods
A literature search was performed in PubMed, including the following terms: bevacizumab, avastin, genotype, genotypes, phenotype, phenotypes, polymorphism, single nucleotide polymorphism, SNP, SNPs, genetic biomarker, biomarker, colorectal neoplasm, colorectal neoplasms, colorectal tumor, colorectal tumors, colorectal carcinoma, colorectal carcinomas, colorectal cancer and colorectal cancers. Relevant references from included manuscripts were revised to expand the initial search.
We include controlled or uncontrolled clinical trials and prospective or retrospective cohort studies. By contrast, case series studies were excluded from the review.
Studies must have included patients with mCRC that received bevacizumab associated with standard chemotherapy as a first or a second-line treatment. We include studies with dosage regimen of 5–10 mg/kg of body weight administered intravenously ever 2–3 weeks.
The efficacy outcomes considered were as follows: tumor response measured by response evaluation criteria in solid tumors; PFS, defined as the time from the beginning of bevacizumab treatment, or randomization, until progression or death from any cause; and OS, defined as the time from the start of treatment with bevacizumab, or randomization, until death from any cause. Single nucleotide polymorphism (SNP), haplotypes and/or products of gene expression were considered as genetic biomarkers.
Results
The search, last performed at March 30, 2015, identified 117 previous studies that were evaluated for inclusion based on title and/or abstract review. Then 16 studies comprising 1612 patients were included [16–29]. Studies included with positive results are summarized in Table 1, and negative results are commented throughout the text. Five studies were excluded because of the inclusion of patients with demographic characteristics out of the scope of this review [30], a low sample size [31–33], or PFS and OS were not evaluated [34].
Evidence summary of biomarkers candidates in patients with colorectal cancer treated with bevacizumab plus chemotherapy.
| Biomarker | Phenotype or Genotype | Study design | PFS (median months) | OS (median months) | References |
|---|---|---|---|---|---|
| Vascular endothelial growth factor (VEGF-A) | rs3025039 | Retrospective (n=89) | C/C=15.0 C/T+T/T=7.0 HR=not informed p=0.044 | C/C=29.1 C/T+T/T=19.7 HR=not informed p=0.016 | [16] |
| rs25648 | Prospective (n=45) | Not significant | Median values not informed HR=3.58 p=0.004 | [21] | |
| rs35569394, rs35569394, rs1005230, rs35864111, rs833061 | Prospective (n=40) | Haplo2/Haplo21=9.0 Other Haplotypes=15.4 HR=2.64 p=0.02 | No significant | [24] | |
| rs13207351 | Prospective (n=40) | G/G=8.9 G/A+A/A=15.4 HR=3.53 p=0.007 | No significant | [24] | |
| rs1570360 | Prospective (n=40) | G/G=9.8 G/A+A/A=16.0 HR=3.53 p=0.03 | No significant | [24] | |
| rs833061 | Retrospective (n=111) | C/C=12.8 C/T=10.5 T/T=7.5 p=0.0046 | C/C=27.3 C/T=20.5 T/T=18.6 p=0.038 | [27] | |
| Vascular endothelial growth factor (VEGFR2) | rs12505758 | Prospective (n=424) | C/C=10.7 C/T=9.5 T/T=10.9 (reference) HR=1.34 (C/T) and 1.57 (C/C) p=0.045 | No significant | [25] |
| MicroRNA-126 (cir-miRNA-126) | cir-miRNA-126 plasma levels | Prospective (n=68) | Above median levels=9.3 Below median levels=7.3 HR=0.53 p=0.02 | – | [17] |
| miRNA-126 levels in tumor sample | Prospective (n=89) | High expression increase PFS compared with low expression p=0.005 | Not informed | [22] | |
| Angiopoietin-2 (Ang-2) | Ang-2 plasma levels | Prospective (n=177) | – | Ang-2 levels≤5 ng/mL=26.2 Ang-2 levels>5 ng/mL=17.8 HR=1.59 p=0.0065 | [18] |
| Lactate dehydrogenase (LDH) | LDH plasma levels | Prospective (n=177) | – | ≤350 vs. >350 ULN HR=1.60 p=0.03 | [18] |
| Fms-related tyrosine kinase 1 (FLT1) | rs9513070 | Prospective (n=125) | 8.7 vs. 6.6 HR=0.50 p=0.012 | A/A=26.4 A/G+G/G=16.1 HR=0.64 p=0.072 | [19] |
| rs9513070/rs9554320/rs9582036 haplotype | Prospective (n=125) | GCA haplotype=6.6 Others haplotypes=8.6 HR=1.82 p=0.004 | GCA haplotype=16.1 Others haplotypes=25.4 HR=2.86 p=0.041 | [19] | |
| Platelet-derived growth factor receptor-β (PDGFR-β) | rs2302273 | Retrospective (n=424) | C/C=9.9 C/T+T/T=11.1 HR=0.76 p=0.016 | No significant | [20] |
| Regulator of G-protein signaling 5 (RGS5) | rs2661280 | Retrospective (n=424) | No significant | G/G=23.5 C/G+C/C=28.6 HR=1.43 p=0.044 | [20] |
| CD133 | rs3130 and rs2086455 | Prospective (n=91) | C/C+C/C or C-T/T+C/T=18.5 C/C in one polymorphism + C/T or T/T in the other=9.8 | No significant | [23] |
| Hypoxia-inducible factor-1α (HIF-1α) | rs11549465 | Prospective (n=132) | T/T+C/T=11.7 C/C=10.2 HR=0.55 p=0.038 | No significant | [26] |
| Epidermal growth factor (EGF) | rs444903 | Prospective (n=132) | No significant | G/G+G/A=32.4 A/A=21.9 HR=0.54 p=0.011 | [26] |
| rs6220 | Prospective (n=132) | No significant | G/G+G/A=32.4 A/A=22.1 HR=0.51 p=0.005 | [26] |
Most relevant results are shown in bold. PFS, progression-free survival; OS, overall survival; HR, hazard ratio; ULN, upper limit of normal; Haplo 2, VEGF -2578, -1512, -1451, -1411, -460 C-18 bp deletion-C-5 G-T haplotype.
Vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR2)
VEGFR1 and VEGFR2 receptors are the main mediators of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. Therefore, an intuitive strategy to identify predictive genetic biomarkers is to look at the VEGFR genes because they are directly related to the mechanism of action of bevacizumab. In line with this, the VEGFA gene is also an interesting candidate because bevacizumab binds specifically to this factor.
A retrospective study that included 89 patients showed an association between VEGFA rs3025039 and the elapsed time until treatment failure, OS and PFS. Patients with CC genotype showed a better response to treatment in all variables when compared with C/T and T/T genotypes (Table 1) [16].
Another retrospective study additionally analyzed VEGFA rs833061, rs2010963, rs699947 and rs3025039 in 111 consecutive mCRC patients treated with a first-line FOLFIRI plus bevacizumab. This study showed a significant association between rs833061 polymorphism and PFS, and also with OS (Table 1): patients with T/T genotype presented a poor prognosis compared with alternative genotypes. However, no significant associations were found for rs3025039 SNP [27], in contrast to the aforementioned study (Table 1).
Twelve SNPs related to angiogenic pathways were analyzed in 125 patients treated with a first-line cytotoxic chemotherapy plus bevacizumab. The VEGFA rs833061 T/T was associated with better overall RR compared with its alternative genotypes (75.9% vs. 50.8%; p=0.008), although no significant correlation was found regarding PFS and OS [19]. These results are discordant with the study of Loupakis et al. [27], in which patients with rs833061 T/T genotype had a reduced PFS and OS (median values) when compared with C/C and C/T genotypes (Table 1).
Two additional studies with reduced sample size (40 and 45 patients) found some positive associations between certain VEGFA SNPs and PFS (Table 1) [21, 24]. One of these two studies reports a significant relation between rs25648 and OS but not with PFS (Table 1) [21].
A total of 424 patients receiving bevacizumab-containing regimens were included in a prospective study that analyzed VEGFA (rs833061, rs699946 and rs699947), VEGFR1 (rs9582036 and rs7993418), and VEGFR2 (rs11133360, rs12505758 and rs2305948). No significant differences were found for VEGFA rs833061 polymorphism. Patients stratified according to rs12505758 showed a statistically significant association with PFS, although it does not seem to be as clinically meaningful (Table 1) [25].
Fms-related tyrosine kinase 1 (FLT1 or VEGFR1)
This gene encodes for a member of the VEGFR family and plays an important role in angiogenesis and vasculogenesis. This receptor is found to be expressed in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes.
A prospective study, including 125 patients, showed higher PFS and OS means in patients with FLT1 rs9513070 A/A genotype when compared with G/A and G/G genotypes (8.7 vs. 6.6 months and 26.4 vs. 16.1 months, respectively). In the haplotype analysis, the FLT1 rs9513070/rs9554320/rs9582036 GCA haplotype was significantly associated with lower PFS and OS when compared with other genotypes (Table 1) [19].
MicroRNA-126 (cir-miRNA-126)
Cir-miRNA-126 is a short noncoding RNA molecule expressed only in endothelial cells and related to angiogenesis regulation. This molecule was identified as a predictive biomarker in a prospective study that included 68 patients treated with a first-line chemotherapy combined with bevacizumab. Patients with increased baseline miRNA-126 plasma levels showed a better PFS when compared with patients with plasma levels below the median value. Likewise, patients with decreasing miRNA-126 levels from baseline to their first clinical evaluation showed a borderline significant increase in the PFS than patients with increasing levels (Table 1) [17].
A prospective study with 230 patients from a randomized phase III study analyzed miRNA-126 expression in tumor samples. Concordantly with the previous study [17], a high tumor expression of miRNA-126 was significantly related to a longer PFS. Patients stratified according to miRNA-126 A24G SNP did not show significant differences (Table 1) [22].
Angiopoietin-2 (Ang-2)
Plasma levels of Ang-2, a vascular growth factor, were determined retrospectively in 177 patients enrolled in two phase II single-arm clinical trials, who were treated with bevacizumab containing chemotherapy. Increased Ang-2 plasma levels were identified as a significant independent OS prognostic factor. Accordingly, patients with plasma levels below or equal to 5 ng/mL showed an increase of 8.4 months in median OS compared with patients with higher Ang-2 plasma levels (Table 1) [18].
Lactate dehydrogenase (LDH)
LDH gene encodes a protein that catalyzes the conversion of L-lactate and NAD to pyruvate and NADH in the final step of anaerobic glycolysis. The protein is found predominantly in muscle tissue and belongs to the LDH family.
The study mentioned in the previous paragraph also reported LDH plasma levels as an independent OS prognostic factor. Patients with higher levels showed an increased risk of death compared with patients with lower levels (Table 1) [18].
Platelet-derived growth factor receptor-β (PDGFR-β)
PDGFR-β gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. The PDGFR-β rs2302273 was analyzed as a predictive marker in a prospective study, including 424 patients. No significant relation was found for OS, but by contrast, a positive correlation with limited clinical significance was identified for PFS. Patients with C/C genotype showed a reduced PFS mean compared with individuals with C/T and T/T genotypes (9.9 vs. 11.1 months, respectively) (Table 1) [20].
Regulator of G-protein signaling 5 (RGS5)
This gene encodes for a member of the regulators of G-protein signaling (RGS) family, which is involved in the induction of endothelial apoptosis. A correlation between SNP rs2661280 and OS was also found in the aforementioned study [20]. In this case, patients with C/C and C/G genotypes showed an increased OS median compared with patients with G/G genotype, although no significant results were identified for PFS (Table 1) [20].
Promin 1 (PROM1)
This gene, also known as CD133, encodes a pentaspan transmembrane glycoprotein, which is often expressed on adult stem cells, where it is thought to play a role in the maintenance of stem cell properties by suppressing differentiation. In a prospective study that included 91 patients, a haplotype analysis (SNPs rs3130 and rs2086455) was correlated with PFS but not to OS (Table 1) [23].
Hypoxia-inducible factor-1α (HIF-1α)
This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. A prospective study showed a significant association between patients stratified according to rs11549465 and PFS, but not with OS (Table 1) [26].
Epidermal growth factor (EGF)
EGF gene encodes a member of the EGF superfamily, which has been associated with the growth and progression of certain cancers. A prospective study with 132 patients showed that subjects with rs444903 G/G and G/A genotypes had a significant higher OS mean if compared with C/C genotype patients, although the correlation was not found for PFS. Similar results were reported for patients stratified according to rs6220 variant (Table 1) [26].
It is important to consider negative results when designing future research. In this sense, a retrospective study that includes 89 patients did not find significant results for the HIF-1α gene polymorphisms. Considering the study design and the limited number of patients, these results should not be considered as conclusive [16]. Moreover, a retrospective study by Volz et al. [20], which includes 424 patients, does not show differences in PFS or OS between patients stratified according to RGS5 rs1056515, PDGFR-β rs2229562, CSPG4 rs8023621, CSPG4 rs1127648, RALBP1 rs10989 and RALBP1 rs329007.
Loupakis et al. [29] found some interesting differences in PFS and OS between patients stratified according to different SNPs of VEGF and VEGFR-2 genes, but no statistical significance was found, probably because of the low number of patients included (n=54). Similar results without statistical significance were reported for the ANXA11 rs1049550 variant in a prospective study with 100 patients [28].
The study of Bates et al. [35] analyzed VEGF(165)B isoform levels relative to total VEGF in tumor samples of patients treated with bevacizumab. The low VEGF(165)B:VEGF(total) ratio may be a predictive marker for bevacizumab in mCRC, with individuals with high relative levels may not benefit from the treatment.
Discussion
Some interesting findings were reported in patients stratified according to rs3025039 and rs833061 VEGFA polymorphisms, showing statistically and clinically significant differences for PFS and OS [16, 27]. However, these results could not be confirmed in another study with a large sample size [25], suggesting that future well-designed prospective studies are needed.
FLT1 (or VEGFR1) rs9513070 seems to be an interesting candidate as a predictive biomarker because 10-month differences in OS mean were found between different patients’ groups. Similar results were also reported in the same study for patients stratified according different haplotypes [19].
Tumor cells and tumor-associated stroma secrete a variety of pro-angiogenic factors that activate endothelial cells on nearby blood vessels, thus promoting angiogenesis via a complex series of events [36]. VEGF, the most prominent of these proangiogenic factors and the target of bevacizumab treatment, is the main candidate as a predictive biomarker. In particular, bevacizumab targets only VEGFA, with other redundant VEGF family members remaining active [37], which may explain the inconsistency between studies. However, some discrepancies could also be explained due to studies with inadequate designs to analyze the pretended differences.
The absence of conclusive results could be related to the existence of multiple angiogenesis pathways, suggesting that a more comprehensive biomarker analysis is needed. Although some positive results are reported, it is not possible to suggest a genetic testing for clinical decision-making process. Larger well-designed randomized controlled trials as well as larger prospective studies are required in order to obtain conclusive results. In our opinion, the polymorphisms rs833061 and rs3025039 of VEGFA, rs9513070 or haplotype analysis of FLT1, rs2661280 of RGS5, rs444903 and rs6220 of EGF, and Ang-2 or LDH plasma levels could be considered as potential biomarkers for future research.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This work was partially supported by the National Agency of Innovation and Research of Uruguay and the National Researchers System of Uruguay.
Employment or leadership: Nicolás González-Vacarezza is employee of Roche International LTD.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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