Importance
Individual variation in response and duration of anti–vascular endothelial growth factor (VEGF) therapy is seen among patients with neovascular age-related macular degeneration. Identification of genetic markers that affect clinical response may result in optimization of anti-VEGF therapy.
Objective
To evaluate the pharmacogenetic relationship between genotypes of single-nucleotide polymorphisms (SNPs) in the VEGF signaling pathway and response to treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration.
Design, Setting, and Participants
In total, 835 of 1149 patients (72.7%) participating in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) at 43 CATT clinical centers.
Intervention
Each patient was genotyped for 7 SNPs in VEGFA (rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, and rs2146323) and 1 SNP in VEGFR2 (rs2071559) using TaqMan SNP genotyping assays.
Main Outcomes and Measures
Genotypic frequencies were compared with clinical measures of response to therapy at 1 year, including the mean visual acuity, mean change in visual acuity, at least a 15-letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on optical coherence tomography, presence of leakage on fluorescein angiography, mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. The method of controlling the false discovery rate was used to adjust for multiple comparisons.
Results
For each of the measures of visual acuity evaluated, no association was observed with any of the genotypes or with the number of risk alleles. Four VEGFA SNPs demonstrated an association with retinal thickness: rs699947 (P = .03), rs833070 (P = .04), rs1413711 (P = .045), and rs2146323 (P = .006). However, adjusted P values for these associations were all statistically nonsignificant (range, P = .24 to P = .45). Among the participants in 2 as-needed groups, no association was found in the number of injections among the different genotypes or for the total number of risk alleles. The effect of risk alleles on each clinical measure did not differ by treatment group, drug, or dosing regimen (P > .01 for all).
Conclusions and Relevance
This study provides evidence that no pharmacogenetic associations exist between the studied VEGFA and VEGFR2 SNPs and response to anti-VEGF therapy.
Trial Registration
clinicaltrials.gov Identifier: NCT00593450
Vascular endothelial growth factor (VEGF) inhibition by ranibizumab, bevacizumab, or aflibercept therapy has dramatically improved the treatment of neovascular age-related macular degeneration (nAMD). VEGF has a key role in the regulation of angiogenesis, vascular leakage, and inflammation that are characteristic of nAMD by stimulating growth of new blood vessels.1,2 Results from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and other multicenter clinical trials that compared ranibizumab and bevacizumab indicate that both drugs provide dramatic and lasting visual improvement in patients.3-6 However, individual variation exists in the initial response to therapy and in the durability of the clinical effect.
One logical explanation for the variability in treatment response might be differences in genetic background. It is well established that several genetic risk variants are associated with the development and progression of AMD.7 Recent research on outcomes determinants has focused on the role of these variants in response to anti-VEGF therapy, with inconsistent results.8 It was recently reported that no statistically significant pharmacogenetic association between single-nucleotide polymorphisms (SNPs) rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3) was identified for any clinical outcome among the CATT participants.9 The study provides evidence that, although these 4 SNPs clearly influence AMD risk, they are not responsible for any substantial variation in response to anti-VEGF therapy.
An obvious next strategy to identify pharmacogenetic markers that may predict antiangiogenic therapy is to analyze polymorphisms in genes within the VEGF signaling pathway. VEGF, encoded by the VEGFA gene (Online Mendelian Inheritance in Man [OMIM] 192240), acts through specific tyrosine receptors, of which VEGFR-2 mediates most of the angiogenic effects of VEGF. Results of numerous studies10-16 suggest that genetic variations in VEGFA and VEGFR2 (OMIM 191306) may have a role in the pathogenesis of AMD; however, other studies12,17-19 have shown no association. A recent meta-analysis20 designed to clarify the association between VEGFA polymorphisms and AMD demonstrated no such association but showed a different association for each polymorphism among various patient populations.
Polymorphisms in the VEGFA gene regulate VEGF expression and its angiogenic properties.21,22 Therefore, it is plausible that different expression levels of VEGF may generate different responses to anti-VEGF drugs. Genetic variants in the VEGFA and VEGFR2 genes have been studied in small-scale investigations for their influence on anti-VEGF treatment outcomes, with different conclusions. One study23 reported a trend toward a better visual outcome after 6 months of ranibizumab treatment in those harboring the risk genotypes at VEGFA SNP rs1413711 compared with those having the nonrisk genotype. However, another study24 found no association between SNP rs1413711 and visual acuity (VA) outcome after treatment. A Japanese study25 reported that SNP rs699946 in the VEGFA gene is associated with a better VA response after 12 months of bevacizumab treatment. Other investigators concluded that SNP rs3025000 was associated with better visual outcomes at 6 months of anti-VEGF treatment.26 A recent study27 evaluating 2 VEGFA SNPs and response to ranibizumab showed that rs699947 determines early functional outcome. Finally, a study28 evaluating 7 VEGFA polymorphisms demonstrated that none are a major predictor of anti-VEGF treatment success with bevacizumab in patients with nAMD. The collective weaknesses of these studies are their small sample size, the variability in treatment paradigms, and the nonstandardized assessment of outcomes measures.
The large cohort of patients treated with anti-VEGF drugs for nAMD in the CATT, along with the many outcomes determinants that were collected following standardized protocols, renders this study population an ideal group in which to evaluate the effects of genetic polymorphisms on treatment response. We investigated the pharmacogenetic relationship between the clinical outcomes of anti-VEGF treatment and 8 SNP variations in the VEGFA and VEGFR2 genes among 835 CATT study participants. The SNPs selected were based on their potential effect on VEGF expression, their associations with nAMD in previous investigations, and their possible influence on anti-VEGF treatment outcome in nAMD or other VEGF-mediated diseases. A comprehensive analysis of genotypic associations with visual and anatomical outcomes evaluated by treatment group, drug, and dosing regimen is described.
Institutional review board approval was obtained from the Cleveland Clinic and all participating CATT clinical centers. Written informed consent was obtained from all CATT participants involved in the genetics ancillary study. Study procedures for the CATT have been previously reported and are available at clinicaltrials.gov (identifier NCT00593450).3 All analyses investigating the effect of genotype on response to treatment were evaluated using outcomes data at 1 year to minimize confounding factors that may occur at later time points in the trial, such as the second randomization at the end of 1 year. Furthermore, most response in morphological and visual outcomes occurred within the first 6 months of treatment.3
Between February 20, 2008, and December 9, 2009, a total of 1185 patients with nAMD were enrolled in the CATT at 43 clinical centers in the United States. Patients were randomly assigned to 1 of the following 4 treatment groups: (1) ranibizumab monthly, (2) bevacizumab monthly, (3) ranibizumab as needed, and (4) bevacizumab as needed. Eligibility criteria and study design for the CATT have been previously defined.3,9 Between July 6, 2010, and October 12, 2011, the genetics ancillary study enrolled 835 of 1149 surviving patients (72.7%). The genetics ancillary study participants were generally comparable to those who were still alive but chose not to participate (n = 314) except that the genetics ancillary study participants were 2 years younger (P < .001) and had better baseline VA (P = .006), a higher percentage with hypertension (P = .04), and a higher percentage with an occult lesion (P = .047).
Measures of Response to Treatment
Clinical measures of response to treatment were based on VA, anatomical features of AMD assessed by optical coherence tomography (OCT) and fluorescein angiography, and the total number of injections given in 1 year. Visual acuities were measured with an electronic VA testing system.29 The mean VA, mean change from baseline in VA, and proportion of patients with at least a 15-letter increase from baseline were the visual measures. The OCT variables were determined by readers using a prospectively defined assessment protocol at an independent OCT Reading Center (Duke University, Durham, North Carolina). The indicators of response to treatment were the proportions of patients with a thin (<120 µm), normal (120-212 µm), and thick (>212 µm) retina, as well as the mean change from baseline in total foveal thickness and the proportion with no fluid (“dry”) on OCT.30 Lesion size and leakage on fluorescein angiography were determined by readers using a prospectively defined assessment protocol at an independent Fundus Photograph Reading Center (University of Pennsylvania, Philadelphia).31 All examiners and readers were masked to treatment assignment.
Approximately 20 mL of peripheral blood was collected from each patient. DNA was extracted and purified from leukocytes as previously described.9 Seven SNPs in VEGFA (rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, and rs2146323) and 1 SNP in VEGFR2 (rs2071559) were evaluated in each patient. Genotyping was performed using custom-made genotyping plates (TaqMan OpenArray loaded with TaqMan SNP genotyping assays; Applied Biosystems) as previously described.9 The genotype assignment was 100.0% for all patients. All laboratory personnel (S.A.H., G.J.T.P., and G.M.S.) were masked to treatment assignment and patient clinical data.
Clinical outcomes were compared among genotypes to determine if an association exists between genotype and response to treatment. The number of risk alleles for each genotype was recorded as 0, 1, or 2, and associations of genotype (in terms of the number of risk alleles) with outcomes were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes at 1 year. To account for multiple comparisons from multiple SNPs and multiple outcomes, we calculated adjusted P values using the false discovery rate approach.32 Because we compared 3 types of outcomes (VA, anatomy, and the number of injections) among genotypes of each SNP and because outcomes in the same type are likely to be highly correlated, we counted the number of tests performed within each type of outcome for the adjustment for multiple comparisons. Specifically, we considered 24 statistical tests performed for VA outcomes (ie, 8 SNPs for 3 VA outcomes), 40 tests for anatomical outcomes, and 8 tests for the number of injections, and we calculated their adjusted P value separately. Adjusted P < .05 was considered statistically significant. Because of the genetic complexity of AMD, we performed a stepwise analysis among the SNPs studied to examine the additive effects based on the total number of risk alleles from 8 SNPs. Five groups were evaluated (0-6, 7, 8, 9 and ≥10 risk alleles).
Data from the CATT provided good power (83%-93%) to detect a mean difference of 2.5 letters in VA and moderate power (56%-71%) to detect a difference of 2 letters in VA associated with 1 risk allele change, under the observed SD of 16 to 18 letters in VA and a false discovery rate of 0.05. For anatomical outcomes, the CATT data provided good power (>80%) to detect a difference of 0.07 or more in the proportion associated with the addition of 1 risk allele.
We evaluated 835 CATT participants who were treated with anti-VEGF therapy across 8 SNPs within the VEGF signaling pathway. Seven polymorphisms are located in the VEGF gene (VEGFA) and 1 in its primary signaling receptor (VEGFR2). Patient demographics and baseline characteristics of all CATT participants have been previously described.9 In brief, the mean (SD) age of the patients at study entry was 78.5 (7.5) years, and 61.2% of patients were female. The mean (SD) baseline VA was 61.3 (13.3) Early Treatment of Diabetic Retinopathy Study letters (Snellen equivalent, approximately 20/63).
Genotypic frequencies for each SNP analyzed were balanced across treatment groups. For each measure of response to treatment, we assessed the interaction between genotypes and treatment group. The effect of risk alleles on each clinical measure did not differ by treatment group, drug, or dosing regimen (P > .01 for all). Therefore, we collapsed all treatment groups and report our findings on the entire 835 patients as a single group (Table 1 and Table 2).
For each of 3 vision measures evaluated at 1 year, no association was observed with any of the genotypes or with the number of risk alleles from 8 SNPs (Table 1). For each of 5 anatomical measures, few noteworthy associations were found (Table 2). Four VEGFA SNPs demonstrated an association with retinal thickness: rs699947 (P = .03), rs833070 (P = .04), rs1413711 (P = .045), and rs2146323 (P = .006). However, adjusted P values for these associations were all statistically nonsignificant (range, P = .24 to P = .45). Furthermore, none of these modest associations were supported by any other anatomical measure. Finally, among the participants in the 2 as-needed groups, no association was found in the number of injections among the different genotypes for any of 8 SNPs or for the total number of risk alleles from 8 SNPs (Table 1).
Choroidal neovascularization, the hallmark of nAMD, is an angiogenic process that is finely regulated between inhibitory and stimulating factors, such as VEGF. Anti-VEGF drugs are highly effective for the treatment of nAMD3-6,33-35 and induce their therapeutic action by blocking the binding of VEGF to its receptors and subsequent initiation and progression of choroidal neovascularization. Therefore, it is logical to assume that any factor that alters this pathway (eg, a genetic polymorphism) might influence the therapeutic effect of these drugs.
Polymorphisms selected for this study are genetic variants in VEGFA and VEGFR2 that are best known to be associated with clinical outcomes in VEGF-mediated diseases such as nAMD, diabetic retinopathy, and several malignant neoplasms.21 Some of these SNPs are located in the promoter region and are known to influence the expression and plasma concentration of VEGF.22 Others are located within the introns, where putative regulatory elements influence the binding of VEGF to its receptor.11 One SNP is located in the promoter region of the gene encoding for VEGFR-2, the primary receptor responsible for most of the angiogenic effects of VEGF.
The 3 SNPs that we evaluated in the promoter region of VEGFA are rs699946, rs699947, and rs2010963. These variants affect gene splicing, resulting in changes in VEGF expression levels. In a pharmacogenetic study25 analyzing rs699946, the mean VA was significantly better in patients having the GG genotype compared with patients having the AG or AA genotypes after 12 months of treatment with bevacizumab for nAMD. Exploration of rs699947 in patients with nAMD has also suggested pharmacogenetic association, but with inconsistent findings. Results of 2 studies suggest that patients carrying the C allele were less likely to respond to treatment with bevacizumab36 or with photodynamic therapy.37 However, the findings in another study27 suggest that patients homozygous for the C allele show significantly improved VA following ranibizumab injections. The third promoter SNP, rs2010963, increases VEGF expression in the retina.38 Although one study10 has demonstrated an association between the development of AMD and this SNP, another study18 did not confirm this observation. In yet another study,36 no association was detected between rs2010963 and response to bevacizumab.
The 4 SNPs that we evaluated in the intron regions of VEGFA are rs1413711, rs2146323, rs833069, and rs833070. The first of these, rs1413711, is located in intron 1. It has been proposed that the proximity of this SNP to a putative stress response element–binding site may influence VEGF receptor binding and increase protein production.11 Studies11,13 have reported an increased risk of developing AMD in patients homozygous for the CC genotype. In contrast, several other studies16,19,24 did not detect an association. One pharmacogenetic analysis suggested that patients with high-risk genotypes (TC or CC) at this SNP trend toward a better response to ranibizumab.23 However, another study24 did not confirm this result.
The remaining 3 intronic SNPs are located in intron 2. The SNP rs2146323 has been reported to be associated with the development of AMD,10 although another study17 did not confirm these results. This SNP has also been associated with anatomical outcome following photodynamic therapy.37 Polymorphisms rs833069 and rs833070 have also been associated with the development and progression of AMD,10,14 although no pharmacogenetic analysis has been performed to date. However, we believe these are potential targets for modification of response to therapy on the basis of in silico analysis. The Ensembl genome browser indicates that rs833069 and rs833070 are located within a putative regulatory element that is enriched with CCCTC-binding factor and deoxyribonuclease I sites that could affect VEGF expression levels.39 A second bioinformatics program (FastSNP) confirmed this possibility.40
Finally, rs2071559 is located in the gene encoding the primary receptor responsible for most of the angiogenic effects of VEGF (VEGFR2). Investigators have shown that the T allele increases transcription activity of the gene and increases receptor function.15 Individuals homozygous for the T allele have a higher risk for the development of AMD.14
The finding of a lack of any significant associations between SNPs in the VEGF pathway and response to anti-VEGF treatment differs from the results of previous investigations, many of which were limited by small sample size and nonstandardized assessment of outcomes. The strengths of our study include the large prospectively defined cohort of patients with nAMD in the CATT drawn from multiple clinical sites, as well as the well-defined protocols that were used to guide follow-up treatment and determine outcomes. Specifically, all VAs were determined by masked examiners using electronic Early Treatment of Diabetic Retinopathy Study testing, all OCT measurements were determined in a masked fashion by an independent OCT Reading Center, and all photographic and fluorescein angiography outcomes were determined by masked assessment at an independent Fundus Photograph Reading Center. Our findings are supported by a recent report from the Alternative Treatments to Inhibit VEGF in Patients With Age-Related Choroidal Neovascularisation (IVAN) Study Group. This comparable pharmacogenetic study41 evaluated 2 of the same SNPs as in our study (rs833069 and rs833070) and demonstrated no association between an anatomical outcome (total retinal thickness) and genotype.
This study provides evidence that no substantial pharmacogenetic associations exist between the studied VEGFA and VEGFR2 SNPs and response to anti-VEGF therapy in patients participating in the CATT. We cannot exclude the possibility that other SNPs in VEGFA, VEGFR2, or other genes that regulate angiogenesis may be associated with response to therapy. Although identification of markers that affect clinical response may result in optimization of anti-VEGF therapy, no rationale exists to date for modifying therapy in individuals based on their genetic profiles. Additional studies, including a genome-wide analysis, are under way to identify novel polymorphisms that may be associated with response to anti-VEGF therapy in patients with nAMD.
Submitted for Publication: July 12, 2013; final revision received November 11, 2013; accepted December 11, 2013.
Corresponding Author: Stephanie A. Hagstrom, PhD, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (hagstrs@ccf.org).
Published Online: March 20, 2014. doi:10.1001/jamaophthalmol.2014.109.
Author Contributions: Drs Hagstrom and Maguire had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: All authors.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by cooperative agreements U10 EY017823, U10 EY017825, U10 EY017826, and U10 EY017828 from the National Eye Institute.
Role of the Sponsor: National Eye Institute staff assisted but did not direct in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group members are listed in the eAppendix in the Supplement.
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