anti-VEGF Treatment Response Research Articles

Meta-Analysis of the Pharmacogenetics of ARMS2 A69S Polymorphism and the Response to Advanced Age-Related Macular Degeneration

Age-related macular degeneration (AMD) causes irreversible vision loss, and targeted anti-vascular endothelial growth factor (VEGF) therapy is now the most common and effective treatment. The aim of this meta-analysis is to discuss whether genetic polymorphism of ARMS2 A69S could confer susceptibility to advanced AMD with the response to anti-VEGF treatment. We performed a meta-analysis of relevant published studies selected through electronic databases. A total of 21 preferred studies regarding the association between ARMS2 gene and anti-VEGF treatment response in advanced AMD were generally included in the meta-analysis. The pooled results demonstrated that the carriage of G allele for ARMS2 A69S presented a better clinical prognosis for advanced AMD treated with anti-VEGF drugs (OR = 1.38, 95% CI = 1.13–1.69, p = 0.002). In addition, in the subgroup analysis based on ethnicity, ARMS2 polymorphisms were more likely to be a positive responder for East Asian patients (OR = 1.67, 95% CI = 1.29–2.16, p < 0.001). This meta-analysis through a series of rigorous methodology data demonstrated a significant association between ARMS2 A69S polymorphism and the anti-VEGF treatment response in advanced AMD, especially among East Asian population. Numerous well-designed, randomized, multicenter clinical trials with large sample size are required to validate the association.

Association of a Variant in VWA3A with Response to Anti-Vascular Endothelial Growth Factor Treatment in Neovascular AMD.

PurposeAnti–vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome.MethodsIsraeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108).ResultsLinear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10−5. The top variant in the gene VWA3A (P = 1.77 × 10−6) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was –0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline.ConclusionsAn VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.

Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study

To investigate the inter-individual variability in duration of anti-vascular endothelial growth factor (VEGF) treatment effect in neovascular age-related macular degeneration (nvAMD). Prospective observational multi-centered study. Forty-eight patients with nvAMD treated with anti-VEGF injections were included. Both treatment naive (n=25) as well as patients who had previously received treatment with ranibizumab (n=23) more than one month prior to their enrollment were recruited. Patients received injection with ranibizumab (0.5 mg/0.05 ml) and were followed weekly for 4 weeks with spectral-domain OCT (SD-OCT) assessing the time to maximal reduction of central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Other data collected included age, gender, visual acuity, axial length, lens status, and previous injections. The Shapiro-Wilk test was used to examine normal distributions for all variables. Correlations were examined by calculating Spearman's correlation coeficient. Distributions of quantitative variables are described as means (±SD). Qualitative variables are summarized by counts and percentage. Time to maximal reduction of CRT and intra- and subretinal fluid after ranibizumab injection. A total of 48 eyes of 48 patients (age 74.8±8.3 years, 62.5% female, 52% treatment naive, 35.4% pseudophakic) were assessed. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week postinjection, 22.9% at 2 weeks postinjection, and 35.4% at 3 weeks postinjection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 μm thicker than the earlier occuring lowest CRT value (nadir). The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections. Optimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Most patients will be classified as complete responders if intervals less than 4 weeks are used to assess anti-VEGF treatment response. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and therefore, dosing interval needs to be optimized in the cohort of short-term responders.

Multimodal imaging based biomarkers predictive of early and late response to anti-VEGFs during the first year of treatment for neovascular age-related macular degeneration

To evaluate baseline predictive markers of early and late anatomical response to anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with neovascular age-related macular degeneration (nAMD). The records of the nAMD patients who underwent intravitreal ranibizumab or aflibercept treatment, received the 3 monthly loading doses, and completed a follow-up period of 12 months were included retrospectively. The anatomical treatment response at month 3 (early) and between month 3 and 12 (late) was classified as good, intermediate or poor. Baseline demographic, fluorescein angiography, and optical coherence tomography findings were compared among the three groups. One hundred and ten eyes (74.3%) showed good, 18 (12.2%) showed intermediate and 20 (13.5%) showed poor anatomical response at month 3, and 114 eyes (77.0%) showed good, 27 (18.2%) showed intermediate and 7 (4.7%) showed poor anatomical response between month 3 and month 12. Of the evaluated parameters, drug type (better in aflibercept), showed a statistically significant difference in regards to anatomical outcomes at both the early and late periods (P=0.02 and P=0.03). The greatest linear dimension of choroidal neovascularization (CNV) and presence of peaked pigment epithelial detachment (PED) were important factors for early anatomical anti-VEGF treatment response. Larger CNV and the presence of a peaked PED appeared to be associated with a good early response, and the drug type seemed to be associated with both early and late poor anatomical response of anti-VEGF treatment in nAMD patients. Aflibercept appears to be more effective than ranibizumab in regards to the percentage of patients with better anatomical response in both the early and late treatment periods.

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration.

Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment response in neovascular age-related macular degeneration.

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration.

Pooled DNA based GWAS to determine genetic association of SNPs with visual acuity (VA) outcome in anti-vascular endothelial growth factor (anti-VEGF) treated neovascular age-related macular degeneration (nAMD) patients. We performed pooled DNA based GWAS on 285 anti-VEGF treated nAMD patients using high density Illumina 4.3 M array. Primary outcome was change in VA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters after 6 months of anti-VEGF treatment (patients who lost ≥5 ETDRS letters classified as non-responders and all remaining classified as responders). GWAS analysis identified 44 SNPs of interest: 37 with strong evidence of association (p < 9 × 10−8), 2 in drug resistance genes (p < 5 × 10−6) and 5 nonsynonymous changes (p < 1 × 10−4). In the validation phase, individual genotyping of 44 variants showed three SNPs (rs4910623 p = 5.6 × 10−5, rs323085 p = 6.5 × 10−4 and rs10198937 p = 1.30 × 10−3) remained associated with VA response at 6 months. SNP rs4910623 also associated with treatment response at 3 months (p = 1.5 × 10−3). Replication of these three SNPs in 376 patients revealed association of rs4910623 with poor VA response after 3 and 6 months of treatment (p = 2.4 × 10−3 and p = 3.5 × 10−2, respectively). Meta-analysis of both cohorts (673 samples) confirmed association of rs4910623 with poor VA response after 3 months (p = 1.2 × 10−5) and 6 months (p = 9.3 × 10−6) of treatment in nAMD patients.

Optical Coherence Tomography Angiography of DME and Its Association with Anti-VEGF Treatment Response

To investigate the structural integrity of the superficial capillary plexuses (SCPs) and deep capillary plexuses (DCPs) using optical coherence tomography (OCT) angiography (OCTA) in patients with diabetic macular edema (DME) and its association with the response to anti-vascular endothelial growth factor (VEGF) treatment. Retrospective, case-control study. We included 51 DME eyes with a poor response to anti-VEGF agents and 32 age-matched DME eyes with a good response to anti-VEGF treatment, along with 20 fellow eyes without DME from the cases and controls. The medical records, including OCTA and spectral-domain OCT (SD OCT), were reviewed and compared between the groups. En face OCTA images of the SCP and DCP were obtained for each eye. An anti-VEGF responder was defined by a reduction of more than 50 μm in central retinal thickness after 3 consecutive anti-VEGF treatments. A poor responder was defined by a reduction of less than 50 μm or an increase in central retinal thickness after 3 monthly injections. We measured the vascular density and foveal avascular zone (FAZ) area and counted the number of microaneurysms in each layer. The SD OCT images were compared with OCTA findings. Compared with non-DME eyes, DME eyes had a lower vascular density (P < 0.001) and larger FAZ area (P < 0.001) in the DCP and more microaneurysms (P < 0.001) in both layers. Although there was no significant difference in the SCP between anti-VEGF responders and poor responders, poor responders tended to show greater damage and more microaneurysms in the DCP (P < 0.001) and a larger FAZ area (P < 0.001). The topographic location of the disrupted synaptic portion of the outer plexiform layer (OPL) in SD OCT exactly corresponded to the nonflow area of the DCP in OCTA. Compared with DME eyes that responded to anti-VEGF treatment, poor responders show significant damage to the integrity of the DCP, but not the SCP. The degree of OPL disruption in SD OCT corresponds well with the extent of DCP loss in DME eyes. The extent of DCP loss and the corresponding OPL disruption could be useful predictors of responsiveness to anti-VEGF treatment.

Epidemiological and Clinical Baseline Characteristics as Predictive Biomarkers of Response to Anti-VEGF Treatment in Patients with Neovascular AMD.

Purpose. To review the current literature investigating patient response to antivascular endothelial growth factor-A (VEGF) therapy in the treatment of neovascular age-related macular degeneration (nAMD) and to identify baseline characteristics that might predict response. Method. A literature search of the PubMed database was performed, using the keywords: AMD, anti-VEGF, biomarker, optical coherence tomography, treatment outcome, and predictor. The search was limited to articles published from 2006 to date. Exclusion criteria included phase 1 trials, case reports, studies focusing on indications other than nAMD, and oncology. Results. A total of 1467 articles were identified, of which 845 were excluded. Of the 622 remaining references, 47 met all the search criteria and were included in this review. Conclusion. Several baseline characteristics correlated with anti-VEGF treatment response, including best-corrected visual acuity, age, lesion size, and retinal thickness. The majority of factors were associated with disease duration, suggesting that longer disease duration before treatment results in worse treatment outcomes. This highlights the need for early treatment for patients with nAMD to gain optimal treatment outcomes. Many of the identified baseline characteristics are interconnected and cannot be evaluated in isolation; therefore multivariate analyses will be required to determine any specific relationship with treatment response.

CFH Y402H and VEGF Polymorphisms and Anti-VEGF Treatment Response in Exudative Age-Related Macular Degeneration

Purpose: The aim of this study was to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in complement factor H (CFH) Y402H and VEGF rs2146323 and rs699947 in exudative age-related macular degeneration (AMD) and their relationship with intravitreal anti-VEGF treatment response. Methods: A total of 109 exudative AMD patients and 70 controls were included. Patients were classified as ‘good responders' and ‘nonresponders' based on the changes in best corrected visual acuity, central foveal thickness, lesion size, and the persistence of retinal hemorrhage after three dosages of anti-VEGF. We examined CFH, VEGF rs2146323 and rs699947 SNPs, and plasma interleukin-6 (IL-6) levels in both groups. Results: In total, 42 patients (38.5%) and 11 controls (15.7%) had homozygote wild genotype TT (p = 0.002). The variant C allele frequency was 45% in controls and 31.7% in patients (p = 0.011). A and C allele frequencies for VEGF rs699947 and rs2416323 were similar between the control and patient groups (p = 0.947, p = 0.378). Both SNPs were similar in responders and nonresponders. No significant difference was detected between plasma IL-6 levels of the control and AMD groups (p = 0.594), but the levels were higher in good responders than nonresponders (p < 0.001). Conclusion: CFH Y402H SNP might be protective for AMD in the Turkish population. VEGF rs2146323 and rs699947 SNPs have no relationship to exudative AMD formation, and none of these seem to have any effect on anti-VEGF response.

Comparison of 18F-FET and 18F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

BackgroundThe radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (FET) and thymidine analogue 3′-deoxy-3′-18F-fluorothymidine (FLT) are widely used for positron emission tomography (PET) brain tumor imaging; however, comparative studies are scarce. The aim of this study therefore was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. MethodsXenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow treatment response. Tracer uptake of FLT and FET was quantified using maximum standardized uptake (SUVmax) values and tumor-to-background ratios (TBRs). Survival, the Ki67 proliferation index and micro-vessel density (MVD) were evaluated. ResultsIn contrast to FLT TBRs, FET TBRs were significantly lower as early as one week after treatment initiation in the anti-VEGF group as compared to the control group. Following two weeks of treatment, both FLT and FET TBRs were significantly lower in the anti-VEGF group. In contrast, no significant difference between the treatment groups was detected using BLI. Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. ConclusionFET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET.Advances in knowledge and implications for patient care FET PET appears to be an early predictor of anti-VEGF efficacy. Confirmation of these results in clinical studies is needed.

18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma.

BackgroundConflicting data exist for anti-cancer effects of anti-placental growth factor (anti-PlGF) in combination with anti-VEGF. Still, this treatment combination has not been evaluated in intracranial glioblastoma (GBM) xenografts. In clinical studies, position emission tomography (PET) using the radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) and magnetic resonance imaging (MRI) add complementary but distinct information about glioma growth; however, the value of 18F-FET MicroPET combined with MicroMRI has not been investigated preclinically. Here we examined the use of 18F-FET MicroPET and MicroMRI for evaluation of anti-VEGF and anti-PlGF treatment response in GBM xenografts.MethodsMice with intracranial GBM were treated with anti-VEGF, anti-PlGF + anti-VEGF or saline. Bioluminescence imaging (BLI), 18F-FET MicroPET and T2-weighted (T2w)-MRI were used to follow tumour development. Primary end-point was survival, and tumours were subsequently analysed for Ki67 proliferation index and micro-vessel density (MVD). Further, PlGF and VEGFR-1 expression were examined in a subset of the xenograft tumours and in 13 GBM patient tumours.ResultsAnti-VEGF monotherapy increased survival and decreased 18F-FET uptake, BLI and MVD, while no additive effect of anti-PlGF was observed. 18F-FET SUVmax tumour-to-brain (T/B) ratio was significantly lower after one week (114±6%, n = 11 vs. 143±8%, n = 13; p = 0.02) and two weeks of treatment (116±12%, n = 8 vs. 190±24%, n = 5; p = 0.02) in the anti-VEGF group as compared with the control group. In contrast, T2w-MRI volume was unaffected by anti-VEGF. Gene expression of PlGF and VEGFR-1 in xenografts was significantly lower than in patient tumours.Conclusion 18F-FET PET was feasible for anti-angiogenic response evaluation and superior to T2w-MRI; however, no additive anti-cancer effect of anti-PlGF and anti-VEGF was observed. Thus, this study supports use of 18F-FET PET for response evaluation in future studies.

Genetic predictive biomarkers of anti-VEGF treatment response in patients with neovascular age-related macular degeneration

Anti-vascular endothelial growth factor (anti-VEGF) therapies for neovascular age-related macular degeneration (nAMD) have proven efficacy at a study-population level, although individual patient responses vary, with most of the patients responding well to anti-VEGF therapies, while a few respond poorly. The pathogenesis of AMD is known to have a genetic component, but it is unclear if any particular genotype can predict response to anti-VEGF therapy. With the advent of less expensive genotyping technology, there have been numerous studies within this area. Here we analyze potential biomarker candidates identified that could be used in a clinical setting to predict response to anti-VEGF treatment of nAMD. We analyze single nucleotide polymorphisms (SNPs) identified from 39 publications. The SNPs that appeared to be of most importance fell into two main groups: those previously associated with AMD pathogenesis and those within the signaling pathway targeted by anti-VEGF therapies. A number of small studies found evidence supporting an association between anti-VEGF treatment response and two SNPs, CFH rs1061170 and VEGFA rs699947, but results from randomized controlled trials found no such association. It is possible that, in the future, the cumulative effect of several high-risk SNPs may prove useful in a clinical setting and that other genetic biomarkers may emerge.