Author Proof

Pharmacogenomics

Review

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Impact of VEGF gene polymorphisms in elderly cancer patients: clinical outcome and toxicity

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Vascular endothelial growth factors (VEGFs) are the key regulators in angiogenesis and have been shown to play a significant role in the progression and prognosis of angiogenesis-related diseases, such as cancer. VEGF inhibitors are a current pharmacological antitumoral strategy. However, despite the strong association between aging and cancer incidence and progression, recent findings suggest impaired angiogenesis accompanied by a reduced expression of VEGF in cells derived from aging subjects. Specific variations of VEGF genes have been demonstrated to be genetic determinants for susceptibility, outcome and therapy response, especially for the solid tumors. Considering the complications present in frail elderly patients, analysis of VEGF genetic polymorphisms in these subjects may further help in tailoring an antiangiogenic pharmacological strategy, and in improving our ability to better understand prognosis during therapy-related to cancer.

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Keywords: angiogenesis • cancer • elderly • genetics • single nucleotide polymorphisms • tumor prognosis • vascular endothelial growth factors • VEGF • VEGF inhibitors

to as VEGF) is a major player in a complex balance involving proangiongenic stimuli and angiostatic factors [3] . VEGF is a dimeric glycoprotein whose role in neoangiogenesis is that of promoting both proliferation and migration of endothelial cells (ECs) [4,5] , as well as activating EC survival and inhibiting antiapoptotic signaling [6] , ultimately leading to formation of immature vasculature. Among the other members of the family, little is known on the precise role of VEGFB in tumor neoangiogenesis. Animal models suggested a role of VEGF-B in inflammatory angiogenesis and early tumor development, but the paucity of available data does not allow drawing any definitive conclusion [7] . On the other hand, VEGF-C and VEGF-D are primarily lymphangiogenic growth factors and VEGF-C has been shown to induce lymphangiogenesis in primary tumors and in draining sentinel lymph-nodes, thus promoting node metastasis [8] . Certain tumors such as breast, lung and gastrointestinal carcinomas have a propensity to metastasize through

1 Department of Systems Medicine, School of Medicine, University of Rome ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, Italy 2 Biomarker Discovery & Advanced Technologies (BioDAT) Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana – Research Center, Rome, Italy *Author for correspondence: Tel.: +39 7259 6893 Fax: +39 7259 6800 david.dellamorte@ uniroma2.it ‡ Authors contributed equally

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Role of VEGF in cancer progression Angiogenesis is a fundamental event both in physiological and pathological conditions, participating, respectively, in the process of tissue regeneration as well as in tumor growth and metastasis dissemination [1] . Vascular endothelial growth factors (VEGFs) are key regulators of angiogenesis – they are the most widely proangiogenic factors studied so far. The VEGF family consists of seven members (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and VEGF-F) sharing a common structure of eight characteristically spaced cysteine residues in a VEGF homology domain and acting through specific tyrosine kinase receptors (VEGFRs) to tightly regulate angiogenesis and lymphangiogenesis. The crucial role of new vessel formation in cancer development is unquestioned. Pioneering studies by Folkman et al. have provided evidence that a cancer mass growing over 200 μm diameter requires neo-angiogenesis to expand and invade surrounding tissues [2] and VEGF-A (from now on simply referred

David Della-Morte*,‡,1,2, Silvia Riondino‡,1,2, Patrizia Ferroni2, Raffaele Palmirotta2, Donatella Pastore1, Davide Lauro1, Fiorella Guadagni2 & Mario Roselli1

10.2217/PGS.14.136 © 2015 Future Medicine Ltd

Pharmacogenomics (2015) 16(1), 00–00

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Review David, Silvia, Patrizia et al.

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that an increased expression of HIF-1α signaling pathway leads to the acquisition of antiapoptotic properties in human colorectal cancer (CRC) cells, [21] and that HIF-1α and STAT3 transcription factors promote VEGF production in hypoxia-related angiogenesis in HCC [22] . Least but not last, HIF-1 subunit-α overexpression has been observed in several cancers [23–25] where it induces VEGFR-1 expression [15] . In malignant neoangiogenesis, VEGFR-2 expression is also significantly upregulated by VEGF and or HIF-1 [10] and concurs to the antitumor immunity inhibition [26] , a hallmark of cancer growth, which is becoming an increasingly important target for new anticancer strategies [27,28] . Such a prominent role of VEGF in promoting tumor angiogenesis and cancer progression has led to the development of targeted agents directed against the VEGF/VEGFR axis. Antiangiogenic strategies: VEGF/VEGFR axis inhibitors Studies focusing on the identification of the points on VEGF/VEGFR interaction axis, which may serve as potential antiangiogenesis targets, led to the development of a variety of antibodies and kinase inhibitors that suppress VEGF/VEGFR signalingpathways. In this context, however, older patients represent a challenge in such targeted therapy. Indeed, the presence of co-morbidities might impair VEGF tyrosine kinase inhibitors (VEGF-TKIs) metabolization due to a decreased liver mass and cytochrome P450 (CYP) enzyme content [29] , and to the frequent presence of concurrent chronic disorders whose treatment might interfere with antineoplastic therapy. Moreover, although the doses of chemotherapy are usually adjusted for age, aging itself may increase the side effects of the therapy [30] . In addition, the use on antiangiogenic drugs in the elderly, must take into account the frequent occurrence of thrombotic phenomena of the microvasculature, such as hypertension and proteinuria, associated both to arterial stiffness and to the progressive decline of renal function [31–33] . Finally, an impairment of the cognitive system might be the cause of therapy discontinuation, which, however, is also a frequent event as a consequence of disease progression or of toxicity [34] . The first, and to date most thoroughly studied, antiangiogenic drug is bevacizumab (Avastin®, RocheGenetech), a recombinant immunoglobulin G targeting all known isoforms of soluble VEGF. Interestingly, this drug has a very limited effect on the majority of advanced malignancies when used as monotherapy, while it has proven efficacious in combination with chemotherapy [35–37] in several cancer types (colorectal,

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lymphatic vessels. For these patients, VEGF-C and VEGF-D might, thus, provide important prognostic information [9] . The VEGF family members bind to three receptors with tyrosine kinase activity, VEGFR-1 (fms-related tyrosine kinase-1 [Flt-1]), VEGFR-2 (kinase insert domain-containing receptor [KDR]) and VEGFR-3 (fms-related tyrosine kinase-4 [Flt-4]), although the angiogenic response to VEGF is mainly transduced through VEGFR-2 [10,11] , which regulates the proliferation, migration and survival of endothelial cells both in physiologic and pathologic conditions [1,12,13] . In particular, intracellular downstream signaling pathways in response to VEGFR-2 activation comprise those of p85 PI3-Kinase (PI3K), PLC-γ, extracellular-regulated kinase (ERK), mediated by Ras-Raf-MEK-ERK [10,11] and the p38 mitogen-activated protein kinase (p38 MAPK), some of which are among the downstream effectors of VEGFR-1: PlCγ, p38 MAPK, p85 PI3K and growth factor receptor-bound-2 (Grb-2) [14,15] . Particularly interesting, given the close association reported between aging and cancer, are the recent findings demonstrating an impaired angiogenesis accompanied by a reduced expression of VEGF in cells derived from aging subjects [16] . These changes were caused by the dysfunctional regulation of factors involved in VEGF expression, cAMP response element-binding protein (CREB) and signal transducer and activator of transcription 3 (STAT 3) [16] . Of note, these age-related defects appear to be common to the vascular cells of various tissues, possibly due to the decline in ATP levels associated with decline in age-dependent changes in mitochondria functions [17] . This might constitute further impairment of angiogenesis in aging endothelial cells, in that STAT3 can activate antiapoptotic genes Bcl-xL thus promoting cell survival [18] . Accordingly, VEGF has been shown to have a significant role in the progression and prognosis of angiogenesis-related diseases such as cancer, where it has been demonstrated that high levels of plasma VEGF correlate with cancer progression, resistance to chemotherapy and poorer prognosis [1] . As stated above, constant levels of VEGF are fundamental to nourish blood vessels inside the tumor that, otherwise, would undergo a necrotic process. In fact, in the presence of hypoxia, VEGF becomes overexpressed not only in tumor cells, but also in the stromal cells that surround the growing tumor [19] . In this context, hypoxia induces the expression of hypoxia-induced factor-1 (HIF-1) and activates the uptake of VEGF and other neovasculature growth factors [20] , thus allowing the tumor cells to gain access to oxygen and nutrients. In further support of cancer cells adaptation under hypoxic conditions within the tumor microenvironment, stands the demonstration

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Pharmacogenomics (2015) 16(1)

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Impact of VEGF gene polymorphisms in elderly cancer patients

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Conflicting results, both in terms of efficacy and toxicity, have been reached in elderly lung cancer patients treated with bevacizumab in addition to chemo therapy. In the ECOG Trial, 4599 fit elderly patients with advanced NSCLC did not show any survival benefit compared with those who received chemotherapy alone, but they experienced higher toxicity [48] . On the other hand, the analysis of the randomized, Phase III AVAiL trial has demonstrated clinical benefits in elderly patients older than 65 years, with advanced or recurrent non squamous NSCLC treated with first-line bevacizumab in combination with standard chemotherapy [49] . A similar study design on a population of 623 elderly patients reached the same positive results in terms both of efficacy and safety [50] . Indeed, median overall survival (OS), time to progression (TTP), response rate (RR), and disease control rate (DCR), were similar in elderly and younger patients. It is very interesting to underline that similar results were seen in a post hoc comparison of the patients older than 70 years with those aged 70 years or younger [50] . Incidence of AEs of special interest was also comparable. Clinical trials on elderly metastatic breast cancer (mBC) patients demonstrated a substantial improvement in PFS and response rate when bevacizumab was combined with standard chemotherapy versus chemotherapy alone. It is worth noting that, such improved efficacy was accompanied by a minimal impact on the safety profile [51–53] . Indeed, the subanalysis of trials specifically designed to evaluate both efficacy and safety of bevacizumab addition to standard firstline chemotherapy in elderly patients with human epidermal growth factor receptor 2 (HER-2)-negative, locally recurrent/mBC (LR/mBC), AVADO (Avastin and Docetaxel®) [51] and RIBBON-1 [52] , demonstrated a clear benefit from the combined treatment. Similar results were later obtained in the open-label international ATHENA study on 2251 elderly LR/mBC patients, which found that first-line bevacizumab combined with standard (nonanthracycline) chemotherapy was active and well tolerated by patients older than 70 years [53] . In this study, however, a direct comparison with chemotherapy alone was missing. Elderly patients with renal cell carcinoma (RCC) represent a cluster of very high-risk patients, since they often present with other comorbidities such as hypertension, diabetes, cardio- and cerebro-vascular diseases, anemia, and respiratory compromise, linked to the pathophysiology of the condition determining renal impairment. Among antiangiogenic drugs, however, metastatic renal cell carcinoma (mRCC) is preferentially treated with the tyrosine kinase inhibitor sunitinib as a monotherapy strategy [54] . In a recent

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renal, breast and lung). Clinical trial data have provided mixed results on the efficacy and safety of bevacizumab for older adults, although we might anticipate that advanced age, per se, should not represent an absolute contraindication to the use of bevacizumab. A large amount of data are available, reporting the use of bevacizumab in advanced CRC patients, the vast majority of them agreeing in the conclusion that bevacizumab efficacy does not seem to be influenced by patients’ age. Indeed, medically fit older CRC patients treated with bevacizumab achieved the same benefits compared with younger patients [38–40] , with a similar toxicity profile, the only exception being represented by an increase in arterial thromboembolic events (ATEs) [41] . This datum confirmed previous results of the Bevacizumab Regimens: Investigation of Treatment Effects and Safety (BriTE) Observational Cohort Study (OCS), which, in a population of patients aged 80 years and older in which bevacizumab was used as first-line therapy for metastatic CRC (mCRC), indicated an increased risk of arterial thromboses [42] . More recently, the BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in fit mCRC patients aged >70 years, and demonstrated that this combined antineoplastic therapy was effective and well tolerated, with a 10% venous thromboembolism (VTE) as adverse effect [43] . These evidences trigger the clinicians to careful monitoring of cardiovascular and renal potential side effects when assessing the benefit-to-risk evaluation, and to perform a careful patient selection in order to minimize adverse event occurrence, especially vascular ones [44] . However, a prospective study evaluating the association between geriatric assessment (GA) metrics and chemotherapy toxicity in 207 patients aged >65 years with CRC and non-small-cell lung cancer (NSCLC) who received bevacizumab with chemotherapy versus chemotherapy alone, demonstrated that older patients who receive the combined treatment had a higher odds of developing a grade 3–5 toxicity compared with those who receive chemotherapy alone [45] . In support of the evidences of an increased toxicity in elderly patients, stands a recent randomized Phase III study (AVEX) [46] that prospectively evaluated the additive effect of bevacizumab in a CRC population (n = 280) of elderly patients ( >70 years) to capecitabine. The results demonstrated that the simultaneous use of bevacizumab produced significant increase of median PFS (9.1 vs 5.1 months; HR = 0.53), compared with capecitabine alone [46] . In terms of toxicity, however, CRC patients aged 70 years and older receiving FOLFOX with bevacizumab versus FOLFOX alone developed more grade 4 and 5 toxicities than younger patients [47] .

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Monoclonal antibodies blocking VEGFR Among the molecules capable of inhibiting the VEGF interaction with VEGFR are aflibercept (a decoy receptor binding to VEGF-A and VEGF-B) and ramucirumab (IMC-1121B, ImClone, anti-VEGFR-2). Aflibercept is a humanized recombinant fusion protein specifically designed to bind VEGF-A, VEGF-B and platelet-derived growth factor PIGF. Aflibercept has proven effective in improving survival in a Phase III study (VELOUR) of patients with mCRC in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) [56] . Indeed, the results of the VELOUR trial demonstrated a longer median OS (13.5 vs 12 months; HR = 0.81) and PFS (6.9 vs 4.6 months; HR = 0.75) in the group receiving aflibercept, which, however, were associated with an increased toxicity in terms of hypertension and proteinuria [56] . The combination of aflibercept with docetaxel and prednisone in the first-line treatment of men with metastatic castrateresistant prostate cancer, is under review in the VENICE Phase III trial that, however, until now reported no differences in survival and increased toxicity among the study groups, including a group of patients older than 75 years [57] . Ramucirumab, is a human mAb VEGFR-2 inhibitor that has been tested in patients with melanoma, gastric adenocarcinoma, uterine leiomyosarcoma and renal cancer. It showed efficacy in a Phase III study on second-line gastric cancer, in combination with FOLFOX, although the population >65 years was relatively small to draw any conclusion [58] . Based on data from the Phase III REGARD trial, the US FDA approved ramucirumab as second-line therapy for patients with advanced stomach cancer and gastroesophageal junction adenocarcinoma [59] . Data from subanalysis on elderly patients are eagerly awaited. Conversely, in a population of patients (median age 62 years) with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, the predetermined efficacy end points were not met [60] .

Multitargeted TK inhibitors The small molecule multitargeted TKIs more commonly used in clinical trials involving elderly patients are sunitinib malate and sorafenib. Sunitinib malate (Sutent®, Pfizer) is an oral multi-TKI that has shown antiangiogenic and antitumor activities in several in vitro and in vivo models, acting by the blockade of all three isoforms of the VEGFRs. Sunitinib is principally employed in RCC, which often results in dysregulation of HIF and VEGF/VEGFR pathways [61] . A retro spective analysis of pooled data from 1059 elderly patients from six different trials (of which 81% 70 years), regarding sunitinib outcome as a function of age in mRCC, revealed that PFS was comparable in younger and older patients (9.9 vs 11.0 months, respectively; HR = 0.89; 95% CI: 0.73–1.09; p = 0.2629), as was median OS (23.6 vs 25.6 months; HR = 0.93; 95% CI: 0.74–1.18; p = 0.5442) [62] . It is interesting to underline that in a retrospective study assessing the use of first-line sunitinib in 185 selected mRCC patients aged >70 years considered fit for the standard regimen therapeutic scheme by their medical oncologist, elderly patients had a poorer safety and efficacy profile compared with younger patients [63] . However, if patients were given an adapted regimen, which appears to influence PFS and OS, and as such they experienced a better tolerance they, had less unfavorable effects of toxicity [63] . Sorafenib (BAY 43–9006) (Nexavar®, Bayer) is an oral multiple kinase inhibitor targeting both tumor cells and the tumor vasculature, possessing activity against VEGFR-1, -2 and -3. Due to sorafenib efficacy in improving the survival time of patients with advanced HCC [64] , clinical outcomes and safety were evaluated between aged and nonaged HCC patients treated with sorafenib [65] . The results demonstrated that older patients had comparable OS rate, PFS rate, disease control rate (DCR) and objective response rate (ORR) as those of the control group patients [65] . In a retrospective subgroup analysis of the Phase III, randomized Treatment Approach in Renal Cancer Global Evaluation Trial comparing the safety and efficacy of sorafenib in 115 patients older than 70 years and in 787 younger patients who received treatment for advanced RCC, sorafenib proved efficacious in increasing PFS and clinical benefits without major toxicity in both older and younger patients [66] .

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retrospective study comparing disease outcomes (RR, treatment duration and OS) between mRCC individuals aged 75 years and older with patients younger than 75 years, targeted therapy with first-line anti-VEGF therapy was not associated with lower overall RR, poorer OS or shorter treatment duration in the older group [55] . Besides bevacizumab, antiangiogenic strategies include selective monoclonal antibody blocking VEGFR external domain and a number of small molecules – multitargeted TK inhibitors (TKIs) – acting on the intracellular domain of VEGFRs, blocking their catalytic function.

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Risk & prognostic value of VEGF SNPs in solid tumors The VEGF gene is located on chromosome 6 at location 6p21. Its coding region is approximately 14 kb and consists of 8 exons [67,68] . Numerous SNPs in the promoter, 5´- and 3´-untranslated regions (UTR) are pres-



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VEGF has shown to be important for development, invasiveness and metastasis of breast cancer [96] . Higher levels of VEGF have been shown to be related with adverse prognosis and decreased overall survival, especially in elderly patients [97–99] . High microvessel density

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(MVD), a marker of VEGF expression and local activity, increases the likelihood of metastatic disease [100] and acts as a prognostic indicator for relapse-free survival and OS in node-negative breast cancer patients [101] . These findings suggest that VEGF genetic variants might play a role in development and progression of breast cancer. In this light, the association between polymorphisms of angiogenesis pathway genes and risk of breast cancer has been widely analyzed in different study populations with controversial results. VEGF -634G>C [71–73] , -7C>T [72,74,75] , and -2489C>A [72,75] SNPs have been shown to not be associated with risk of breast cancer. Similarly, VEGF -1154G>A had no relationship with overall risk of breast cancer [71,73,76] , however the G allele was related with increased risk of invasive disease [73,76,77] . Moreover, also VEGF -1498C>T was shown to have no relation [72,74,75] or predicted higher risk of breast cancer [77] . Instead, regarding 936C>T SNP, three studies showed a protective role against breast cancer and a better prognosis on patients carrying the 936T allele [72,78,79] , four failed to find any correlation with risk of it [71,74,75,77] , and one study found 936C as a protective allele just for in situ breast cancer [73] . Difference in geographic location of the studied populations is not sufficient to explain the variances in the role of the 936C>T SNP in the risk and prognosis of breast cancer.

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ent in VEGF gene: (-2578C>A, -2489C>T, -1498C>T, and -1154G>A), 5´-UTR (-634G>C and -7C>T), and 3´-UTR (936C>T and 1612G>A) [3] . The nomenclature of various VEGF gene polymorphisms is confusing because some authors conventionally numbered the SNPs starting from the transcription start based on the sequence of the VEGFA gene (Genebank Accession Number Accession Number AF022375 and Ensembl ENSG00000112715) [69] , while other authors use the translation start or the most official reference SNP ID number (“rs #”, “refSNP clusters”) of the Single Nucleotide Polymorphism Database (dbSNP), a free public archive for genetic variation hosted by the National Center for Biotechnology Information (NCBI) (www.ncbi.nlm.nih.gov/snp/) (Table 1) [69,70] . Many studies have investigated the role of VEGF polymorphisms as a genetic determinant for susceptibility and outcome of breast, kidney, ovarian, bladder, prostate, NSCLC and CCR (Table 2) .

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Table 1. List of genetic variants of VEGF gene. Transcription or translational start site-based numbering

SNP ID number

Gene region

NA

rs833052

PROMOTER

NA NA

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NA NA

NA

-2489 T/C NA

-1540A/C

rs699947

-151218bp del

rs35569394

-1451T/C

rs1005230

A

-2578A/C -245918bp del

rs1109324

rs1547651

-1411 4G/5G

rs35864111

-1498C/T

-460C/T

rs833061

-1190G/A

-152G/A

rs13207351

-1154G/A

-116G/A

rs1570360

NA

NA

NA

TRANSCRIPTION

-634G/C

+405G/C

rs2010963

5´-UTR TRANSLATION

-7C/T

NA

rs25648

NA

NA

rs833068 G/A

NA

NA

rs302533 A/G

NA

NA

rs2146323 C/A

NA

IVS2+1378C/T

rs3024994

936C/T

NA

rs3025039

1612G/A

NA

rs10434


3´-UTR


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Table 2. Role of VEGF polymorphisms as a genetic determinant for susceptibility and outcome of different cancers. VEGF polymorphisms

Race-ethnicity

Genotypes

Cancer prognosis

Breast cancer

634G >C

NA

NA

↔

[71–73]

-7C >T

NA

NA

↔

[72–75]

-2489C >A

NA

NA

↔

[72–75]

-1154G >A

UK

NA

↔

[71–76]

-1498C >T

NA

NA

↔

[72–75]

936C >T

Austrian

936T

↑

[72–79]

NA

NA

936 C

↑

[73]

+936 C/T

Spain (women)

+936 CT + TT

↑

[80]

Ovarian cancer

-2578 C/A

NA

2578C

↓

[81]

-1154 G/A

NA

NA

[81]

-460 T/C

NA

460T

↓

[81]

+405 G/C

NA

405C

↓

[81]

+936C/T

NA

NA

[81] [82]

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Ref.

rs3025033

Australian (women)

NA

rs2146323

NA

NA

↔

[82]

rs833068

NA

NA

↓

[82]

rs2010963

NA

NA

↓

[82]

Bladder cancer

rs25648, -7C >T

Hispanic

NA

↓

[83]

rs833052

NA

NA

↓

[83]

rs1109324

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↔

NA

NA

↓

[83]

rs1547651

NA

NA

↓

[83]

rs3024994

NA

NA

↑

[83]

rs833052

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Chinese

rs833052AA

↓

[84]

Prostate cancer

-1154 G >A

UK

-1154AA

↑

[85]

-1498C >T

Taiwanese

-1498T

↓

[86]

-1154G >A

Tunisian

-1154A

↑

[87]

-634G >C

NA

-634GC+CC

↓

[87]

A

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936C >T

NA

NA

[87]

-1498C >T

Turkish

NA

↔

[88]

-2578C >A

Austrian

NA

↔

[89]

-2489C >T

NA

NA

↔

[89]

-1498C >T

NA

NA

↔

[89]

-634G >C

NA

NA

↔

[89]

-7C >T

NA

NA

↔

[89]

936C >T

NA

NA

↔

[89]

1612G >A

NA

NA

↔

[89]

↔ No association with cancer prognosis. ↑ Better cancer prognosis association. ↓ Worse cancer prognosis association.

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Table 2. Role of VEGF polymorphisms as a genetic determinant for susceptibility and outcome of different cancers (cont.). VEGF polymorphisms

Genotypes

Cancer prognosis

Ref.

-2578C >A

NA

-2578CC

↓

[90]

NA

-2578CA

↓

[90]

-634G >C

NA

-634GG

↑

[90]

NA

-634GC

↓

[90]

-1154G >A

NA

-1154AA/GA

↑

[90]

NA

-1154GG

↓

[90]

936C >T

NA

NA

↔

[90]

-1498C >T

Caucasian

NA

↔

[91]

-634C >G

NA

-634CC+CG

↓

[91]

-634C >G

NA

NA

↔

[91]

936C >T

NA

NA

↔

[91]

-460T/C

NA

-460TT

↓

[92]

NA

↔

[92]

936CT+TT

↓

[93]

-634GC, -634CC

↑

[94]

+405G/C

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Non-small-cell lung cancer (NSCLC)

Race-ethnicity

NA

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Solid tumors

Asiatic

-634G >C

NA

936C >T

NA

936T

↓

[93]

-2578C >A

NA

NA

↔

[95]

-2578C >A

Korean women

-2578CA/AA

↑

[95]

↑ Better cancer prognosis association. ↓ Worse cancer prognosis association.

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↔ No association with cancer prognosis.

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Colorectal cancer 936C >T

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A study recently conducted in Spanish women, analyzed four commonly studied polymorphisms in VEGF, rs3025039 (known as +936C/T), rs1109324, rs154765 and rs833052, a polymorphism at the promoter of the VEGF receptor 1 (VEGFR1) (-710C/T) to explore their association with breast cancer susceptibility and prognosis [80] . Women carriers of +936CT+TT genotype have overall a protective effect against this disease (p = 0.014; OR: 0.67; 95% CI: 0.48–0.92). Similarly, the haplotype TGAC of VEGF (rs3025039 [936C>T], rs1109324, rs154764 and rs833052) shows a reduction of the risk to develop breast cancer and a better prognosis (p = 3e-04 ; OR: 0.48; 95% CI: 0.32–0.72). In this study, authors found that also carriers of -710CT+TT VEGFR1 genotypes have a protective effect on breast cancer (p = 0.039; OR = 0.55; 95% CI: 0.31–0.98) [80] . Therefore, based on these results, +936C/T VEGF and -710 C/T VEGFR1 genotypes are likely the more important genetic markers of susceptibility and better prognosis for breast cancer. Another genetic study conducted in a Shanghai population, analyzed genetic variation across four VEGF family genes, two VEGF ligands (VEGFA and VEGFC), and two VEGF recep-


tors (FLT1/VEGFR1 and KDR/VEGFR2) [102] . Two SNPs were consistently associated with breast cancer risk and prognosis and were significant in combined analyses. Compared with FLT1 rs9551471 major allele homozygotes (AA), reduced risks were associated with AG (OR = 0.92; 95% CI: 0.84–1.00) and GG (OR = 0.78; 95% CI: 0.64–0.95) genotypes (p = 0.005). Compared with VEGFA rs833070 major allele carriers CC or CT, however increased risk was associated with TT genotypes (OR = 1.26; 95% CI: 1.05–1.52; p = 0.016) [102] . Kidney cancer

VEGF has been implicated in the pathogenesis of renal dysfunction. VEGF is a key mediator of normal and abnormal angiogenesis and is important in maintaining the integrity of the renal vasculature [103] . VEGF expression is upregulated in mesangial proliferative disease, minimal change disease, chronic tubule interstitial injury, membranous nephropathy and diabetic nephropathy [104] . It has been suggested that some VEGF genotypes may have effects on RCC progression or prognosis, possibly through altered VEGF


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Ovarian cancer

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In a recent study, Steffensen et al. [81] , evaluated the relationship between five SNPs (-2578C/A, -1154G/A, -460T/C, +405G/C, and +936C/T) in the VEGF with epithelial ovarian cancer. VEGF serum levels were significantly higher in these patients carrying the 2578C, 460T and 405C, alleles compared with noncarriers (p = 0.003, p = 0.003, and p = 0.001, respectively). There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, the multivariate survival analysis showed that PFS for the patients with the AGCGC haplotype was significantly improved compared with patients with other haplotypes (HR = 1.9; p = 0.036). Another study evaluated the effect of variants in the VEGF gene on OS in ovarian cancer patients. A sample of 319 women diagnosed with primary invasive ovarian cancer in Australia between 1985 and 1997, recruited as incident cases, were genotyped for four VEGF SNPs (three tagSNPs, and one functional SNP) [82] . VEGF tagSNPs rs3025033 and rs2146323 were not associated with ovarian cancer survival in this sample. In contrast, ovarian cancer patients homozygous for tagSNP rs833068 or the functional SNP rs2010963 displayed significantly shortened OS in the Australian sample (HR = 2.09; 95% CI: 1.16–3.78) with an effect most apparent during the first 5 years after diagnosis. However, this association was not replicated in two independent datasets [82] .

influence risk and prognosis for bladder cancer. The analysis of 1086 cases and 1033 controls from Hispanic population demonstrated that the most significant SNP associated with variability in risk and prognosis for bladder cancer was in the 5´-UTR of VEGF (rs25648, -7C>T) [83] . Three additional SNPs in the promoter region (rs833052, rs1109324, and rs1547651) were also associated with increased risk for bladder cancer: OR (95% CI): 2.52 (1.06–5.97), 2.74 (1.26–5.98), and 3.02 (1.36–6.63), respectively; while a polymorphism in intron 2 (rs3024994) was associated with reduced risk, OR: 0.65 (0.46–0.91) [83] . Recently, a study conducted in a Chinese population demonstrated that the frequency of the rs833052 AA genotype in VEGF gene was significantly higher in patients with bladder cancer (OR = 1.75; 95% CI: 1.05–2.92; p = 0.03) compared with healthy controls [84] . These findings support a role of VEGF genetic variant in prognosis and risk for bladder cancer. Molecular studies on VEGF have been performed to understand the exact mechanism in the genesis and progression of bladder cancer. Interesting, VEGF mRNA level emerged as a potential prognostic indicator of progression in bladder cancer as well as the expression level of the different VEGF splice variants [107] . However, the exact mechanisms by which VEGF is involved in such type of disease progression, are still not well defined [108] .

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expression [105] . Recently, an interesting study aimed to assess the role of VEGF and VEGFR polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients receiving firstline sunitinib [106] . The SNP results were correlated with PFS and overall survival OS. The significant VEGF-A SNPs were: rs833061 for PFS (p A, -634G>C, and 936C>T VEGF SNPs on risk and prognosis of prostate cancer in 101 patients and 100 age-matched healthy controls [87] . Carriers of at least one -1154A allele were at reduced risk (OR = 0.42) and lower susceptibility to high-grade (OR = 0.25), and advanced prostate cancer (OR = 0.37). The OR for -1154 GA and AA genotypes were 0.46 and 0.27, respectively [87] . The VEGF -634GC+CC genotypes have been demonstrated to be linked with increased risk of prostate cancer (OR = 1.95), and the -634GC and CC genotypes



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Colorectal cancer

Colorectal cancer is the third most common type of cancer and the fourth most frequent cause of cancer death. Literature indicates that VEGF as predominant angiogenic factor plays an important role in the progression of CRC [113] . VEGF has shown to be an important predictor of prognosis in cases of advanced CRC [113] . High VEGF expression was related with poor relapsefree and OS [114] . Therefore, VEGF SNPs has been proposed to play an important role in determining the risk, prognosis, and survival in CRC patients. A study on the VEGF 936C>T germline SNP in Asiatic CRC patients (n = 262) and healthy controls (n = 229) showed that the frequency of T allele-bearing genotypes (CT+TT) was higher in cases than in controls. The frequency of CT+TT was significantly associated with increased risk for CRC in women and patients younger than 55 years old, thus suggesting that the VEGF 936C>T SNP might be a genetic determinant for CRC in Asiatic population [93] . The analysis of two VEGF SNPs (-634G>C and 936C>T) in 465 patients and 413 controls showed that the -634GC and CC genotypes were associated with a decreased risk and a better prognosis of CRC. Haplotype analysis showed that -634C/936C and -634G/936T were associated with decreased susceptibility of CRC [94] . In conclusion, 936T allele has shown to be associated with increased risk [93] , advanced stage of disease [94] , worse survival [115] , and longer time to relapse [116] , whereas other studies have shown no correlation with tumor size, grade, and stage [117] , and no relation with survival [118] in patients with CRC. The -634C allele was predictive of decreased risk [94] and better survival [115] . The VEGF -2578C>A SNP was not related with risk [95] , survival [115] , tumor size and stage [117] , but -2578CA and AA had a borderline protective role in Korean women [95] .

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NSCLC

but a variant allele for these SNPs, -634C and 936T has been shown to predict longer OS [112] . Recently, to evaluate the role of VEGF genetic variants in lung cancer, Maeda et al. [92] examined the expression of several angiogenesis-related proteins such as delta-like ligand 4 (Dll4) in resected NSCLC. Blood and tumor tissue from 83 patients with NSCLC were examined for VEGF -460T/C (rs833061) and +405G/C (rs2010963) SNPs. Patients with the VEGF -460TT genotype had significantly higher Dll4 expression compared with those with the TC or CC genotypes, while the VEGF +405G/C SNP displayed no association with Dll4 expression. These findings indicate that the VEGF -460T/C SNP may have a functional influence on tumor angiogenesis in NSCLC and therefore be implicated in the worse prognosis reported in these subjects.

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with high-grade tumors (OR = 3.83 and 4.89, respectively) [87] . These results are suggesting that both VEGF -1154G>A and -634G>C SNPs may act as important genetic markers of risk and aggressiveness of prostate cancer. However, on the contrary, a case–control study in 133 sporadic prostate cancer patients and 157 healthy controls found no relationship with -1498C>T VEGF SNP and susceptibility and progression to disease [88] . Finally, a case–control study conducted in 702 European patients and 702 age-matched healthy controls analyzed seven VEGF SNPs (-2578C>A, -2489C>T, -1498C>T, -634G>C, -7C>T, 936C>T, and 1612G>A) and their haplotypes, and failed to find any relationship between these genetic variants and the risk and progression for this tumor [89] . Therefore, at this moment the role of VEGF in the prognosis of prostate cancer is quite controversial. For example the -634C allele was predictive of increased risk and high tumor grades [87] in Tunisian subjects, but had no relation with risk in Austrian subjects [89] . Further studies are needed to demonstrate the role of VEGF genetic variants as biomarkers for risk and prognosis of prostate tumor.

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High VEGF protein expression in tumor or in serum have shown to be associated with NSCLC and its metastasis [111] . A study on DNA samples extracted from tumor and normal lung tissues from 36 patients examined the effect of VEGF -2578C>A, -634G>C, -1154G>A, and 936C>T SNPs on tumor VEGF expression and vascular density, which has been associated with progression of lung cancer. The -2578CC, -634GG, and -1154AA and GA genotypes were associated with low VEGF expression, whereas high VEGF levels were detected in samples carrying the -2578CA, -634GC, and -1154GG genotypes [90] . The vascular density in tumors bearing the -2578CC and -634GG VEGF genotypes was significantly lower compared with the -2578CA and -634CC+GC genotypes, respectively. VEGF -1154G>A and 936C>T were not related with tumor VEGF expression and vascular density [90] . An important study conducted on 1900 NSCLC Caucasian patients and 1458 healthy controls failed to find a correlation between germline VEGF -1498C>T, -634C>G, and 936C>T SNPs singularly analyzed on risk and prognosis of NSCLC after adjusting for age, gender, smoking status, pack-years of smoking, and years since smoking cessation [91] . However, male patients bearing the -634CC+CG genotype and -1498T/-634G/936C haplotype, respectively, had higher and reduced risk of developing lung adenocarcinoma [91] . Interesting, considering both males and females together, -634G>C, 936C>T and -1498C>T had no significant association with risk of disease,



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for the same class of patients [77] . In agreement with the results of the ECOG study E2100, -634CC and -1498TT VEGF genotypes showed a protective effect on hypertension (p = 0.03 in both cases) [125] . In addition, an association was observed between the occurrence of -2578CC polymorphism and protective effect toward hypertensive complications. In particular patients carrying the -634GG genotype showed a higher percentage of duration of hypertension during treatment with sunitinib than patients with the CC genotype (95% CI: 12–29%). The large number of SNPs analyzed in this study also made it possible to perform a haplotype analysis. Strong evidence for linkage disequilibrium was found for SNPs -2578, -2549, -1498 and -634, three of which were strongly associated with a protective effect towards hypertension [125] . In contrast with the results obtained by Schneider et al. [77] , and Kim et al. [125] , a French study conducted on 137 recurrent or metastatic breast cancer patients treated with bevacizumab showed that subjects carrying -634C allele had an increased toxicity including hypertension, arterial or venous thromboembolism and hemorrhages [126] . Garcia-Donas et al. assessed 16 SNPs in nine genes potentially relevant for sunitinib action, metabolism and transport in 95 clear-cell renal-cell carcinoma patients in an observational prospective study of the Spanish Oncology Genitourinary Group [122] . Relatively to analyzed VEGF polymorphisms the results indicated that the -634G/C SNP was associated with mucositis protection (p = 0.034) while -2578A/C and -1154G/A seemed significantly related with an increased risk of hypertension [122] . Different correlations between VEGF gene polymorphisms and treatment toxicity were identified in a group of 137 advanced inoperable gastrointestinal stromal tumors (GIST) patients treated with sunitinib. In this case the authors observed an elevated risk of hypothyroidism during sunitinib therapy in patients carrying the C allele in 460T/C (OR: 10.l; p = 0.041) and the T allele in 936C/T (OR: 10.5; p = 0.015) SNPs. No other correlations between the presence of VEGF SNPs and hypertension, hand–foot syndrome, mucositis or gastrointestinal disorder were found [127] . Furthermore, the sinergistic effects of bevacizumab plus sorafenib were evaluated by Galanis et al. in a Phase II study of 54 patients with recurrent glioblastoma [123] . In this study, 14 SNPs from VEGF, VEGFR2 and HIF-1α genes were analyzed in order to find any possible correlation with efficacy or impaired tolerance to treatment. Toxicity, calculated according to the onset of symptoms such as fatigue, hypertension and hypophosphatemia, was associated to high doses of sorafenib. In addition, a positive correlation was

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VEGF gene polymorphisms & treatment toxicity As detailed above, angiogenesis inhibitors (e.g., bevacizumab) and receptor TKIs have different targets and mechanisms of action. It has been addressed that both these types of drugs have the same toxicity profile, as a consequence of inhibition of VEGF pathway and angiogenesis [119] . However genetic variability may impact on biologic pathways controlling angiogenesis during cancer development and, hence, influence the response to various therapies in terms of benefits or side effects [120,121] . The most common adverse effect to be observed was the treatment induced-hypertension, probably due to the inhibition of nitric oxide and prostaglandin I2 release, which are controlled by VEGFR-2 signaling. Other side effects associated with these agents are fatigue, muscle weakness, hypophosphatemia, headache, mucositis, hand–foot syndrome, cardiomyopathy and congestive heart failure, renal damage, arterial thromboembolic events, anaemia and hemorrhage, bowel perforation and reversible posterior leukoencephalopathy syndrome [119,122,123] . In this regard, several genetic association studies have been performed, with the aim to find any correlation between VEGF SNPs and toxicity with both bevacizumab and TKIs [119] (Table 3) . In one of the first pilot pharmacogenetic studies performed in 2006 by Zhang et al. on 39 mCRC patients treated with single-agent cetuximab, no association between VEGF C936T gene polymorphism and toxicity was found [118] . Subsequently, Schneider et al. evaluated a panel of VEGF SNPs (-2578C/A, -1498C/T, -1154G/A, -634G/C, and 936C/T) in a Phase III randomized trial (Eastern Cooperative Oncology Group: ECOG-E2100) of bevacizumab plus paclitaxel as firstline therapy in 180 patients with metastatic breast cancer. The genotypes -634CC and -1498TT had a protective effect towards grade 3 or 4 hypertension (p = 0.005 and 0.022 respectively) [132] . As commented by other investigators, however, the study could have been more interesting if the circulating levels of VEGF were measured, since the VEGF 936C/T polymorphism is related to plasma VEGF levels [119] . In an abstract presented at the 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO), Kim et al. replicated the study of Schneider on 63 patients affected by mRCC treated with sunitinib and analyzed only for -634 and -1498 VEGF SNPs. However, while the -634CC genotype was associated with significantly less grade of hypertension, a similar correlation for the -1498TT genotype was not found [124] . These results, however, were not confirmed in a later study in which the molecular analysis was extended to a larger number of VEGF polymorphisms

70




NA

40

NA

NA

137

54

NA

95

NA

NA

137

40

NA

63

107

NA

63

111

183

180

NA

NA

39

53

Controls

Patients


USA

Italy Caucasic

Italy Caucasic

USA

USA

Poland Caucasian

Recurrent glioblastoma

Metastatic colorectal cancer

Metastatic colorectal cancer

Recurrent/metastatic epithelial ovarian cancer

Recurrent, ormetastatics quamous cell carcinoma of the head and neck

Advanced inoperable/ metastatic gastrointestinal stromal tumors

-2578C/A -634G/C +936C/T

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ro -2578 C/A +936C/T -634G/C -1498 C/T

Bevacizumab plus Sorafenib

FOLFIRI plus bevacizumab

FOLFIRI plus bevacizumab

-2578 A/C -2489T/C -1498C/T -1154G/A -634G/C rs25648 +936C/T rs10434

-2578 C/A -1512 del18 bp -2489 T/C -1411 4G/5G -1498 C/T -1190G/A -1154 G/A -634 G/C

-2578 C/A -1498 C/T -634G/C +936 C/T

Cyclophosphamide -634G/C +936C/T and Bevacizumab

Pemetrexed plus Bevacizumab

Sunitinib

-634G/C -2578 C/ A -1154G/A

-2578 C/A -1498 C/T -1154G/A -634G/C 936 C/T

-2578 C/A -2459ins/ del18bp -1498 C/T -1154 G/A -634 G/C +936 C/T

-634 G/C -1498C/T

-2578 C/A -1498 C/T, -1154 G/A -634 G/C +936 C/T

936C/T

VEGF SNPs genotype

rP

Sunitinib

Bevacizumab

Sunitinib

Sunitinib

Paclitaxel plus Bevacizumab

Cetuximab

Treatment

ho

Locally recurrent or metastatic breast cancer

Metastatic clear cell carcinoma

Metastatic renal cell carcinoma

ut

Metastatic breast cancer

A

Advanced colorectal cancer

Cancer

Spain Caucasian Advanced renal-cell carcinoma

France Caucasic

USA

USA

USA

Asian, Hispanic, Caucasic

Race-ethnicity

Table 3. Genetic association studies on VEGF SNPs and toxicity related to antiangiogenic therapy.

Heterozygous rs10434 associated with decreased incidence of fatigue. heterozygous -2489T/C, -2578 A/C and -1498C/T associated with fatigue and hypertension

No associations

No associations

No associations

No associations

-460 C and +936T alleles associated with risk of hypothyroidism

-2578 C/A and -1154G/A significantly associated with an increased risk of hypertension. -634G/C associated with mucositis protection.

-634 C allele presented a significant higher risk to develop toxicity (hypertension, arterial/venous thromboembolism, or hemorrhages)

-634CC, -1498 T and -2578CC protective effect towards hypertension ,

Only -634 C/C protective effect towards hypertension

-634 CC and -1498 TT protective effect towards hypertension

No associations

Toxicity

[123]

[131]

[130]

[129]

[128]

[127]

[122]

[126]

[125]

[124]

[77]

[118]

Ref.


Review

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Executive summary VEGF role in cancer progression • Angiogenesis plays a crucial role in new vessel formation in cancer development. • VEGF is a dimeric glycoprotein whose role in neoangiogenesis is that of promoting both proliferation and migration of endothelial cells. • Recent findings reported an impaired angiogenesis accompanied by a reduced expression of VEGF in cells derived from aging subjects.

Antiangiogenic strategies: VEGF/VEGFR axis inhibitors • VEGF/VEGFR interaction axis may serve as potential antiangiogenesis targets, led to the development of a variety of antibodies and kinase inhibitors which suppress VEGF/VEGFR signaling pathways. • The use on antiangiogenic drugs in the elderly, must take into account the frequent occurrence of thrombotic phenomena of the microvasculature, such as hypertension and proteinuria, associated both to arterial stiffness and to the progressive decline of renal function. • The most thoroughly studied antiangiogenic drug is bevacizumab. Clinical trials demonstrated a substantial improvement in response rate when bevacizumab was combined with standard chemotherapy versus chemotherapy alone in elderly patients with cancer.

Monoclonal antibodies blocking VEGFR

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Multitargeted tyrosine kinase inhibitors

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• Aflibercept (anti-VEGFR-1/2) and ramucirumab (anti-VEGFR-2) are monoclonal antibodies selectively directed against the extracellular domains of VEGFR. • Trial until now reported no differences in survival and increased toxicity among the study groups, including cancer patients older than 75 years.

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• The small molecule multitargeted tyrosine kinase inhibitors (TKIs) more commonly used in clinical trials involving elderly patients are sunitinib malate and sorafenib. • A trial assessing the use of first-line sunitinib in cancer patients aged >70 years demonstrated that elderly patients had a poorer safety and efficacy profile compared with younger patients. • Trials using sorafenib showed no differences in clinical outcomes and safety between aged and non-aged cancer patients.

Risk & prognostic value of VEGF SNPs in solid tumors

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• Many studies have investigated the role of VEGF polymorphisms as a genetic determinant for susceptibility and outcome of solid tumors. • +936C/T VEGF and -710C/T VEGFR1 genotypes are likely the more important genetic markers of susceptibility and better prognosis for breast cancer. • Patients with kidney cancer carrying VEGF TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 have worse prognosis. • VEGF tagSNP rs833068 or the functional SNP rs2010963 displayed significantly shortened overall survival after diagnosis for ovarian cancer with an effect most apparent during the first 5 years after diagnosis. • rs25648 -7C>T is the most significant VEGF SNP associated with variability in risk and prognosis for bladder cancer. • The VEGF -634GC+CC genotypes have been demonstrated to be linked with increased risk of prostate cancer, and the -634GC and CC genotypes with high-grade tumors. • Male patients bearing the VEGF -634CC+CG genotype and -1498T/-634G/936C haplotype, respectively, had higher and reduced risk of developing lung adenocarcinoma. • The VEGF -634C allele has been shown to be predictive of decreased risk and better survival in patients with colorectal cancer.

VEGF gene polymorphisms & treatment toxicity • Several are the side effects associated with the therapy with angiogenesis inhibitors (e.g., bevacizumab). • The VEGF genotypes -634CC and -1498TT has a protective effect towards grade 3 or 4 hypertension induced by bevacizumab. • Controversial results are present on the impact of VEGF genotypes -634CC allele intoxicity induced by bevacizumab. • An adverse relationship has been observed in cancer patients treated with sunitinib carrying the VEGF C allele in 460T/C.

Conclusion • In frail elderly patients genetic and epigenetic factors may add up to realize higher toxicities profiles for antiangiogenic cancer therapy, which may significantly impair patients’ performance and quality of life.

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Future perspective Antiangiogenic agents are now part of the therapeutic strategies in the management of several solid tumors. Results of clinical trials suggest that comprehensive analyses of the association between VEGF SNPS and clinical outcomes might help delineate risk/benefit ratios in designing tailored anti-VEGF-based treatments. However, available data are conflicting and do not point to a univocal direction, making difficult to draw any definitive conclusion. Indeed, if it is true that some studies highlighted an association between certain VEGF polymorphisms and improved response rate, other studies did not reach the same conclusion. The situation is even more complex when considering the risk of adverse events. This is the case of hypertension, one of the most common complications of antiVEGF agents, which has been recently associated to a favorable outcome, as demonstrated by an increase in PFS and OS of patients treated with bevacizumab [133] . This observation implies that a given genotype (associated with hypertensive complications), rather than representing a noneligibility criterion, could be

used, instead, to select particular clusters of patients who may mostly benefit from the use of anti-VEGF drugs. Conversely, a special issue is represented by elderly patients carrying other polymorphisms implicated, for example, in the pathogenesis of venous and/or arterial thromboembolism. In these patients, in fact, a preexisting condition of acquired thrombophilia, with or without co-morbidities, causes an increased incidence of thromboembolism, possibly due to alterations of the structural and functional properties of hemostatic and vascular system [134] . This is an important aspect to keep in mind in health care management of elderly cancer patient, especially in the presence of frailty. As discussed above, although efficacy does not seem to be influenced by patients’ age, this appears to be true only for medically fit older patients who retain a similar toxicity profile than younger ones. Conversely, in frail elderly patients genetic and epigenetic factors may add up to realize higher toxicities profiles that may significantly impair patients’ performance and quality of life. Future studies, specifically designed to address these issues, are still required to translate VEGF molecular analysis and pharmacogenetic studies into clinical practice.

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found between patients heterozygous for the VEGF 3´-UTR rs10434 polymorphism and a decreased incidence of fatigue, while carriers of heterozygous alleles of the VEGF promoter SNPs rs1005230, rs699947 and rs833061 showed higher incidence of fatigue and hypertension [123] . Other studies analyzing various combinations of bevacizumab with FOLFIRI in mCC [130,131] , with pemetrexed in head and neck cancer [128] or with cyclophosphamide in ovarian cancer [129] have not shown any association between drug toxicities and VEGF polymorphisms.

Review

Financial & competing interests disclosure

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Papers of special note have been highlighted as: • of interest; •• of considerable interest.

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••

A very important study reporting for the first time 15 novel sequence VEGF polymorphisms, most of which were rare, associated with variability in VEGF expression.

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112 Heist RS, Zhai R, Liu G et al. VEGF polymorphisms and

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VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann. Oncol. 19, 1734–1741 (2008).

117 Hofmann G, Langsenlehner U, Renner W et al. Common

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•

The first study showing that polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal cell carcinoma with decreased sunitinib response and tolerability.

123 Galanis E, Anderson SK, Lafky JM et al. Phase II study of

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125 Kim JJ, Vaziri SA, Rini BI et al. Association of VEGF

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131 Formica V, Palmirotta R, Del Monte G et al. Predictive

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129 Schultheis AM, Lurje G, Rhodes KE et al. Polymorphisms

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128 Argiris A, Karamouzis MV, Gooding WE et al. Phase II trial

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and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin. Cancer Res. 14, 7554–7563 (2008).

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