Bevacizumab pharmacogenetics in tumor treatment: still looking for the right pieces of the puzzle
2011; Future Medicine; Volume: 12; Issue: 8 Linguagem: Inglês
10.2217/pgs.11.75
ISSN1744-8042
Autores Tópico(s)Ubiquitin and proteasome pathways
ResumoPharmacogenomicsVol. 12, No. 8 EditorialFree AccessBevacizumab pharmacogenetics in tumor treatment: still looking for the right pieces of the puzzleGuido Bocci & Fotios LoupakisGuido Bocci† Author for correspondenceDivision of Pharmacology, Department of Internal Medicine, University of Pisa, Via Roma 55, 1–56126 Pisa, Italy and Istituto Toscano Tumori, Via Alderotti 26/N, 50139 Firenze, Italy. & Fotios LoupakisU.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliera-Universitaria Pisana, Via Roma 67, 50126 Pisa, Italy and Istituto Toscano Tumori, Via Alderotti 26/N, 50139 Firenze, ItalyPublished Online:15 Aug 2011https://doi.org/10.2217/pgs.11.75AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: bevacizumabcomplement factor HIL-8pharmacogeneticsVEGFVEGFR-2The available pieces of the puzzleBevacizumab is the first molecular-targeted antiangiogenic therapy to be approved by the US FDA and EMEA and, despite the numerous clinical successes, many challenges remain. Indeed, no genetic and molecular markers to predict or monitor the efficacy of – or the resistance to – bevacizumab have been found yet [1]. Thus, any efforts to identify these markers represent a challenging field of clinical oncology research.The important role of both tumor cells and tumor microenvironment in determining the complex process of angiogenesis clearly supports a pharmacogenetic investigation of tumor and germline SNPs for antiangiogenic drugs such as bevacizumab. An obvious strategy to pursue this aim is to look at the VEGF-A SNPs because the inhibition of the biologically active VEGF represent the best known mechanism of action of the antibody. Although VEGF-A SNPs seem to play a relevant part in determining the risk, prognosis and survival of cancer patients, their role as predictors of benefit from bevacizumab has not yet been clearly demonstrated and is still controversial [2]. In particular, a pioneering and fundamental article by Schneider and colleagues [3] reported the association between different VEGF-A genotypes and median overall survival (OS) when using bevacizumab (with paclitaxel chemotherapy) in a Phase III clinical trial of metastatic breast cancer. Indeed, the authors showed, in a retrospective review of cases, that VEGF-A -2578AA genotype was associated with a superior OS in the arm treated with paclitaxel and bevacizumab versus paclitaxel alone. Moreover, patients carrying the VEGF-A -1154A allele also demonstrated a superior OS in the combination arm. Etienne-Grimaldi and colleagues analyzed 137 women with locally recurrent or metastatic breast cancer receiving first-line bevacizumab-containing therapy for VEGF-A polymorphisms at position -2578 C/A, -1498 T/C, -1154 G/A, -634 G/C and +936 C/T [4]. None of the polymorphisms were significantly linked to clinical response. However, the analysis of the +936C/T polymorphism revealed that the patients homozygous for the 936C allele exhibited a marked tendency for a shorter time to progression than the patients bearing the 936T allele.These important experiences have greatly stimulated the bevacizumab pharmacogenetic research on VEGF-A SNPs. In particular, with regard to metastatic colorectal cancer (mCRC), a recent retrospective experience has shown a significant correlation of VEGF-A -1498TT genotype with worse progression free survival (PFS) in a population of mCRC patients treated with folinic acid, fluorouracil, irinotecan (FOLFIRI) plus bevacizumab as first-line regimen [5]. On the basis of these encouraging results, our group has recently investigated the VEGF-A -2578 A/C, -1498 C/T, -1154 A/G, -634 C/G and +936 C/T polymorphisms in a population of 54 mCRC patients enrolled in a Phase II study (FOIB trial) that has recently investigated the safety and activity of Gruppo Oncologico Nord Ovest – folinic acid, fluorouracil, oxaliplatin, irinotecan (GONO–FOLFOXIRI) plus bevacizumab as first-line treatment [6]. The translational program of the study was exploratory and conducted to give some preliminary perspectives for future nested pharmacogenetic studies in larger Phase III clinical trials. Unfortunately, none of the analyzed genotypes was significantly related to the PFS [7]. Even more interestingly, plasma VEGF-A levels of patients at the baseline were not influenced by any of the studied VEGF-A SNPs. However, our 'negative' data have been, in a certain way, anticipated by the pilot study of Schultheis et al. in 70 recurrent/metastatic ovarian cancer patients treated with metronomic cyclophosphamide and bevacizumab. Indeed, although patients with the VEGF-A +936 CT genotype had a longer median PFS, compared with those with the CC and TT genotype, these results did not reach a statistically significant difference [8]. Moreover, two other VEGF-A SNPs, the -634C/G and +405C/G SNPs, did not achieve any significant correlation with the outcome. These data were recently confirmed by Smerdel et al. who find out that VEGF-A gene polymorphisms -2578C/A, -1154G/A, +405C/G and +936C/T did not reveal any association with response or survival in 38 ovarian cancer patients administered with bevacizumab as a single agent [9]. This lack of a significant relationship between VEGF-A genotypes and PFS was also described by a recent article by Pander and colleagues [10], who analyzed, in 279 mCRC patients treated with capecitabine, oxaliplatin and bevacizumab (CAPOX-B), a selection of 17 polymorphisms in genes encoding drug targets, pathway molecules and detoxification enzymes. None of the studied polymorphisms were individually associated with PFS. However, differently from other studies, these authors found that a genetic interaction profile consisting of the TYMS enhancer region and VEGF-A +405G/C polymorphisms was significantly associated with PFS [10].Are pilot studies & methodology important to identify the new pieces of the bevacizumab pharmacogenetic puzzle?One of the major key points in pharmacogenetics – and in translational research as a whole – seems to be the extremely low rate of 'successful' determinants that enter the clinics compared with the huge amount of enthusiastic preliminary data. This point is certainly closely related to the hot issue of methodology. Initial data should be scrutinized with the most accurate statistical correction to avoid the risk of false-positive associations [11] and every effort should be made to have 'clean' validation sets [12]. On the other hand, the winding road of genetic determinants discovery should unavoidably start from pilot exploratory studies. First of all, researchers should move from a hypothesis with a strong rationale; indeed, SNPs should be related as much as possible to plausible biological explanations of their role. Moreover, researchers should do their best to avoid spurious positive results and look at their data in a rigorous and critical way because their preliminary results would lay the basis for the next step of confirmatory validating trials. As an example, these considerations have led our group to the design of a prospective confirmatory study (Pro.Ve.TT.A. study [101]) to verify the results initially reported on the VEGF-A -1498TT genotype [5].Furthermore, the abovementioned results raise some important issues about the role of VEGF-A SNPs in the pharmacogenetics of bevacizumab. These are considered below.Should negative data be part of the puzzle? When looking for the right piece, a key part of the game is to exclude the wrong ones. To this extent, the publication of 'good' negative data is much more important than an 'uncontrolled' proliferation of weak positive hypotheses. This could save, at best, the costly and time-consuming validating research.Are the chosen VEGF-A SNPs really players whose presence is indispensable for the 'success of the team'? What is the basis of the choice of these so-called 'functional' VEGF-A SNPs? Of course, these results detected in 'first-stage' genetic analyses require further validation. This is usually accomplished by both replication studies and functional analyses. Replication studies serve not only for confirmation a of true association between a pharmacogenetic marker and an outcome, but they are also a means for better assessing the true magnitude of the detected effect. Functional studies are aimed at revealing direct causality between the reported SNP and measurable functional modifications elicited in the encoded molecule such as VEGF-A or in its plasma (or serum) levels. Moreover, demonstration of unambiguous association between VEGF-A genotypes and bevacizumab-response features in controlled retrospective datasets, albeit promising, does not guarantee the usefulness of this routine genetic testing for the clinical decision-making process in the daily clinical environment.What is the role of chemotherapeutic drugs in this puzzle? With the exception of renal carcinoma, bevacizumab should be used in combination with chemotherapy. Could the chemotherapeutic drugs modulate the VEGF-A gene expression (and protein secretion)? Such a scenario clearly makes companion chemotherapeutic drugs extremely important when looking at genetic determinants of bevacizumab effect, since different agents could induce provascular effects to different degrees.Both germline and somatic SNPs are logical candidates for future research because angiogenesis is both a largely host-mediated event and a process mediated by somatic mutation occurring in the tumor. The DNA evaluated in Schneider's study [3] was derived from the surgical specimens of primary tumors because, from previous experiences, it seemed that the majority of variability seen in the common polymorphic sites was inherited [13]. Although a case report demonstrated the possibility of a discordant VEGF-A genotype between tumor and normal tissue [14], no further studies have been conducted in order to determine and, finally, suggest which type of samples (blood or tumor cells) should be investigated. Moreover, the importance of obtaining the information for both has not been established yet in order to predict a superior survival or a lower risk of hypertension in patients treated with bevacizumab.Although the investigated SNPs have been defined functionally by some studies [15], their effects on VEGF-A expression are still quite controversial because of the different results on in vitro and in vivo experimental settings [16]. Is the baseline VEGF-A plasma (or serum) concentration the right phenotype to look at in cancer patients for germline SNPs? Is the VEGF-A immunohistochemistry of the primary tumor the proper approach to quantify the functionality of tumor VEGF-A SNPs? Based on the available data, in our opinion both the experimental approaches seem to have numerous methodological pitfalls that limit their extensive use in randomized clinical trials and clinical routine. Thus, any future effort in this field is greatly needed in order to identify VEGF-A SNPs with a well-defined phenotype.Are VEGF-A polymorphisms the only & right pieces for this puzzle?A different approach, and a possible new perspective, to the pharmacogenetics of bevacizumab could come from studies that investigate genes not directly linked to the known mechanism of action of the anti-VEGF-A antibody. Interestingly, a year before the description of the possible role of VEGF-A gene polymorphisms in bevacizumab pharmacogenetics [3], Brantley and colleagues demonstrated, in a retrospective cohort study with 86 patients being treated for neovascular age-related macular degeneration (AMD) with bevacizumab alone, that the CFH Y402H CC genotype determined a significantly worse clinical course in patients after the intravitreal bevacizumab than those with the CFH Y402H TC and TT genotypes, suggesting a potential pharmacogenetic relationship [17]. Not surprisingly, this study has recently been confirmed by Nischler et al.[18] in a larger AMD population treated with bevacizumab (197 patients); the authors observed a significantly worse outcome in the CFH Y402H CC genotype group. Could these results also be applied in diseases other than AMD? Is it scientifically correct to investigate apparently no disease-related genes in other settings such as colorectal or breast cancer? In our opinion the answer should be affirmative.The bevacizumab pharmacogenetic perspective should at least involve other genes closely related to VEGF-dependent angiogenesis. In 2007, our group suggested investigating some polymorphisms of genes related to the angiogenic process such as VEGFR-2, HIF-1a, TIMP-3 and eNOS[15]. Thus, polymorphisms of these genes might reasonably influence anti-VEGF treatments such as bevacizumab. Surely, this experimental approach guided the pilot study from Schultheis and colleagues [8] to evaluate the associations between angiogenesis gene polymorphisms and clinical outcome in bevacizumab-treated ovarian cancer patients. The authors investigated 29 different SNPs on the same number of angiogenesis-related genes (e.g., Nrp1, VEGFR-2 and PlGF). Even though the majority of analyses did not reach any statistical difference, some promising results were found. Patients genotyped A/A or A/T for the IL-8 T251A gene polymorphism had a statistically significantly lower response rate than those with the genotype T/T. Moreover, interesting results were obtained with some CXCR2 (the receptor of IL-8) and adrenomedullin polymorphisms and repeats, respectively. This information, although from a pilot study and without any statistical correction (such as a stringent Bonferroni-corrected significance), may highlight possible new scenarios on the pharmacogenetics of bevacizumab alone or combined with a metronomic chemotherapy [19].A different approach to identify SNPs of new genes related to the bevacizumab response was used by Kim et al.[20], using a genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers. Surprisingly, angiogenesis-unrelated genes, such as ANXA11 and LINS1, were found to be significantly linked to the bevacizumab response. Are these results relevant for future studies or just to advance a novel hypothesis on bevacizumab mechanism of action? Are they clinically meaningful and helpful or just a single and accidental observation? Further research is needed to answer these questions.AcknowledgementsThe authors would like to thank Professor Franco Bocci for his helpful suggestions.Financial & competing interests disclosureThis work was supported in part by the Italian Association for Cancer Research (AIRC). The authors have no other 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 apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Loupakis F, Bocci G, Pasqualetti G et al. Targeting vascular endothelial growth factor pathway in first-line treatment of metastatic colorectal cancer: state-of-the-art and future perspectives in clinical and molecular selection of patients. Curr. Cancer Drug Targets10(1),37–45 (2010).Crossref, Medline, CAS, Google Scholar2 Jain L, Vargo CA, Danesi R et al. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors. Mol. Cancer Ther.8(9),2496–2508 (2009).Crossref, Medline, CAS, Google Scholar3 Schneider BP, Wang M, Radovich M et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J. Clin. Oncol.26(28),4672–4678 (2008).Crossref, Medline, CAS, Google Scholar4 Etienne-Grimaldi MC, Formento P, Degeorges A et al. Prospective analysis of the impact of VEGF-A gene polymorphisms on pharmacodynamics of bevacizumab-based therapy in metastatic breast cancer patients. Br. J. Clin. Pharmacol.71(6),921–928 (2011).Crossref, Medline, CAS, Google Scholar5 Loupakis F, Ruzzo A, Salvatore L et al. VEGF gene polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts). Eur. J. Cancer (Suppl. 7), 357 (2009).Crossref, Google Scholar6 Masi G, Loupakis F, Salvatore L et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a Phase 2 trial. Lancet Oncol.11(9),845–852 (2010).Crossref, Medline, CAS, Google Scholar7 Loupakis F, Cremolini C, Fioravanti A et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br. J. Cancer104(8),1262–1269 (2011).Crossref, Medline, CAS, Google Scholar8 Schultheis AM, Lurje G, Rhodes KE et al. Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab. Clin. Cancer Res.14(22),7554–7563 (2008).Crossref, Medline, CAS, Google Scholar9 Smerdel MP, Steffensen KD, Waldstrom M et al. The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab. Gynecol. Oncol.118(2),167–171 (2010).Crossref, Medline, CAS, Google Scholar10 Pander J, Wessels JA, Gelderblom H et al. Pharmacogenetic interaction analysis for the efficacy of systemic treatment in metastatic colorectal cancer. Ann. Oncol.22(5),1147–1153 (2011).Crossref, Medline, CAS, Google Scholar11 Maitland ML, Ratain MJ, Cox NJ. Interpreting P values in pharmacogenetic studies: a call for process and perspective. J. Clin. Oncol.25(29),4513–4515 (2007).Crossref, Medline, Google Scholar12 Buyse M, Sargent DJ, Grothey A et al. Biomarkers and surrogate end points – the challenge of statistical validation. Nat. Rev. Clin. Oncol.7(6),309–317 (2010).Crossref, Medline, Google Scholar13 Schneider BP, Skaar TC, Sledge GW et al. Analysis of angiogenesis genes from paraffin-embedded breast tumor and lymph nodes. Breast Cancer Res. Treat.96(3),209–215 (2006).Crossref, Medline, CAS, Google Scholar14 Coltelli L, Allegrini G, Orlandi P et al. Discordant somatic and germline VEGF-A genotype in a cancer patient resistant to paclitaxel/bevacizumab with chemosensitive hepatic metastasis. Pharmacogenomics10(8),1225–1229 (2009).Link, CAS, Google Scholar15 Pasqualetti G, Danesi R, Del Tacca M et al. Vascular endothelial growth factor pharmacogenetics: a new perspective for anti-angiogenic therapy. Pharmacogenomics8(1),49–66 (2007).Link, CAS, Google Scholar16 Radovich M, Hancock BA, Kassem N et al. Resequencing of the vascular endothelial growth factor promoter reveals haplotype structure and functional diversity. Angiogenesis13(3),211–218 (2010).Crossref, Medline, CAS, Google Scholar17 Brantley MA Jr, Fang AM, King JM et al. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology114(12),2168–2173 (2007).Crossref, Medline, Google Scholar18 Nischler C, Oberkofler H, Ortner C et al. Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration. Acta Ophthalmol.89(4),e344–349 (2011).Crossref, Medline, CAS, Google Scholar19 Garcia AA, Hirte H, Fleming G et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital Phase II consortia. J. Clin. Oncol.26(1),76–82 (2008).Crossref, Medline, CAS, Google Scholar20 Kim JC, Kim SY, Cho DH et al. Novel chemosensitive single-nucleotide polymorphism markers to targeted regimens in metastatic colorectal cancer. Clin. Cancer Res.17(5),1200–1209 (2011).Crossref, Medline, CAS, Google Scholar101 Evaluation of VEGF Polymorphism as Predictive Factor in Metastatic Colorectal Cancer Treated with FOLFIRI Plus Bevacizumab (PROVETTA) http://clinicaltrials.gov/ct2/show/NCT01363739Google ScholarFiguresReferencesRelatedDetailsCited ByA pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients21 March 2022 | npj Breast Cancer, Vol. 8, No. 1Pharmacogenetics and breast cancer management: current status and perspectives18 February 2015 | Expert Opinion on Drug Metabolism & Toxicology, Vol. 11, No. 5Genes involved in pericyte-driven tumor maturation predict treatment benefit of first-line FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer29 July 2014 | The Pharmacogenomics Journal, Vol. 15, No. 1Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumabGiacomo Allegrini, Luigi Coltelli, Paola Orlandi, Andrea Fontana, Andrea Camerini, Antonella Ferro, Marina Cazzaniga, Virginia Casadei, Sara Lucchesi, Eleonora Bona, Marco Di Lieto, Ilaria Pazzagli, Federica Villa, Domenico Amoroso, Marco Scalese, Giada Arrighi, Sabrina Molinaro, Anna Fioravanti, Chiara Finale, Renza Triolo, Teresa Di Desidero, Sara Donati, Lorenzo Marcucci, Orlando Goletti, Marzia Del Re, Barbara Salvadori, Ilaria Ferrarini, Romano Danesi, Alfredo Falcone & Guido Bocci18 December 2014 | Pharmacogenomics, Vol. 15, No. 16Clinical genotyping and efficacy outcomes: Exploratory biomarker data from the phase II ABIGAIL study of first-line bevacizumab plus chemotherapy in non-squamous non-small-cell lung cancerLung Cancer, Vol. 86, No. 1VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide16 July 2013 | British Journal of Cancer, Vol. 109, No. 4Prospective Validation of Candidate SNPs of VEGF/VEGFR Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab4 July 2013 | PLoS ONE, Vol. 8, No. 7Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degenerationElisa Agosta, Stefano Lazzeri, Paola Orlandi, Michele Figus, Anna Fioravanti, Teresa Di Desidero, Maria Sole Sartini, Marco Nardi, Romano Danesi & Guido Bocci27 July 2012 | Pharmacogenomics, Vol. 13, No. 9Research Highlights: Highlights from the latest articles in colorectal cancer pharmacogenomicsSharon Marsh17 May 2012 | Pharmacogenomics, Vol. 13, No. 7 Vol. 12, No. 8 Follow us on social media for the latest updates Metrics History Published online 15 August 2011 Published in print August 2011 Information© Future Medicine LtdKeywordsbevacizumabcomplement factor HIL-8pharmacogeneticsVEGFVEGFR-2AcknowledgementsThe authors would like to thank Professor Franco Bocci for his helpful suggestions.Financial & competing interests disclosureThis work was supported in part by the Italian Association for Cancer Research (AIRC). The authors have no other 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 apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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