The role of VEGF in predicting progression-free survival (PFS) and overall survival (OS) for ovarian carcinoma patients
Abstract
Vascular endothelial growth factor (VEGF) plays a pivotal role in highly vascularized tumors such as ovarian cancer. It can be detected in serum and ascitic fluid. This study aimed to determine the difference between VEGF in the blood serum level and ascitic fluid in predicting progression-free survival (PFS) and overall survival (OS) in patients with ovarian cancer. A prospective cohort study was conducted between 2018 and 2021 at Dr Sardjito General Hospital, Yogyakarta, Indonesia. The study included patients who underwent primary surgery for epithelial ovarian cancer. VEGF levels in both serum and ascitic fluid were measured using the human cytokine magnetic 10-plex panel for Luminex (Invitrogen commercial kit), based on the enzyme-linked
immunosorbent assay (ELISA). PFS and OS were monitored until the end of the study period. A total of 40 patients were enrolled, with a median follow-up duration of 24 mo. Among participants, 22 patients (55%) experienced disease progression, and 50% survived. The median VEGF levels in serum and ascitic fluid were 720 and 1925 pg/mL, respectively. Receiver operating characteristic (ROC) curve analyses of PFS and OS revealed that VEGF levels in ascitic fluid had better predictive value than serum VEGF levels. The area under the curve
(AUC) of ascites vs serum was 0.646 vs 0.567, with sensitivity of 83.3% vs 100% for PFS, whereas the AUC of ascites vs serum was 0.565 vs 0.548, with sensitivity of 50.0% vs 93.8% for OS. However, no statistical significance was observed (p>0.05). In conclusion, both VEGF ascites and serum failed to predict PFS and OS in ovarian cancer patients.
References
Gondhowiardjo S, Christina N, Ganapati NPD, Hawariy S, Radityamurti F, Jayalie VF, et al. Five-year cancer epidemiology at the national referral hospital: hospital-based cancer registry data in Indonesia. JCO Global Oncol, 2021; 7:190-203.
https://doi.org/10.1200/GO.20.00155
Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. Angiogenesis in normal and neoplastic ovaries. Angiogenesis, 2005; 8(2):169-82.
https://doi.org/10.1007/s10456-005-9001-1
Chung AS, Ferrara N. Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol, 2010; 27:563-84.
https://doi.org/10.1146/annurev-cellbio-092910-154002
Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, et al. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun Signal, 2022; 20(1):49.
https://doi.org/10.1186/s12964-022-00838-y
Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer, 2004; 4(Suppl 2):S81-5.
https://doi.org/10.3816/ccc.2004.s.013
Melincovici CS, Bosca AB, Susman S, Marginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018; 59(2):455-67.
Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019; 176(6):1248-64.
https://doi.org/10.1016/j.cell.2019.01.021
Hefler LA, Zeillinger R, Grimm C, Sood AK, Cheng WF, Gadducci A, et al. Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer. Gynecol Oncol, 2006; 103(2):512-7.
https://doi.org/10.1016/j.ygyno.2006.03.058
Pourgholami MH, Cai ZY, Lu Y, Wang L, Morris DL. Albendazole: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation in OVCAR-3 tumor-bearing nude mice. Clin Can Res, 2006; 12(6):1928-35.
https://doi.org/10.1158/1078-0432.CCR-05-1181
Rudlowski C, Pickart AK, Fuhljahn C, Friepoertner T, Schlehe B, Biesterfeld S, et al. Prognostic significance of vascular endothelial growth factor VEGF expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer, 2006; 16(Suppl 1):183-89.
https://doi.org/10.1111/j.1525-1438.2006.00307.x
Liang B, Guo Z, Li Y, Liu C. Elevated VEGF concentrations in ascites and serum predict adverse prognosis in ovarian cancer. Scand J Clin Lab Invest, 2013; 73(4):309-14.
https://doi.org/10.3109/00365513.2013.773593
Schumacher JJ, Dings RP, Cosin J, Subramanian IV, Auersperg N, Ramakrishnan S. Modulation of angiogenic phenotype alters tumorigenicity in rat ovarian epithelial cells. Cancer Res, 2007; 67(8):3683-90.
https://doi.org/10.1158/0008-5472.CAN-06-3608
Shen GH, Ghazizadeh M, Kawanami O, Shimizu H, Jin E, Araki T, et al. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma. Brit J Cancer, 2000; 83(2):196-203.
https://doi.org/10.1054/bjoc.2000.1228
Horiuchi A, Imai T, Shimizu M, Oka K, Wang C, Nikaido T, et al. Hypoxia-induced changes in the expression of VEGF, HIF-1 alpha and cell cycle-related molecules in ovarian cancer cells. Anticancer Res, 2002; 22(5):2697-702.
Weis S, Cui J, Barnes L, Cheresh D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol, 2004; 167(2):223-9.
https://doi.org/10.1083/jcb.200408130
Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer, 2005; 5(5):355-66.
https://doi.org/10.1038/nrc1611
Trifanescu OG, Gales LN, Tanase BC, Marinescu SA, Trifanescu FA, Gruia LM, et al. Prognostic role of vascular endothelial growth factor and correlation with oxidative stress markers in locally advanced and metastatic ovarian cancer patients. Diagnostics, 2023; 13(1):166.
https://doi.org/10.3390/diagnostics13010166
Harloziňska A, Sedlaczek P, Kulpa J, Grybos M, Worjik E, Dalen VA, et al. Vascular endothelial growth factor (VEGF) concentration in sera and tumor effusions from patients with ovarian carcinoma. Anticancer Res, 2004; 24(2 C):1149-57.
Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol, 2002; 20(21):4368-80.
https://doi.org/10.1200/JCO.2002.10.088
Mahner S, Woelber L, Eulenburg C, Schwarz J, Carney C, Jeanicke F, et al. TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients. BMC Cancer, 2010; 10:139.
https://doi.org/10.1186/1471-2407-10-139
González-Palomares B, Coronado Martín PJ, Maestro de Las Casas ML, Veganzones de Castro S, Rafael Fernández S, Vidaurreta Lázaro M, et al. Vascular endothelial growth factor (VEGF) polymorphisms and serum VEGF levels in women with epithelial ovarian cancer, benign tumors, and healthy ovaries. Int J Gynecol Cancer, 2017; 27(6):1088-95.
https://doi.org/10.1097/IGC.0000000000001006
Gadducci A, Ferdeghini M, Fanucchi A, Annicchiarico C, Ciampi B, Prontera C, et al. Serum preoperative vascular endothelial growth factor (VEGF) in epithelial ovarian cancer: relationship with prognostic variables and clinical outcome. Anticancer Res, 1999; 19(2B):1401-5.
Bandiera E, Franceschini R, Specchia C, Bignotti E, Trevisiol C, Gion M, et al. Prognostic significance of vascular endothelial growth factor serum determination in women with ovarian cancer. ISRN Obstet Gynecol, 2012; 2012:245756.
https://doi.org/10.5402/2012/245756
Okunade KS, Adejimi AA, Ohazurike EO, Salako O, Osunwusi B, Adenekan MA, et al. Predictors of survival outcomes after primary treatment of epithelial ovarian cancer in Lagos, Nigeria. JCO Glob Oncol, 2021; 7:89-98.
https://doi.org/10.1200/GO.20.00450
Wimberger P, Lehmann N, Kimmig R, Burger A, Meier W, Hoppenau B, et al. Impact of age on outcome in patients with advanced ovarian cancer treated within a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol, 100(2):300-7.