In this study, we have designed a prospective research to investigate the relationship between tumor-specific biomarkers and VTE in GBM patients. We have examined 7 routinely tested molecular factors in IDHwt patients, shows that the status of EGFR and PTEN are significantly correlated with VTE by univariate analysis. Other prognostic factors such as TERTp, P53, BRAF and MGMT has no influence in the risk of VTE. PTEN is no longer significantly correlated with VTE events by multivariable analysis.We finally found 1 clinical marker, 1 molecular and 1 plasma biomarker predicting substantially increased risk of VTE in IDHwt GBM patients: namely, ECOG score, EGFR status and D-dimer. We tested the biomarkers by a VTE risk assessment model and found that patients with low ECOG score (≤ 2), low D-dimer (< 1.6µg/mL) and no EGFR amplification have the lowest risk of developing VTE (17.2%, score = 0), the risk of VTE was 63.8% for patients assigned to the high-risk group (score = 2 or 3).
Our findings that combined analysis of ECOG score, EGFR and D-dimer to built a GBM specific VTE risk assessment model is completely novel. Most of previous studies have tested different biomarkers in pooled patient populations with different types of cancer, however, the numbers of samples for specific cancer are small [17–19]. A multinational cohort study evaluated four clinical prediction scores for VTE in patients with advanced cancer and found that the prediction scores were poor at predicting VTE in cancer patients . The sensitivity and specificity of current prediction models for VTE in clinical practice is not satisfied in cancer patients, explore new models based on biomarkers and pathways of cancer-associated thrombosis in individual cancers are thought to be the best way to solve this problem .
With the publication of the 2016 WHO Classification of Tumors of the Central Nervous system, the official diagnostic and grading system of glioma has changed from solely on morphologic features to both on molecular and morphologic features.
Some molecular biomarkers like IDH, TERTp, EGFR, P53, PTEN, BRAF, MGMT are reported to be closely related with prognosis in GBM and recommened to test in clinical practice to assist diagnosis and treatment. Some preclinical and clinical research revealed that these biomarkers are also closely related with the risk of VTE. A study by Unruh et al. reported that mutant IDH1 has potent antithrombotic activity by the production of D-2-hydroxyglutarate (D-2-HG) in glioma patients . NAZARI et al analyzed the different risk of VTE in brain tumor patients and found that the status of IDH1 was closely linked to the risk of VTE, patients with IDH1 mutation were at very low risk of VTE . In line with the present study, we also found that IDH1 mutation was highly linked with low risk of VTE, none of 14 IDH1 mutant patients in this study developed VTE during follow-up. Rong et al have evaluated the relationship between the expression of EGFR and PTEN and tissue factor expression in glioblastoma and found that they are also highly correlated . Recently, a retrospective study showing no difference in VTE risk according to EGFR amplification status in Grade II-IV Glioma patients. However, only 73 GBM patients had information on EGFR expression and they were not analyzed separately . In contrast with this study, our data shows that the status of EGFR amplication significantly related with VTE risk in IDHwt GBM patients. Our large number of available EGFR information patients and separate analysis may partially explain this discrepancy.
On the other hand, we also evaluated the predictive value of clinical and plasma markers. Previous study have shown that glioma patients with age > 44 years linked with high risk of VTE . However, our result shows no difference between patients with different ages. The median age of diagnosis of GBM is reported to be 64 years old and more than 80% is over 50 years old . In our study, the median age of diagnosis is 57 years old and less than 10% with age < 50 years old. The difference in age distribution may explain this discrepancy. Besides, by univariate and multivariable competing risk analysis, we found that ECOG score is the strongest independent predictors of increased risk of VTE among age, gender, ECOG score, BMI and hemiparesis. Platelet count and D-dimer have been used widely as useful indicators of intravascular thrombosis, consist with previous study , our result shows that patients with VTE have significant higher D-dimer than patients without VTE, D-dimer is an independent predictors of VTE. However, no significant difference in Platelet count has been noted between two groups.
Some limitations of our study need to be addressed. This study is a single-center study, the number of IDHmt patients and VTE events is relatively low. Moreover, based on the results of previous studies and routine clinical practice, although we have analyzed 7 oncogenetic mutations and 2 plasma biomarkers and developed a RAM in IDHwt GBM patients, some information of other oncogenetic mutations is not available; for example, CDKN2A and NFKB1A deletion mut
In conclusion, we have combined analysis of clinical and laboratory markers in routine clinical practice of GBM and found that patients with IDH1 mutation were at very low risk of VTE. In IDHwt GBM patients, 1clinical marker,1 molecular mutation and 1 plasma biomarkers predict substantially increased risk of VTE : namely, ECOG score, EGFR status and D-dimer. by applying a VTE risk assessment model, we could identify patients with a very high and low risk of VTE in clinical practice.