Abstract
Dismal prognosis of glioblastoma (GBM) prompts for the identification of response predictors and therapeutic resistance mechanisms of current therapies. The authors investigated the impact of c-Met, HGF, VEGFR2 expression and microvessel density (MVD) in GBM patients submitted to second-line chemotherapy with bevacizumab. Immunohistochemical expression of c-Met, HGF, VEGFR2, and MVD was assessed in tumor specimens of GBM patients treated with bevacizumab, after progression under temozolomide. Survival analysis was evaluated according to the expression of the aforementioned biomarkers. c-Met overexpression was associated with a time-to-progression (TTP) after bevacizumab of 3 months (95% CI, 1.5–4.5) compared with a TTP of 7 months (95% CI, 4.6–9.4) in patients with low or no expression of c-Met (p = 0.05). VEGFR2 expression was associated with a TTP after bevacizumab of 3 months (95% CI, 1.8–4.2) compared with a TTP of 7 months (95% CI, 5.7–8.3) in patients with no tumoral expression of VEGFR2 (p = 0.009). Concomitant c-Met/VEGFR2 overexpression was associated with worse overall survival (13 months) compared with concomitant c-Met/VEGFR2 negative expression (19 months; p = 0.025). Our data support the hypothesis that c-Met and VEGFR2 overexpression have a role in the development of glioblastoma early resistance and might predict poorer responses to anti-angiogenic therapies.
Highlights
Dismal prognosis of glioblastoma (GBM) prompts for the identification of response predictors and therapeutic resistance mechanisms of current therapies
The median time to progression after temozolomide was 8 months and the median time to progression after bevacizumab was 5 months
The BELOB phase 2 trial supported the use of bevacizumab in combination with lomustine in the recurrent GBM setting, showing a benefit in overall survival (OS); it was not validated in EORTC 26101 phase 3 trial
Summary
Dismal prognosis of glioblastoma (GBM) prompts for the identification of response predictors and therapeutic resistance mechanisms of current therapies. Defining populations of patients who can benefit most from a particular therapy will improve cost-effectiveness and therapeutic outcomes, avoiding futile or harmful t reatments[13] In this perspective, it is crucial to identify response predictors and therapeutic resistance mechanisms of presently available therapies in GBM patients. In the early phase, tumors are dependent on VEGF and resistance emerges from the upregulation of HGF/c-MET p athway[15,16]. In this standpoint, our purpose was to evaluate the prognostic and therapeutic significance of c-Met, HGF and VEGFR2 expression, together with microvessel density (MVD), in patients with recurrent GBM undergoing second-line chemotherapy with bevacizumab-based therapy
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