Predictive factors for response to regorafenib in recurrent glioblastoma, IDH-wildtype, are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform. We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a clinically available platform. Moreover, MGMT methylation and EGFRvIII expression analyses were performed. Six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months, in line with literature data. NGS analysis revealed a mutation in the EGFR pathway in 18% of cases and a mutation in the mitogen-activated protein-kinase (MAPK) pathway in 18% of cases. In the remaining cases, no mutations were detected. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p = 0.0061; for OS, 7 vs 9 months, p = 0.1076). Multivariate analysis confirmed that MAPK pathway mutations independently predicted a shorter PFS after regorafenib treatment (p = 0.0188). The negative prognostic role of MAPK pathway alteration was reinforced when we combined EGFR-mutated with EGFRvIII-positive cases. Recurrent glioblastoma tumors with an alteration in MAPK pathway could belong to the mesenchymal subtype and respond poorly to regorafenib treatment, while EGFR-altered cases have a better response to regorafenib. We thus provide a molecular selection criterion easy to implement in the clinical practice.

Chiesa, S., Mangraviti, A., Martini, M., Cenci, T., Mazzarella, C., Gaudino, S., Bracci, S., Martino, A., Della Pepa, G. M., Offi, M., Gessi, M., Russo, R., Martucci, M., Beghella Bartoli, F., Larocca, L. M., Lauretti, L., Olivi, A., Pallini, R., Balducci, M., D'alessandris, Q. G., Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma, <<SCIENTIFIC REPORTS>>, 2022; 12 (1): N/A-N/A. [doi:10.1038/s41598-022-20417-y] [https://hdl.handle.net/10807/218991]

Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma

Chiesa, S.
Primo
;
Martini, M.;Cenci, T.;Mazzarella, C.;Gaudino, S.;Martino, A.;Della Pepa, G. M.;Offi, M.;Gessi, M.;Russo, R.;Martucci, M.;Larocca, L. M.;Lauretti, L.;Olivi, A.;Pallini, R.
;
Balducci, M.
Penultimo
;
D'Alessandris, Q. G.
Ultimo
2022

Abstract

Predictive factors for response to regorafenib in recurrent glioblastoma, IDH-wildtype, are scarcely recognized. The objective of this study was to identify molecular predictive factors for response to regorafenib using a clinically available platform. We analyzed a prospective cohort of 30 patients harboring recurrent glioblastoma, IDH-wildtype, and treated with regorafenib. Next-generation sequencing (NGS) analysis was performed on DNA extracted from paraffin-embedded tissues using a clinically available platform. Moreover, MGMT methylation and EGFRvIII expression analyses were performed. Six-month progression-free survival (PFS) was 30% and median overall survival (OS) was 7.5 months, in line with literature data. NGS analysis revealed a mutation in the EGFR pathway in 18% of cases and a mutation in the mitogen-activated protein-kinase (MAPK) pathway in 18% of cases. In the remaining cases, no mutations were detected. Patients carrying MAPK pathway mutation had a poor response to regorafenib treatment, with a significantly shorter PFS and a nonsignificantly shorter OS compared to EGFR-mutated patients (for PFS, 2.5 vs 4.5 months, p = 0.0061; for OS, 7 vs 9 months, p = 0.1076). Multivariate analysis confirmed that MAPK pathway mutations independently predicted a shorter PFS after regorafenib treatment (p = 0.0188). The negative prognostic role of MAPK pathway alteration was reinforced when we combined EGFR-mutated with EGFRvIII-positive cases. Recurrent glioblastoma tumors with an alteration in MAPK pathway could belong to the mesenchymal subtype and respond poorly to regorafenib treatment, while EGFR-altered cases have a better response to regorafenib. We thus provide a molecular selection criterion easy to implement in the clinical practice.
Inglese
Chiesa, S., Mangraviti, A., Martini, M., Cenci, T., Mazzarella, C., Gaudino, S., Bracci, S., Martino, A., Della Pepa, G. M., Offi, M., Gessi, M., Russo, R., Martucci, M., Beghella Bartoli, F., Larocca, L. M., Lauretti, L., Olivi, A., Pallini, R., Balducci, M., D'alessandris, Q. G., Clinical and NGS predictors of response to regorafenib in recurrent glioblastoma, <<SCIENTIFIC REPORTS>>, 2022; 12 (1): N/A-N/A. [doi:10.1038/s41598-022-20417-y] [https://hdl.handle.net/10807/218991]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/218991
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