Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer
Articolo
Data di Pubblicazione:
2015
Citazione:
Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer / L. Barault, A. Amatu, F.E. Bleeker, C. Moutinho, C. Falcomatà, V. Fiano, A. Cassingena, G. Siravegna, M. Milione, P. Cassoni, F. de Braud, R. Rudà, R. Soffietti, T. Venesio, A. Bardelli, P. Wesseling, P. de Witt Hamer, F. Pietrantonio, S. Siena, M. Esteller, A. Sartore Bianchi, F. di Nicolantonio. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - 26:9(2015 Sep), pp. 1994-1999. [10.1093/annonc/mdv272]
Abstract:
BACKGROUND:
O(6)-methyl-guanine-methyl-transferase (MGMT) silencing by promoter methylation may identify cancer patients responding to the alkylating agents dacarbazine or temozolomide.
PATIENTS AND METHODS:
We evaluated the prognostic and predictive value of MGMT methylation testing both in tumor and cell-free circulating DNA (cfDNA) from plasma samples using an ultra-sensitive two-step digital PCR technique (methyl-BEAMing). Results were compared with two established techniques, methylation-specific PCR (MSP) and Bs-pyrosequencing.
RESULTS:
Thresholds for MGMT methylated status for each technique were established in a training set of 98 glioblastoma (GBM) patients. The prognostic and the predictive value of MGMT methylated status was validated in a second cohort of 66 GBM patients treated with temozolomide in which methyl-BEAMing displayed a better specificity than the other techniques. Cutoff values of MGMT methylation specific for metastatic colorectal cancer (mCRC) tissue samples were established in a cohort of 60 patients treated with dacarbazine. In mCRC, both quantitative assays methyl-BEAMing and Bs-pyrosequencing outperformed MSP, providing better prediction of treatment response and improvement in progression-free survival (PFS) (P < 0.001). Ability of methyl-BEAMing to identify responding patients was validated in a cohort of 23 mCRC patients treated with temozolomide and preselected for MGMT methylated status according to MSP. In mCRC patients treated with dacarbazine, exploratory analysis of cfDNA by methyl-BEAMing showed that MGMT methylation was associated with better response and improved median PFS (P = 0.008).
CONCLUSIONS:
Methyl-BEAMing showed high reproducibility, specificity and sensitivity and was applicable to formalin-fixed paraffin-embedded tissues and cfDNA. This study supports the quantitative assessment of MGMT methylation for clinical purposes since it could refine prediction of response to alkylating agents.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Alkylating agent; Cell free circulating DNA; Digital PCR; DNA methylation; Metastatic colorectal cancer; MGMT; Oncology; Hematology
Elenco autori:
L. Barault, A. Amatu, F.E. Bleeker, C. Moutinho, C. Falcomatà, V. Fiano, A. Cassingena, G. Siravegna, M. Milione, P. Cassoni, F. de Braud, R. Rudà, R. Soffietti, T. Venesio, A. Bardelli, P. Wesseling, P. de Witt Hamer, F. Pietrantonio, S. Siena, M. Esteller, A. Sartore Bianchi, F. di Nicolantonio
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