[ Title ]
- Digital PCR quantification of MGMT methylation refines prediction of
clinical benefit from alkylating agents in glioblastoma and metastatic
colorectal cance
[ Journal ]
- ANNALS OF ONCOLOGY
[ Abstract ]
- O-6-methyl-guanine-methyl-transferase (MGMT) silencing by promoter
methylation may identify cancer patients responding to the alkylating
agents dacarbazine or temozolomide.
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.
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).
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.
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