Refining the selection of patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of O6-methylguanine-DNA-methyltransferase

Background: The repair enzyme O6-methylguanine-DNA-methyltransferase
(MGMT) is a validated predictor of benefit from temozolomide (TMZ) in glioblastoma. How ever, only 10% of patients with MGMT-methylated metastatic colorectal cancer (mCRC)
respond to TMZ. Methods: Archived tumour samples (N Z 41) from three phase II TMZ trials carried out in
MGMT-methylated mCRC (assessed by methylation-specific polymerase chain reaction
[PCR]) were stratified by MGMT status as assessed by three different methods: mass spec trometry, PCR/methyl-BEAMing and RNA-seq. The performance of each method was as sessed in relation to overall response rate, progression-free survival (PFS) and overall
survival (OS).
Results: Overall, 9 of 41 patients responded to TMZ. Overall response rates were 50% (9/18),
50% (6/12) and 35% (8/23) among patients determined likely to respond to TMZ by mass spec trometry, methyl-BEAMing and RNA-seq, respectively. Low/negative MGMT protein ex pressors by mass spectrometry had longer PFS than high MGMT expressors (3.7 vs 1.8
months; HR Z 0.50, P Z 0.014). Results for OS were similar but statistically non significant (8.7 vs. 7.4 months; HR Z 0.55, P Z 0.077). No significant association between
survival and MGMT status by methyl-BEAMing or RNA-seq could be demonstrated as com parable subgroups survival could not be confirmed/excluded. Specifically, the association of
high versus low methyl-BEAMing MGMT hypermethylation with survival was
HR Z 0.783, P Z 0.46 for PFS and 0.591, P Z 0.126 for OS, while association of low versus
high RNA-seq MGMT level with survival was HR Z 0.697, P Z 0.159 for PFS and
HR Z 0.697, P Z 0.266 for OS.
Conclusions: Quantitative proteomic analysis of MGMT may be useful for refining the selec tion of patients eligible for salvage treatment with single-agent TMZ.