1. Refining the selection of patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of O6-methylguanine-DNA-methyltransferase
- Author
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Steve Benz, Maurizio Martini, Alessandra Raimondi, Carlo Barone, Filippo de Braud, Maria Alessandra Calegari, Giovanni Fucà, Antonia Martinetti, Salvatore Corallo, Massimo Milione, Maria Di Bartolomeo, Federica Di Nicolantonio, Antonino Belfiore, Ivana De Pascalis, Sarit Schwartz, Yuan Tian, Ludovic Barault, Armando Orlandi, Fabiola Cecchi, Filippo Pietrantonio, Todd Hembrough, Christopher Szeto, and Federica Morano
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Biomarker ,Colorectal cancer ,MGMT ,Molecular diagnostics ,Temozolomide ,Lung Neoplasms ,Proteome ,Phases of clinical research ,0302 clinical medicine ,DNA Modification Methylases ,Peritoneal Neoplasms ,Aged, 80 and over ,O6-methylguanine ,Liver Neoplasms ,Middle Aged ,Prognosis ,Survival Rate ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,Colorectal Neoplasms ,medicine.drug ,medicine.medical_specialty ,DNA methyltransferase ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Overall survival ,Humans ,Progression-free survival ,Antineoplastic Agents, Alkylating ,neoplasms ,Aged ,Retrospective Studies ,business.industry ,Patient Selection ,Tumor Suppressor Proteins ,DNA Methylation ,medicine.disease ,digestive system diseases ,DNA Repair Enzymes ,030104 developmental biology ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
Background The repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) is a validated predictor of benefit from temozolomide (TMZ) in glioblastoma. However, only 10% of patients with MGMT-methylated metastatic colorectal cancer (mCRC) respond to TMZ. Methods Archived tumour samples (N = 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 spectrometry, PCR/methyl-BEAMing and RNA-seq. The performance of each method was assessed 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 spectrometry, methyl-BEAMing and RNA-seq, respectively. Low/negative MGMT protein expressors by mass spectrometry had longer PFS than high MGMT expressors (3.7 vs 1.8 months; HR = 0.50, P = 0.014). Results for OS were similar but statistically non-significant (8.7 vs. 7.4 months; HR = 0.55, P = 0.077). No significant association between survival and MGMT status by methyl-BEAMing or RNA-seq could be demonstrated as comparable subgroups survival could not be confirmed/excluded. Specifically, the association of high versus low methyl-BEAMing MGMT hypermethylation with survival was HR = 0.783, P = 0.46 for PFS and 0.591, P = 0.126 for OS, while association of low versus high RNA-seq MGMT level with survival was HR = 0.697, P = 0.159 for PFS and HR = 0.697, P = 0.266 for OS. Conclusions Quantitative proteomic analysis of MGMT may be useful for refining the selection of patients eligible for salvage treatment with single-agent TMZ.
- Published
- 2019
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