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

Sarit Schwartz, Chris Szeto, Yuan Tian, Fabiola Cecchi, Salvatore Corallo, Maria Alessandra Calegari, Maria Di Bartolomeo, Federica Morano, Alessandra Raimondi, Giovanni Fucà, Antonia Martinetti, Ivana De Pascalis, Maurizio Martini, Antonino Belfiore, Massimo Milione, Armando Orlandi, Ludovic Barault, Carlo Barone, Filippo de Braud, Federica Di NicolantonioSteve Benz, Todd Hembrough, Filippo Pietrantonio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)164-174
Number of pages11
JournalEuropean Journal of Cancer
Volume107
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Biomarker
  • Colorectal cancer
  • MGMT
  • Molecular diagnostics
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schwartz, S., Szeto, C., Tian, Y., Cecchi, F., Corallo, S., Calegari, M. A., Di Bartolomeo, M., Morano, F., Raimondi, A., Fucà, G., Martinetti, A., De Pascalis, I., Martini, M., Belfiore, A., Milione, M., Orlandi, A., Barault, L., Barone, C., de Braud, F., ... Pietrantonio, F. (2019). Refining the selection of patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of O6-methylguanine-DNA-methyltransferase. European Journal of Cancer, 107, 164-174. https://doi.org/10.1016/j.ejca.2018.11.016