title: Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer.
abstract: Objective response to dacarbazine, the intravenous form of temozolomide (TMZ), in metastatic colorectal cancer (mCRC) is confined to tumors harboring O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation. We conducted a phase II study of TMZ enriched by MGMT hypermethylation in archival tumor (AT), exploring dynamic of this biomarker in baseline tumor (BT) biopsy and plasma (liquid biopsy).
  
  
  
  We screened 150 mCRC patients for MGMT hypermethylation with methylation-specific PCR on AT from FFPE specimens. Eligible patients (n = 29) underwent BT biopsy and then received TMZ 200 mg/m(2) days 1-5 q28 until progression. A Fleming single-stage design was used to determine whether progression-free survival (PFS) rate at 12 weeks would be ≥35% [H0 ≤ 15%, type I error = 0.059 (one-sided), power = 0.849]. Exploratory analyses included comparison between MGMT hypermethylation in AT and BT, and MGMT methylation testing by MethylBEAMing in solid (AT, BT) and LB with regard to tumor response.
  
  
  
  The PFS rate at 12 weeks was 10.3% [90% confidence interval (CI) 2.9-24.6]. Objective response rate was 3.4% (90% CI 0.2-15.3), disease control rate 48.3% (90% CI 32.0-64.8), median OS 6.2 months (95% CI 3.8-7.6), and median PFS 2.6 months (95% CI 1.4-2.7). We observed the absence of MGMT hypermethylation in BT in 62.7% of tumors.
  
  
  
  Treatment of mCRC with TMZ driven by MGMT promoter hypermethylation in AT samples did not provide meaningful PFS rate at 12 weeks. This biomarker changed from AT to BT, indicating that testing BT biopsy or plasma is needed for refined target selection.
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: A
authors.initials: A
authors.lastname: Amatu
authors.affiliation: Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Barault
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: A
authors.initials: A
authors.lastname: Cassingena
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: K
authors.initials: K
authors.lastname: Bencardino
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: S
authors.initials: S
authors.lastname: Ghezzi
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: L
authors.initials: L
authors.lastname: Palmeri
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: E
authors.initials: E
authors.lastname: Bonazzina
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: F
authors.initials: F
authors.lastname: Tosi
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: R
authors.initials: R
authors.lastname: Ricotta
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: T
authors.initials: T
authors.lastname: Cipani
authors.affiliation: Department of Oncology, CLIOSS s.r.l., Nerviano, Milan.
authors.forename: P
authors.initials: P
authors.lastname: Crivori
authors.affiliation: Department of Oncology, CLIOSS s.r.l., Nerviano, Milan.
authors.forename: R
authors.initials: R
authors.lastname: Gatto
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Chirico
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Marrapese
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
authors.forename: M
authors.initials: M
authors.lastname: Truini
authors.affiliation: Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin.
authors.forename: A
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy; Department of Oncology, University of Torino, Candiolo, Turin.
authors.forename: F
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan. Electronic address: andrea.sartorebianchi@ospedaleniguarda.it.
authors.forename: A
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan; Department of Oncology, Università degli Studi di Milano, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Siena
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001706:Biopsy; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000097:blood / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000097:blood / Q000235:genetics*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000097:blood / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: MGMT; MethylBEAMing; colorectal cancer; liquid biopsy; temozolomide