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Ann Oncol. 2016 Jun;27(6):1062-7. doi: 10.1093/annonc/mdw071. Epub 2016 Feb 24.

Tumor MGMT promoter hypermethylation changes over time limit temozolomide efficacy in a phase II trial for metastatic colorectal cancer.

Author information

1
Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan.
2
Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy.
3
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
4
Department of Oncology, CLIOSS s.r.l., Nerviano, Milan.
5
Experimental Clinical Molecular Oncology Cancer Epigenetics, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Turin, Italy Department of Oncology, University of Torino, Candiolo, Turin.
6
Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan andrea.sartorebianchi@ospedaleniguarda.it.
7
Department of Hematology & Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan Department of Oncology, Università degli Studi di Milano, Milan, Italy.

Abstract

BACKGROUND:

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).

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

MGMT; MethylBEAMing; colorectal cancer; liquid biopsy; temozolomide

PMID:
26916096
DOI:
10.1093/annonc/mdw071
[Indexed for MEDLINE]

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