A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of theO6-Methylguanine-DNA Methyltransferase Promoter

Abstract

Responses of patients with gliomas to temozolomide are determined by O 6 -methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) pathways. This phase II study (NCT00423150) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers (CRC). Tumor and serum samples were screened for MGMT promoter methylation. In methylation-positive patients, 150 mg/m 2 temozolomide was administered daily on a seven-day-on, sevenday-off schedule for each 28-day cycle. The primary efficacy endpoint was response rate (RR). MMR status was determined by a microsatellite instability assay. Among 740 patients screened, 86 were positive for MGMT promoter methylation and enrolled. Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non-small cell lung carcinoma. Among patients with valid methylation results in both tissue and serum samples, concordance was 81% (339 of 419). The majority of enrolled patients (69 of 86; 80%) had microsatellite stable cancer. Overall RR was 6% (5 of 86 partial responses); all responders had microsatellite stable cancer. Temozolomide resulted in low RRs in patients enriched for MGMT methylation. MGMT methylation status varied considerably in the patient population. Although serum methylation assay is an option for promoter methylation detection, tissue assay remains the standard for methylation detection. The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types, and tumor-specific factors may override validated biomarkers. Mol Cancer Ther; 12(5); 809-18. Ó2013 AACR.

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

“…The MGMT-dependent response to temozolomide-PARPi treatment is also seen in other cancer types To determine whether the impact of MGMT expression on the PARPi response is specific for melanoma cells or cancer type independent, we assessed the response to temozolomide and olaparib in cells from three cancer types where temozolomide is used as a therapeutic option: glioblastoma, pancreatic neuroendocrine tumors (NET), and colorectal carcinoma (11,33,34). We treated seven glioblastoma cell lines (4 MGMT þ and 3 MGMT À cell lines) known to be MMR þ (25) and observed that MGMT expression correlated with the response to temozolomide combined with olaparib ( Fig.…”

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

“…While the trial was still ongoing, four similar phase 2 studies on patients with MGMT -methylated refractory mCRC were published, with conflicting results (Hochhauser et al , 2013; Pietrantonio et al , 2014, 2016; Amatu et al , 2016). Hochhauser et al (2013) reported a disappointing RR of 3% among 31 patients treated with a 7-day-on/7-day-off schedule for each 28-day cycle.…”

“…Hochhauser et al (2013) reported a disappointing RR of 3% among 31 patients treated with a 7-day-on/7-day-off schedule for each 28-day cycle. Similarly, Amatu et al (2016) failed to demonstrate a meaningful activity of TMZ, reporting a PFS rate at 12 weeks of 10.3% for 29 patients treated with a standard schedule of TMZ (200 mg m −2 on days 1–5 of 28-day cycles).…”

“…Another suggested biomarker is the MMR pathway status, on whose integrity could rely the mechanism of cell death induced by TMZ (Inno et al , 2014). The study by Hochhauser et al (2013) suggested that a proficient MMR seems to be required to achieve the therapeutic effects of TMZ. Indeed, all patients achieving a PR as best response were MMR-proficient and most patients with an SD or PD were MMR-deficient.…”

“…This evidence provided the rationale for investigating TMZ in mCRC. Four mono-institutional, phase 2 trials have been published so far with different results (Hochhauser et al , 2013; Pietrantonio et al , 2014, 2016; Amatu et al , 2016). Here, we report the results of a multicentre phase 2 trial assessing activity and safety of TMZ in refractory patients with mCRC.…”