Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma (original) (raw)
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Oncology Reports, 2012
The O 6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical trials with temozolomide plus bevacizumab therapy in metastatic melanoma patients are ongoing, although the predictive value of the MGMT promoter methylation status in this setting remains unclear. We assessed MGMT promoter methylation in formalin-fixed, primary tumor tissue of metastatic melanoma patients treated with first-line temozolomide and bevacizumab from the trial SAKK 50/07 by methylation-specific polymerase chain reaction. In addition, the MGMT expression levels were also analyzed by MGMT immunohistochemistry. Eleven of 42 primary melanomas (26%) revealed a methylated MGMT promoter. Promoter methylation was significantly associated with response rates CR + PR versus SD + PD according to RECIST (response evaluation criteria in solid tumors) (p<0.05) with a trend to prolonged median progression-free survival (8.1 versus 3.4 months, p>0.05). Immunohistochemically different protein expression patterns with heterogeneous and homogeneous nuclear MGMT expression were identified. Negative MGMT expression levels were associated with overall disease stabilization CR + PR + SD versus PD (p=0.05). There was only a poor correlation between MGMT methylation and lack of MGMT expression. A significant proportion of melanomas have a methylated MGMT promoter. The MGMT promoter methylation status may be a promising predictive marker for temozolomide therapy in metastatic melanoma patients. Larger sample sizes may help to validate significant differences in survival type endpoints.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2011
O 6 -Methylguanine-DNA methyltransferase (MGMT) is a suicide enzyme that repairs the pre-mutagenic, precarcinogenic and pre-toxic DNA damage O 6 -methylguanine. It also repairs larger adducts on the O 6 -position of guanine, such as O(6)-[4-oxo-4-(3-pyridyl)butyl]guanine and O 6 -chloroethylguanine. These adducts are formed in response to alkylating environmental pollutants, tobacco-specific carcinogens and methylating (procarbazine, dacarbazine, streptozotocine, and temozolomide) as well as chloroethylating (lomustine, nimustine, carmustine, and fotemustine) anticancer drugs. MGMT is therefore a key node in the defense against commonly found carcinogens, and a marker of resistance of normal and cancer cells exposed to alkylating therapeutics. MGMT also likely protects against therapy-related tumor formation caused by these highly mutagenic drugs. Since the amount of MGMT determines the level of repair of toxic DNA alkylation adducts, the MGMT expression level provides important information as to cancer susceptibility and the success of therapy. In this article, we describe the methods employed for detecting MGMT and review the literature with special focus on MGMT activity in normal and neoplastic tissues. The available data show that the expression of MGMT varies greatly in normal tissues and in some cases this has been related to cancer predisposition. MGMT silencing in tumors is mainly regulated epigenetically and in brain tumors this correlates with a better therapeutic response. Conversely, up-regulation of MGMT during cancer treatment limits the therapeutic response. In malignant melanoma, MGMT is not related to the therapeutic response, which is due to other mechanisms of inherent drug resistance. For most cancers, studies that relate MGMT activity to therapeutic outcome following O 6 -alkylating drugs are still lacking.
BMC cancer, 2018
It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients. A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases ...
MGMT promoter methylation in plasma of glioma patients receiving temozolomide
Journal of Neuro-Oncology, 2014
Promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene plays 2 a role in cellular response to alkylating agents. In the present study aimed to: i) evaluate the 3 concordance between MGMT promoter methylation status in tumor tissue and plasma; ii) 4 monitor MGMT promoter methylation status in plasma taken before and during 5 temozolomide treatment; iii) explore the value of MGMT promoter methylation status in 6 plasma as a prognostic/predictive biomarker in glioma patients. 7 We enrolled 58 patients with histologically confirmed glioma at different grades of 8 malignancy. All patients underwent surgical resection and temozolomide treatment. Paraffin-9 embedded tumor tissue was available for 48 patients. Blood samples were collected from all 10 patients before temozolomide treatment (baseline) and at each MRI examination for a 12-11 month period. MGMT promoter methylation status was assessed in both sample types by real 12 time PCR with a specific probe. 13 The frequency of MGMT promoter methylation was 60.4% in tumor tissue and 41.38% in 14 plasma. MGMT promoter methylation status was concordant in the two sample types 15 (Kappa=0.75, 95% confidence interval [CI] 0.57-0.93; p-value <0.001). Overall and 16 progression-free survival were longer in patients with methylated MGMT promoter. 17 Mortality was higher in patients with unmethylated MGMT promoter, whether in tumor 18 tissue (hazard ratio [HR]: 2.21; 95% CI 0.99-4.95) or plasma (HR: 2.19; 95% CI 1.02-4.68). 19 Progression-free survival was shorter in patients with unmethylated MGMT promoter, 20 whether in tissue (HR: 2.30; 95% CI 1.19-4.45) or plasma (HR: 1.77; 95% CI 0.95-3.30). 21 The cumulative incidence of unmethylated MGMT promoter in plasma at baseline was 58%, 22 and reached virtually 100% at 12 months. In conclusion MGMT promoter methylation status 23 in tumor tissue and plasma was highly concordant, and both were associated with longer treatment response. However we suggest caution in using plasma as a surrogate of tumor 1 tissue due to possible false-negative results.
Neurological Research, 2003
Background To date, no predictive biomarker for the efficacy of FOLFIRINOX in metastatic pancreatic adenocarcinoma has been demonstrated. Deficiency in O 6methylguanine-DNA methyltransferase (MGMT) has been associated with a therapeutic response in endocrine tumors of the pancreas and the lack of expression of protein 53 (p53) could interfere with the action of MGMT. Objective The aim of our study was to assess the prevalence of MGMT and p53 in patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX as a first-line treatment and to investigate their association with therapeutic response and survival. Patients and Methods The immunohistochemical expression of MGMT was recorded as present or absent and the expression of p53 was semi-quantitatively scored in 30 patients with metastatic pancreatic adenocarcinoma, at Angers Hospital in France between September 2011 and June 2015. Clinical and radiologic data were collected retrospectively. Results The presence or absence of MGMT expression entailed no significant differences in response rate. Median values of progression-free survival (PFS) and overall survival (OS) were lower in patients with MGMT expression, but sample size is too small to conclude that there is a statistically significant difference. No significant relationship for response rate and PFS was observed in relation with p53 expression. By contrast, patients with a strong tumor expression of p53 had a significantly lower OS compared to patients with no or weak expression of the protein (p = 0.027). There was a positive correlation between the expression of p53 and MGMT (p = 0.08). Conclusions These preliminary findings suggest that for patients treated with FOLFIRINOX as a first-line treatment for metastatic pancreatic adenocarcinoma, the immunohistochemical evaluation of MGMT could not predict the clinical outcome; however, the survival was not significant probably because of the under-powered study (due to small sample size). A strong tumor expression of p53 is associated with a poor prognosis of OS. Key Point No biological markers allow to predict the response to chemotherapy in patients with metastatic pancreatic cancer. However, tumoral markers (MGMT and p53) could be interesting to predict the prognosis of disease in these patients.
Liver metastasis in uveal melanoma — treatment options and clinical outcome
Frontiers in Bioscience-Landmark, 2022
Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults with a stable incidence rate between five and seven cases per million in Europe and the United States. Although UM and melanoma from other sites have the same origin, UM has different epidemiological, biological, pathological and clinical features including characteristic metastatic hepatotropism. Despite improvements in the treatment of primary tumours, approximately 50% of patients with UM will develop metastases. In 90% of cases the liver is the first site of metastasis, however the mechanisms underlying this hepatic tropism have not been elucidated. Metastatic disease is associated with a very poor prognosis with a median overall survival of 6 to 12 months. Currently, there is no standard systemic treatment available for metastatic UM and once liver metastases have developed, prognosis is relatively poor. In order to prolong survival, close follow-up in all patients with UM is recommended for early detection and treatment. The treatment of metastatic UM includes systemic chemotherapy, immunotherapy and molecular targeted therapy. Liver-directed therapies, such as resection, radioembolization, chemoembolization, immunoembolization, isolated and percutaneous liver perfusion as well as thermal ablation represent available treatment options. However, to date a consensus regarding the optimal method of treatment is still lacking and the importance of setting guidelines in the treatment and management of metastatic UM is becoming a priority. Improvement in knowledge and a better insight into tumour biology, immunology and metastatic mechanism may improve current treatment methods and lead to the development of new strategies paving the way for a personalized approach.
International Journal of Cancer, 2000
O 6-Methylguanine-DNA methyltransferase (MGMT) is a major determinant of resistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MGMT nadir could enhance its effectiveness, by increasing the amount of O 6-methylguanine (O 6-meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O 6-meG formation in DNA following treatment. Thirty patients with advanced malignant melanoma were treated with temozolomide 1,000 mg/m 2 equally split into 5 doses over a 16 hr period every 28 days. O 6-meG formation was determined in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patients, in tumor tissue during the first treatment cycle. MGMT levels fell rapidly with dosing, reaching a nadir in PBMCs of 18.0 ؎ 2.26% of initial levels. O 6-meG levels increased during the treatment period, peaking at 11.1 ؎ 1.25 mol/mol dG in PBMCs and at 4.25 ؎ 0.79 mol/mol dG in tumor biopsies. The main toxicities were grade IV thrombocytopenia in 12 patients (42.8%) and grade IV neutropenia in 11 patients (39.2%), associated with fever in 8 cases. There were 7 responses (1 complete), for an overall response rate of 23.3%; median overall survival was 6.1 months. The compressed schedule has activity against melanoma, with greater MGMT depletion and O 6-meG formation than previously reported for O 6-alkylating agent regimens. Myelosuppression precludes its wider application, but MGMT in PBMCs predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified.
Molecular Cancer Therapeutics, 2013
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.