MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

Abstract

Approximately 25% of melanoma patients with locoregional metastases are nonresponsive to new molecular target therapy and immunotherapy. When metastases are located in the pelvis, melphalan hypoxic perfusion can be an optional treatment. Because methylation of MGMT promoter increases the efficacy of alkylating agents, studies on melanoma outcome of patients treated with melphalan regional chemotherapy should consider this epigenetic change. This study aims to evaluate whether the survival of stage III melanoma patients treated with melphalan regional chemotherapy may be correlated with MGMT methylation status. The metastatic tissues of 27 stage III melanoma patients with locoregional metastases located in the pelvis subjected to melphalan hypoxic pelvic perfusion were examined. The methylation status of the MGMT promoter was investigated by MS-MLPA probes analysis and the presence of the BRAF V600E mutation was analyzed by CAST-PCR. The median survival times were estimated using the Kaplan–Meier curves and were stratified according to the clinicopathological characteristics of patients and lesions. The overall median survival time was 17 months. The 1-year, 3-year, and 5-year survival rates were 66.7, 18.5, and 7.4%, respectively. Disease stage, burden, and percentage of MGMT methylation significantly affected survival. We estimated an MGMT promoter methylation cut-off of at least 14%, which was significantly associated with a longer survival after melphalan regional chemotherapy. Our data suggest that MGMT promoter methylation could be an important factor in determining which melanoma patients should receive melphalan regional chemotherapy, but its prognostic significance in the routine clinical setting needs to be clarified in a larger study.

Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma

“…Likewise, a 17‐gene methylation signature has been associated with a poorer disease‐free survival (DFS) and overall survival (OS) in patients with melanoma with a highly methylated phenotype . Other genes that have shown prognostic impact are ESR1 , MGMT , RASSF1 and HOXD9 …”

“…10 Other genes that have shown prognostic impact are ESR1, MGMT, RASSF1 and HOXD9. [11][12][13][14] However, the role of DNA methylation in melanoma is still unclear and its characterization may be clinically relevant as methylation profiles could be established as diagnostic and/or prognostic biomarkers. The primary goal of this research is to analyse the prevalence of CpG island methylation in TSGs frequently silenced in cancer, to identify methylation profiles associated with the main clinicopathological features, and to explore the prognostic significance of TSG promoter methylation in melanoma survival.…”

Circulating tumour cell liquid biopsy in selecting therapy for recurrent cutaneous melanoma with locoregional pelvic metastases: a pilot study

“…Histopathological analysis revealed that all metastases exhibited an epithelioid phenotype. BRAF status and MGMT promoter methylation status were assessed as previously described [14]. Exclusion from immunotherapy was due to concomitant Hepatitis C infection in 4 patients, in treatment with sofosbuvir (400 mg) and daclatasvir (30 mg) and acute phase inflammatory bowel disease in 3 patients, treated with high dose corticosteroids.…”

“…This pilot study was initiated to assess the feasibility of using purified CTCs, in terms of reproducibility, sampling, storage, transport, purification and enrichment methodologies, and the utility and suitability of subsequent CTC chemosensitivity assays in selecting therapeutic strategies and predicting response. For this purpose, we selected a homogeneous group of 7 stage IIIC melanoma patients with BRAF wild-type status and locoregional metastases located exclusively to the pelvic region, all of whom were un-eligible for novel immunotherapy and were treated with melphalan HPP, in accordance with percentage MGMT promoter methylation levels in tissue-specimen, as a relevant index of melphalan efficacy [14].…”

“…The HPP rational, as for isolated limb infusion, is based upon the potential to expose locoregional melanoma metastases to higher drug concentrations, with the cytotoxicity of agents, such as melphalan, augmented by hypoxia [12]. We recently reported that melphalan HPP in 36 pretreated patients with stage III and IV melanoma, with pelvic locoregional metastases in progression, resulted in an overall response rate of 94%, a median survival time of 15 months and a 5-years survival rate of 8% [3,[13][14][15]. Systemic therapies, either alone or in combination with local and/or regional therapies, are currently proposed when pelvic melanoma metastases are considered unresectable for technical and clinical reasons.…”