title: MGMT expression levels predict disease stabilisation, progression-free and overall survival in patients with advanced melanomas treated with DTIC.
abstract: Metastatic melanoma responds poorly to systemic treatment. We report the results of a prospective single institution study evaluating O(6)-methylguanine-DNA methyltransferase (MGMT) status as a potential predictive and/or prognostic marker among patients treated with dacarbazine (DTIC) 800-1000 mg/m(2) monotherapy administered as a 3-weekly schedule for advanced malignant melanomas. The study was approved by the Regional Ethical Committee. Surgical biopsies from metastatic or loco-regional deposits obtained prior to DTIC treatment were snap-frozen immediately upon removal and stored in liquid nitrogen up to processing. Median time from enrolment to end of follow-up was 67 months. MGMT expression levels evaluated by qRT-PCR correlated significantly to DTIC benefit (CR/PR/SD; p=0.005), time to progression (TTP) (p=0.005) and overall survival (OS) (p=0.003). MGMT expression also correlated to Breslow thickness in the primary tumour (p=0.014). While MGMT promoter hypermethylation correlated to MGMT expression, MGMT promoter hypermethylation did not correlate to treatment benefit, TTP or OS, suggesting that other factors may be critical in determining MGMT expression levels in melanomas. In a Cox proportional regression analysis, serum lactate dehydrogenase (LDH, p<0.001), MGMT expression (p=0.022) and p16(INK4a) expression (p=0.037) independently predicted OS, while TTP correlated to DTIC benefit after 6 weeks only (p=0.001). Our data reveal MGMT expression levels to be associated with disease stabilisation and prognosis in patients receiving DTIC monotherapy for advanced melanoma. The role of MGMT expression as a predictor to DTIC sensitivity versus a general prognostic factor in advanced melanomas warrants further evaluation.
authors.affiliation: Section of Oncology, Institute of Medicine, University of Bergen, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Busch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.forename: Johan R
authors.initials: JR
authors.lastname: Lillehaug
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003606:Dacarbazine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005134:Eye Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes