Decreased Frequency of MGMT Promoter Hypermethylation in Locally Relapsed Versus Locally Controlled p16 Negative Head and Neck Squamous Cell Carcinoma Patients after Chemoradiotherapy

Abstract

The O6-methylguanine-DNA methyltransferase (MGMT) gene plays a role in DNA damage repair. MGMT promoter hypermethylation (MGMT -HM), which leads to silencing of the gene, predicts for improved treatment response in glioblastoma patients treated with chemotherapy and/or radiotherapy. The aim of this study is to determine the frequency of MGMT -HM in head and neck squamous cell carcinoma (HNSCC) patients in relation to p16 status and outcomes after chemoradiotherapy. Pre-treatment tumor blocks from 58 primary HNSCC patients treated with chemoradiotherapy with a median age of 60 years (range 36-85) diagnosed between the years 1993 and 2015 were identified for MGMT pyrosequencing using a commercially available kit. Eighty-three percent of patients were male and 17% female. HPV infection status was independently ascertained by p16 immunohistochemistry. After institutional review board approval, clinicopathological characteristics and treatment outcomes data were extracted from patients’ charts. Among the analyzed HNSCC patients, MGMT -HM was identified in 38% (22/58) and p16 positivity was identified in 64% (37/58) of cases. The frequency of MGMT -HM was 38% in both p16 positive (14/37) and p16 negative (8/21) patients. With a median follow-up of 3.7 years (range 0.4-13.9 years), 17 (29%) local relapses were observed overall. Local control was observed in 86% (32/37) of p16 positive patients. The frequency of MGMT -HM was similar between locally controlled and locally relapsed p16 positive patients at 38% (12/32) and 40% (2/5), respectively. Conversely, local control was observed in 43% (9/21) of p16 negative patients. The frequency of MGMT -HM was more than double in locally controlled p16 negative patients than in locally relapsed p16 negative patients at 56% (5/9) and 25% (3/12), respectively. As expected, p16 negative HNSCC patients demonstrated increased local relapses after chemoradiotherapy. The rates of MGMT -HM were similar between p16 positive and p16 negative HNSCC patients. To our knowledge, this is the first report demonstrating a decreased frequency of MGMT -HM in p16 negative HNSCC patients who experienced local relapse. Accordingly, the potential role of MGMT -HM in modulating differential treatment outcomes in p16 negative HNSCC patients needs to be further investigated.