5813 - Is MGMT methylation a new therapeutic target for Biliary Tract Cancer?

Background

Biliary Tract Cancers (BTC) are a devastating and molecularly heterogeneous group of diseases, with significant differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gall bladder (GB) cancer. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Reductions in MGMT expression and MGMT promoter methylation result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This alterations have been described in BTC in small reports with variable frequencies. Here we present data on MGMT methylation tested in BTC pts admitted at our center.

Methods

MGMT promoter methylation was studied via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), while protein expression was assessed with immunohistochemistry (IHC). Formalin-fixed paraffin-embedded (FFPE) tissue samples were also examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®”).

Results

Archived FFPE tissue sections from 100 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to February 2019 were analyzed. Amongst the 89 samples with adequate tissue, 73% were ICC, 16% were ECC and 8 % were GC. 34 pts (38%) had MGMT promoter methylation, while low/negative MGMT protein expression was found in 45 pts (50%). MGMT methylation was identified in 38% of ICC, 26% of ECC and 62% of GC. As expected, we identified IDH1/2 mutations in 15%, all affected by ICC. Of note, amongst MGMT methylated pts, there were 4 pts (11%) with concomitant IDH1/2 mutations, which are reported to be associated with CpG Island Methylator Phenotype.

Conclusions

MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in gastrointestinal cancer, with phase II studies showing a response rate of 10% in chemorefractory MGMT- methylated colorectal cancer treated with TMZ. In our single center experience, MGMT methylation was found in 38% of patients with BTC. This data warrant further confirmation, but there is a growing interest in novel targeted therapies exploiting the role of MGMT methylation as a predictive and prognostic biomarker in BTC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Morano: Honoraria (institution): Servier. F. Pietrantonio: Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: EMD Serono; Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Servier; Research grant / Funding (self): BMS. M. Di Bartolomeo: Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: ACCMED; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Fondazione Menarini; Speaker Bureau / Expert testimony: MSD. All other authors have declared no conflicts of interest.