Abstract 4988
Background
Metastatic pancreatic cancer (mPAC) is a devastating disease with few therapeutic options. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene and there are reports of MGMT alterations in various gastrointestinal cancers, including colorectal cancer and mPAC. Low MGMT expression by immunohistochemistry (IHC) and MGMT promoter methylation ultimately result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This report presents data on MGMT testing mPAC pts admitted at our center.
Methods
Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), to assess MGMT promoter methylation, and IHC, to assess protein expression. Furthermore, Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI) were performed.
Results
Archived FFPE tissue sections obtained from 90 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to April 2019 were analyzed. At the time of this report, 60 samples (66%) had adequate tissue for extended analyses. As expected, 55 (92%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 (5%), 4( 6%) and 2 (3%) pts, respectively. MGMT promoter methylation was found in 21 pts (35%), of which 13 (61%) had low/negative MGMT protein expression. Of note, amongst MGMT methylated pts, there were 5 (23%) BRCA1/2 somatic mutant and 2 (9%) MSI, suggesting possible genomic instability.
Conclusions
MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 35% of patients with mPAC. This data warrant further prospective confirmation; nevertheless, considering the growing interest in the role of DNA-damage response genes in mPAC, there is definitely a rationale in investigating MGMT methylation as a predictive and prognostic biomarker in mPAC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
F. Morano: Honoraria (self): Servier. F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Servier; Research grant / Funding (institution): BMS. F.G.M. De Braud: Advisory / Consultancy: TizianaLife Sciences; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy: Amgen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Octimet Oncology; 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: Novartis; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: AstraZeneca. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
Resources from the same session
5773 - A prospective study of diffusion-weighted magnetic resonance imaging for predicting outcome following chemoradiotherapy, in squamous cell carcinomas of the anus.
Presenter: Rebecca Muirhead
Session: Poster Display session 2
Resources:
Abstract
4581 - Timing to achieve complete response (CR) after definitive chemoradiotherapy (ChRT) in patients with squamous cell carcinoma of the anal (SCCAC) with and without HIV infection: a multicenter retrospective study
Presenter: Marcos Camandaroba
Session: Poster Display session 2
Resources:
Abstract
1712 - Planned organ preservation for T2 T3 M0 rectal adenocarcinoma. A possible option using chemoradiotherapy (CRT) and Contact X-ray Brachytherapy (CXB). A French multicenter study.
Presenter: Jean-Pierre Gérard
Session: Poster Display session 2
Resources:
Abstract
4639 - A Phase 1b Study of E7046 (AN0025) in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Rectal Cancer
Presenter: Lucjan Wyrwicz
Session: Poster Display session 2
Resources:
Abstract
2310 - Upfront radical surgery with total mesorectal excision (TME) versus preoperative chemoradiotherapy followed by TME in clinical stage II/III patients with rectal cancer: a propensity score analysis
Presenter: Ahrong Ham
Session: Poster Display session 2
Resources:
Abstract
2747 - Neoadjuvant chemoradiotherapy with/without lateral lymph node dissection for low rectal cancer: Which patients can benefit?
Presenter: Daisuke Nishizaki
Session: Poster Display session 2
Resources:
Abstract
2877 - The impact of completeness of chemotherapy on the efficacy of irinotecan in the preoperative chemoradiotherapy of locally advanced rectal cancer.
Presenter: Jingwen Wang
Session: Poster Display session 2
Resources:
Abstract
3050 - Feasibility of robot-assisted surgery in elderly patients with rectal cancer
Presenter: Wei-Chih Su
Session: Poster Display session 2
Resources:
Abstract
4109 - Feasibility of chemoradiotherapy in rectal cancer patients with peritumoral abscesses and fistulas: a case-control non-inferiority trial
Presenter: Valerii Ivanov
Session: Poster Display session 2
Resources:
Abstract
4813 - Differential of the nutritional index before and after neoadjuvant chemoradiotherapy as a prognostic factor of recurrence in patients with locally advanced adenocarcinoma of the rectum
Presenter: Leslie Navia-Ortuño
Session: Poster Display session 2
Resources:
Abstract