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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2019; 11(7): 551-566
Published online Jul 15, 2019. doi: 10.4251/wjgo.v11.i7.551
TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer
Anastasios Ntavatzikos, Aris Spathis, Paul Patapis, Nikolaos Machairas, Georgia Vourli, George Peros, Iordanis Papadopoulos, Ioannis Panayiotides, Anna Koumarianou
Anastasios Ntavatzikos, Anna Koumarianou, Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
Aris Spathis, Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
Paul Patapis, Nikolaos Machairas, 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Athens 12462, Greece
Georgia Vourli, Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
George Peros, Iordanis Papadopoulos, Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, Athens 11528, Greece
Ioannis Panayiotides, 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, Athens 12462, Greece
Author contributions: Ntavatzikos A, Spathis A, Panayiotides I and Koumarianou A designed the research; Ntavatzikos A, Patapis P, Spathis A and Koumarianou A collected the data; Ntavatzikos A, Spathis A and Panayiotides I performed the research; Ntavatzikos A, Patapis P, Spathis A and Koumarianou A analyzed the data; Ntavatzikos A and Koumarianou A wrote the paper; Panayiotides I and Papadopoulos I offered the technical or material supports; Ntavatzikos A, Spathis A and Koumarianou A drafted the manuscript; all authors critically revised the manuscript for important intellectual content.
Supported by Kapodistrias, National and Kapodistrian University of Athens, No. 70/3/8006 (Pythagoras II, EPEAEK II, GSRT) and No. 70/3/9114; Spathis A was supported during data collection from No. 70/3/8462 [PENED - European Social Fund (75%) and the Greek Ministry of Development-GSRT (25%)].
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board and Ethical Committee of University General Hospital Attikon, Athens, Greece.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Anastasios Ntavatzikos, MD, Research Scientist, Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Rimini 1, Haidari, Athens 12462, Greece. dmaal2@yahoo.gr
Telephone: +30-210-5831687 Fax: +30-210-5326446
Received: March 14, 2019
Peer-review started: March 15, 2019
First decision: April 16, 2019
Revised: April 30, 2019
Accepted: June 12, 2019
Article in press: June 13, 2019
Published online: July 15, 2019
BACKGROUND
Patients with stage II-III colorectal cancer (CRC) treated with adjuvant chemotherapy, gain a 25% survival benefit. In the context of personalized medicine, there is a need to identify patients with CRC who may benefit from adjuvant chemotherapy. Molecular profiling could guide treatment decisions in these patients. Thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF could be included in the molecular profile under consideration.
AIM
To investigate the association of TYMS gene polymorphisms, KRAS and BRAF mutations with survival of CRC patients treated with chemotherapy.
METHODS
A retrospective study studied formalin-fixed paraffin-embedded tissues (FFPEs) of consecutive patients treated with adjuvant chemotherapy during January/2005-January/2007. FFPEs were analysed with PCR for the detection of TYMS polymorphisms, mutated KRAS (mKRAS) and BRAF (mBRAF). Patients were classified into three groups (high, medium and low risk) according to 5’UTR TYMS polymorphisms Similarly, based on 3’UTR polymorphism ins/loss of heterozygosity (LOH) patients were allocated into two groups (high and low risk of relapse, respectively). Cox regression models examined the associated 5-year survival outcomes.
RESULTS
One hundred and thirty patients with early stage CRC (stage I-II: 55 patients; stage III 75 patients; colon: 70 patients; rectal: 60 patients) were treated with surgery and chemotherapy. The 5-year disease free survival and overall survival rate was 61.6% and 73.9% respectively. 5’UTR polymorphisms of intermediate TYMS polymorphisms (2RG/3RG, 2RG/LOH, 3RC/LOH) were associated with lower risk for relapse [hazard ratio (HR) 0.320, P = 0.02 and HR 0.343, P = 0.013 respectively] and death (HR 0.368, P = 0.031 and HR 0.394, P = 0.029 respectively). The 3’UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (P = 0.001) and death (P = 0.005). mBRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas mKRAS (39% of patients) not.
CONCLUSION
Prospective validating studies are required to confirm whether 2RG/3RG, 2RG/LOH, 3RC/LOH, absence of ins/LOH and wild type BRAF may indicate patients at lower risk of relapse following adjuvant chemotherapy.
Core tip: There is a need to identify patients with colorectal cancer (CRC) who may benefit from adjuvant chemotherapy. We investigated the survival in 130 patients with stage II-III CRC treated with adjuvant chemotherapy based on thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF status. We found that TYMS polymorphisms and BRAF status associate independently with the survival outcomes. Prospective validating studies are required.
