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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer
Anastasios Ntavatzikos, Aris Spathis, Paul Patapis, Nikolaos Machairas, George Peros, Stefanos Konstantoudakis, Danai Leventakou, Ioannis G Panayiotides, Petros Karakitsos, 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, 12462 Athens, Greece
Aris Spathis, Danai Leventakou, Petros Karakitsos, Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
Paul Patapis, Nikolaos Machairas, 3rd Department of Surgery, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, 12462 Athens, Greece
George Peros, Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., “I AGIA TRIAS”, 11528 Athens, Greece
Stefanos Konstantoudakis, Ioannis G Panayiotides, 2nd Department of Pathology, University of Athens, Medical School, “ATTIKON” University Hospital, 12462 Athens, Greece
Author contributions: Ntavatzikos A, Spathis A, Patapis P and Koumarianou A collected and analyzed the data; Ntavatzikos A, Spathis A and Koumarianou A drafted the manuscript; Patapis P, Peros G, Panayiotides IG and Karakitsos P provided analytical oversight; Peros G, Machairas N, Panayiotides IG, Karakitsos P and Koumarianou A designed and supervised the study; Ntavatzikos A, Spathis A, Leventakou D, Karakitsos P and Koumarianou A performed the research; Panayiotides IG and Karakitsos P contributed new analytic tools; Spathis A, Konstantoudakis S, Panayiotides IG and Karakitsos P offered technical or material support; Machairas N, Peros G, Panayiotides IG, Karakitsos P and Koumarianou A provided administrative support; all authors revised the manuscript for important intellectual content, and read and approved the final version to be published.
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 by No. 70/3/8462 [PENED European Social Fund (75%) and the Greek Ministry of Development-GSRT (25%)].
Institutional review board statement: The 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: We have no conflicts of interest to disclose.
Data sharing statement: No additional data are available.
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/
Correspondence to: Anastasios Ntavatzikos, MD, General Surgeon, Research Scientist, Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, “ATTIKON” University Hospital, Rimini 1, Haidari, 12462 Athens, Greece. dmaal2@yahoo.gr
Telephone: +30-210-5831687 Fax: +30-210-5326446
Received: April 12, 2017
Peer-review started: April 14, 2017
First decision: June 7, 2017
Revised: June 22, 2017
Accepted: July 22, 2017
Article in press: July 24, 2017
Published online: August 28, 2017
AIM
To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy.
METHODS
Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3’ untranslated region (UTR) and 5’UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.
RESULTS
The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3’UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively).
CONCLUSION
The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.
Core tip: The etiology of resistance to new targeted agents and chemotherapy is currently being investigated based upon the patients’ genetic profile in order to develop a prognostic model that could lead to individualized treatment. In this context, we studied the effect of thymidylate synthase (TYMS) polymorphisms that have been described so far, taking into account the presence of KRAS and BRAF mutations in association with the treatment. TYMS 3’ untranslated region polymorphism ins/ins and ins/loss of heterozygosity emerged as an independent factor that increases the risk of both disease progression and death. Regimens that included irinotecan had reduced risk of disease progression and death.
