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

doi:10.4251/wjgo.v11.i7.551

TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer

World J Gastrointest Oncol. 2019 Jul 15;11(7):551-566. doi: 10.4251/wjgo.v11.i7.551.

Authors

Anastasios Ntavatzikos¹, Aris Spathis², Paul Patapis³, Nikolaos Machairas³, Georgia Vourli⁴, George Peros⁵, Iordanis Papadopoulos⁵, Ioannis Panayiotides⁶, Anna Koumarianou⁷

Affiliations

¹ Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Athens 12462, Greece. dmaal2@yahoo.gr.
² Department of Cytopathology, National and Kapodistrian University of Athens, Medical School, "ATTIKON" University Hospital, Athens 12462, Greece.
³ 3 Department of Surgery, Medical School, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Athens 12462, Greece.
⁴ Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece.
⁵ Department of Surgery, Medical School, National and Kapodistrian University of Athens, Evgenideio Therapeutirio S.A., "I AGIA TRIAS", Athens 11528, Greece.
⁶ 2 Department of Pathology, University of Athens, Medical School, "ATTIKON" University Hospital, Athens 12462, Greece.
⁷ Hematology-Oncology Unit, 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Athens 12462, Greece.

Abstract

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.

Keywords: BRAF; Colorectal neoplasms; Fluorouracil; KRAS; Prognosis; Thymidylate synthase; Untranslated regions.