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

World Journal of Gastrointestinal Oncology 2019年第7期11卷 551-566页

作者： Anastasios Ntavatzikos Aris Spathis paul patapis Nikolaos Machairas Georgia Vourli George Peros Iordanis Papadopoulos Ioannis Panayiotides Anna Koumarianou Hematology-Oncology Unit 4th Department of Internal Medicine Medical School National and Kapodistrian University of Athens“ATTIKON” University Hospital Athens 12462 Greece Department of Cytopathology National and Kapodistrian University of Athens Medical School“ATTIKON” University Hospital Athens 12462 Greece 3rd Department of Surgery Medical School National and Kapodistrian University of Athens“ATTIKON” University Hospital Athens 12462 Greece Department of Hygiene Epidemiology and Medical Statistics Medical School National and Kapodistrian University of Athens Athens 11527 Greece Department of Surgery Medical School National and Kapodistrian University of Athens Evgenideio Therapeutirio S.A.“I AGIA TRIAS” Athens 11528 Greece 2nd Department of Pathology University of Athens Medical School“ATTIKON” University Hospital Athens 12462 Greece

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 *** 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,

关键词： Colorectal neoplasms Thymidylate synthase Untranslated regions Fluorouracil KRAS BRAF Prognosis

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Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer

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World Journal of Gastroenterology 2017年第32期23卷 5913-5924页

作者： Anastasios Ntavatzikos Aris Spathis paul patapis Nikolaos Machairas George Peros Stefanos Konstantoudakis Danai Leventakou Ioannis G Panayiotides Petros Karakitsos Anna Koumarianou Hematology-Oncology Unit 4^th Department of Internal MedicineMedical SchoolNational and Kapodistrian University of Athens“ATTIKON”University Hospital Department of Cytopathology National and Kapodistrian University of AthensMedical School“ATTIKON”University Hospital 3^rd Department of Surgery Medical SchoolNational and Kapodistrian University of Athens“ATTIKON”University Hospital Department of Surgery Medical SchoolNational and Kapodistrian University of AthensEvgenideio Therapeutirio S.A.“I AGIA TRIAS”11528 AthensGreece 2^nd Department of Pathology University of AthensMedical School“ATTIKON”University Hospital

AIM To investigate the impact of thymidylate synthase(TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer(m CRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectively from records of consecutive patients with m CRC 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 *** The analysis recovered 89 patients with m CRC(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

关键词： Thymidylate synthase Polymorphisms m CRC Loss of heterozygosity Survival Chemotherapy KRAS BRAF TYMS

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