Clinical and Pathological Properties of Patients with Metastatic Colorectal Cancer According to the RAS Mutation Status

Öz

We aimed to compare the clinical and histopathologic features at the time of diagnosis of patients with metastatic colorectal cancer according to the RAS mutation status. In this cross-sectional study, archive records of patients with diagnosing colorectal cancer who were followed-up and treated at oncology center of an university hospital in Turkey between 01.04.2012 and 24.08.2017  was analyzed retrospectively. A totally 530 patients' archive records were evaluated. The relationship between the RAS mutant/wild groups and primary tumor localization, location of metastases at diagnosis, tumor markers, tumor differentiation grade and overall survival rates were compared with the literature data. We found no statistically significant difference between RAS mutant and wild groups. When overall survival rates were compared with the RAS mutation status, the overall survival of 2 years in patients with RAS wild type was 59% while the 2 year overall survival of RAS mutant patients was 27.8% and this difference was statistically significant (p = 0.004). However, there was no statistically significant difference between the median survival of patients receiving bevacizumab or cetuksimab/panitumumab in th efirst line treatment of RAS wild patients (57.1% versus 70.7%; p=0.221, respectively). In this study, we determined that RAS mutation status of our patients with metastatic colorectal cancer is more similar to Western countries and the clinical and pathological characteristics of patients at the time of diagnosis are independent of RAS mutation status. However, there is still need broader participation and prospective trials in this subject.

Anahtar Kelimeler

• Clinical and pathological properties,Colorectal cancer,RAS mutation

Metastatik Kolorektal Kanserli Hastaların RAS Mutasyon Durumuna Göre Klinik ve Patolojik Özellikleri

Öz

Bu çalışmada metastatik kolorektal kanserli hastalarda tanı anındaki histopatolojik ve klinik özelliklerin RAS mutasyon durumuna göre karşılaştırılması amaçlandı. Bu kesitsel çalışma için, 01.04.2012-24.08.2017 tarihleri arasında bir üniversite hastanesinin onkoloji merkezinde takip ve tedavisi yapılmış toplam 530 kolorektal kanser tanısı almış hastanın dosyası retrospektif olarak incelendi. Çalışmaya 18 yaşından büyük, tanı anında metastatik hastalığa sahip veya takipleri boyunca metastaz gelişen ve RAS mutasyonu bakılmış 75 hasta dahil edildi. Rasmutant olan ve olmayan hastaların tümör lokalizasyonu, tanı anındaki metastaz yerleri, tümör belirteçleri, tümör diferansiyasyon derecesi ve genel sağkalım süreleri arasındaki farklılıklar analiz edildi. RAS mutasyonu sıklığı %50.7 olarak saptandı. Klinik ve patolojik özellikler açısından bakıldığında RAS mutant ve wild gruplar arasında istatistiksel anlamı farklılık saptamadık. RAS mutasyon durumuna göre genel sağkalım süreleri incelendiğinde, RAS wild tip olan hastaların 2 yıllık genel sağkalımı% 59 iken, RAS mutant hastalarımızın 2 yıllık genel sağkalımı %27.8 idi ve bu fark istatiksel olarak anlamlıydı (p=0.004). Ancak, RAS wild hastaların ilk hat tedavisinde bevacizumab veya cetuksimab/panitumumab alan hastaların ortalama sağkalımları arasında (sırasıyla %57.1'e karşı %70.7; p=0.221) istatistiksel fark saptanmadı. Bu çalışmada, metastatik kolorektal kanserli hastalarımızın RAS mutasyon durumunun daha ziyade Batılı ülkelere benzer olduğunu ve hastaların tanı anındaki klinik ve patolojik özelliklerinin RAS mutasyon durumundan bağımsız olduğunu saptadık. Ancak bu konuda yapılacak prospektif ve daha geniş katılımlı çalışmalara hala ihtiyaç duyulmaktadır.

Anahtar Kelimeler

• Klinik ve patolojik özellikler,Kolorektal kanser,RAS mutasyonu

Kaynakça

1. Referans 1. Zeng M, Kikuchi H, Pino MS, Chung DC. Hypoxia activates the K-ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells. PLoS One 2010;5(6). e10966.
2. Referans 2. Jiang Y, Mackley H, Cheng H, Ajani JA. Use of K-Ras as a predictive biomarker for selecting anti-EGF receptor/pathway treatment. Biomark Med 2010 Aug; 4(4): 535-41.
3. Referans 3. Kim D, Hong YS, Kim JE, et al. Use of a high-throughput genotyping platform (OncoMap) for RAS mutational analysis to predict cetuximab efficacy in patients with metastatic colorectal cancer. Cancer Res Treat 2017;49(1):37–43.
4. Referans 4. Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369(11):1023–1034.
5. Referans 5. Heinemann V, Rivera F, O’Neil BH, et al. A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer. Eur J Cancer 2016;67:11–20.
6. Referans 6. Levi M, Prayogi G, Sastranagara F, et al.ClinicopathologicalAssociations of K-RAS and N-RAS Mutations in Indonesian Colorectal Cancer Cohort. J Gastrointest Cancer 2017;1–8.
7. Referans 7. Zekri J, Karim SM, Al-Shehri A, Mahrous M, Darwish T, El Taani H. Frequency and clinical impact of KRAS mutations in patients with colorectal cancer from the middle east. J Anal Oncol 2016;5(2):67–74.
8. Referans 8. Ribeiro KB, Feres O, Ribeiro da Rocha JJ, et al.Clinical-pathological correlation of KRAS mutation status in metastatic colorectal adenocarcinoma. World J Oncol 2013;4(4–5):179–187.

9. Referans 9. Morris VK, Lucas FAS, Overman MJ, et al. Clinicopathologic characteristics and gene expression analyses of non-KRAS 12/13, RAS-mutated metastatic colorectal cancer. Ann Oncol 2014;25(10):2008–2014.
10. Referans 10. Phua LC, Ng HW, Yeo AHL, et al. Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer. Oncol Lett 2015;10(4):2519–2526.
11. Referans 11.Kawazoe A, Shitara K, Fukuoka S, et al. A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer. BioMed Cent Cancer 2015;15:258.
12. Referans 12.Koochak A, Rakhshani N, Karbalaie Niya MH, et al. Mutation Analysis of KRAS and BRAF Genes in Metastatic Colorectal Cancer: a First Large Scale Study from Iran. Asian Pac J Cancer Prev 2016;17(2):603–608.
13. Referans 13.Akman T, Oztop I, Baskin Y, et al. The association of clinicopathological features and survival in colorectal cancer patients with kras mutation status. J Cancer Res Ther 2016;12(1):96–102.
14. Referans 14. Heinemann V, Weikersthal LF Von, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. LancetOncol 2014;15(10):1065–1075.
15. Referans 15. Venook AP, Niedzwiecki D, Lenz H-J, et al. Metastatic adenocarcinoma of the colon or re CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) oroxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated. J Clin Oncol 2014 :20; 32(15_suppl): LBA3-LBA3.
16. Referans 16. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with ras wild-type metastatic colorectal cancer retrospective analyses of the CRYSTAL and FIRE-3 trials. In: JAMA Oncology 2017;194–201.