Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first‑line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Garde Noguera,Javier; Jantus‑Lewintre,Eloisa; Gil‑Raga,Mireia; Evgenyeva,Elena; Maciá Escalante,Sonia; Llombart‑Cussac,Antonio; Camps Herrero,Carlos

doi:10.3892/mco.2017.1149

Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first‑line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Authors:
- Javier Garde Noguera
- Eloisa Jantus‑Lewintre
- Mireia Gil‑Raga
- Elena Evgenyeva
- Sonia Maciá Escalante
- Antonio Llombart‑Cussac
- Carlos Camps Herrero
View Affiliations

Affiliations: Medical Oncology Department, Hospital Arnau de Vilanova of Valencia, 46015 Valencia, Spain, Molecular Oncology Laboratory, University General Hospital of Valencia, Research Foundation, 46014 Valencia, Spain, Medical Oncology Department, Hospital de Sagunto, 46520 Valencia, Spain, Pathology Department, Hospital Marina‑Salud de Denia, 03700 Dénia, Spain, Medical Oncology Department, Hospital General de Elda, 03600 Elda, Spain, Medical Oncology and Molecular Laboratory Department, University General Hospital of Valencia, University of Valencia, 46014 Valencia, Spain
Published online on: February 3, 2017 https://doi.org/10.3892/mco.2017.1149
Pages: 403-408

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti‑epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti‑vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first‑line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild‑type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7‑15.2 vs. RAS wild‑type: 12 months, 95% CI: 9.67‑14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3‑25.6 vs. RAS wild‑type: 24 months, 95% CI: 18.7‑29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild‑type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5‑19.4 vs. 10 months, 95% CI: 4.2‑15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5‑35.4 vs. 15 months, 95% CI: 12.4‑17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine‑oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.

View Figures

View References

1	National Cancer Institute, . Surveillance, Epidemiology and End Results Program. https://seer.cancer.gov/Accessed. May;2013.
2	Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL and Trotti A: AJCC cancer staging manual. 7th. Springer; New York, NY: pp. 1432010
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
4	Bleiberg H: Role of chemotherapy for advanced colorrectal cancer. New oportunities. Semin Oncol. 23:(Suppl 3). 42–50. 1996.PubMed/NCBI
5	de Gramont A, Louvet C, André T, Tournigand C and Krulik M: A review of GERCOD trials of bimonthly leucovorin plus 5-fluorouracil 48-h continuous infusion in advanced colorectal cancer: Evolution of a regimen. Groupe d'Etude et de Recherche sur les Cancers de l'Ovaire et Digestifs (GERCOD). Eur J Cancer. 34:619–626. 1998. View Article : Google Scholar : PubMed/NCBI
6	Capdevila J, Elez E, Peralta S, Macarulla T, Ramos FJ and Tabernero J: Oxaliplatin-based chemotherapy in the management of colorectal cancer. Expert Rev Anticancer Ther. 8:1223–1236. 2008. View Article : Google Scholar : PubMed/NCBI
7	McCormack PL and Keam SJ: Bevacizumab: A review of its use in metastatic colorectal cancer. Drugs. 68:487–506. 2008. View Article : Google Scholar : PubMed/NCBI
8	Blick SK and Scott LJ: Cetuximab: A review of its use in squamous cell carcinoma of the head and neck and metastatic colorectal cancer. Drugs. 67:2585–2607. 2007. View Article : Google Scholar : PubMed/NCBI
9	Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 26:1626–1634. 2008. View Article : Google Scholar : PubMed/NCBI
10	Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 359:1757–1765. 2008. View Article : Google Scholar : PubMed/NCBI
11	Schubbert S, Shannon K and Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 7:295–308. 2007. View Article : Google Scholar : PubMed/NCBI
12	Irahara N, Baba Y, Nosho K, Shima K, Yan L, Dias-Santagata D, Iafrate AJ, Fuchs CS, Haigis KM and Ogino S: NRAS mutations are rare in colorrectal cancer. Diagn Mol Pathol. 19:157–163. 2010. View Article : Google Scholar : PubMed/NCBI
13	De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, et al: Effects of KRAS, BRAF, NRAS, and PIK3Ca mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorrectal cancer: A retrospective consortium analisis. Lancet Oncol. 11:753–762. 2010. View Article : Google Scholar : PubMed/NCBI
14	Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O'Hagan R, Pantginis J, Zhou H, et al: Essential role for oncogenic Ras in tumour maintenance. Nature. 400:468–472. 1999. View Article : Google Scholar : PubMed/NCBI
15	Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T and Kerbel RS: Mutant ras oncogenes upregulate VEGF/VPF expression: Implications for induction and inhibition of tumor angiogenesis. Cancer Res. 55:4575–4580. 1995.PubMed/NCBI
16	Watnick RS, Cheng YN, Rangarajan A, Ince TA and Weinberg RA: Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell. 3:219–231. 2003. View Article : Google Scholar : PubMed/NCBI
17	Klump B, Nehls O, Okech T, Hsieh CJ, Gaco V, Gittinger FS, Sarbia M, Borchard F, Greschniok A, Gruenagel HH, et al: Molecular lesions in colorectal cancer: Impact on prognosis? Original data and review of the literature. Int J Colorectal Dis. 19:23–42. 2004. View Article : Google Scholar : PubMed/NCBI
18	Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, et al: Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 28:466–474. 2010. View Article : Google Scholar : PubMed/NCBI
19	Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M and Slattery ML: Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: A population-based study. Cancer Epidemiol Biomarkers Prev. 9:1193–1197. 2000.PubMed/NCBI
20	Ince WL, Jubb AM, Holden SN, Holmgren EB, Tobin P, Sridhar M, Hurwitz HI, Kabbinavar F, Novotny WF, Hillan KJ and Koeppen H: Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst. 97:981–989. 2005. View Article : Google Scholar : PubMed/NCBI
21	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
22	Doudillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorrectal cancer. N Engl J Med. 369:1023–1034. 2013. View Article : Google Scholar : PubMed/NCBI
23	González-Aguilera JJ, Oliart S, Azcoita MM and Fernández-Peralta AM: Simultaneous mutations in K-ras and TP53 are indicative of poor prognosis in sporadic colorectal cancer. Am J Clin Oncol. 27:39–45. 2004. View Article : Google Scholar : PubMed/NCBI
24	Westra JL, Schaapveld M, Hollema H, de Boer JP, Kraak MM, de Jong D, ter Elst A, Mulder NH, Buys CH, Hofstra RM and Plukker JT: Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol. 23:5635–5643. 2005. View Article : Google Scholar : PubMed/NCBI
25	Kim ST, Park KH, Kim JS, Shin SW and Kim YH: Impact of KRAS mutation status on otucome in metastatic colon cancer patients without anti-epidermal growth factor receptor therapy. Cancer Res Treat. 45:55–62. 2013. View Article : Google Scholar : PubMed/NCBI
26	Andreyev HJ, Norman AR, Cunningham D, Oates JR and Clarke PA: Kirsten ras mutations in patients with colorectal cancer: The multicenter ‘RASCAL’ study. J Natl Cancer Inst. 90:675–684. 1998. View Article : Google Scholar : PubMed/NCBI
27	Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, Hawkins N, et al: Kirsten ras mutations in patients with colorectal cancer: The ‘RASCAL II’ study. Br J Cancer. 85:692–696. 2001. View Article : Google Scholar : PubMed/NCBI
28	Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 350:2335–2342. 2004. View Article : Google Scholar : PubMed/NCBI
29	Price TJ, Hardingham JE, Lee CK, Weickhardt A, Townsend AR, Wrin JW, Chua A, Shivasami A, Cummins MM, Murone C and Tebbutt NC: Impact of KRAS and BRAF gene mutation status on outcomes from the Phase III AGITG MAX Trial of capecitabine alone or in Combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol. 29:2675–2682. 2011. View Article : Google Scholar : PubMed/NCBI
30	Kim ST, Park KH, Shin SW and Kim YH: Does KRAS mutation status affect on the effect of VEGF therapy in metastatic colon cancer patients? Cancer Res Treat. 46:48–54. 2014. View Article : Google Scholar : PubMed/NCBI