Efficacy of bevacizumab and chemotherapy in the first-line treatment of metastatic colorectal cancer: broadening KRAS-focused clinical view

BMC Gastroenterology

Lenka Zdrazilova-Dubska⁴  Rostislav Vyzula⁵  Dalibor Valik¹  Ladislav Dusek⁵  Tomas Pavlik⁵  Bohuslav Melichar⁷  Igor Kiss⁶  Lenka Ostrizkova²  Jana Halamkova³  Zbynek Bortlicek⁵  Beatrix Bencsikova⁶ 

[1] Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno 656 53, Czech Republic;Department of Internal Medicine and Hematooncology, University Hospital Brno, Brno, Czech Republic;Department of Complex Oncology Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic;Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic;Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic;Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic;Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic

关键词: Clinical practice;    Antineoplastic agents;    Biomarkers;    KRAS;    Bevacizumab;    Angiogenesis inhibitors;    Colorectal cancer;   

Others  :  1211547
DOI  :  10.1186/s12876-015-0266-6

 received in 2014-04-08, accepted in 2015-03-11,  发布年份 2015

【 摘 要 】

Background

The aim of the present retrospective study was to analyze clinical outcome and risk factors associated with treatment outcomes according to KRAS status in patient with metastatic colorectal cancer (mCRC) treated with bevacizumab (bev) plus chemotherapy in the first-line setting.

Methods

We performed observational study on 1622 patients with mCRC treated with bev plus oxaliplatin- or irinotecan-based chemotherapy, and correlated treatment outcomes with KRAS mutation status. The primary endpoint was progression-free survival (PFS) and additionally overall survival (OS). Adverse events of bevacizumab and risk factors including location of metastases were evaluated.

Results

Mutation in KRAS was present in 40.6% of mCRC cases. The median PFS in patients with wild-type KRAS (wtKRAS) vs mutant KRAS was 11.5 vs 11.4 months, respectively. The median OS was 30.7 vs 28.4 months (p = 0.312). Patients with KRAS mutation had lung metastases more frequently than wtKRAS individuals (32.0% vs 23.8%; p = 0.001). We observed no difference in clinical outcome between hepatic and extrahepatic metastatic disease.

Conclusion

KRAS mutation does not interfere with clinical benefit from first-line treatment with bevacizumab plus chemotherapy in mCRC patients.

【 授权许可】

   
2015 Bencsikova et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, et al.: Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995, 55:4575-80.
• [2]Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM: Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 1995, 55:3964-8.
• [3]Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335-42.
• [4]Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al.: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007, 25:1539-44.
• [5]Rak J, Yu JL, Kerbel RS, Coomber BL: What do oncogenic mutations have to do with angiogenesis/vascular dependence of tumors? Cancer Res 2002, 62:1931-4.
• [6]Sparmann A, Bar-Sagi D: Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 2004, 6:447-58.
• [7]Monticone M, Biollo E, Maffei M, Donadini A, Romeo F, Storlazzi CT, et al.: Gene expression deregulation by KRAS G12D and G12V in a BRAF V600E context. Mol Cancer 2008, 7:92. BioMed Central Full Text
• [8]Watnick RS, Cheng YN, Rangarajan A, Ince TA, Weinberg RA: Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. Cancer Cell 2003, 3:219-31.
• [9]Dubska L, Vyskocilova M, Nenutil R, Valik D, Knoflickova D, Fabian P, et al.: KRAS mutation testing in therapeutic algorithm for treatment of metastatic colorectal carcinoma. Cas Lek Cesk 2011, 150:321-6.
• [10]Diaz-Rubio E, Gomez-Espana A, Massuti B, Sastre J, Reboredo M, Manzano JL, et al.: Role of Kras status in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab: a TTD group cooperative study. PLoS One 2012, 7:e47345.
• [11]Van Cutsem E, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, et al.: Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009, 20:1842-7.
• [12]Kozloff M, Yood MU, Berlin J, Flynn PJ, Kabbinavar FF, Purdie DM, et al.: Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 2009, 14:862-70.
• [13]Bendell JC, Bekaii-Saab TS, Cohn AL, Hurwitz HI, Kozloff M, Tezcan H, et al.: Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: results from ARIES, a bevacizumab observational cohort study. Oncologist 2012, 17:1486-95.
• [14]Slavicek L, Pavlik T, Tomasek J, Bortlicek Z, Buchler T, Melichar B, et al.: Efficacy and safety of bevacizumab in elderly patients with metastatic colorectal cancer: results from the Czech population-based registry. BMC Gastroenterol 2014, 14:53. BioMed Central Full Text
• [15]Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004, 22:229-37.
• [16]Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, et al.: Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007, 370:135-42.
• [17]Lin YL, Liau JY, Yu SC, Ou DL, Lin LI, Tseng LH, et al.: KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells. PLoS One 2012, 7:e50701.
• [18]Basso M, Strippoli A, Orlandi A, Martini M, Calegari MA, Schinzari G, et al.: KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients. Br J Cancer 2013, 108:115-20.
• [19]Rossi L, Veltri E, Zullo A, Zoratto F, Colonna M, Longo F, et al.: Metastatic colorectal cancer first-line treatment with bevacizumab: the impact of K-ras mutation. Onco Targets Ther 2013, 6:1761-9.
• [20]Tie J, Lipton L, Desai J, Gibbs P, Jorissen RN, Christie M, et al.: KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res 2011, 17:1122-30.
• [21]Modest DP, Stintzing S, Laubender RP, Neumann J, Jung A, Giessen C, et al.: Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status. Anticancer Drugs 2011, 22:913-8.
• [22]Cejas P, Lopez-Gomez M, Aguayo C, Madero R, de Castro CJ, Belda-Iniesta C, et al.: KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS One 2009, 4:e8199.
• [23]Kim MJ, Lee HS, Kim JH, Kim YJ, Kwon JH, Lee JO, et al.: Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer. BMC Cancer 2012, 12:347. BioMed Central Full Text
• [24]Morikawa T, Tanaka N, Kuchiba A, Nosho K, Yamauchi M, Hornick JL, et al.: Predictors of lymph node count in colorectal cancer resections: data from US nationwide prospective cohort studies. Arch Surg 2012, 147:715-23.
• [25]Erpenbeck L, Schon MP: Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010, 115:3427-36.
• [26]Rao B, Gao Y, Huang J, Gao X, Fu X, Huang M, et al.: Mutations of p53 and K-ras correlate TF expression in human colorectal carcinomas: TF downregulation as a marker of poor prognosis. Int J Colorectal Dis 2011, 26:593-601.
• [27]Wang XQ, Li H, Van Putten V, Winn RA, Heasley LE, Nemenoff RA: Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9. Mol Biol Cell 2009, 20:791-800.
• [28]Chan AT, Baba Y, Shima K, Nosho K, Chung DC, Hung KE, et al.: Cathepsin B expression and survival in colon cancer: implications for molecular detection of neoplasia. Cancer Epidemiol Biomarkers Prev 2010, 19:2777-85.
• [29]Nash GM, Gimbel M, Shia J, Nathanson DR, Ndubuisi MI, Zeng ZS, et al.: KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. Ann Surg Oncol 2010, 17:572-8.
• [30]Modest DP, Jung A, Moosmann N, Laubender RP, Giessen C, Schulz C, et al.: The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int J Cancer 2012, 131:980-6.
• [31]Er TK, Chen CC, Bujanda L, Herreros-Villanueva M. Clinical relevance of KRAS mutations in codon 13: Where are we? Cancer Lett 2013.
• [32]Figueras A, Arbos MA, Quiles MT, Vinals F, Germa JR, Capella G: The impact of KRAS mutations on VEGF-A production and tumour vascular network. BMC Cancer 2013, 13:125. BioMed Central Full Text
• [33]Wangefjord S, Sundstrom M, Zendehrokh N, Lindquist KE, Nodin B, Jirstrom K, et al.: Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study. Biol Sex Differ 2013, 4:17. BioMed Central Full Text
• [34]Khong TL, Thairu N, Larsen H, Dawson PM, Kiriakidis S, Paleolog EM: Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer. BMC Cancer 2013, 13:518. BioMed Central Full Text
• [35]Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, et al.: Biomarker results from the AVADO phase 3 trial of first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer. Br J Cancer 2013, 108:1052-60.