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BMC Medicine
Published in: BMC Medicine 1/2012

Open Access 01-12-2012 | Research article

Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease

Authors: Gemma Bruera, Katia Cannita, Daniela Di Giacomo, Aude Lamy, Giancarlo Troncone, Antonella Dal Mas, Gino Coletti, Thierry Frébourg, Jean Christophe Sabourin, Mario Tosi, Corrado Ficorella, Enrico Ricevuto

Published in: BMC Medicine | Issue 1/2012

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Abstract

Background

Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated.

Methods

Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test.

Results

In all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively.

Conclusions

The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.
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Literature
1.
Bruera G, Ricevuto E: Intensive chemotherapy of metastatic colorectal cancer: weighing between safety and clinical efficacy. Evaluation of Masi G, Loupakis F, Salvatore L, et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol 2010;11:845-52. Exp Opin Biol Ther. 2011, 11: 821-824. 10.1517/14712598.2011.582462.CrossRef
2.
Masi G, Vasile E, Loupakis F, Cupini S, Fornaro L, Baldi G, Salvatore L, Cremolini C, Stasi I, Brunetti I, Fabbri MA, Pugliesi M, Trenta P, Granetto C, Chiara S, Fioretto L, Allegrini G, Crinò L, Andreuccetti M, Falcone A: Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst. 2011, 103: 21-30. 10.1093/jnci/djq456.CrossRefPubMed
3.
Masi G, Loupakis F, Salvatore L, Fornaro L, Cremolini C, Cupini S, Ciarlo A, Del Monte F, Cortesi E, Amoroso D, Granetto C, Fontanini G, Sensi E, Lupi C, Andreuccetti M, Falcone A: Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010, 11: 845-852. 10.1016/S1470-2045(10)70175-3.CrossRefPubMed
4.
Bruera G, Santomaggio A, Cannita K, Lanfiuti Baldi P, Tudini M, De Galitiis F, Mancini M, Marchetti P, Antonucci A, Ficorella C, Ricevuto E: "Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study. BMC Cancer. 2010, 10: 67-10.1186/1471-2407-10-67.CrossRef
5.
Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, Vennarecci G, Mottolese M, Sperduti I, Cognetti F: Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadiuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer. 2010, 103: 1542-1547. 10.1038/sj.bjc.6605940.CrossRefPubMedPubMedCentral
6.
Bruera G, Cannita K, Giuliante F, Lanfiuti Baldi P, Vicentini R, Marchetti P, Nuzzo G, Antonucci A, Ficorella C, Ricevuto E: Effectiveness of liver metastasectomies in patients with metastatic colorectal cancer treated with FIr-B/FOx triplet chemotherapy plus bevacizumab. Clin Colorectal Cancer. 2012, 11: 119-126. 10.1016/j.clcc.2011.11.002.CrossRefPubMed
7.
Yarden Y, Sliwkowsky MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001, 2: 127-137. 10.1038/35052073.CrossRefPubMed
8.
Scaltriti M, Baselga J: The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006, 12: 5268-5272. 10.1158/1078-0432.CCR-05-1554.CrossRefPubMed
9.
McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D'Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M: Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006, 46: 249-279. 10.1016/j.advenzreg.2006.01.004.CrossRefPubMed
10.
Forbes S, Clements J, Dawson E, Bamford S, Webb T, Dogan A, Flanagan A, Teague J, Wooster R, Futreal PA, Stratton MR: Cosmic 2005. Br J Cancer. 2006, 94: 318-322. 10.1038/sj.bjc.6602928.CrossRefPubMedPubMedCentral
11.
Bos JL: ras oncogenes in human cancer: a review. Cancer Res. 1989, 49: 4682-4689.PubMed
12.
Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young Y, Walsh T, Ward R, Hawkins N, Beranek M, Jandik P, Benamouzig R, Jullian E, Laurent-Puig P, Olschwang S, Muller O, Hoffmann I, Rabes HM, Zietz C, Troungos C, Valavanis C, Yuen ST, Ho JWC, Croke CT, O'Donoghue DP, Giaretti W, Rapallo A, Russo A, Bazan V, et al: Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer. 2001, 85: 692-696. 10.1054/bjoc.2001.1964.CrossRefPubMedPubMedCentral
13.
Normanno N, Tejpar S, Morbillo F, De Luca A, Van Cutsem E, Ciardiello F: Implication of KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Onc. 2009, 6: 519-527. 10.1038/nrclinonc.2009.111.CrossRef
14.
Schubbert S, Shannon K, Bollag G: Hyperactive ras in developmental disorders and cancer. Nat Rev Cancer. 2007, 7: 295-308. 10.1038/nrc2109.CrossRefPubMed
15.
De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, et al: Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010, 11: 753-762. 10.1016/S1470-2045(10)70130-3.CrossRefPubMed
16.
Zauber P, Sabbath-Solitare M, Marotta SP, Bishop DT: Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchorous metastases compared with the findings in accompanying adenomas. Mol Pathol. 2003, 56: 137-140. 10.1136/mp.56.3.137.CrossRefPubMedPubMedCentral
17.
Artale S, Sartore-Bianchi A, Veronese S, Gambi V, Sarnataro CS, Gambacorta M, Lauricella C, Siena S: Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol. 2008, 26: 4217-4219. 10.1200/JCO.2008.18.7286.CrossRefPubMed
18.
Etienne-Grimaldi MC, Formento JL, Francoual M, Francois E, Formento P, Renee N, Laurent-Puig P, Chazal M, Benchimol D, Delpero JR, Letoublon C, Pezet D, Seitz JF, Milano G: K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res. 2008, 14: 4830-4835. 10.1158/1078-0432.CCR-07-4906.CrossRefPubMed
19.
Albanese I, Scibetta AG, Migliavacca M, Russo A, Bazan V, Tomasino RM, Colomba P, Tagliavia M, La Farina M: Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of K-ras and p53 mutations. Biochem Biophys Res Commun. 2004, 325: 784-791. 10.1016/j.bbrc.2004.10.111.CrossRefPubMed
20.
Oudejans JJ, Slebos RJ, Zoetmulder FA, Mooi WJ, Rodenhuis S: Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer. 1991, 49: 875-879. 10.1002/ijc.2910490613.CrossRefPubMed
21.
Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O: The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist. 2009, 14: 22-28.CrossRefPubMed
22.
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009, 351: 1408-1417.CrossRef
23.
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schch G, Stroh C, Loos AH, Zubel A, Koralewski P: Fluorouracil, leucoverin, and oxaliplatin with or without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009, 27: 663-671. 10.1200/JCO.2008.20.8397.CrossRefPubMed
24.
Ficorella C, Ricevuto E, Morelli MF, Morese R, Cannita K, Cianci G, Di Rocco ZC, De Galitiis F, De Tursi M, Tinari N, Iacobelli S, Marchetti P: Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: a dose-finding study. Oncol Rep. 2006, 15: 1345-1350.PubMed
25.
Morelli MF, Santomaggio A, Ricevuto E, Cannita K, De Galitiis F, Tudini M, Bruera G, Mancini M, Pelliccione M, Calista F, Guglielmi F, Martella F, Lanfiuti Baldi P, Porzio G, Russo A, Gebbia N, Iacobelli S, Marchetti P, Ficorella C, on behalf of CINBO (Consorzio Interuniversitario Nazionale per la Bio-Oncologia): Triplet schedule of weekly 5-Fluorouracil and alternating irinotecan or oxaliplatin in advanced colorectal cancer: a dose-finding and phase II study. Oncol Rep. 2010, 23: 1635-40.PubMed
26.
Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, Bastit L, Killian A, Sesboué R, Tuech JJ, Queniet AM, Paillot B, Sabouirin JC, Michot F, Michel P, Frebourg T: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer. 2007, 96: 1166-1169. 10.1038/sj.bjc.6603685.CrossRefPubMedPubMedCentral
27.
Lamy A, Blanchard F, Le Pessot F, Sesboué R, Di Fiore F, Bossut J, Fiant E, Frébourg T, Sabourin JC: Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls. Mod Pathol. 2011, 24: 1090-1100. 10.1038/modpathol.2011.60.CrossRefPubMed
28.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Glabbeke MV, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000, 92: 205-216. 10.1093/jnci/92.3.205.CrossRefPubMed
29.
Kaplan EL, Meier P: Nonparametric estimation of incomplete observations. J Am Stat Assoc. 1958, 53: 457-481. 10.1080/01621459.1958.10501452.CrossRef
30.
Peto R, Peto J: Asymptomatically efficient rank invariant test procedures. J R Stat Soc A. 1972, 135: 185-206. 10.2307/2344317.CrossRef
31.
Hecht JR, Mitchell E, Chidiac T, scroggin C, Hagenstad C, Spigel D, Marshall J, Cohn A, McCollum D, Stella P, Deeter R, Shahin S, Amado RG: A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009, 27: 672-680. 10.1200/JCO.2008.19.8135.CrossRefPubMed
32.
Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJM, Schrama JG, Erdkamp FLG, Vos AH, van Groeningen CJ, Sinnige HAM, Richel DJ, Voest EE, Dijkstra JR, Vink-Borger ME, Antonini NF, Mol L, van Krieken JHJM, Dalesio O, Punt CJA: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009, 360: 563-572. 10.1056/NEJMoa0808268.CrossRefPubMed
33.
Douillard J, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocàkova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J: Randomized, phase III trial of Panitumumab with infusional fluorouracil, leicovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME trial. J Clin Oncol. 2010, 28: 4697-4705. 10.1200/JCO.2009.27.4860.CrossRefPubMed
34.
Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P: Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011, 22: 1535-1546. 10.1093/annonc/mdq632.CrossRefPubMed
35.
Ince WL, Jubb AM, Holden SN, Holmgren EB, Tobin P, Sridhar M, Hurwitz HI, Kabbinavar F, Novotny WF, Hillan KJ, Koeppen H: Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst. 2005, 97: 981-989. 10.1093/jnci/dji174.CrossRefPubMed
36.
Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, Kohne CH: Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with Cetuximab: the CELIM randomized phase 2 trial. Lancet Oncol. 2010, 11: 38-47. 10.1016/S1470-2045(09)70330-4.CrossRefPubMed
37.
Guerrero S, Casanova I, Farrè L, Mazo A, Capellà G, Mangues R: K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Res. 2000, 60: 6750-6756.PubMed
Metadata
Title
Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease
Authors
Gemma Bruera
Katia Cannita
Daniela Di Giacomo
Aude Lamy
Giancarlo Troncone
Antonella Dal Mas
Gino Coletti
Thierry Frébourg
Jean Christophe Sabourin
Mario Tosi
Corrado Ficorella
Enrico Ricevuto
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2012
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-10-135

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