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

Abstract

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers. ABSTRACTPurpose. Mutations of the K-ras gene were identified as a prognostic marker in metastatic colorectal cancer (mCRC). In addition, emerging data suggest that K-ras mutations are a negative predictor of clinical benefit from anti-epidermal growth factor receptor treatment in mCRC. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab treatment in mCRC is independent of alterations in the Ras/ Raf/Mek/Erk pathway. We conducted additional analyses to better describe the clinical benefit of bevacizumab treatment in mCRC relative to K-ras mutation status.Patients and Methods. Additional statistical analyses were done with data from K-ras mutation analyses in 230 patients who were treated with irinotecan, fluorouracil, and leucovorin (IFL) in combination with either bevacizumab or placebo in a randomized phase III study. Following microdissection, tissue was subject to DNA sequencing to identify K-ras mutations in codons 12 and 13. Hazard ratios for the bevacizumab group relative to the control group were estimated from an unstratified Cox regression model. The median progression-free survival (PFS), OS times, and objective response rates were compared.Results. K-ras status was assessed in 230 patients (28.3%). The median PFS was significantly longer in bevacizumab-treated patients with wild-type (wt)-(13.5 versus 7.4 months; hazard ratio 0.44, p < .0001) and mutant (m)-K-ras (9.3 versus 5.5 months; hazard ratio

The prevalent KRAS exon 2 c.35 G>A mutation in metastatic colorectal cancer patients: A biomarker of worse prognosis and potential benefit of bevacizumab-containing intensive regimens?

“…In KRAS exon 2 mutant patients BEV addition to IFL compared to IFL significantly increased PFS up to 9.3 months, while not OS and activity [4,30]. KRAS exon 2 status, wildtype or mutant, does not significantly affect clinical outcome of MCRC patients treated with BEV-containing chemotherapy.…”

“…Retrospective analysis showed that KRAS exon 2 mutant status did not significantly affect median OS (19.9 and 27.7 months, in KRAS mutant and wild-type patients, respectively) of MCRC patients treated with BEV added to IFL [29,30]. Prognostic relevance of KRAS exon 2 or BRAF mutant genotype was not significantly different compared to KRAS or BRAF wild-type status.…”

“…Clinical factors, related to the patient's fitness for more effective treatment strategies (according to age and comorbidity status) [23,24], to the extension of metastatic disease (liver-limited or other/multiple metastatic) [25,26], to the proper treatment strategy (integrated medical and surgical, different medical regimens, lines of effective treatments) [25,27], and biological factors, in particular BRAF and KRAS genotype status [28][29][30][31], contribute to determine the clinical outcome in the individual MCRC patient. The proper definition of a bioclinical algorithm could help address tailored clinical management of individual patients.…”

“…KRAS exon 2 wild-type genotype significantly predicts favourable clinical outcome of antiepidermal growth factor receptor (anti-EGFR) or anti-VEGF drugs added to doublet chemotherapy [30,[33][34][35]. In KRAS exon 2 mutant genotype, bevacizumab (BEV) addition to irinotecan, 5-fluorouracil and leucovorin (IFL) significantly prolonged progression-free survival (PFS) up to 9.3 months, while not overall survival (OS) and activity, compared to IFL [30,33]. Addition of anti-EGFR treatment is not effective in mutant patients, and detrimental if associated to oxaliplatin [34,35].…”

Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice

“…Hurwitz et al (2004) demonstrated that bevacizumab significantly improved OS in mCRC patients, with median OS (mOS) of 20.3 months in patients receiving irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab, relative to 15.6 months in patients who received IFL alone. They also retrospectively analyzed plasma and tumor VEGF levels and KRAS mutational status but found no association between these biomakers and survival benefits from bevacizumab (Hurwitz et al, 2009). Scartozzi et al (2009) suggested a possible correlation between bevacizumab-induced hypertension and clinical outcomes in CRC patients treated with first-line bevacizumab.…”