Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab.
BACKGROUND
A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin (IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab.


METHODS
Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53. Nuclear P53 expression was determined by immunohistochemistry. Hazard ratios and 95% confidence intervals (CI) for overall survival were estimated using Cox regression analysis.


RESULTS
In all biomarker subgroups, estimated hazard ratios for risk of death were less than 1 for bevacizumab-treated patients as compared with those for placebo-treated patients. Mutations in k-ras and/or b-raf were observed in 88 of 213 patients (41%). Hazard ratios for death among patients with tumors with wild-type k-ras/b-raf status, as compared with those of patients with mutations in one or both genes, were 0.51 (95% CI = 0.28 to 0.95) among those treated with IFL plus bevacizumab and 0.66 (95% CI = 0.37 to 1.18) among those treated with IFL plus placebo. Mutations in p53 were found in 139 of 205 patients (68%), and P53 was overexpressed in 191 of 266 patients (72%); neither p53 mutation nor P53 overexpression was statistically significantly associated with survival.


CONCLUSIONS
We did not find a statistically significant relationship between mutations of k-ras, b-raf, or p53 and the increase in median survival associated with the addition of bevacizumab to IFL in metastatic colorectal cancer.
Ince
William L
WL
Department of Pathology, Genentech Inc., San Francisco, CA, USA.
Jubb
Adrian M
AM
Holden
Scott N
SN
Holmgren
Eric B
EB
Tobin
Patti
P
Sridhar
Meera
M
Hurwitz
Herbert I
HI
Kabbinavar
Fairooz
F
Novotny
William F
WF
Hillan
Kenneth J
KJ
Koeppen
Hartmut
H
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053685:Laser Therapy; D008297:Male; D042282:Microdissection / Q000295:instrumentation; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D000068258:Bevacizumab; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)