Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection.
OBJECTIVE
The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial.


METHODS
ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial).


RESULTS
Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm.


CONCLUSIONS
This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts.
Authors' Affiliations: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds; St James's Institute of Oncology, Bexley Wing; Cancer Research UK Centre, Leeds Institute of Molecular Medicine, St James's University Hospital; Department of Clinical Biochemistry and Immunology, Leeds General Infirmary, Leeds; MRC Clinical Trials Unit; UCL Cancer Institute, University College, London; and Christie Hospital, University of Manchester, Withington, Manchester, United Kingdom.
Fiona
F
Collinson
Michelle
M
Hutchinson
Rachel A
RA
Craven
David A
DA
Cairns
Alexandre
A
Zougman
Tobias C
TC
Wind
Narinder
N
Gahir
Michael P
MP
Messenger
Sharon
S
Jackson
Douglas
D
Thompson
Cybil
C
Adusei
Jonathan A
JA
Ledermann
Geoffrey
G
Hall
Gordon C
GC
Jayson
Peter J
PJ
Selby
Rosamonde E
RE
Banks
D018262:Adenocarcinoma, Clear Cell / Q000097:blood / Q000188:drug therapy / Q000401:mortality; D002288:Adenocarcinoma, Mucinous / Q000097:blood / Q000188:drug therapy / Q000401:mortality; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood*; D002853:Chromatography, Liquid; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000097:blood / Q000188:drug therapy / Q000401:mortality; D016889:Endometrial Neoplasms / Q000097:blood / Q000188:drug therapy / Q000401:mortality; D005185:Fallopian Tube Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D018579:Patient Selection; D010534:Peritoneal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D011379:Prognosis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015996:Survival Rate; D054928:Validation Studies as Topic
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000068258:Bevacizumab