Bevacizumab May Differentially Improve Ovarian Cancer Outcome in Patients with Proliferative and Mesenchymal Molecular Subtypes.
Purpose:Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer.Experimental Design:DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed.Results:Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34-0.90),P= 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44-1.40),P= 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months;P= 0.08) or differentiated subtype (3.7 months;P= 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27-0.74),P= 0.0015].Conclusions:Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost.Clin Cancer Res; 23(14); 3794-801. ©2017 AACR.
Department of Women's Health, Tuebingen University Hospital, Tuebingen, Germany.
Stefan
S
Kommoss
Division of Gynecologic Surgery, Mayo Clinic, Minnesota.|Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minnesota.
Boris
B
Winterhoff
Department of Health Sciences Research, Mayo Clinic, Minnesota.
Ann L
AL
Oberg
Division of Medical Oncology, UCLA, California.
Gottfried E
GE
Konecny
Department of Health Sciences Research, Mayo Clinic, Minnesota.
Chen
C
Wang
Department of Health Sciences Research, Mayo Clinic, Minnesota.
Shaun M
SM
Riska
AnchorDx Corporation, Guangzhou, China.|Illumina Inc., San Diego, California.
Jian-Bing
JB
Fan
Department of Health Sciences Research, Mayo Clinic, Minnesota.
Matthew J
MJ
Maurer
Illumina Inc., San Diego, California.
Craig
C
April
Department of Laboratory Medicine, Mayo Clinic, Minnesota.
Viji
V
Shridhar
Institute of Pathology, Mannheim, Germany.
Friedrich
F
Kommoss
Kliniken Essen Mitte (KEM), Deptartment of Gynecology and GynecologicOncology, Essen, Germany.
Andreas
A
du Bois
Department of Gynecology and Obstetrics, Schleswig-Holstein University, Kiel, Germany.
Felix
F
Hilpert
Department of Obstetrics and Gynecology, Ludwig Maximillian University Munich, Germany.
Sven
S
Mahner
Department of Gynecology and Gynecologic Oncology, Philipps University Marburg, Germany.
Klaus
K
Baumann
Gynaecologicum Bremen, Bremen, Germany.
Willibald
W
Schroeder
Klinikum der Universitaet Muenchen, Campus Grosshadern, Klinik und Poliklinik fuer Frauenheilkunde und Geburtshilfe, Munich, Germany.
Alexander
A
Burges
Department of Gynecology and Obstetrics, Technical University Dresden, Dresden, Germany.
Ulrich
U
Canzler
Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, Kansas.
Jeremy
J
Chien
Medical Research Council Clinical Trials Unit at University College London, UK.
Andrew C
AC
Embleton
Medical Research Council Clinical Trials Unit at University College London, UK.
Mahesh
M
Parmar
Medical Research Council Clinical Trials Unit at University College London, UK.
Richard
R
Kaplan
Leeds Institute of Cancer Medicine and Pathology, University of Leeds, UK.
Timothy
T
Perren
Division of Medical Oncology, Mayo Clinic, Minnesota.
Lynn C
LC
Hartmann
Department of Health Sciences Research, Mayo Clinic, Minnesota.
Ellen L
EL
Goode
Division of Gynecologic Surgery, Mayo Clinic, Minnesota. dowdy.sean@mayo.edu.
Sean C
SC
Dowdy
Gynecologic Oncology Center, Kiel, Germany.
Jacobus
J
Pfisterer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D000068258:Bevacizumab