Markers of angiogenesis in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study.
OBJECTIVE
To determine whether markers of tumor angiogenesis were associated with progression-free survival (PFS) and overall survival (OS) in women with high-risk, early-stage cervical cancer treated on a phase III trial.


METHODS
One hundred seventy-three tumor specimens were analyzed by semi-quantitative immunohistochemical (IHC) staining for vascular endothelial growth factor (VEGF, pro-angiogenesis factor), thrombospondin-1 (TSP-1, anti-angiogenesis factor), CD31 (non-specific endothelial marker), and CD105 (tumor-specific endothelial marker). Tumoral histoscores (HS) were calculated for VEGF using the formula: [% cells positivex(intensity+1)]. TSP-1 specimens were categorized as negative or positive. CD31 and CD105 microvessel density (MVD) "hotspots" were counted in three 20x high-power fields. Associations between angiogenesis markers and survival were evaluated.


RESULTS
TSP-1 expression was observed in 65% of cases while 66% expressed high VEGF (>or=200), 34% exhibited high CD31 (CD31>or=110) and 66% displayed high CD105 (CD105>or=28). In univariate analyses CD31 MVD, but not tumor TSP-1, was associated with improved PFS (HR=0.37; 95% CI=0.18-0.76; p=0.007) and OS (HR=0.37; 95% CI=0.17-0.79; p=0.010). After adjusting for prognostic clinical covariates, high CD31 MVD, but not TSP-1, VEGF or CD105 MVD, was an independent prognostic factor for PFS (HR=0.36; 95% CI=0.17-0.75; p=0.006) and OS (HR=0.36; 95% CI=0.17-0.79; p=0.010).


CONCLUSIONS
Tumor angiogenesis measured by CD31 MVD is an independent prognostic factor for both PFS and OS in high-risk, early-stage cervical cancer. We hypothesize that this finding may be explained by improved treatment response in well-vascularized, well-oxygenated tumors.
Randall
Leslie M
LM
Chao Family Comprehensive Cancer Center, University of California-Irvine Medical Center, Orange, CA 92868, USA.
Monk
Bradley J
BJ
Darcy
Kathleen M
KM
Tian
Chunqiao
C
Burger
Robert A
RA
Liao
Shu-Yuan
SY
Peters
William A
WA
Stock
Richard J
RJ
Fruehauf
John P
JP
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D000071063:Endoglin; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012307:Risk Factors; D019700:Thrombospondin 1 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015703:Antigens, CD; D014408:Biomarkers, Tumor; C064206:ENG protein, human; D000071063:Endoglin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A