Angiogenesis-associated sequence variants relative to breast cancer recurrence and survival.
BACKGROUND
Breast cancer (BrCA) risk stratification using clinico-pathological biomarkers helps improve disease prognosis prediction. However, disease recurrence rates remain unfavorable and individualized clinical management strategies are needed. Consequently, we evaluated the influence of 14 sequence variants detected in IL-10, TGF-β1, VEGF, and their associated receptors as effective predictors of BrCA clinical outcomes.


METHODS
Tumor DNA samples collected from 441 BrCA patients were genotyped using TaqMan-PCR. Most selected targets alter cytokine serum/plasma levels or signaling pathways. Relationships between genetic profiles and recurrence as well as disease-related mortality were evaluated using cumulative incidence curves and competing risk regression models.


RESULTS
The VEGF(-2578)C allele was associated with a 1.3- to 1.6-fold increase in BrCA recurrence (HR(trend) = 1.28; 95% CI = 0.96-1.72) and disease-related mortality (HR(trend) = 1.56; 95% CI = 0.93-2.56). Although this marker was marginally significant relative to BrCA outcomes, there were substantial gains in the 5- and 8-year predictive accuracy compared to standard prognostic indicators. Among ER(+)/PR(+) status patients, there was a significant impact of the VEGF(-2578)CC genotype on disease recurrence and predictive accuracy.


CONCLUSIONS
Our findings suggest inheritance of the VEGF(-2578)C allele could serve as an independent prognostic indicator of BrCA prognosis. The VEGF(-2578) marker may have clinical implications among a subset of ER(+)/PR(+) patients with an aggressive phenotype. Because the VEGF(-2578)C allele is linked to high VEGF expression, this cytokine is a potential prognostic and targeted clinical management tool.
Kidd
LaCreis R
LR
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA. lrkidd01@louisville.edu
Brock
Guy N
GN
VanCleave
Tiva T
TT
Benford
Marnita L
ML
Lavender
Nicole A
NA
Kruer
Traci L
TL
Wittliff
James L
JL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D005260:Female; D005838:Genotype; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D014408:Biomarkers, Tumor; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10