The association between vascular endothelial growth factor expression in invasive breast cancer and survival varies with intrinsic subtypes and use of adjuvant systemic therapy: Results from the Nurses' Health Study

Vascular endothelial growth factor (VEGF) is important in breast carcinogenesis. However, whether the effect of VEGF expression on survival varies with intrinsic subtypes of breast cancer remains unclear and the prognostic significance of VEGF expression in breast cancer remains controversial. Using immunostaining of tissue microarray sections, VEGF expression was determined in 1,788 primary invasive breast cancers identified from the Nurses' Health Study cohort. Cox proportional hazards models were used to estimate hazard ratios (HR) of breast cancer-specific and overall mortality and distant recurrence, adjusted for epidemiological, clinicopathological, and related molecular factors, and year of diagnosis. Overall, 72.5% of breast cancers were positive for VEGF. VEGF expression was correlated with intrinsic subtypes (P < 0.0001), with higher frequency in luminal B, HER2, and basal-like types versus luminal A type. Although VEGF expression was not significantly related to worse survival when all cases were considered together, it was significantly associated with increased risks for breast cancer-specific mortality (BCSM) (HR = 1.41, 95% CI = 1.01, 1.97) and distant recurrence (HR = 1.49, 95% CI = 1.07, 2.07) among women with luminal A tumors. In 262 women untreated systemically, VEGF expression was significantly associated with BCSM (HR = 5.58, 95% CI = 1.17, 26.66). In 902 women receiving adjuvant hormonal therapy, VEGF expression did not significantly predict clinical outcomes. The VEGF-associated increased risk of BCSM is limited to luminal A tumors. VEGF expression is a prognostic but not predictive marker of hormonal response in non-metastatic invasive breast cancer.