The main prognostic variables in early breast cancer are tumor size, histological grade, ER/PgR status, number of positive nodes and HER2 status. The present study evaluated the prognostic and/or predictive value of VEGF family members in high-risk early breast cancer patients treated with adjuvant chemo-hormonotherapy.

RNA was isolated from 308 formalin-fixed paraffin-embedded primary tumor samples from breast cancer patients enrolled in the HE10/97 trial, evaluating adjuvant dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel (E-T-CMF vs. E-CMF). A fully automated method based on magnetic beads was applied for RNA extraction, followed by one-step quantitative RT-PCR for mRNA analysis of VEGF-A, -B, -C and VEGFR1, 2, 3.

With a median follow-up of 8 years, 109 patients (35%) developed a relapse and 80 patients (26%) died. In high VEGF-C and VEGFR1 mRNA expressing tumors, ER/PgR-negative tumors (Fisher's exact test, p=0.001 and p=0.021, respectively) and HER2-positive tumors (p<0.001 and p=0.028, respectively) were more frequent than in low VEGF-C and VEGFR1 expressing tumors, respectively. From the VEGF family members evaluated, high VEGFR1 mRNA expression (above the 75th percentile) emerged as a significant negative prognostic factor for overall survival (OS; HR=1.60, 95% CI: 1.01-2.55, Wald's p=0.047) and disease-free survival (DFS; HR=1.67, 95% CI: 1.13-2.48, p=0.010), when adjusting for treatment group. High VEGF-C mRNA expression was predictive for benefit from adjuvant treatment with paclitaxel (E-T-CMF arm) for OS (test for interaction, Wald's p=0.038), while in multivariate analysis the interaction of VEGF-C with taxane treatment was significant for both OS (Wald's p=0.019) and DFS (p=0.041) and continuous VEGF-B mRNA expression values for OS (p=0.019).

The present study reports for the first time that VEGF-C mRNA overexpression, as assessed by qRT-PCR, has strong predictive value in high-risk early breast cancer patients undergoing adjuvant paclitaxel-containing treatment. Further studies are warranted to validate the prognostic and/or predictive value of VEGF-B, VEGF-C and VEGFR1 in patients treated with adjuvant therapies and reveal which members of the VEGF family could possibly be useful markers in identifying patients that will benefit most from anti-VEGF strategies. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998

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