Details

Autor(en) / Beteiligte

• KONECNY, Gottfried E
• MENG, Y. Gloria
• BERYT, Malgorzata
• HEPP, Hermann
• SLAMON, Dennis J
• PEGRAM, Mark D
• UNTCH, Michael
• WANG, He-Jing
• BAUERFEIND, Ingo
• EPSTEIN, Melinda
• STIEBER, Petra
• VERNES, Jean-Michel
• GUTIERREZ, Johnny
• KYU HONG

Titel

Association between HER-2/neu and Vascular Endothelial Growth Factor Expression Predicts Clinical Outcome in Primary Breast Cancer Patients

Ist Teil von

• Clinical cancer research, 2004-03, Vol.10 (5), p.1706-1716

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• Purpose: Activation or overexpression of HER-2/ neu is associated with up-regulation of vascular endothelial growth factor (VEGF) in human breast cancer cells in vitro . Preclinical experiments indicate that increased expression of VEGF may in part mediate the biologically aggressive phenotype of HER-2/ neu -overexpressing human breast cancer. It was the purpose of this study to: ( a ) evaluate the association between HER-2/ neu and VEGF expression in a large clinical cohort of primary breast cancer patients; ( b ) compare the prognostic significance of VEGF isoforms; and ( c ) analyze the combined effects of HER-2/ neu and VEGF on clinical outcome. Experimental Design: HER-2/ neu and VEGF were measured by ELISA in primary breast tumor tissue lysates from 611 unselected patients with a median clinical follow-up of 50 months. At least six VEGF isoforms consisting of 121, 145, 165, 183, 189, or 206 amino acids are generated as a result of alternative splicing. The VEGF 121–206 ELISA uses antibodies that bind to VEGF 121 and, therefore, detects all of the VEGF isoforms with 121 and more amino acids. The VEGF 165–206 ELISA uses antibodies that bind to VEGF 165 and, therefore, detects all of the VEGF isoforms with 165 and more amino acids. VEGF 121–206 and VEGF 165–206 were analyzed both as continuous and categorical variables, using detectable expression as a cutoff for positivity. Cell lines with defined HER-2/ neu expression levels were used to establish a cutoff point for HER-2/ neu overexpression in breast tumor samples. Results: Our findings indicate a significant positive association between HER-2/ neu and VEGF expression. VEGF 121–206 and VEGF 165–206 expression was detectable in 88 (77.2%) and 100 (87.7%), respectively, of the 114 patients with HER-2/ neu -overexpressing tumors, in contrast to 271 (54.5%) and 353 (71.0%), respectively, of the 497 patients with nonoverexpressing tumors (χ 2 test: P < 0.001 for both VEGF 121–206 and VEGF 165–206 ). VEGF 121–206 and VEGF 165–206 demonstrate a comparable prognostic significance for survival in unselected primary breast cancer patients (univariate analysis: VEGF 121–206 , P = 0.0068; VEGF 165–206 , P = 0.0046; multivariate analysis: VEGF 121–206 , P = 0.1475; VEGF 165–206 , P = 0.1483). When the analyses were performed separately for node-negative and node-positive patients, VEGF 121–206 and VEGF 165–206 were of prognostic significance for survival only in node-positive patients (univariate analysis: VEGF 121–206 , P = 0.0003; VEGF 165–206 , P = 0.0038; multivariate analysis: VEGF 121–206 , P = 0.0103; VEGF 165–206 , P = 0.0150). A biological concentration-effect relationship between VEGF expression and survival (VEGF 121–206 , P = 0.0280; VEGF 165–206, P = 0.0097) suggests that VEGF levels, as determined by ELISA, could be of importance as a predictive marker for therapeutic strategies that target VEGF. Combining HER-2/ neu and VEGF 121–206 /VEGF 165–206 results in additional prognostic information for survival (VEGF 121–206 , P = 0.0133; VEGF 165–206 , P = 0.0092). Conclusion: The positive association between HER-2/ neu and VEGF expression implicates VEGF in the aggressive phenotype exhibited by HER-2/ neu overexpression, and supports the use of combination therapies directed against both HER-2/ neu and VEGF for treatment of breast cancers that overexpress HER-2/ neu .