Prognostic value of the quantitative measurement of the oncoprotein p185^Her‐2/neu in a group of patients with breast cancer and positive node involvement

Abstract

Our study attempts to determine the prognostic value of the quantitative measurement of the oncoprotein p185Her-2/neu in a group of patients with breast cancer and positive node involvement. In a series of 217 patients with breast cancer and positive nodes in whom the oncoprotein p185 was quantitatively determined by ELISA, we analyzed the clinicopathological variables including age, menopausal status, tumor size, number of affected nodes, type and histology grade and the molecular variables such as the oestrogen and progesterone receptors (ER and PR, respectively), pS2 and Cathepsin D (CD). Using 260 fmol/mg protein as a cut-off point, 18% of the tumors presented as overexpressing p185. The p185 showed no relationship with any of the clinico-pathological variables studied except that its concentration was elevated in ductal and lobular histology types and in the moderate and poorly differentiated histology grades. With a median follow-up of 50 months (range 1-90), the univariate analysis of disease-free survival (DFS) and overall survival (OS) showed that the histology grade, tumor size, the number of infiltrated nodes, the p185 and the ER were the variables associated with the clinical course of the disease in the patients. In the multivariate analysis, however, only the tumor size, number of affected ganglia, the p185 and the ER remained associated with the clinical progression of the disease. The patients with p185 overexpression had a risk, not only of relapse but also death from the disease, of more than twice that of the patients who had normal p185 concentrations. When the p185 was divided into 3 categories based on ؎1 ؋ SD above or below the mean, the patients with high and low p185 showed, in the univariate analysis, a similar relationship with DFS but not with OS. In the multivariate analysis, both with the DFS as with the OS, only a high p185 concentration retained its association with the clinical course of the disease in the patients. Our results suggest that by quantitatively determining (using ELISA) the p185 oncoprotein, groups of cancer patients of high risk could be better identified for more effective clinical management. © 2002 Wiley-Liss, Inc. Key words: breast cancer; p185 oncoprotein; ELISAThe HER-2/neu proto-oncogene encodes a 185-kDa trans-membrane glycoprotein (p185) that is a growth factor receptor with tyrosine-kinase activity. The gene amplification or p185 oncoprotein is overexpressed in ϭ30% of cases of human breast cancer 1,2 and has been shown to be associated with a poorer prognosis. [3][4][5][6] The HER-2 gene status has also been studied in conjunction with other prognostic biological markers such as positive node involvement, histological grade, size of tumor, oestrogen (ER) and progesterone (PR) steroid receptor, Cathepsin D (Cat D) and pS2. 7-10The overexpression of p185 has been measured, usually, using immunohistochemical methods and Western blot analysis. 4,[11][12][13][14][15] Recently, a quantitative assay 16 -18 has been employed for the determination of p185. We ha...

Cathepsin D as an Indicator of Clinical Outcome in Early Breast Carcinoma During the First 3 Years of Follow-Up

“…Since previous reports have shown that HER2 overexpression and/or amplification does not exhibit a clear correlation to cathepsin D levels in breast cancers [31][32][33], it seems unlikely that results obtained for the analyzed group of patients reflect differences between triplenegative (ER -/PR -HER2-) and HER2-positive tumors. Taken together, these data suggest that, within the ER -/PR -phenotype, there might be a singular, biologically-related difference between patients with different nodal statuses or tumor sizes.…”

Clinical significance of the quantitative assessment of the cytosolic concentration of HER-2/neu protein in breast cancer by immunoenzymatic assay (ELISA)

“…In previous ELISA studies on tissue extract from breast carcinomas, this value was chosen in compliance with several criteria, such as validation according to the percentages of positives within the range of the cases observed by using gene amplification or overexpression of HER-2/neu in breast carcinomas (Valeron et al 1997;Koscielny et al 1998;Bohn et al 2002) or in cell lines (Konecny et al 2003;Konecny et al 2004), defined as the highest level of expression in non-malignant tissue (Piffanelli et al 1996), or as an intermodal value of a bimodal distribution of the oncoprotein levels (Eppenberger-Castori et al 2001). In the present work, we have investigated the clinical interest of all the obtained values of HER-2/ neu cytosolic levels.…”

“…Nevertheless, we consider that the large sample size in the present study allowed us to overcome some of the potential limitations introduced by stromal cell or DCIS contaminations in the ELISA. Our results are in accordance with prior studies where HER-2/neu was also determined in cytosolic samples of breast carcinomas using ELISA, and reporting an association between the elevated concentration of the oncoprotein and different parameters indicative of tumor aggressiveness, such as ductal histology and poorly differentiated histological grades (Bohn et al 2002), as well as with shortened relapse-free and/or overall survival (Nugent et al 1992;Eissa et al 1997;Bohn et al 2002;Konecny et al 2003Konecny et al , 2004. In addition, our results indicate that HER-2/neu cytosolic levels are significantly associated with aneuploidy and with higher Sphase fraction in breast carcinomas.…”

“…In addition, recent studies suggest that ELISA-based measurement of HER-2/neu protein concentration in breast cancer tissue extracts correlates with tumor aggressiveness and poor outcome (Eppenberger-Castori et al 2001;Bohn et al 2002;Konecny et al 2003Konecny et al , 2004.…”

Houttuyninum, an active constituent of Chinese herbal medicine, inhibits phosphorylation of HER2/neu receptor tyrosine kinase and the tumor growth of HER2/neu-overexpressing cancer cells

“…Overexpression of HER2/neu has also been shown to correlate with tumor grade, tumour size, lymph node metastasis, survival and resistance to hormonal therapy and chemotherapy in breast cancer patients (Korkolis et al, 2004;Fehm et al, 2004;Guarneri et al, 2004). An intact kinase domain is essential for activation of numerous downstream effectors, including phospholipase Cγ, PI3K/AKT and ERK1/2, which result in DNA synthesis and cell proliferation (Bohn et al, 2002;Alimandi et al, 1997;Montgomery et al, 2005;Price et al, 1999). The known oncogenic potential of HER2/neu and its high level of expression in tumour tissues when compared with that in normal tissues make this oncoprotein an ideal target for antitumour therapies (Fig.…”