Annals of Surgical Oncology, Vol 7, Issue 4 305-311, Copyright © 2000 by Society of Surgical Oncology

ARTICLES

Prognostic significance of immunohistochemically localized biomarkers in stage II and stage III breast cancer: a multivariate analysis

J. M. Bhatavdekar, D. D. Patel, N. G. Shah, H. H. Vora, T. P. Suthar, P. R. Chikhlikar, N. Ghosh and T. I. Trivedi
Department of Cancer Biology, Gujarat Cancer and Research Institute, Ahmedabad, India.

BACKGROUND: The aim was to investigate the expression of a panel of biomarkers such as prolactin (PRL), p53, Bcl-2, c-erb B2, Ki-67, CD44, and factor VIII-related antigen (FVIII-RA) in primary tumors of stage II and stage III breast cancer and its correlation with disease prognostication. METHODS: The streptavidin-biotin peroxidase complex technique was used for the detection of these antigens. Cytoplasmic staining pattern was observed for PRL, Bcl-2, and Ki-67. Staining pattern for p53 was nuclear. Membranous and/or cytoplasmic staining was noted for c-erb B2 and CD44. Microvessel staining was noted for FVIII-RA. RESULTS: Of the 93 primary breast tumors analyzed, positivity for PRL was noted in 82%, for p53 in 56%, for Bcl-2 in 73%, for c-erb B2 in 68%, and for Ki-67 and CD44 in 78% each. The microvessel count (MVC) for FVIII-RA ranged from 0.0 to 29.0, with a median of 6.0, which was used as a cutoff. MVC > or = 6.0 was noted in 51% of breast tumors. With increasing tumor size, the higher frequency of positivity of MVC > or = 6.0 (P = .0001), CD44 (P = .001), PRL (P = .002), and c-erb B2 (P = .008), and higher frequency of Bcl-2 negativity (P = .033), was noted. In stage III patients, a higher positivity of the following biomarkers was noted, compared with stage II patients: MVC > or = 6.0 (P = .0004), PRL (P = .0002), c-erb B2 (P = .001), and CD44 (P = .005). Further, Bcl-2 positivity was significantly lower in patients with stage III disease compared with those with stage II disease (P = .024). In patients with nodal involvement, the frequency of c-erb B2 (P = .006), MVC > or = 6.0 (P = .011), and PRL (P = .032) was higher than in those without nodal involvement. Moreover, in these patients, with the increase in the number of involved lymph nodes, there was a significant increase in frequency of CD44+ (P = .0004) and PRL+ (P = .013) tumors. Abnormal expression of one biomarker was seen in 7% of tumors, of two biomarkers in 4%, of three in 15%, of four in 19%, of five in 28%, of six in 20%, and of all seven biomarkers in 7% of tumors. The frequency of an increasing number of biomarkers coexpressed was higher in stage III patients compared with stage II patients (P = .00003). In the total number of patients (n = 93), tumors with Bcl-2 negativity (P = .00001), MVC > or = 6.0 (P = .001), PRL positivity (P = .02), and CD44 positivity (P = .034) had a significantly poorer overall survival (OS) compared with their respective counterparts. In stage II patients (n = 40), only p53 expression was significantly associated with reduced relapse-free survival (P = .009) and OS (P = .040). In multivariate analysis, p53 expression was an independent prognostic factor that influenced relapse-free survival (P = .034) of stage II breast cancer patients. However, it failed to attain statistical significance for OS. In stage III patients (n = 53), tumors with Bcl-2 negativity (P = .0005) and MVC > or = 6.0 (P = .039) had a significantly poorer OS compared with their respective counterparts. In multivariate analysis of stage III patients, Bcl-2 was the only independent prognostic factor (P = .001) for predicting OS. There was a significant association between coexpression of the biomarkers and OS (P = .001). The OS rates decreased with the increase in number of abnormally expressed biomarkers. CONCLUSIONS: p53 expression in primary tumors was an independent prognostic factor that influenced relapse-free survival in patients with stage II disease. In stage III patients, lack of Bcl-2 expression was independently associated with a poor prognosis and, thus, may be an indicator of aggressive phenotype.

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