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Tumor Histology and Stage but Not P53, Her2-Neu Or Cathepsin-D Expression Are Independent Prognostic Factors in Breast Cancer Patients

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Tumor Histology and Stage but Not P53, Her2-Neu Or Cathepsin-D Expression Are Independent Prognostic Factors in Breast Cancer Patients ANTICANCER RESEARCH 24: 2061-2068 (2004) Tumor Histology and Stage but Not p53, Her2-neu or Cathepsin-D Expression are Independent Prognostic Factors in Breast Cancer Patients D. P. KORKOLIS1, E. TSOLI2,3, D. FOUSKAKIS2, J. YIOTIS4, G. J. KOULLIAS1, D. GIANNOPOULOS5, E. PAPALAMBROS6, N. I. NIKITEAS7, C. A. SPILIOPOULOU3, E. PATSOURIS8, P. ASIMACOPOULOS9,10 and V.G. GORGOULIS2 1Department of Surgery and 4Department of Biochemistry, "St Savvas" Hospital, Athens; 2Molecular Carcinogenesis Group, Department of Histology-Embryology, 3Department of Forensic Medicine and Toxicology, 7Second Department of Propaedeutic Surgery, 8Department of Pathology and 9Department of Surgery, School of Medicine, University of Athens, Athens; 5Department of Pathology, "Evangelismos" Hospital, Athens; 6Department of Surgery, "Laiko" Hospital, School of Medicine, University of Athens, Athens, Greece; 10Baylor College of Medicine, Houston, Texas, U.S.A. Abstract. Background: Several factors are currently employed for both negative nodal status and Her2-neu overexpression tended to prognosis assessment and treatment determination in breast display an elevated risk of death. Conclusion: Our results support cancer. An array of molecular parameters, such as p53, Her2-neu the prognostic power of tumor histology and stage and emphasize (c-erbB 2) and Cathepsin-D, are also examined to improve clinical the need for further studies on the prognostic impact of p53, Her2- patient management. We have conducted a statistically powerful neu and Cathepsin-D in breast cancer. Additionally, our analysis study of the prognostic value of conventional factors and of the indicates that deregulation of Her2-neu might characterize a investigational factors p53, Her2-neu and Cathepsin-D in patients subgroup of node-negative patients with poor prognosis who could with invasive breast carcinoma, in order to compare their benefit from an aggressive adjuvant therapy. significance. Our analysis was extended to determine the associations of p53 and Her2-neu with risk of death and relapse Primary breast cancer (PBC) is the most common among patients with and without lymph node metastases. malignancy in the female population worldwide with more Materials and Methods: In a set of 125 primary breast tumors, p53 than a million new cases being diagnosed every year (1). and Her2-neu expression were immunohistochemically evaluated. Extensive studies have shown that tumor clinicopathological Cathepsin-D, estrogen and progesterone receptor concentrations parameters are well established breast cancer prognostic were determined in cytosols by a standard immunoradiometric factors and useful for treatment decision (2). assay. Results: Over a mean of 62 months, 49 patients (39%) had Carcinogenesis represents a complex process that a relapse and 29 patients (23%) died. Overexpression of p53, involves multiple changes in the controlling pathways of cell Her2-neu and Cathepsin-D was observed in 31%, 46% and 88% proliferation, apoptosis, invasiveness and metastatic spread of cases, respectively. Overall survival was associated with histology (3). For this reason, much effort has been placed on the (hazard ratio 0.04, 95% confidence interval: 0.01, 0.49 for lobular identification of novel molecular prognostic factors that tumors) and stage (hazard ratio 5.94, 95% confidence interval: alone or in combination with clinicopathological factors may 1.30, 27.15 for stage III samples). Disease-free survival was also improve the prediction of clinical outcome and determine related to histology (hazard ratio 0.23, 95% confidence interval: the appropriate therapeutic approach. 0.08, 0.73 for lobular tumors) and stage (hazard ratio 4.27, 95% The oncosuppressor protein p53 is a stress response confidence interval: 1.36, 13.36 for stage III tumors). Patients with protein that mediates growth suppression through cell cycle arrest or induction of apoptosis in response to DNA damage (4). Inactivation of the p53 protein in breast tumors is caused mainly by chromosomal deletion and gene Correspondence to: Vassilis G. Gorgoulis, Antaiou 53 Str., mutations, although epigenetic mechanisms also exist, Lamprini, Ano Patissia, Athens, Greece, GR-11146. Tel: ++3-01- 6535894, Fax: ++3-01-6535894, e-mail: [email protected] including mislocalization, increased degradation and inactivation through binding to amplified mdm2 (4). In Key Words: Breast cancer, p53, Her2-neu, Cathepsin D, survival. breast cancer, overexpression of the growth factor receptor 0250-7005/2004 $2.00+.40 2061 ANTICANCER RESEARCH 24: 2061-2068 (2004) Her2-neu is another pathway leading to increased cell antibodies (Abs) were used: mouse monoclonal antibody against proliferation and evasion from apoptosis by mechanisms p53 (Clone DO-7, code COM108, YLEM) and rabbit polyclonal independent of p53 action (5). Her2-neu overexpression antibody against Her2-neu (code A 0485, DAKO, Denmark). b) Method. Immunohistochemistry was performed according to the mainly results from gene amplification and represents a indirect streptavidin-biotin-peroxidase method (34). Antibodies were critical event in the process of breast carcinogenesis and used at 1:250 and 1:200 dilutions for p53 and Her2-neu, respectively. chemoresistance (5). On the other hand, invasiveness of c) Evaluation. Fifteen high power fields (x 400) were examined in breast cancer cells is linked to lysosomal digestion of ECM each slide under light microscopy. Samples were considered p53- fragments, plasma proteins and cellular debris that enters positive when more than 10% of tumor cells exhibited nuclear cells by phagocytosis (6). Cathepsin-D is an important expression (21, 24). According to the HerceptTest TM scoring enzyme that participates in this process (6). system, samples with more than 10% of cells exhibiting staining of the entire membrane were considered Her2-neu-positive (35). Slide Published evidence of the prognostic impact of p53, Her2- examination was performed by two independent observers (VG, neu and Cathepsin-D expression on PBC has been quite DG) and inter-observer variability was minimal (p<0.01). confusing due to different evaluation methodologies, cut-off levels, statistical tests and particularly controversial findings (7- Assessment of the levels of Cathepsin-D, estrogen and progesterone 31). Interestingly, general recommendations on the assessment receptors. Primary tumor samples were collected and stored at -70ÆC. of these molecular parameters have been given to increase the Cytosols were prepared from the frozen tissue by homogenization quality of data collection and subsequently enable application in 10 mmol/1 Tris-HCl buffer, pH 7.4, containing 1.5 mmol EDTA, 0.5 mmol/1 monothioglycerol and 10 mmol sodium molybdate and of these data in clinical patient management (2, 32). subsequent centrifugation at 10,000xg, for 30 min at 4ÆC. Cathepsin-D In view of these controversies, we performed a concentrations were measured in the prepared cytosols by a standard statistically powerful analysis of the prognostic significance immunoradiometric assay (IRMA, ELSA Cath-D kits, CiS Bio- of the conventional clinicopathological markers, p53, Her2- International, Gif-sur-Yvette, France), following the manufacturer's neu and Cathepsin-D expression in a set of females with instructions (36). The cut-off value for CD positivity/negativity was primary breast cancer. Emphasis was given to multivariate 60 pmol/mg protein, as previously described (26). analysis after adjustment for age, tumor diameter, histology, Estrogen and progesterone receptor (ER, PgR) levels were determined in the same cytosols by the Ligand Binding Assay nodal status, grade, stage, hormone receptor status, p53, procedure using the Dextran-Coated Charcoal technique; the cut- Her2-neu and Cathepsin-D expression, type of surgery and off value for both ER and PgR was 10fmol/mg protein according therapeutic approach to specify the best model for survival to previous work (25). prediction. The possible interactions between nodal status, p53 and Her2-neu on death and relapse were also examined Statistical evaluation. All analyses were carried out using STATA in an attempt to discriminate patients with different risks software, version 8 (37). We used Cox proportional hazard models who might need a particular therapeutic approach. to assess the influence of clinicopathological and molecular parameters on the incidences of death and relapse. Examination of Materials and Methods the interaction between nodal status, p53 and Her2-neu, as well as between p53 and Her2-neu on death and relapse, was based on likelihood ratio tests comparing models with and without the Patients. This study included 125 consecutive women suffering from relevant explanatory variables. Such analysis could not be invasive breast carcinoma, grade I to III who were assessed and treated performed for Cathepsin-D because of the small number of failures at the Hellenic Anticancer Institute, "Saint Savvas" Hospital in Athens, and relapses in patients with negative Cathepsin-D expression. Greece, during the period 1993-1998. Forty-nine of these patients (39%) underwent modified radical mastectomy whereas the remaining 76 (61%) followed a breast-conserving treatment with limited excision. Results After surgery, all patients were given adjuvant treatment such as radiotherapy and/or systemic therapy (hormono- and/or Tumor clinicopathological characteristics. The age of the chemotherapy). The mean postsurgical follow-up time of patients was patients ranged between
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