p53 gene alterations in lymph node-positive breast cancer patients on adjuvant chemotherapy

M. Brankovic-Magic a, R. Jankovic a, Z. Magic b, B. Cikota b, S. Radulovic a

a Institute for Oncology and Radiology of Serbia, Belgrade, Yugoslavia b Institute for Medical Research, MMA, Belgrade, Yugoslavia

Background: Since chemotherapeutics may act by inducing apoptosis in malignant cells, p53 mutations can be associated with drug resistance in malignant tumors. The aim of this study was to investigate possible correlation of p53 core domain mutations (exon 5-8) with patientsÂ’ clinical course of disease. Patients and Methods: 47 lymph node-positive premenopausal breast cancer patients with surgery as primary treatment were included in this study. All the patients underwent adjuvant chemotherapy; mostly CMF modified intravenous treatment (44/47). The patients were followed-up from 6 to 85, median 43 months. In this time interval 18/47 patients developed relapse of disease. DNA isolation was performed by phenol extraction on breast cancer tissue samples, which were routinely collected for steroid receptor determination after the surgery. Specific DNA regions were amplified by polymerase chain reaction (PCR). Detection of mutations was further done by single stranded conformational polymorphism -SSCP- electrophoresis. Estrogen (ER) and progesterone (PR) receptors were measured by five-point dextrane-coated charcoal (DCC) assay. Results: The obtained results showed 18 p53 mutations in 15/47 patients (double mutations in three patients). Mutations were predominantly located within exon 5 (7/18) and exon 7 (8/18). Concerning estrogen dependence of breast cancer, mutations were almost equally distributed within ER, PR positive and ER, PR negative tumors. Only 5/18 mutations were detected in the patients who developed recurrence. Nevertheless, disease-free interval (DFI) of these patients ranged from 9 to 16 months, while in the relapsed patients without p53 mutations DFI ranged from 6 to 63, median 29 months. Conclusion: our preliminary results obtained in the small group of patients show no firm correlation between p53 mutations and clinical course of disease, but early relapse occurring in mutated p53 carriers, may support data about its predictive value.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.