BIOLOGICAL AND CLINICAL-SIGNIFICANCE OF CONCURRENT P53 GENE ALTERATIONS, MDR1 GENE-EXPRESSION, AND S-PHASE FRACTION ANALYSES IN BREAST-CANCER PATIENTS TREATED WITH PRIMARY CHEMOTHERAPY OR RADIOTHERAPY

We investigated the interrelationship between p53 gene alterations, MD R1 gene expression, and S-phase fraction (SPF) in breast carcinomas tr eated primarily with chemotherapy or radiotherapy and correlated the r esults with patient outcome to determine the potential clinical signif icance of these factors, In a consecutive series of 64 fine-needle sam plings of breast cancer patients who underwent either neoadjuvant chem otherapy (n = 53) or radiotherapy (n = 11), p53 (exons 5-9) gene alter ations by denaturating gradient gel electrophoresis and subsequent dir ect sequencing, MDR1 gene expression by semiquantitative reverse trans cription-PCR, and SPF by DNA flow cytometry were determined, Our resul ts show that p53 mutations (n = 20) were significantly associated (P = 0.01) with high SPF but not with de novo MDR1 gene expression, Most p atients with wild-type p53 tumors were found to be resistant to neoadj uvant chemotherapy, No correlation was observed between p53 mutations and the induction of MDR1 gene expression during treatment, Although a significant correlation between shorter distant disease-free survival and high (greater than or equal to 5 %) SPF (P = 0.016) was found, no correlation between distant disease-free survival and p53 status or i ntrinsic MDR1 gene expression was found, Poor overall survival was obs erved in patients with tumors with high SPF (P < 0.0001) or lacking MD R1 gene expression (P = 0.03) before treatment, but not with p53 alter ations, These data suggest that SPF remains the most relevant biologic al factor for breast cancer patients treated by primary chemotherapy o r radiotherapy and that p53 and MDR1 status may identify a small subse t of patients that may resist therapy or pursue an aggressive course.