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.

Abstract

We investigated the interrelationship between p53 gene alterations, MDR1 gene expression, and S-phase fraction (SPF) in breast carcinomas treated primarily with chemotherapy or radiotherapy and correlated the results with patient outcome to determine the potential clinical significance of these factors. In a consecutive series of 64 fine-needle samplings of breast cancer patients who underwent either neoadjuvant chemotherapy (n = 53) or radiotherapy (n = 11), p53 (exons 5-9) gene alterations by denaturating gradient gel electrophoresis and subsequent direct sequencing, MDR1 gene expression by semiquantitative reverse transcription-PCR, and SPF by DNA flow cytometry were determined. Our results show that p53 mutations (n = 20) were significantly associated (P = 0.01) with high SPF but not with de novo MDR1 gene expression. Most patients with wild-type p53 tumors were found to be resistant to neoadjuvant 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 (>/=5%) SPF (P = 0.016) was found, no correlation between distant disease-free survival and p53 status or intrinsic MDR1 gene expression was found. Poor overall survival was observed in patients with tumors with high SPF (P < 0.0004) or lacking MDR1 gene expression (P = 0.03) before treatment, but not with p53 alterations. These data suggest that SPF remains the most relevant biological factor for breast cancer patients treated by primary chemotherapy or radiotherapy and that p53 and MDR1 status may identify a small subset of patients that may resist therapy or pursue an aggressive course.