Mutant p53 protein overexpression in women with ipsilateral breast tumor recurrence following lumpectomy and radiation therapy

BACKGROUND. The p53 tumor suppressor gene encodes a nuclear phosphoprotein that is thought to be important to cell cycle regulation and DNA repair and that also may regulate induction of apoptosis by ionizing radiation. Somat ic p53 gene mutations occur in 30-50% of breast carcinomas and are associat ed With poor prognosis. Mutations in the p53 gene result in prolonged stabi lity of the protein that can be detected by immunohistochemical techniques. In a matched case-control study of breast carcinoma patients with ipsilate ral breast tumor recurrence (IBTR) following lumpectomy and radiation thera py, the authors investigated the frequency and prognostic significance of s omatic p53 mutations as well as the clinical characteristics of patients wi th these mutations. METHODS. Between 1973 and 1995, there were 121 breast carcinoma patients wi th IBTR following lumpectomy and radiation therapy, and the authors identif ied 47 patients in whom the paraffin embedded tissue blocks from the primar y breast tumors were available for further molecular analysis. Forty-seven control breast carcinoma patients from the breast carcinoma data base were individually matched to the index cases who did not have IBTR for age, trea tment date, follow-up, histology, margin status, radiation dose, and adjuva nt treatment. Immunohistochemistry using a monoclonal antibody to mutant p5 3 protein was used to determine mutant p53 protein overexpression in breast tumors and appropriately scored. RESULTS. A total of 12 of 47 tumor specimens (26%) from index patients with breast tumor relapses demonstrated mutant p53 protein overexpression, wher eas only 4 of 47 specimens from controls (9%) demonstrated high mutant p53 immunoreactivity (P = 0.02). The authors found that 9 of 23 patients (39%) with early breast tumor recurrences (recurrences within 4 years of diagnosi s) had overexpression of mutant p53 protein, whereas only 1 of 23 control c ases (4%) had high mutant p53 protein immunoreactivity (P = 0.003). In cont rast, index cases from patients with late breast tumor relapses (more than 4 years after diagnosis), which are more likely to represent de novo breast tumors, and control cases from the breast carcinoma data base without IBTR had similar levels of mutant p53 protein overexpression (P = not significa nt). The 10-year distant disease free survival for patients with mutant p53 protein was 48%, compared with 67% for breast carcinoma patients without d etection of mutant p53 protein (P = 0.08). The authors found that 13 of 14 primary breast tumors (93%) with mutant p53 protein overexpression were est rogen receptor negative (P = 0.01) and 11 of 14 (79%) were progesterone rec eptor negative (P = not significant). CONCLUSIONS. In a matched case-control study, overexpression of mutant p53 protein has prognostic significance with respect to IBTR following lumpecto my and radiation therapy. Breast tumors with p53 mutations are generally es trogen receptor negative and are associated with compromised distant diseas e free survival. (C) 2000 American Cancer Society.