Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma 10-year follow-up data

• Published in: Cancer Vol. 97; no. 3; pp. 527 - 536
• Main Authors: GOFFIN, John R, CHAPPUIS, Pierre O, BEGIN, Louis R, WONG, Nora, BRUNET, Jean-Sébastien, HAMEL, Nancy, PARADIS, Ann-Josée, BOYD, Jeff, FOULKES, William D
• Format: Journal Article
• Language: English
• Published: New York, NY Wiley-Liss 01.02.2003
• Subjects: Adult; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - therapy; Chemotherapy; Chemotherapy, Adjuvant; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Jews - genetics; Lymphatic Metastasis; Mammary gland diseases; Medical sciences; Middle Aged; Multivariate Analysis; Pharmacology. Drug treatments; Prognosis; Proportional Hazards Models; Survival Analysis; Tumor Suppressor Protein p53 - metabolism; Tumors; Canada; North America; America; Antineoplastic agent; Human; Carcinoma; Prognosis; Gene overexpression; Malignant tumor; Hereditary; Ethnic group; Genetic disease; Mammary gland diseases; Chemotherapy; TP53 Gene; Treatment; Follow up study; Germ line; Genetics; Hormone replacement therapy; Mammary gland; Mutation; Jew; Tumor suppressor gene
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.11080

Overexpression of p53 has been associated with poor survival following breast carcinoma. BRCA1 interacts biochemically with p53 and may also contribute to poor outcome when constitutionally mutated. The joint effect of both abnormalities has not been studied. The primary objective of this study was to assess the impact of germline BRCA1 mutations and p53 overexpression on survival after 10 years of follow-up. A historical cohort of Ashkenazi Jewish women 65 years or younger with invasive breast carcinoma was tested for BRCA1 founder mutations. p53 overexpression was assessed by immunohistochemistry. Clinicopathologic information was obtained by chart review. In total, 278 women were analyzed. On univariate analysis, p53 overexpression (n = 63) was prognostic for worse overall survival (relative risk [RR] 2.6, P = 0.001) whereas BRCA1 germline mutations (n = 30) were of borderline significance (RR 1.9, P = 0.052). In the lymph node-negative subpopulation, BRCA1 mutation status conferred a higher mortality on univariate (RR 5.6, P < 0.001) and multivariate (RR 3.5, P = 0.03) analyses. There was a trend in favor of a worse prognosis for women who carried a germline BRCA1 mutation and whose tumor overexpressed p53. When compared with noncarriers, BRCA1 mutation carriers had a worse overall survival if they did not receive adjuvant chemotherapy (RR 3.3, P= 0.01) or adjuvant hormonal therapy (RR 2.3, P = 0.02). Germline BRCA1 mutations and p53 overexpression carry a negative prognosis that is not additive to known prognostic factors. Given the experimental sensitivity of BRCA1-mutated cells to chemotherapy, the worse survival among BRCA1 mutation-carrying lymph node-negative breast carcinoma patients may be partly explained by the significantly lower proportion of lymph node-negative patients who received adjuvant chemotherapy (P < 0.001).