Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma

10-Year follow-up data

Authors

  • John R. Goffin M.D.,

    1. Department of Oncology, McGill University, Montreal, Quebec, Canada
    Current affiliation:
    1. Thoracic Oncology Program, Dana Farber Cancer Center, Boston, MA 02115
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  • Pierre O. Chappuis M.D.,

    1. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
    Current affiliation:
    1. Divisions of Oncology and Medical Genetics, University Hospital of Geneva, Geneva, CH 211, Switzerland
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  • Louis R. Bégin M.D.,

    1. Department of Pathology and Surgery, McGill University, Montreal, Quebec, Canada
    Current affiliation:
    1. Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, H4J 1C5, Canada
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  • Nora Wong M.Sc.,

    1. Cancer Prevention Centre, Sir M.B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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  • Jean-Sébastien Brunet M.Sc.,

    1. Algorithme Pharma, Montreal, Quebec, Canada
    2. Program in Cancer Genetics, Department of Oncology, McGill University, Montreal, Quebec, Canada
    3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
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  • Nancy Hamel M.Sc.,

    1. Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
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  • Ann-Josée Paradis B.Sc.,

    1. Cancer Prevention Centre, Sir M.B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
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  • Jeff Boyd Ph.D.,

    1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
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  • William D. Foulkes M.B., Ph.D.

    Corresponding author
    1. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
    2. Cancer Prevention Centre, Sir M.B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
    3. Program in Cancer Genetics, Department of Oncology, McGill University, Montreal, Quebec, Canada
    4. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    5. Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
    • Room L10-116, Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada
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    • Fax: (514) 934-8273

    • W.D.F. is a Chercheur Clinicien Boursier (J2) of the Fonds de la Recherche en Santé du Québec.


Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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). Cancer 2003;97:527–36. © 2003 American Cancer Society.

DOI 10.1002/cncr.11080

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