Abstract
It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.
Original language | English |
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Pages (from-to) | 375-384 |
Number of pages | 10 |
Journal | Breast Cancer Research and Treatment |
Volume | 140 |
Issue number | 2 |
DOIs | |
Publication status | Published - Jul 2013 |
Bibliographical note
Funding Information:Acknowledgements We are indebted to the women who participated in the family studies at the Icelandic Cancer Society, Prof. Helga M. Ogmundsdottir and Dr. Tryggvi Thorgeirsson for inspiring and constructive discussions and Holmfridur Hilmarsdottir for mutation analyses. This study was supported by the Icelandic Cancer Society and the US Army Medical Research Acquisition Activity (DAMD17-97-1-7002 and DAMD17-99-1-9216).
Other keywords
- BRCA2 mutation
- Breast cancer
- Ploidy
- Prognostic factors
- Survival