BRCA Genes Increase Breast Cancer Risks
The discovery of the BRCA1 and BRCA2 genes was an important milestone in breast cancer (and ovarian cancer) research. Women carrying inherited mutations in BRCA1 and BRCA2 have an extremely high lifetime risk for developing breast and/or ovarian cancer. Moreover, breast cancer occurs at an earlier age in mutation carriers, and a higher prevalence of adverse pathological features has been reported in breast cancers occurring in BRCA1 mutation carriers. For example, the Breast Cancer Linkage Consortium examined pathological features of breast cancer in women with BRCA 1 mutations and, when compared to controls, showed an excess of high grade tumors in BRCA 1 carriers. Another study among women of Jewish descent found that BRCA1-associated tumors were significantly more likely to be poorly differentiated and estrogen-receptor negative. These observations raise concern that that mutation-associated cancers are more aggressive and result in higher mortality rates. Thus far, studies examining the role of inherited mutations in BRCA 1 or BRCA2 in survival among patients with breast cancer have been small in size and conflicting in their findings.
In two recent European studies, women with BRCA1-associated tumors showed survival rates that were similar to or worse than sporadic cases, with a significantly increased risk of contralateral breast cancer. In contrast, previous studies have indicated that BRCA1 breast cancer patients may have a survival advantage compared with other breast and ovarian cancer patients. The prognosis for BRCA mutation carriers who develop breast cancer is important, because this knowledge may influence the management of women at risk. Additionally, if there are indeed differences in hereditary breast cancer that improve survival, we should elucidate the mechanism(s) that contribute to this advantage and apply the knowledge to the more common occurrences of breast cancer in the general population.
It is generally agreed that the discrepancies in these studies may be due to limitations in the study designs. In particular, the studies contain a relatively small number of BRCA carriers. Additionally, because of the extremely early age of onset of patients with BRCA mutations, it was not always possible to obtain controls who could adequately be matched for age. Lastly, there has been a technical limitation due to selection bias. Only with a large population-based study, in a defined subgroup can we begin to clarify these discrepancies.
Research on BRCA genes and Breast Cancer Risk at Columbia University Medical Center
Study Examines BRCA genes and Breast Cancer Survival
Columbia University Investigators studied breast cancer survival in relation to BRCA1 and BRCA2 genetic status. The study's purpose was to compare survival and tumor pathological differences in breast cancer patients with BRCA1 and BRCA2 mutations to those without hereditary mutations. The study was funded by The Women At Risk program at Columbia University Medical Center.
In this study, we used Columbia University Medical Center's large hospital-based breast tumor registry and bank to investigate the effect of the three founder mutations in BRCA1 and BRCA2 on survival among Ashkenazi Jewish patients with breast cancer. The advantages of our study design were that:
- within the Ashkenazi Jewish population, a relatively large number of mutation carriers were identified more efficiently to estimate survival after cancer,
- selection bias was reduced because families were not selected for study by virtue of strong family history or early age of onset, but instead consecutive archived samples were analyzed, and
- all pathobiologic and clinical follow data were based on the experience of one large medical institution.
The study was a collaborative effort of the Cancer Genetics Program and the Departments of Surgery and Surgical Pathology. Over 700 archived breast tumor samples (from 1989-1997) were retrieved and recoded to remove all patient identifiers, and analyzed for BRCA1 and BRCA2 mutations. Histopathological and clinical information for each case was gathered and recoded to be used to compare the pathological characteristics and survival differences between the BRCA1 and BRCA2 mutation associated tumors and non-BRCA tumors.
The study found that women with BRCA1 mutations had a higher frequency of estrogen and progesterone-negative breast tumors, and had a higher incidence of cancer that spread to the lymph nodes, compared to patients without BRCA mutations. Those with mutations of BRCA1 or BRCA2 had a higher incidence of cancer in both breasts. However at 5 and 10 years after diagnosis, breast cancer patients with and without BRCA1/2 gene mutations had about the same survival rates.
Reference: El-Tamer MB, Russo D, Troxel A, Ditkoff B, Schnabel F, Mansukhani M. Survival and recurrence following breast cancer in BRCA-1 & 2 mutation carriers. Annals of Surgical Oncology 2004; 11:157-164.
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