Numerous high-risk epithelial lesions in familial breast cancer
Introduction
Little is known about the early stages of breast cancer development in women with a strong family history. This applies equally to those testing negative for a BRCA mutation and to those carrying a BRCA1 or a BRCA2 mutation. There might be differences in breast cancer development between BRCA1 and BRCA2 mutation carriers because the features of fully developed invasive breast cancers from BRCA1 and BRCA2 mutation carriers are different.1, 2, 3 Women with hereditary predisposition to breast cancer are prone to develop epithelial lesions that indicate a high risk of subsequent invasive breast cancer.4, 5, 6 These high-risk lesions include atypical lobular hyperplasia (ALH), atypical ductal hyperplasia (ADH), lobular carcinoma-in situ (LCIS) and ductal carcinoma-in situ (DCIS).4, 7
The options for women with a deleterious germline mutation in BRCA1 or BRCA2 to handle their high risk are either regular surveillance or prophylactic mastectomy. Bilateral prophylactic mastectomy in healthy women with a BRCA mutation is associated with a 90% reduction in breast cancer incidence.8, 9 When applied at young age, around or before the age of 40 years, this may lead to a significant survival advantage.10 This procedure is much less accepted for women who appeared to be negative for a BRCA mutation even though they have an apparent autosomal dominant family history for breast cancer.11, 12, 13, 14 Especially women with breast cancer at young age and a strong family history but without a BRCA mutation may want to opt for contralateral prophylactic mastectomy. While cancer-free survival is the ultimate test of effectiveness, a first indication may be gleaned from examining mastectomy specimens.
Information is lacking on whether the prevalence of high-risk lesions differs between women with and without a BRCA mutation. In a previous study by our group, of women at high hereditary risk of breast cancer, the prevalence of a BRCA mutation was lower in the group with high-risk lesions compared to the group without high-risk lesions.4 At that time the group that was tested negative for a mutation was not strictly defined and the groups with a BRCA1 or a BRCA2 mutation were too small to be studied separately. In the present study, we investigated the differences in prevalence of high-risk epithelial lesions in women with an exceptionally strong family history for breast cancer with and without a BRCA mutation, who chose for prophylactic mastectomy because of their high risk for breast cancer. These results may be relevant for breast cancer prevention in women with an autosomal dominant family history for breast cancer.
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Patient characteristics
Women at high hereditary risk of breast cancer, who underwent prophylactic mastectomy between 1989 and 2004 with and without previous breast cancer, were included. In case a woman had previous breast cancer, prophylactic mastectomy of the contralateral breast was performed. All women had extensive genetic counseling and were shown to have a strong family history for breast cancer, often in combination with ovarian cancer, suggestive for autosomal dominant transmission of the disease, occurring
Histological findings in women with a BRCA1 or a BRCA2 mutation
Eighty-two patients with a deleterious BRCA mutation underwent prophylactic mastectomy (68 BRCA1 mutation carriers and 14 BRCA2 mutation carriers). The total prevalence of all high-risk lesions in BRCA1 and BRCA2 mutation carriers was 44% versus 36% (p = 0.56), with ALH in 26% versus 21% (p = 0.69), ADH in 18% versus 14% (p = 0.70), LCIS in 16% versus 7% (p = 0.38) and DCIS in 9% versus 7% (p = 0.83), respectively.
Risk factors for breast carcinoma were documented at the time of mastectomy. The youngest
Discussion
We here show that women with an autosomal dominant family history for breast cancer that is not caused by a BRCA1 or BRCA2 mutation have an even higher prevalence of epithelial high-risk lesions than mutation carriers. Furthermore, the presence of high-risk lesions is associated with age; especially at age over 40 years a large number of women with and without a BRCA mutation have epithelial high-risk lesions. These epithelial lesions may predict the occurrence of subsequent invasive breast
Conflict of interest statement
None declared.
Acknowledgement
Prof. Dr. J.H. van Krieken, pathologist, generously contributed comments on the study.
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