FaCD Online Syndrome Fact Sheet

Last updated: 01 Sep 2008

Name: Breast Cancer, Familial Clustering of

Mode of Inheritance: multifact

OMIM number: 114480  

Tumor features

breast cancer
colorectal cancer
endometrial cancer
ovarian cancer (i.e. epithelial origin)
prostate cancer

Tumor features (possible)

juvenile papillomatosis of the breast

Non-tumor features

breast, proliferative disease
mutagen sensitivity, increased


Family History and Breast Cancer Risk
Given the high risk of breast cancer in women[1], familial occurrence of breast cancer is not rare. A family history of breast cancer has been reported in 14% to 30% of female breast cancer patients[2;3]. Familial male breast cancer is rare[4-6]. Having a relative with breast cancer is one of the strongest risk factors for this tumor[7-10]. A relative risk (RR) of 34.7 to develop breast cancer has been reported in monozygotic twins of women in whom breast cancer had occurred before age 35[11]. Although male breast cancer could instinctively be presumed to have a stronger genetic background, in general, the risk of breast cancer in women does not appear to depend heavily on the gender of their affected family member[12-15]. The Collaborative Group on Hormonal Factors in Breast Cancer re-analyzed data from 58,209 women with breast cancer and 101,986 women without the disease[44]. It concluded that eight out of nine women who develop breast cancer do not have an affected female first-degree relative; that most women who have first-degree relatives with a history of breast cancer will never develop breast cancer, and that most who do will be aged over 50 years at the time of diagnosis. In countries where breast cancer is common, the lifetime excess incidence of breast cancer was calculated to be 5.5% for women with one affected first-degree relative and 13.3% for women with two.

Other Cancers
Compared with the general population, breast cancer is also found more frequently in women with family history of ovarian, endometrial, colorectal and/or prostate cancer and vice versa [16-24]. One study reported a RR of 5.6 for parotid cancer in first-degree relatives of breast cancer patients[25]. Juvenile papillomatosis of the breast may be a marker for increased personal and familial breast cancer risk[43].

Risk Prediction Models
Depending on the number of affected relatives, the degree of kinship and the age at onset of the tumors, the empirical risk of developing breast cancer in a female relative may be close to 50 % (even higher if she already has children with breast cancer). Several models have been developed to estimate breast cancer risk in a specific family situation[21,26-33,46,47,50-51]. Those by Gail et al. [26-30], focussing on white females who are being examined annually, and by Claus et al.[21;31;32] are probably the ones most widely used in clinical practice. Users should be aware of the specific limitations of these models[33]. For example, the risk tables may need to be adapted for use in different countries and or ethnic groups[48] to account for differences in genetic background and exogenous risk factors[34]. The Claus model includes first and second degree relatives as opposed to the Gail model which looks at first degree relatives only which limits its discriminatory power[45]. However, the latter method also takes into account the risk factors of age at menarche, age at first live birth and number of previous biopsies. More advanced models have recently been published, like IBIS[49] and BOADICEA[50] that take into account more details from the family, which is especially usefull in the genetic counseling setting where usually more detailed family history is avaliable.

Given a positive or negative family history of breast cancer, other known risk factors may differ in their contribution to overall risk. Colditz et al[35] reported on an adverse effect of first pregnancy among women with a family history of breast cancer that was approximately 50 % greater in magnitude than among women without a family history. Past use of oral contraceptives and use of postmenopausal hormones and history of benign breast disease showed similar relative risks between the two groups. Sellers et al concluded the same with regard to hormone replacement therapy in women with a family history of breast cancer[36]. However, with respect to benign breast disease, Dupont et al[37] found that fibroadenomas have an increased effect on breast cancer risk in patients with a family history of breast cancer compared to patients without a family history of breast cancer. In addition, Skolnick et al[38] analyzed families with a clustering of breast cancer and suggested that genetic susceptibility may cause both proliferative benign breast disease and breast cancer in those kindreds. Among women aged 30-49 years, a family history of breast cancer was associated with an increased risk of ductal carcinoma-in-situ (DCIS), and among those aged 50 and older it was associated with an increased risk of both DCIS and invasive breast cancer[39]. Egan et al[40] demonstrated a stronger inverse association of high parity with breasts cancer risk in women who reported first-degree relatives with breast cancer compared with women who did not have affected first-degree relatives. In a study by Schouten et. al.[41], family history of breast cancer was not correlated with survival. When looking at predicting age at onset, de Bock et al[52] calculated in an unselected population of close to 2000 breast cancer patients that a family history of breast cancer, early age at diagnosis and bilateral disease was not strongly predictive of early onset breast cancer (positive predictive value of only 1% for breast cancer before the age of 30).

Molecular Background
Chromosomes of breast cancer patients (and some of their unaffected relatives) with a family history of breast cancer are more sensitive to the action of the mutagen bleomycin compared with sporadic breast cancer patients[42], hinting at the involvement of genes responsible for DNA repair. Polymorphisms/variants in a wide number have genes gave been associated with small to moderately increased breast cancer risk. Discussing these genes is beyond the scope of this synopsis.


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