Epidemiological Studies Of Familial Breast Cancer

Much of the impetus for breast cancer genetics has come from observations of families with extraordinary numbers of cases of the disease (5). These families have often been critical to the identification of the high-risk susceptibility genes. They are, however, less useful for evaluating the risks associated with a family history of breast cancer or with any particular gene, because they are not collected in a systematic fashion. To provide useful information for genetic counseling, risk estimates from epidemiological studies are required. Fortunately, many such studies have been conducted. Most are case-control studies that compare the family history of breast cancer in cases with the family history in controls. Other studies are cohort studies of relatives of breast cancer patients. These latter studies include those based on record linkage with national records, notably those done in Sweden, Iceland, and Utah, and they provide estimates that are free from any potential recall bias (8,9,17).

The largest systematic analysis of the risks associated with a family history of breast cancer was a combined analysis of 52 studies by the Collaborative Group on Hormonal Factors in Breast Cancer (1). The results from this study are broadly consistent with the results of other studies, but because the Collaborative Group study is larger, the risk estimates are more reliable. One potential concern is that most of these studies were retrospective case-control studies, raising the possibility that some of the difference is due to differential reporting of family history. However, very similar effects have been observed in cohort studies (8,9,17,18).

The Collaborative Group study estimated that a first-degree family history of breast cancer is associated with an approximately twofold risk of breast cancer. The relative risks associated with an affected mother and an affected sister were very similar (indicating little evidence for any recessive breast cancer susceptibility loci). An important observation was that the relative risk increases progressively with the number of affected first-degree relatives (Table 1).

For women with one affected relative, the risk is inversely related to the age at diagnosis of the breast. Note, however, that the increased risk is present at all ages, and there is no particular age below which the risk is more markedly increased. These observations are consistent with a model in which some predisposition genes confer higher relative risks at young ages.

Table 1 Estimated Risk Ratios for Breast Cancer

Risk ratio (95% FCI)

Table 1 Estimated Risk Ratios for Breast Cancer

Risk ratio (95% FCI)

Number of affected


1.0 (0.97-1.03)



1.80 (1.70-1.91)


2.93 (2.37-3.63)

3 or more

3.90 (2.03-7.49)

Age at diagnosis


2.91 (2.05-4.13)


2.53 (1.97-3.23)


2.13 (1.76-2.57)


1.84 (1.55-2.17)


1.99 (1.71-2.32)


1.53 (1.29-1.80)


1.46 (1.23-1.74)


1.61 (1.37-1.89)


1.64 (1.36-1.99)

Abbreviation: FCI, floating confidential internal. Source: From Ref. 1.

Abbreviation: FCI, floating confidential internal. Source: From Ref. 1.

A limitation of the Collaborative Group study is that it was only able to consider first-degree family history. However, the cohort studies from Utah and Iceland provide reliable data on more distant relatives and show a progressive decline in the risk with degree of relationship, so that the relative risk of breast cancer is approximately 1.5 for second-degree relatives of cases for example (19). This relationship is consistent with the hypothesis that the familial aggregation is driven by one or more susceptibility genes (20).

These risks are used as the basis for classifying women for management purposes. For example, according to the National Institute for Clinical Excellence guidelines in the United Kingdom, women with a first-degree relative affected below age 40, or two affected relatives at any age, are considered to be at "moderate" risk. Women with two affected first-degree relatives diagnosed under age 50 are considered to be at "high risk."

There is little consistent evidence that familial risks of breast cancer vary by histological type or grade. Some studies have suggested a strong familial association for lobular breast cancer, but this has not been substantiated (17). The familial risks extend to both ductal and lobular carcinoma in situ (21). There is also a strong familial association between breast cancer in males and breast cancer in the female relatives (22).

There is surprisingly little consistent evidence for the familial aggregation of breast cancer with other cancers, indicating that, to a large extent, susceptibility to breast cancer is site specific. The clearest evidence for clustering with another cancer type is for ovarian cancer for which the risk is approximately 30% higher in mothers and sisters of breast cancer cases (18). This clustering probably reflects the effects of mutations in the BRCA1 and BRCA2 genes that predispose to both these cancer types. Associations between breast cancer and colorectal cancer have been suggested but not proven.

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