A population-based assessment of the clustering of breast cancer in families eligible for testing of BRCA1 and BRCA2 mutations

J. Lorenzo Bermejo1,* and K. Hemminki1,2

1 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; 2 Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden

* Correspondence to: Dr J. Lorenzo Bermejo, Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany. Tel: +49-6221-421805; Fax: +49-6221-421810; Email: j.lorenzo{at}dkfz.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The prevalence of families eligible for BRCA1/2 mutation testing in the population burden of breast cancer was analysed and the aggregation of breast cancer in these families was explored.

Patients and methods: The families of the Swedish Family-Cancer Database with at least three generations (N=944 723) were classified according to the criteria proposed by the German Consortium for Hereditary Breast and Ovarian Cancer for BRCA1/2 mutation testing. We calculated the proportion of women with breast cancer in the classified families and used standardised incidence ratios (SIRs) to estimate the risk of histology specific breast cancers in families with suspected BRCA1/2 mutations.

Results: Families with two breast cancers before the age of 50 years included 1.8% of the breast cancer patients; 1% of the women with breast cancer belonged to families with breast and ovarian cancers. The SIR of female breast cancer was lowest in families with male breast cancer and highest in families with two women affected by breast cancer under the age of 50 years. The SIRs of medullary breast cancer agreed with the BRCA1 mutation prevalences detected by the German Consortium for Hereditary Breast and Ovarian Cancer.

Conclusions: Most of the breast malignancies in families with male breast cancer are likely to be related to BRCA2 mutations. Non-BRCA1/2 related effects are probably involved in the strong clustering of breast cancer in families with early onset breast and ovarian cancers.

Key words: BRCA1, BRCA2, clinical criteria, mutation testing


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Germline mutations in BRCA1/2 substantially increase the lifetime risk of developing breast and ovarian cancer. In a combined analysis of 22 studies, Antoniou et al. [1Go] reported cumulative risks for breast cancer by the age of 70 years of 65% in BRCA1 and 45% in BRCA2 mutation carriers. However, the contribution of BRCA1/2 mutations to breast cancer is limited. For example, Loman et al. [2Go] detected mutations in only 22 (9.4%) of 234 Swedish women diagnosed with breast cancer before the age of 41 years. The majority of women with a family history of breast/ovarian cancer do not carry BRCA1/2 mutations [3Go, 4Go]. Breast cancer histologies probably vary, depending on the presence of BRCA1/2 mutations. Medullary or atypical medullary carcinoma has been found more often in BRCA1 (13%) mutation carriers than in BRCA2 mutation carriers (3%) or controls unselected for family history (2%) [5Go]. Invasive lobular breast cancer may be more common in non-BRCA1/2 families than among BRCA1 mutation carriers [6Go]. Data on histological differences among breast cancers associated with specific familial histories of breast/ovarian cancer are sparse and may help to identify new, non-BRCA-related components of familial breast cancer.

Criteria based on a familial history of breast and ovarian cancer are the most common tool used to recommend individuals for genetic testing of BRCA1/2 germline mutations [7Go]. The German Consortium for Hereditary Breast and Ovarian Cancer (GCHBO) recently classified 989 individuals according to their family history of breast/ovarian cancer [8Go]. Similar criteria of classification have been used by Verhoog et al. and by the National Comprehensive Cancer Network [9Go, 10Go]. However, only fragmentary data are available on the true population-level frequencies of families that fulfil the criteria for mutation testing [11Go]. Family histories are not uniformly recorded in the clinics and they are based on patients’ recall, which may be inaccurate [11Go]. Thus, in order to present the full scope of familial breast cancer and the needs for mutation screening services, population-based data are needed on the proportions of families with familial breast cancer, classified according to the criteria used for mutation testing, and on the clustering of breast cancer in such families.

In this study, we apply the criteria used by the GCHBO for recommending BRCA1/2 mutation testing to classify the families of the nationwide Swedish Family-Cancer Database. Our purpose is to analyse the prevalence of the classified families at the population level and to explore the aggregation of breast cancer in families eligible for mutation testing. The Swedish Family-Cancer Database offers unique possibilities for a reliable estimation of risk in the classified families since the data on family relationships and cancers are obtained from registered sources of practically complete coverage and are free from bias [12Go].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The Swedish Family-Cancer Database was created in the middle of the 1990s by linking census information, death notifications and the administrative family register at Statistics Sweden to the Swedish Cancer Registry. The Database includes all persons who were born in Sweden after 1931 with their biological parents. The Database was updated at the end of 2002 to include more than 10.2 million individuals. The Swedish Cancer Registry relies on separate compulsory notifications of cases from clinicians who diagnosed a neoplasm and from pathologists/cytologists. A four-digit diagnostic code according to the 7th revision of the International Classification of Diseases (ICD-7) and subsequent ICD classifications are available. Because cancer histology has been recorded according to the Systematised Nomenclature of Medicine [13Go] since 1993, the analysis of histology-specific breast carcinomas has considered diagnoses between 1993 and 2000. The percentage of histologically or cytologically verified cases of cancer has been close to 100% [14Go].

The families in the Database were identified by their founder parents. If a founder parent of the family was missing or if she had married several times, the family was excluded. Only families in the Database with at least three generations were considered in this study. Overlap between families was possible, e.g. individuals in the fourth generation belonged to four different families. The families were classified according to the clinical criteria proposed by the GCHBO, as described in Table 1. These criteria considered bilateral breast cancers as two independent cases. ‘Breast and ovarian cancer families’ were those families with at least one breast cancer patient and at least one ovarian cancer patient. This study also analysed separately the families with two affected members under the age of 50 years and the families with bilateral breast cancer before the age of 50 years.


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Table 1. Classification criteria used by the German Consortium for Hereditary Breast and Ovarian cancer (GCHBO) and BRCA1/2 mutation rates in the classified families

 
The median number of individuals and the median number of individuals older than 50 years were used to summarise the size of the families. The relevance of the classified families in the population burden of breast cancer was assessed by the percentage of breast/ovarian cancers within those families. The number of families that fulfilled two sets of criteria and the distribution of breast/ovarian cancer patients in families eligible for BRCA1/2 mutation testing were also investigated. The risk of developing female breast cancer before the age of 50 in the absence of other causes of death was estimated by dividing the number of cases of breast cancer diagnosed under the age of 50 by the number of women who reached this age. Women who emigrated before the age of 50, women younger than 50 years by 2000, women diagnosed with cancer at sites different from the breast before the age of 50 and women who died from other causes before this age were excluded from the denominator. The same procedure was used to calculate the percentage of women with breast cancer by the age of 70 years.

The BRCA1/2 prevalences from the GCHBO study [8Go] and the average risks associated with BRCA1/2 mutations estimated by Antoniou et al. [1Go] were used to calculate the cumulative risks of breast cancer attributable to BRCA1/2 mutations in families eligible for mutation testing. For example, 24% of the families with two cases of breast cancer under the age of 50 years had BRCA1 mutations and 13% of those families showed BRCA2 mutations in the GCHBO study. The average cumulative risks of breast cancer by age 70 years estimated by Antoniou et al., 65% in BRCA1 and 45% in BRCA2 mutation carriers, would result in 24•0.65 + 13•0.45 = 21.45% of the women affected with breast cancer by age 70 years in families with two cases of breast cancer before age 50 years.

The standardised incidence ratio (SIR) was used to estimate the relative risk of breast cancer in the classified families. The relative risk for women with a first-degree relative affected by breast cancer was based on women from the second generation because information on mothers and sisters was only available for those women. Follow-up started at birth, immigration date or first year of the study (1961 or 1993 for histology-specific cancers), whichever came latest. Follow-up terminated at diagnosis of cancer, death, emigration date or 31 December 2000. The SIR was calculated as the ratio of observed to expected number of cases. The expected numbers were computed from age- (5-year bands), parity- (six groups from ‘any parturition’ to ‘more than five parturitions’), socioeconomic status- (six groups), age at first birth- (five groups, 5-year bands between ‘before age of 20’ and ‘after age of 35’) and residential area- (four groups) standardised incidence rates. The confidence intervals (95% CI) were calculated assuming a Poisson distribution [15Go]. The distribution of histology-specific breast cancers among individuals with a first-degree relative affected by breast cancer and for members of the classified families was also calculated.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Table 2 presents the number and size of the families that fulfilled the GCHBO criteria for the testing of BRCA1/2 mutations. The ‘general population’ analysed in this study (N=944 723 families) had a median family size of nine persons; the median number of family members who reached the age of 50 years was three. The most stringent criteria required that two family members were affected by breast cancer before the age of 50 years; only 345 families fulfilled these criteria. In contrast, two breast cancers were diagnosed after the age of 50 in 3130 families. Families that fulfilled the criteria were slightly larger than families from the general population. The percentage of cases of breast cancer in the classified families varied from 0.6% in families with male breast cancer, to 5.5% in families with two cases of breast cancer after the age of 50. Families that fulfilled any of the classification criteria included 14% of the cases of breast cancer, i.e. the impact of the follow-up of women in those families, which would generally lead to 8047 genetic tests being carried out in a population of one million families, would be limited to 14% of the cases of breast cancer. The percentage of cases of ovarian cancer in families with breast and ovarian cancers was 4.8%.


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Table 2. Number, proportion and size of the families that fulfilled the criteria for testing of BRCA1/2 mutations, and percentage of cases of breast and ovarian cancer within the classified familiesa

 
The number of families that fulfilled two different sets of criteria was relatively small (Table 3). For example, among the 915 families with two cases of breast cancer under the age of 50, no male was affected by breast cancer, 31 families presented with breast and ovarian cancers, and breast cancer under the age of 35 years was found in 178 families. Families with two cases of breast cancer could be divided into two different, almost non-overlapping groups: those with two women affected by breast cancer before the age of 50 (345 families) and those with bilateral breast cancer under the age of 50 years (610 families).


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Table 3. Number of families that fulfilled two sets of criteria for testing of BRCA1/2 mutationsa

 
The relationship among the affected members in families that fulfilled the GCHBO criteria is presented in Table 4. This classification counted bilateral cancers as two independent cases. In more than 50% of the 915 families with two cases of breast cancer under the age of 50, only one member had breast or ovarian cancer; 228 families included affected mother–daughter pairs and affected sister-pairs were found in 132 families. Among the 426 families with male breast cancer, 371 (87% of the families) showed only one case of breast cancer. Of the 720 families with both breast and ovarian cancers 76.2% included parent–offspring pairs affected by breast/ovarian cancer and 11.9% of these families included affected sibling-pairs. We found some families with affected members in the first and third generations, but without cases of breast/ovarian cancer in the second generation: eight families with two cases of breast cancer under the age of 50 years, 27 families with male breast cancer and 42 families with both breast and ovarian cancers.


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Table 4. Distribution of breast and breast/ovarian cancer patients in families that fulfilled the criteria for testing of BRCA1/2 mutationsa

 
The percentage of women with breast cancer by the age of 50 or 70 in families eligible for testing of BRCA1/2 mutations is presented in Table 5. The proportion of women with breast cancer by the age of 50 was highest (66%) in families with two members affected by breast cancer by age 50 years. In contrast, the percentage of women with breast cancer in families with male breast cancer was only 1.7%. The proportion of women diagnosed with breast cancer by the age of 70 was highest among families with two women affected by breast cancer under the age of 50 (84%) and in families with two cases of breast cancer, at least one of them diagnosed before the age of 50 (79%). Table 5 also shows the cumulative risks of breast cancer based on the literature data about BRCA1/2 mutation frequency and the percentage of breast cancer. Families with breast and ovarian cancers showed the highest cumulative risks of breast cancer attributable to BRCA1/2 mutations: 32% of the women in those families were affected by breast cancer by the age of 70 due to BRCA1/2 mutations.


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Table 5. Percentage of women with breast cancer in families eligible for BRCA1/2 mutation testing based on this study and cumulative risks of breast cancer attributable to BRCA1/2 mutations based on the literaturea

 
Table 6 shows the number of cases and the risk of breast cancer for women with first-degree relatives affected by breast cancer, and for women in families with suspected BRCA1/2 mutations. Among the 22 553 women affected by breast cancer in the second generation, 2835 (12.6%) had a first-degree relative affected by breast cancer. The SIR of breast cancer was significantly higher in families with two women diagnosed under the age of 50 (34.7, 95% CI 32.2–37.4) than for the other classified families. The SIR of female breast cancer was 14.0 (range 13.0–15.1) in families with breast and ovarian cancers. Female breast cancer was only marginally increased in families with male breast cancer.


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Table 6. Risk of breast cancer and of histology-specific breast cancer for women with first-degree relatives affected by breast cancer and for women in families that fulfilled the criteria for testing of BRCA1/2 mutationsa

 
SIRs and the distribution of histology-specific breast cancers in families that fulfilled the criteria for mutation testing are also presented in Table 6. Individuals with a first-degree relative affected by breast cancer showed the highest SIR for mucinous breast cancer (2.4, 95% CI 1.6–3.4) and the lowest significant SIR for tubular breast cancer (1.6, 95% CI 1.3–1.9); the differences among histological types were not statistically significant. In families with two cases of breast cancer under the age of 50, SIRs could be ranked as SIRmedullary > SIRcomedo > SIRpapillary > SIRtubular > SIRlobular > SIRductal > SIRmucinous. The rank in families with breast and ovarian cancers was SIRmedullary > SIRcomedo > SIRductal > SIRlobular > SIRtubular. Families with two affected women under the age of 50 did not show any papillary carcinomas.

Morbus Paget carcinomas and cystosarcomas phylloides were also analysed (results not shown). Four Morbus Paget carcinomas were found in families with breast cancer under the age of 35, five cases in families with two breast cancers, at least one of them under 50, and three Morbus Paget carcinomas occurred in families with two breast cancers diagnosed after the age of 50. Three cystosarcomas phylloides were found in families with breast cancer under the age of 35 years and two cases occurred in families with two breast cancers, at least one of them under the age of 50 years.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study classified 944 723 Swedish families according to the criteria for mutation testing proposed by the GCHBO. The first objective was to assess the prevalence of families eligible for BRCA1/2 mutation testing at the population level and as the proportion of the total breast cancer burden. The large number of cases analysed resulted in accurate risk estimates, even for uncommon breast cancer histologies. Most studies use interview data to classify families. For breast cancer such data appear to be reasonably reliable with probably little need for adjustment for ascertainment bias [16Go, 17Go]. In contrast, this study relied entirely on registered data. Another important feature of this study was the standardisation for age, parity and age of first birth in order to account for these effects in the classified families, thus yielding comparable SIRs. Only families with at least three generations were included in the study, but the maximum age of individuals in the second generation (68 years) was a limitation of this study.

Many types of data indicates genetic similarity between Germans and Swedes in relation to breast/ovarian cancer incidences [18Go] and BRCA1/2 mutation prevalences [2Go, 8Go, 19Go], which justify certain conclusions between the GCHBO study and this study. The cumulative risk of breast cancer has been estimated to be 0.97% by the age of 45 years, 2.8% by the age of 55 and 6.4% by the age of 65, in both Sweden and Germany [18Go]. According to the same source, the estimated cumulative risk of ovarian cancer in Sweden has been 0.18% by the age of 45 years, 0.39% by the age of 55 years and 0.90% by the age of 65 years. For Germany, the corresponding estimates have been very similar: 0.15%, 0.42% and 0.80%, respectively. Moreover, the frequencies of BRCA1 (22.6%) and BRCA2 (11.3%) mutation carriers among high-risk Swedish breast cancer families, reported by Hakansson et al. [19Go], are in concordance with the 21.4% BRCA1 and the 9.1% BRCA2 mutation carriers found by the GCHBO among the classified German families. Loman et al. [2Go] reported percentages of mutation carriers of 7.3% (BRCA1) and 2.1% (BRCA2) among 234 Swedish breast cancer patients diagnosed before the age of 41 years, which are also in agreement with the 8.8% BRCA1 and the 4.4% BRCA2 mutation carriers found by the GCHBO among 45 German patients diagnosed before the age of 35 years. Unfortunately, no information was available about the mutation status of the 75 606 breast cancer patients included in this study.

The definition of clinical criteria for genetic testing of BRCA1/2 mutations is a challenging issue. The proportion of cases attributable to BRCA1/2 mutations is limited, even in high-risk breast or ovarian cancer families, and the percentage of BRCA1/2 mutation carriers with a familial history of breast or ovarian cancer may, on average, be less than half [3Go]. The inclusion of second-degree relatives, as proposed by Sibert et al. [7Go], may result in improved classification criteria, but the proportion of identified BRCA1/2 mutation carriers will probably remain low. For example, among the 1008 Ashkenazi Jewish women diagnosed with cancer who were screened in a recent study, 52% of them had neither mother, sister, grandmother nor aunt with breast or ovarian cancer [20Go]. In this study, 12.6% of the women with breast cancer had a first-degree relative affected by breast cancer. The criteria that were associated with the highest BRCA1/2 mutation rates in the GCHBO study permitted classification of only 1.8% (two breast cancers under age 50) and 1% (breast and ovarian cancers) of the cases of breast cancer. These data show the limited percentage of breast cancers that are ascertained by familial criteria, even if the criteria are based on relatively loose familial relationships. The criterion ‘two breast cancers, at least one of them before age 50’ covered 4.9% of the breast cancers. This criterion is also included in the Practice Guidelines in Oncology of the National Comprehensive Cancer Network as suggestive of hereditary breast/ovarian cancer syndrome [10Go]. The GCHBO study found BRCA1/2 mutations in 21% of the families that fulfilled this criterion, but a lower prevalence of mutations (7.5%) among those families was reported by Frank et al. [21Go].

Among Swedish families, few of them fulfilled more than one set of criteria. The GCHBO counted bilateral breast cancer as two independent cases, but some differences were found among families with two women affected by breast cancer before the age of 50 years and those families that included bilateral breast cancer under the age 50 years. In 84.6% of the families with early bilateral breast cancer, only one woman had breast cancer. The percentages of women diagnosed with breast cancer by the ages of 50 and 70 years in families with two affected women under the age of 50 were significantly higher than the corresponding percentages for families with early bilateral breast cancer. The SIRs of ductal, lobular and tubular breast carcinoma were significantly higher in families with two women affected by breast cancer under the age of 50 years than in families with bilateral breast cancer before the age of 50. Therefore, the two classification criteria, which may result in different BRCA1/2-mutation prevalences, should be used separately in future studies.

The GCHBO found 42% BRCA1 and 10% BRCA2 mutation carriers in German families with both breast and ovarian cancers [8Go]. Families with those malignancies have shown 46% BRCA1 and 5.6% BRCA2 mutation rates in the Netherlands [9Go], 30% BRCA1 and 22% BRCA2 mutation rates in Finland [22Go] and 23% BRCA1 and 18% BRCA2 mutation rates in Spain [23Go]. The average risks associated with BRCA1/2 mutations [1Go] would result in 23%–32% of the women with breast cancer, but we found that 69% of the women had breast cancer by the age of 70 in families with breast and ovarian cancers. These data suggest that, in addition to BRCA1/2 mutations, other effects are involved in the aggregation of breast cancer in those families. Table 5 presents the cumulative risks of breast cancer attributable to BRCA1/2 mutations based on the BRCA1/2 prevalences from the GCHBO study [8Go] and the average risks associated with BRCA1/2 mutations estimated by Antoniou et al. [1Go]. According to these data, about 30% of the clustering of breast cancer in families with two breast cancers before age 50 years would be attributable to BRCA1/2 mutations. Most studies have identified BRCA2 mutations exclusively in families with male breast cancer, with prevalences ranging from 4% to 100% [21Go, 23Go–26Go]. In the GCHBO study, 23% of the families with male breast cancer showed BRCA2 and 2% of those families presented with BRCA1 mutations. Based on our data, BRCA2 mutations would explain most of the familial aggregation of breast cancer in families with male breast cancer, in contrast to the other families eligible for mutation testing.

Data on the association of BRCA1/2 mutations with specific histological types of breast cancers can be used to improve the criteria for mutation testing and may help to identify new heritable causes for breast cancer. The high SIRmedullary in this study was in agreement with the prevalences of BRCA1 mutations detected by the GCHBO; the SIRmedullary was 57.1 in families with breast and ovarian cancers (BRCA1 mutation rate 42%), 37.1 in families with two breast cancers before the age of 50 (BRCA1 mutation rate 24%) and 36.2 in families with two breast cancers, at least one of them before the age of 50 (BRCA1 mutation rate 18%). These data agree with earlier studies, which have found medullary carcinomas more often in BRCA1 than in BRCA2 mutation carriers or in other familial cancers [5Go, 6Go]. The association of mucinous carcinoma with familial breast cancer suggested by the Breast Cancer Linkage Consortium [5Go] was also corroborated in this study at a population level. We have shown that patients with a first-degree familial history of breast cancer showed the highest SIR for the mucinous histology. The number of histology-specific breast cancers in families with male breast cancer was small, but the distribution of ductal and lobular types in those families agreed with the findings of Lakhani et al. in BRCA2 mutation carriers [6Go]. However, Lakhani et al. did not find any tubular carcinomas, whereas we found two tubular breast cancers in families with male breast cancer. The SIRcomedo was significantly higher than the SIRductal in families with two cases of breast cancer under the age of 50 years, which may be associated with an increased prevalence of BRCA1 mutations among patients affected by comedo breast cancer. Contrary to the medullary histology, lobular breast cancer has been found more often in non-BRCA1/2 families than in BRCA1 mutation carriers [6Go]. Furthermore, lobular carcinomas are more likely to be oestrogen receptor positive, whereas BRCA1 tumours are mostly oestrogen receptor negative [27Go]. Families with both breast and ovarian cancer showed a SIRlobular lower than the SIRductal in this study, but the inverse relationship was observed in families with two cases of breast cancer before the age of 50. The lower prevalence of BRCA1 mutations found by the GCHBO in families with two breast cancers before the age of 50 years than in families with breast and ovarian cancers indicates that, in addition to BRCA1 mutations, other effects are probably involved in the aggregation of lobular breast cancer in families with two early breast cancers.

In conclusion, families that fulfilled the clinical criteria for BRCA1/2 mutation testing included a limited proportion of women with breast cancer: less than 1% of the women with breast cancer belonged to families with breast and ovarian cancers. Most of the breast malignancies in families with male breast cancer are likely to be related to BRCA2 mutations. In contrast, non-BRCA1/2 related effects are probably involved in the strong aggregation of breast cancer among families with early breast and ovarian cancers. This study confirmed the association between BRCA1 mutations and the medullary histology of breast cancer at a population level.


    Acknowledgements
 
The study was supported by Deutsche Krebshilfe and the Swedish Cancer Society. The Family-Cancer Database was created by linking registers maintained by Statistics Sweden and the Swedish Cancer Registry.

Received for publication June 23, 2004. Revision received August 31, 2004. Accepted for publication September 9, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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