Benign Breast Disease among First-Degree Relatives of Young Breast Cancer Patients

American Journal of Epidemiology ª The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org. Vol. 168, No. 3 DOI: 10.1093/aje/kwn133 Advance Access publication June 4, 2008 Original Contribution Benign Breast Disease among First-Degree Relatives of Young Breast Cancer Patients Lisbeth Bertelsen 1, Lene Mellemkjær 1, Eva Balslev 2, and Jørgen H. Olsen 1 1 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. 2 Pathology Department, Herlev Hospital, Herlev, Denmark. Received for publication January 9, 2008; accepted for publication April 22, 2008. Benign breast disease is associated with increased risk of breast cancer. To further clarify whether there is a genetic link between benign and malignant breast lesions, the authors identified 14,648 first-degree female relatives of 8,807 patients in whom breast cancer was diagnosed at <50 years of age by using Danish nationwide cancer and population registers. Hospital register data were used to follow the relatives for occurrence of benign breast disease from 1977 to 2003 and to calculate rates of benign breast disease in the general population of Danish women for comparison. Risk for relatives was increased for benign breast diseases (observed/expected ratio ¼ 1.54, 95% confidence interval: 1.42, 1.66), particularly for relatives aged <40 years. Higher risks were observed after breast cancer had been diagnosed in the family; however, an increased risk for relatives aged <50 years (observed/ expected ratio ¼ 1.24, 95% confidence interval: 1.02, 1.51) was present before breast cancer was diagnosed in the family. Enhanced surveillance of close relatives of breast cancer patients seems to be an important factor to address when investigating the association between benign breast disease and familial breast cancer. A genetic link between benign breast disease and breast cancer was indicated by our data but needs to be confirmed in future studies. breast diseases; breast neoplasms; Denmark; family; linkage (genetics); registries; women Abbreviations: CI, confidence interval; ICD, International Classification of Diseases; O/E, observed/expected. The importance of heritability in the etiology of breast cancer is extensively documented (1, 2). Several studies (3 6), although not all (7, 8), have shown that a family history of breast cancer is also a risk factor for benign breast disease. Particularly strong associations have been reported for benign breast disease in young relatives (3, 5) and for atypical hyperplasia (3), indicating the existence of a genetic link between benign and malignant disease. The results of the studies published so far, however, may have been influenced by recall bias in the assessment of family history or by increased surveillance for breast diseases in families with known breast cancer cases, both potentially leading to false-positive associations. Here, we report the results of a large, population-based record-linkage study from Denmark on the occurrence of epithelial benign breast diseases in female relatives of women with early-onset breast cancer assessed from national population and cancer registers. The study was designed specifically to determine the rates of hospital contacts due to epithelial benign breast disease both before and after breast cancer was diagnosed in the family to address the issue of increased surveillance of families with known breast cancer cases. MATERIALS AND METHODS Index patients From the Danish population of women born in 1935 or later, we previously identified 2,857 women diagnosed with breast cancer at less than age 40 years during 1943 1990 (9). Correspondence to Lisbeth Bertelsen, Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark (e-mail: lisbethb@cancer.dk). 261

262 Bertelsen et al. TABLE 1. Data on index patients diagnosed with breast cancer at age <40 years during 1943 1999 and at age 40 49 years during 1991 1999, Denmark Age at breast cancer diagnosis (years) This material was updated by including 1,239 cases diagnosed during 1991 1999, for a total of 4,096 breast cancer cases diagnosed at less than age 40 years during 1943 1999 (table 1). In addition, we included 4,772 women diagnosed with breast cancer when they were 40 49 years of age during 1991 1999 (table 1). We restricted year of diagnosis for this age group because of constraints regarding the possibility of identifying relatives of older subjects in the Central Population Register (described below). Patients with breast cancer were identified from the files of the Danish Cancer Register on the basis of the International Classification of Diseases (ICD), Seventh Revision, code for breast cancer (ICD-7, code 170). For each patient, the register provided name, date of birth, and personal identification number. Completeness of registration of breast cancer in the Danish Cancer Register has been found to be 100 percent (10). Identification of female relatives Year of diagnosis of breast cancer <1991 1991 1999 The Central Population Register was established in Denmark on April 1, 1968, and includes all Danish inhabitants alive on this date or born thereafter who are assigned a unique personal identification number, which incorporates sex and date of birth and enables accurate linkage of information between registers. The Central Population Register maintains a cross-reference between parents and children for children born since the 1950s. The mothers of the 2,857 index patients younger than age 40 years diagnosed in 1943 1990 were identified by a computerized search of the Central Population Register using the personal identification number or, if this search was unsuccessful, by manual searches of relevant local parish and/or population registers. For nine women who died before 1968 and thus had no Central Population Register records, only manual searches were performed. The sisters of the patients were also located in the Central Population Register by use of the personal identification number of the mother or from local All No. % 10 14 1 0 1 0.0 15 19 2 0 2 0.0 20 24 40 10 50 0.6 25 29 268 93 361 4.1 30 34 807 344 1,151 13.0 35 39 1,739 792 2,531 28.5 All <40 2,857 1,239 4,096 46.2 40 44 1,728 1,728 19.5 45 49 3,044 3,044 34.3 All 40 49 4,772 4,772 53.8 All ages 2,857 6,011 8,868 100.0 population registers. Details of these procedures are given elsewhere (2). Family members of patients younger than age 40 years diagnosed in 1991 1999 were traced through the Central Population Register only. The mother was identified for 80 percent of the index patients in this group. For patients who were 40 49 years of age at diagnosis of breast cancer, family data were also available from only the Central Population Register. To avoid inclusion of too many patients without data on mother/sister in the Central Population Register, we restricted the years of breast cancer diagnoses to 1991 1999 for these patients. The search in the Central Population Register provided us with approximately 70 percent of the mothers of index patients born in the mid-1950s until 1959; for the subgroup of patients born before this period, a reference to their mother was provided for 10 percent. Daughters of all the breast cancer patients included were located through the Central Population Register by use of the personal identification numbers of the patients (except for the nine index patients who died before 1968, for whom searches for daughters were not performed). An overview of birth years and years of diagnosis of breast cancer in index patients is given in figure 1 (separately for those aged <40 years and those aged 40 years) as well as birth years for the relatives. Linkage of relatives to the files of the Central Population Register and the Danish mortality files provided the date of death or date of emigration, whichever was applicable. Probands and first-degree relatives To unambiguously define first-degree relatives of patients with early-onset breast cancer, we had to define the proband of the family. If the index patient was the only female member of the nuclear family who was affected by early-onset breast cancer, she became the proband. The search for family members revealed, however, that 49 pairs of the earlyonset breast cancer patients were sisters and 12 were mother-and-daughter pairs. In these 61 families, the woman whose breast cancer was diagnosed earliest was regarded as the proband. Thus, the 8,868 early-onset breast cancer patients were distributed in 8,807 different families. In these families, 15,311 female relatives (mothers, sisters, and daughters) were identified, of whom 14,648 (3,872 mothers, 3,043 sisters, and 7,733 daughters) were alive and free of breast cancer on January 1, 1977, when the Danish National Hospital Register was established. Table 2 gives selected information on the groups of female relatives. Follow-up for benign breast disease By use of the personal identification number, the relatives were linked to the files of the Danish National Hospital Register, which was instituted on January 1, 1977, and contains information on almost all hospitalizations for somatic diseases in Denmark (11). Since January 1, 1994, inpatient registration has been supplemented by information from outpatient visits. Each hospital visit initiates a record, which is flagged by the personal identification number and includes dates of admission and discharge, start and end dates

Familial Breast Cancer, Benign Breast Disease 263 FIGURE 1. Overview of how data on index patients and their first-degree female relatives and data from registries are distributed over calendar time, Denmark. of outpatient visits, one primary discharge diagnosis, and supplementary diagnoses. The diagnoses were coded according to a Danish version of the ICD, Eighth Revision (ICD-8) until the end of 1993 (12, 13) and according to the ICD, 10th Revision (14) thereafter. In the category of epithelial benign breast disease, we included benign breast tumor including fibroadenoma (ICD-8 code 217.1-9; ICD-10 code D24.9), fibroadenomatosis or other benign disorders of the breast (ICD-8 code 610.00; ICD-10 codes N60.2-3, N60.8-9), and benign breast cysts (ICD-8 codes 610.01, 610.08-09; ICD-10 codes N60.0-1, N60.4). From 1994 onward, we also included breast tumor, not otherwise specified (ICD-10 code N63.9). Follow-up of mothers, sisters, and daughters extended from January 1, 1977, or their 18th birthday, whichever occurred last, until the date of an epithelial benign breast disease or the censoring date defined as the date of breast cancer diagnosis, date of death, date of emigration, or the end of the study on December 31, 2003, whichever occurred first. If a woman had more than one diagnosis of benign breast disease, only the first diagnosis was counted. Both inpatient and outpatient diagnoses were included. Benign breast disease diagnosed less than 1 month before a diagnosis of breast cancer was disregarded in all analyses. The Danish Pathology Data Bank was used to validate the diagnoses of benign breast disease in the National Hospital Register. The Pathology Data Bank contains diagnoses coded according to a Danish modified version of the Systematized Nomenclature of Medicine (SNOMED) (15) since the early 1970s, with increasing coverage over time (16). An overview of the calendar years covered by the data from the various registers used (Central Population Register, Hospital Register, Pathology Data Bank) is shown in figure 1. Statistical analysis Occurrence of benign breast disease among the female relatives of women with early-onset breast cancer was compared with that for Danish women in general. Thus, for all women in Denmark who were free of breast cancer, we used information on inpatients and outpatients in the Danish National Hospital Register to calculate the rates for benign breast disease in 5-year age groups and calendar periods of

264 Bertelsen et al. TABLE 2. Numbers of first-degree female relatives of patients diagnosed with breast cancer at age <50 years, Denmark Relationship Numbers located Died/ emigrated Vital status and breast cancer status in 1977 Had breast cancer Were alive and breast cancer free Year of birth (range) Mothers 4,351 308 166 3,877* 1891 1954 Sisters 3,184 135 6 3,043 1914 1986 Daughters 7,776 43 0 7,733 1953 2003 All female relatives 15,311 486 172 14,648 1891 2003 * Five mothers, each the mother of two breast cancer patients (half-sisters), were counted only once. observation covering the study period 1977 2003. These age- and period-specific rates were applied to the appropriate person-years of observation to obtain the expected number of benign breast disease cases among the relatives. Ratios of observed to expected (O/E) cases of benign breast disease, and 95 percent confidence intervals, were computed on the assumption that the observed numbers followed a Poisson distribution. Risk analyses were stratified by type of familial relationship (mother, sister, or daughter), and outcomes were categorized according to age at diagnosis of benign breast disease (18 29, 30 39, 40 49, or 50 years). Risks of benign breast disease for relatives were also estimated separately for the periods preceding the date of diagnosis of early-onset breast cancer and for periods following that date. Finally, absolute measures were derived as the difference between the observed and expected rates (excess risk) of benign breast disease among relatives, and the associated attributable risk percentages were calculated as the excess risk divided by the observed rate. The latter gives an estimate of the percentage of cases of benign breast disease in relatives attributed to genetic factors shared by family members under the assumption that the association is causal. RESULTS For the 14,648 first-degree female relatives included in the study, 229,268 person-years of follow-up were accrued (median: 17 years; minimum: 8 days; maximum: 27 years). Overall, in the Hospital Register, we identified 634 female relatives with a diagnosis of benign breast disease during follow-up. Of these women, 45 percent (n ¼ 287) had an informative pathology record in the Pathology Data Bank within 2 months before or after the hospital diagnosis showing either no malignancy (n ¼ 65) or specific histologic information (n ¼ 222). Of the records that included histologic information, 91 percent (n ¼ 203) confirmed the diagnosis of a benign breast disease of epithelial origin. While the observed number of women with a hospital diagnosis of benign breast disease was 634, the expected number was 412.3, yielding a significantly increased O/E ratio of 1.54 (95 percent confidence interval (CI): 1.42, 1.66) and an excess risk of 9.7 cases of benign breast disease per 10,000 person-years at risk (table 3). The pattern of risk of benign breast disease by age of the relatives was quite similar for relatives of probands aged less than 40 years and relatives of probands aged 40 years or older at breast cancer diagnosis. The observed and expected rates of benign breast disease in relatives were clearly highest in the age range 30 49 years, while the relative risks of benign breast disease were highest in the age range 18 39 years. For the age group 40 years or older, the relative risks were only slightly increased. The relative risk was higher for the daughters (observed number ¼ 257; O/E ratio ¼ 1.87, 95 percent CI: 1.65, 2.11) than for the sisters (observed number ¼ 240; O/E ratio ¼ 1.48, 95 percent CI: 1.30, 1.68), with the lowest risk for the mothers (observed number ¼ 137; O/E ratio ¼ 1.21, 95 percent CI: 1.02, 1.43). However, stratification on age at diagnosis of benign breast disease in the relatives revealed that this ranking entirely reflected the age composition of the three groups of relatives (daughters: 99 percent of person-years at ages <40 years; sisters aged <40 years: observed number ¼ 116; O/E ratio ¼ 1.80, 95 percent CI: 1.49, 2.17; sisters aged 40 years: observed number ¼ 124; O/E ratio ¼ 1.27, 95 percent CI: 1.06, 1.33; mothers: 98 percent of person-years at ages 40 years). In a subanalysis, we estimated the relative risk of benign breast disease for female relatives before and after the date of diagnosis of the proband s breast cancer (table 3). A total of 80,141 person-years at risk among relatives were accumulated prior to the date of diagnosis of breast cancer in the proband, and 149,127 person-years were accumulated after that date. The risk of benign breast disease in relatives was significantly increased after the date of breast cancer diagnosis in the proband (O/E ratio ¼ 1.70, 95 percent CI: 1.55, 1.86) and borderline significantly increased before this date (O/E ratio ¼ 1.15, 95 percent CI: 0.97, 1.36). The excess risk of benign breast disease prior to the date of early-onset breast cancer in the family was 2.3 cases per 10,000 personyears, with an attributable risk percentage of 13. The O/E ratio before the date of the proband s breast cancer diagnosis was 1.24 (95 percent CI: 1.02, 1.51) among relatives aged 18 49 years. After the date of the proband s breast cancer diagnosis, the risk was twofold and was significantly elevated for relatives aged 18 39 years, whereas the risk was 1.3-fold and borderline significantly elevated for those in older age groups (table 3).

Familial Breast Cancer, Benign Breast Disease 265 TABLE 3. Denmark Risk of BBD* in first-degree relatives of breast cancer patients diagnosed at age <50 years, Relatives and age at risk of BBD (years) No. of personyears No. of BBD cases Rates per 10,000 person-years O/E* ratio 95% CI* Observed Expected Excess risky AR%*,z All female relatives 229,268 634 27.7 18.0 1.54 1.42, 1.66 9.7 35 Of probands aged <40 163,555 440 26.9 18.3 1.47 1.34, 1.62 8.6 32 years at breast cancer diagnosis Age at risk of BBD (years) 18 29 40,445 80 19.8 11.0 1.79 1.42, 2.23 8.8 44 30 39 28,360 139 49.0 26.2 1.87 1.57, 2.21 22.8 47 40 49 24,008 109 45.4 36.2 1.25 1.03, 1.51 9.2 20 50 70,743 112 15.8 13.1 1.21 0.99, 1.45 2.7 17 Of probands aged 40 years at breast cancer diagnosis 65,713 194 29.5 17.3 1.71 1.48, 1.96 12.2 41 Age at risk of BBD (years) 18 29 38,564 99 25.7 13.9 1.84 1.50, 2.24 11.7 46 30 39 9,899 60 60.6 29.8 2.04 1.55, 2.62 30.8 51 40 49 3,242 17 52.4 40.9 1.28 0.75, 2.06 11.6 22 50 14,010 18 12.8 12.2 1.05 0.62, 1.66 0.6 5 Person-years before breast 80,141 141 17.6 15.3 1.15 0.97, 1.36 2.3 13 cancer in proband Age at risk of BBD (years) 18 39 38,707 55 14.2 11.4 1.25 0.94, 1.63 2,8 20 40 49 10,556 47 44.5 36.5 1.22 0.90, 1.62 8.0 18 50 30,878 39 12.6 12.9 0.98 0.70, 1.34 0.3 2 Person-years after breast 149,127 493 33.1 19.4 1.70 1.55, 1.86 13.6 41 cancer in proband Age at risk of BBD (years) 18 39 78,559 323 41.1 20.1 2.04 1.83, 2.28 21.0 51 40 49 16,694 79 47.3 37.0 1.28 1.01, 1.60 10.4 22 50 53,875 91 16.9 13.0 1.30 1.04, 1.59 3.9 23 * BBD, benign breast disease; O/E, observed/expected; CI, confidence interval; AR%, attributable risk percentage. y Difference between observed and expected rate per 10,000 person-years. z Excess risk divided by the observed rate. DISCUSSION In this large, population-based follow-up study, we found that first-degree relatives of patients with early-onset breast cancer had significantly higher rates of hospital-based diagnoses of benign breast disease than women in the general population. The increase was clearest for daughters and sisters less than 40 years of age and after the date of diagnosis of breast cancer in the family. However, a significantly increased rate was also observed before the proband s diagnosis of breast cancer among relatives younger than age 50 years. Our overall findings of higher rates of benign breast diseases among women with a family history of breast cancer are in agreement with the results of a recent prospective cohort study of approximately 81,000 female nurses, which showed a significantly increased incidence of both self-reported physician diagnoses (rate ratio ¼ 1.38) and self-reported biopsy-confirmed diagnoses (rate ratio ¼ 1.67) of benign breast diseases among women reporting a family history of breast cancer at baseline compared with women who had reported no family history of breast cancer (3). Among women with proliferative disease, those with a family history were more likely than those with

266 Bertelsen et al. no family history to have atypical hyperplasia (3). Two casecontrol studies (4, 5) showed a positive association between a family history of breast cancer and the occurrence of benign breast disease, although, in one of the studies (5), the association was significant for premenopausal cases only. In two case-control studies (7, 8), the association was within the limits of chance; however, one of these studies included only breast cysts. A Japanese case-control study (6) reported that proliferative disease, but not nonproliferative disease, was associated with a positive family history of breast cancer in a mother or a sister. The results of the case-control studies were based on few cases, and the information on a family history of breast cancer was obtained by participant self-reports. The latter opens up the possibility of recall bias because the information was obtained from women after they had received a diagnosis of benign breast disease, except in the Japanese study (6). In the prospective study (3), the number of benign breast disease cases might have been falsely inflated because of increased surveillance of women who reported the occurrence of breast cancer in the family at baseline. More concern for and among young relatives in such families might also possibly explain why the association was strongest at young ages. In contrast to previous studies, we were able to estimate the risk of relatives receiving a hospital diagnosis of benign breast disease both before and after the breast cancer appeared in the family, thereby revealing any major effect of surveillance. Our results show a certain influence of enhanced surveillance because the excess was most pronounced after a family member received a diagnosis of breast cancer. However, among the youngest women, the incidence rate of benign breast disease was also significantly increased before the date of diagnosis, suggesting a genuine association between benign breast disease and a family history of breast cancer. If so, the aggregation of especially young benign breast disease cases in these families marked by early-onset breast cancer indicates a potential role of genetic factors. This prospect is supported by the results of methodical examinations of breasts removed prophylactically from carriers of mutations in the breast-cancerpredisposing genes, BRCA1 and BRCA2, which revealed high frequencies of both malignant and benign lesions (17). However, common risk factors for benign breast disease and breast cancer, including parity and age at birth of the first child (4, 6, 8, 18), may also contribute to familial aggregation. The strengths of our study include its size and the cohort design; the population-based approach, with unbiased identification of probands and female relatives from the combined use of national cancer and population registers; and hospital-based ascertainment of benign breast disease. In particular, we were able to estimate the rates of benign breast disease before the date of diagnosis of breast cancer in the family, approximately one third of the total number of person-years at risk occurring in the prediagnostic period. Although we restricted the years of breast cancer diagnoses to 1991 1999 for index patients diagnosed with breast cancer at ages 40 49 years, tracing of mothers and sisters for this group was incomplete. The main effect of this, however, should be reduction of sample size for relatives. It should not affect the validity of the findings because lack of the mother-daughter link in the Central Population Register is unlikely to be related to registration of benign breast disease among relatives in the Hospital Register. In relation to registration of diagnoses of benign breast disease in the Hospital Register, a higher degree of completeness was achieved when diagnoses made at outpatient visits were added to the register after 1994. Another limitation of our study is the use of diagnostic information on benign breast disease from a hospital register instead of pathology data. Validation was possible for only a subset of the hospital diagnoses, mainly because the Pathology Data Bank has not been complete over time. However, for diagnoses that could be validated by use of the Pathology Data Bank, the pathology record confirmed that more than 90 percent of the cases of benign breast disease were of epithelial origin. 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