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Originally published as JCO Early Release 10.1200/JCO.2007.14.3198 on June 30 2008 © 2008 American Society of Clinical Oncology. Breast Cancer Onset in Twins and Women With Bilateral Disease
From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet; Department of Surgery, South Hospital, Stockholm, Sweden; Department of Public Health, University of Helsinki; Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland; The Danish Twin Registry, University of Southern Denmark, Odense, Denmark; Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London; and the Section of Epidemiology, Institute of Cancer Research, Surrey, United Kingdom Corresponding author: Mikael Hartman, MD, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, 171 77 Stockholm, Sweden; e-mail: Mikael.Hartman{at}ki.se
Purpose Little is known of the onset of breast cancer in high-risk populations. We investigated the risk of breast cancer in twin sisters and in the contralateral breast taking family history into consideration. Patients and Methods We analyzed a Scandinavian population-based cohort of 2,499 female twin pairs, in which at least one had a diagnosis of breast cancer and estimated the risk of breast cancer in the sister. Using a total of 11 million individuals in Sweden with complete family links, we identified 93,448 women with breast cancer and estimated the risk of a bilateral breast cancer. Results The incidence of breast cancer in twin sisters of breast cancer patients was 0.64% per year and 0.42% per year in mono- and dizygotic twin sisters, respectively. In comparison, the risk of familial (affected first-degree relative) and nonfamilial bilateral breast cancer was 1.03% per year and 0.68% per year, respectively. Contrary to the risk of unilateral disease, the risk of cancer in the nonaffected twin and the opposite breast was not affected by age or time since first event. The relative risk of familial bilateral cancer was 52% higher (incidence rate ratio [IRR] = 1.52; 95% CI, 1.42 to 1.64) and the relative risk in the dizygotic twin sister was 25% lower (IRR = 0.75; 95% CI, 0.61 to 0.91) compared with the risk of nonfamilial bilateral cancer. Conclusion The elevated risk of breast cancer in high-risk groups is little affected by age and time since diagnosis. Our findings suggest that susceptible groups of women might have already aggregated genetic prerequisites for breast cancer.
Family history is a strong risk factor for breast cancer,1-3 and incidence patterns of bilateral disease and in patients’ twins are particularly informative in developing genetic models of breast cancer susceptibility.4 A small percentage of cases are carriers of BRCA1 or BRCA2, but the genetic basis of susceptibility in noncarriers is not yet known. The polygenic model, which assumes a large number of low-penetrance genes is now widely accepted,5 but only a few such polygenes have been identified.6 The risk of breast cancer in the opposite breast in women previously diagnosed with the disease (ie, bilateral breast cancer) is considered high,4 especially in women who have a family history of the disease.7 Similarly, the risk of breast cancer in twin sisters of women diagnosed with breast cancer has been reported to be substantial, and considerably higher in monozygotic twin sisters.8 The literature thus suggests a completely different incidence pattern for these high-risk groups compared with sporadic unilateral breast cancer,4,8,9 where the risk of unilateral cancer is much lower and highly age dependent. To date there have been no large population-based studies comparing bilateral cancer risk and breast cancer risk in twin sisters, especially since most familial studies have focused on the relative risk of disease rather than absolute risks.10 The etiology of bilateral disease is multifactorial, but there are interesting genetic similarities between a woman who develops a bilateral cancer and breast cancer among monozygotic twin sisters. A woman with bilateral disease is 100% genetically identical to herself, as are monozygotic twin sisters to each other, thus making a comparison between these two groups important. Our aim was to investigate the onset patterns of breast cancer in these high-risk sub-populations in relation to family history of the disease in large population-based studies, and to compare them against each other and the rate in the general population.
Study Cohort Twin cohorts. The twin cohorts have been described in detail previously.2 The Swedish Twin Register consists of two birth cohorts,11 of which the first was made up of 10,503 pairs of twins of the same sex who were born between 1886 and 1925, and who were alive in 1961. The second birth cohort comprises 12,883 twin pairs of the same sex, born between 1926 and 1958, who were living in Sweden in 1972. The Danish Twin Register was established in 1954 and holds data on more than 75,000 pairs of twins born in Denmark from 1870 to 2004.12,13 The register initially included all twins born in Denmark from 1870 through 191014 and was later expanded to include twins of the same sex born from 1911 through 1930.14-16 In the 1990s, the register was further expanded with twin pairs born from 1931 to 1982 utilizing information in the Danish Civil Registration System. The Finnish Twin Cohort was compiled from the Central Population Register in 1974. It includes 12,941 pairs of twins who were born from 1880 through 1958 and who were both living in Finland on December 31, 1975.17 Record linkages with national population and health registers including the national and essentially complete registers of migration, death and cancer18-22 were performed using unique personal identification numbers assigned to all residents of these three countries and provided excellent cancer and vital status information for all participants. Zygosity was determined by questionnaires that have been shown in validation studies for all three national cohorts to classify more than 95% of pairs of twins correctly.15,23,24 Until the end of follow-up (Sweden, 2002; Denmark, 1998; Finland, 2005) a total of 2,499 female twin pairs, with at least one having a diagnosis of breast cancer, were identified and included in our study. }Bilateral breast cancer cohort. In the Multigeneration Register, individuals born in Sweden in 1932 or later are registered with their biologic parents as 3.2 million families. Family history of breast cancer information was collected on all first-degree relatives and defined as the occurrence of at least one primary breast cancer in a first-degree relative. The Swedish Cancer Register holds information on date and side of the primary breast cancer, but no information is available on stage, treatment, or type of surgery. A total of 93,448 women with breast cancer of whom 6,110 had a family history of breast cancer recorded at any time in the register were identified and included in our study. A bilateral breast cancer was defined as a second primary breast cancer in the opposite breast. Bilateral breast cancers diagnosed within 3 months of primary cancer were categorized as synchronous bilateral breast cancers, and the remainder as metachronous disease.4,25 Women having only cancer in situ were not included in the study, and the event of an in situ breast cancer diagnosis in women with invasive disease was ignored.
Statistical Methods The incidence rate of bilateral breast cancer was calculated as the ratio of the number of second breast cancers to the accumulated person-years at risk among women who have a diagnosis of a primary breast cancer. The person-time at risk started at the date of diagnosis of first breast cancer and continued until the date of diagnosis of bilateral breast cancer or of any other malignant disease, emigration, death, or end of follow-up (December 31, 2002), whichever came first. The incidence rate of unilateral breast cancer was calculated as the ratio of the number of first primary breast cancers to the accumulated person-years at risk among the entire Swedish female population. We used Poisson regression to model the relative risk of breast cancer comparing the incidence rates of bilateral breast cancer and the incidence rate of breast cancer in the unaffected twin sisters. The cumulative incidence of breast cancer in twin pairs and in women having a previous breast cancer with and without a family history of the disease was graphically displayed using Nelson-Aalen estimates.26 All data preparation and analysis was done using the SAS Statistical package, version 9.1 (SAS Institute, Cary, NC).27
We identified a total of 2,499 twin pairs (1,221 from Sweden, 774 from Denmark and 504 from Finland) in which at least one twin was diagnosed with breast cancer during the study period (Table 1). Of these, 855 pairs were monozygotic and 1,644 were dizygotic. In addition we identified 4,872 women without family history who developed bilateral cancers and 443 women with a family history who developed a bilateral cancer.
The incidence rates of unilateral breast cancer in Swedish women, breast cancer in the unaffected twin sisters and, bilateral breast cancer are presented in Table 2. The overall incidence rate of unilateral breast cancer was 0.09% per year. The incidence of breast cancer in dizygotic twins (0.42% per year) was 66% of that of monozygotic twins (0.64% per year; Table 2). Exactly the same relation was found when comparing the rates of nonfamilial and familial bilateral breast cancers (0.68% v 1.03% per year). Age at diagnosis of first cancer did not seem to affect the risk of the bilateral breast cancer (Table 2). Disregarding the first 3 months of follow-up, a period of intense medical surveillance, time since primary cancer did not affect risk of bilateral breast cancer. For twin sisters, we saw a tendency, albeit nonsignificant, of a decreasing risk of developing a cancer if the twin sister had her diagnosis at a higher age. It also seemed that the risk decreased over time since index sister's cancer (Table 2). In summary, we observed differences in risk of breast cancer that are up to five- to seven-fold larger in absolute terms with an entirely different age pattern when comparing the risk of disease in the opposite breast and in twin sisters to the general female population.
The cumulative risk of breast cancer after 20 years of follow-up was 14% in the monozygotic twin sister and close to 9% in the dizygotic twin sister (Fig 1). The 20-year risk of a second primary cancer was 18% with a family history of breast cancer and 11% without. The association of time since diagnosis with the risk of disease for all categories (twins and bilateral disease) seemed constant from time of first cancer in previously diagnosed women and time since the first twin sisters’ diagnosis, with the exception of the first 3 months of follow-up in women who developed a bilateral cancer.
We modeled the relative risk to develop breast cancer for twin sisters with affected siblings and the risk of familial bilateral cancer both compared with the risk of nonfamilial bilateral cancer adjusted for possible confounders (Table 3). As presented in Table 3, the relative risk of bilateral cancer among women with a first-degree family history was 52% higher (incidence rate ratio [IRR] = 1.52; 95% CI, 1.42 to 1.64) compared with risk of bilateral cancer among women without a family history. The monozygotic twin sister experienced a nonsignificant 21% higher risk (IRR = 1.21; 95% CI, 0.97 to 1.48) compared with risk of nonfamilial bilateral cancer. Finally, the relative risk of breast cancer in the dizygotic twin sister was 25% lower (IRR = 0.75; 95% CI, 0.61 to 0.91) compared with risk of nonfamilial bilateral cancer. In Table 3, lower part we repeat the previous analysis excluding the first 3 months of follow-up, a time period with a large proportion of prevalent bilateral breast cancers.
We observed that the onset of breast cancer in susceptible subpopulations differs from that normally seen in unilateral disease. Interestingly, age at diagnosis did not influence risk of breast cancer in bilateral breast or unaffected twin sisters. There seemed to be a constant elevated risk of a bilateral breast cancer regardless of time since diagnosis of the first cancer after excluding the first 3 months. Similarly, the risk of being diagnosed with a breast cancer after the twin sister had been diagnosed with a cancer is not to any larger extent affected by time since first sister's diagnosis. After 20 years of follow-up, the proportion of women experiencing an event was 9% to 18% in these high-risk groups. Higher proportion of shared genes, monozygotic versus dizygotic, and familial versus nonfamilial bilateral disease, increased the risk of disease less than expected, indicating important role of environmental factors. The strength of our study was the ability to generate large population-based data sets with virtually no loss to follow-up. Despite these unique features and more than 20 years of follow-up, we had limited statistical power to predict risk of breast cancer as a function of time since first diagnosis. Our incidence rates of bilateral cancer were generated from the Multigeneration Register to get information on family history, but incidence rates were similar to that of the Swedish Cancer Registry.28 Our definition of family history, although unbiased, is dependent on family structure, and it excludes history of only ovarian cancer that is known to increase risk of breast cancer. There is also a concern of changing background incidence rates of breast cancer over time when comparing absolute rates over long time periods from different countries. The aggregation of bilateral tumors diagnosed within 3 months is most likely the result of screening of the opposite breast at the time of the unilateral diagnosis. Diagnostic work-up of a first primary cancer may determine whether a preclinical bilateral cancer becomes detected early and classified as synchronous disease or diagnosed later as metachronous disease.29 In more recent years, both adjuvant endocrine and chemotherapy have been introduced and, as a consequence, there have been reports of up to 30% reductions of contralateral breast cancers.30,31 There is also a concern that prophylactic mastectomies in high-risk women will possibly bias the incidence rates, although historically in Sweden, such practices have been rare.32 We used a large data set of twin sister pairs in which at least one sister had a diagnosis of breast cancer. This design enabled convenient analyses of the onset of breast cancer in the twin sister. The breast cancer risk in twins was found to be little dependent of the first twin's age at diagnosis, with monozygotic twin sisters of women with breast cancer having higher risk than dizygotic twin sisters (Table 2). This finding is in sharp contrast to the age dependency seen in unilateral breast cancers, which may suggest that the contribution from genetic factors are more important than environmental risk factors among relatives. The effect of time since diagnosis in twin pairs must be viewed in light of limitations in sample size (Table 2). The risk decreased slightly with time since the sister's diagnosis. As previously described,33 the risk during the first 15 years is higher than the subsequent years, which can be explained by a high contribution from genetic factors. The overall risk in dizygotic sisters was 66% of that of monozygotic sisters, indicating that a completely shared genome increases the risk of 50% compared with that of any sisters (Table 3). Our observed rate in monozygotic twins is considerably lower than the rate observed by Peto et al.8 The observed differences are probably the result of differences in sampling techniques, our ability to generate a population-based data set, and the calendar period of ascertainment. The incidence of bilateral breast cancer is reportedly not modified by age and is approximately constant at 0.5% per year.4,7We observe, similar to previous findings, that the risk of bilateral breast cancer in our study is independent of both age and time since diagnosis (Table 2). Women with a family history of the disease experience a 50% higher risk of bilateral cancer compared with those without a family history, but the pattern of risk, age and time since diagnosis, was not dependent on family history. A constant risk might be consequence of an accumulation of a sufficient number of mutations (germline and somatic) at the point of the primary breast cancer, resulting in a high-risk group with an imminent risk of yet another cancer. A polygenic basis for this observation is likely since the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm),34 a familial breast cancer model that has been developed to predict breast and ovarian cancer using an underlying assumption of a polygenic etiology, does predict similar risks, as observed in our study. In the comparison of the risk of bilateral breast cancer and the risk of disease in twin sisters, there are several obvious similarities. Firstly, studies of bilateral breast cancer could be viewed as a familial study, where the opposite breast is unaffected and related to the first breast. Having accepted this, we use bilateral breast cancer as a model to assess risk of familial cancer. Secondly, we observe an increased risk of disease between familial and nonfamilial bilateral cancer of approximately 50% and similarly an increased risk of disease between monozygotic and dizygotic pairs of the same magnitude (Table 3). Thirdly, the risk with increasing follow-up was fairly constant in all four categories. A difference between the groups is the fact that a significant proportion of the women with a contralateral breast cancer have died as a result of breast cancer; that would not be as likely for the twin sisters. The use of incidence rates should take care of differences in the follow-up in these two groups, given no existing association between risk of contralateral disease and lethality. Because the diagnosis of prevalent synchronous cancers artificially inflates the bilateral rates in close proximity after the diagnosis of the first primary cancer, it is reasonable to exclude the first 3 months of follow-up when comparing bilateral disease to, for example twin sisters (Table 3, lower part). The unaffected monozygotic twin sister has two breasts at risk compared with one breast at risk for the twin with previous breast cancer. The risk in monozygotic twins might therefore be expected to be twice as high as the bilateral risk if twins had identical risk factor profiles. A doubling of risk was reported by Peto and Mack,8 but their monozygotic twin series was not population based. The IRRs in our data were 1.31 in patients’ monozygotic twins and 1.03 in their contralateral breasts (Table 3, lower part). This suggests an intrinsic nongenetic relative risk of approximately 1.57 (1.03 x 2/1.31) in women with breast cancer compared with their identical twins. These nongenetic factors may include developmental differences in utero35 as well as recognized reproductive, hormonal, and dietary factors.36-38 The combination of family history and the few low-penetrance genetic variants that are known can already identify a small proportion of women at very high risk, and the number is likely to increase substantially in the near future. The risk is approximately doubled in carriers of rare inactivating variants in CHEK2, ATM, BRIP1, and PALB2.6,39,40 A few very common variants in other genes that increase risk by 10% to 30% have recently been identified, and women who carry several such variants are expected to be at substantially increased risk. The next generation of genome-wide studies is likely to discover a much larger number of common low-penetrance genes, leading to the identification of substantial numbers of women whose risk is at least double the rate in the population. The lifetime breast cancer risk in first-degree relatives of women with bilateral disease is approximately 30%, and this risk likely to be increased to 50% in relatives of bilateral cases who carry a combination of variants that doubles the risk of breast cancer. This has already been shown for CHEK2*1100delC.41 A predicted doubling of lifetime risk, whether caused by family history or genetic testing, is probably too low to justify counseling or prophylactic treatment, but a family history plus a genetic test that in combination predict a risk of 50% or more will become increasingly common within a few years.
The author(s) indicated no potential conflicts of interest.
Conception and design: Mikael Hartman, Per Hall, Gustaf Edgren, Kamila Czene Financial support: Mikael Hartman, Per Hall, Kamila Czene Administrative support: Mikael Hartman, Per Hall, Kamila Czene Provision of study materials or patients: Mikael Hartman, Paul Lichtenstein, Jaakko Kaprio, Axel Skytthe, Kamila Czene Collection and assembly of data: Mikael Hartman, Linda Lindstrom, Kamila Czene Data analysis and interpretation: Mikael Hartman, Per Hall, Gustaf Edgren, Marie Reilly, Linda Lindstrom, Paul Lichtenstein, Jaakko Kaprio, Axel Skytthe, Julian Peto, Kamila Czene Manuscript writing: Mikael Hartman, Per Hall, Gustaf Edgren, Marie Reilly, Linda Lindstrom, Paul Lichtenstein, Jaakko Kaprio, Axel Skytthe, Julian Peto, Kamila Czene Final approval of manuscript: Mikael Hartman, Per Hall, Gustaf Edgren, Marie Reilly, Linda Lindstrom, Paul Lichtenstein, Jaakko Kaprio, Axel Skytthe, Julian Peto, Kamila Czene
We thank the national twin registries of Sweden and Denmark and the Finnish Twin Cohort for providing data.
published online ahead of print at www.jco.org on June 30, 2008. Supported by Swedish Cancer Foundation and US Army, DAMD 17-03-1-1-0771. The Finnish Twin Cohort is supported by the Academy of Finland Center of Excellence in Complex Disease Genetics. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer—Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350:1047-1059, 1997[CrossRef][Medline] 38. Michels KB, Mohllajee AP, Roset-Bahmanyar E, et al: Diet and breast cancer: A review of the prospective observational studies. Cancer 109:2712-2749, 2007[CrossRef][Medline] 39. Einarsdóttir K, Humphreys K, Bonnard C, et al: Linkage disequilibrium mapping of CHEK2: Common variation and breast cancer risk. PLoS Med 3:e168, 2006[CrossRef][Medline] 40. Tischkowitz M, Xia B, Sabbaghian N, et al: Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A 104:6788-6793, 2007 41. Weischer M, Bojesen SE, Ellervik C, et al: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: Meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26:542-548, 2008 Submitted September 7, 2007; accepted May 6, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
