Abstract
Purpose
The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed.
Patients and Methods
The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data.
Results
Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates.
Conclusion
Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.
INTRODUCTION
A family history of breast cancer is a strong and consistent risk factor for breast cancer. Compared with women without a family history, those with a positive family history have a two- to four-fold increased risk of developing breast cancer, which depends on the number of affected relatives and their ages at diagnosis.1,2 Among breast cancer survivors, second primary breast cancer incidence rates exceed those of a first breast cancer in the general population,3,4 and risk of contralateral breast cancer (CBC) is increased further for women with a breast cancer family history.5-9
Deleterious mutations in the BRCA1 and BRCA2 genes, although relatively rare, have been associated with increased risks of breast cancer, as have mutations in DNA damage response genes PALB2, CHEK2, and ATM.10-15 Recent collaborative genotyping efforts identified over 100 commonly occurring single-nucleotide polymorphisms (SNPs) that are associated with small increases in risk of first primary breast cancer.16-49
The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a population-based, case-control study of CBC cases and matched controls with unilateral breast cancer (UBC). In the first phase of the WECARE Study wherein analyses involved a considerably smaller sample than that of the current study, we reported that family history remained a strong risk factor for CBC in the absence of BRCA1/2 mutations.50,51 Among noncarriers of BRCA1/2 mutations, any history of breast cancer in first-degree relatives (mother, sisters, or daughters) versus no such history was associated with a nearly two-fold increased CBC risk. Additional increases in risk were associated with family history of relatives diagnosed at a young age and relatives with bilateral disease. We also have reported an increased CBC risk associated with a polygenic risk score (PRS) that comprises 67 common breast cancer susceptibility SNPs (per-risk allele trend rate ratio [RR], 1.04; 95% CI, 1.03 to 1.06).52
The completion of the second phase of WECARE allows us to clarify the relationship between family history of breast cancer and CBC risk. We report on a larger, updated study of 3,733 women as well as a subset of women who tested negative for deleterious mutations in BRCA1, BRCA2, ATM, CHEK2*1100delC, and PALB2. Furthermore, we adjusted for known common breast cancer susceptibility SNPs by incorporating a PRS.
PATIENTS AND METHODS
The WECARE Study Population
The WECARE Study is a multicenter, population-based, case-control study of CBC cases and individually matched UBC controls conducted in two phases: the WECARE I Study53 and the WECARE II Study.54 Eligible women were identified through eight population-based cancer registries: six in the United States and one each in Canada and Denmark (Table 1). The study protocol was approved by institutional review boards at each site and by the ethics committee system in Denmark.
Table 1.
Characteristics of the WECARE Study, United States and Denmark, 1985 to 2008
Cases were women diagnosed between 1985 and 2008 with a first invasive breast cancer that had not spread beyond regional lymph nodes at diagnosis and had a second primary CBC diagnosed at least 1 year after the first diagnosis (1 year for the WECARE I Study; 2 years for the WECARE II Study), younger than 55 years at first diagnosis, without previous or intervening cancer diagnoses except nonmelanoma skin cancer or cervical carcinoma in situ, alive at contact, willing to provide informed consent and a blood or saliva sample, and residents of the same cancer registry reporting region for both diagnoses. These eligibility criteria, in addition to no contralateral mastectomy, were used to select controls individually matched to cases (2:1 in the WECARE I Study; 1:1 in the WECARE II Study) on the basis of the following criteria: diagnosis age (5-year strata), diagnosis year (4-year strata), cancer registry region, and ethnicity. The WECARE I Study cases and controls also were countermatched on cancer registry–reported treatment with radiation such that two members of the case-control triad had received radiation therapy for their index breast cancer to improve statistical power to detect gene-radiation interactions. The at-risk period for each control was the same length as the interval between the first and second cancer diagnoses of her matched case. This at-risk period began on the control’s date of diagnosis and ended on the reference date defined by the end of her at-risk period.
Participants were interviewed by telephone using a structured questionnaire to obtain data on known or suspected breast cancer risk factors, including demographics, medical and reproductive history, hormone use, smoking, and alcohol intake. Detailed breast cancer family history was obtained and included the relative’s age at diagnosis and whether the disease was bilateral. Participants who reported having a mother, sister, or daughter with breast cancer were classified as having first-degree family history; women with at least one grandmother, aunt, or half-sister with breast cancer were classified as having second-degree family history. When considering a relative’s age at diagnosis, we used the youngest age reported for analyses. Thirty-eight participants (13 cases, 25 controls) were adopted or had unknown family history; they were included in models with an indicator variable.60
Data on treatment and tumor characteristics, including estrogen receptor and progesterone receptor status, were obtained from cancer registry records or by abstracting medical records (eg, pathology, surgery, systemic adjuvant reports) and radiation oncology clinic notes. For participants with missing treatment information in their medical records (chemotherapy, 4%; hormonal therapy, 5%), self-reported data were used.
Genotyping
The WECARE Study participants were genotyped for known breast cancer susceptibility SNPs to create a PRS. Briefly, blood samples from the WECARE I Study participants were genotyped with the HumanOmni1-Quad BeadChip (Illumina, San Diego, CA). Default Omni1-Quad cluster definitions from Illumina were used to call genotypes. Saliva samples from the WECARE II Study participants were genotyped using two custom Infinium iSelect arrays (Illumina). IMPUTE2 software was used to impute missing genotypes on the basis of the cosmopolitan panel of reference haplotypes from the 1000 Genomes Project (phase 1, March 2012 release).61 Thirty-five SNPs had imputed missing genotypes. Imputation quality and accuracy filters, as well as the individual 67 breast cancer susceptibility SNPs and their relation to CBC risk, have been previously described.52 Population substructure was investigated using EIGENSTRAT, which generated principal components (eigenvectors) included in analyses.62 In addition, 705 cases and 1,398 controls in the WECARE I Study were screened for BRCA1/2 mutations,55 708 cases and 1,397 controls for ATM,56,57 708 cases and 1,395 controls for CHEK2*1100delC,58 and 559 cases and 565 controls for PALB2.59
Statistical Analyses
In the WECARE Study design, controls are independently sampled from the failure time risk sets; thus, the estimated parameters are RRs in the proportional hazards model for cohort data.63,64 Multivariable-adjusted RRs and corresponding 95% CIs were estimated by fitting conditional logistic regression models. To account for the countermatched design in the WECARE I Study, models included log-weight offset terms. Models included the following known and suspected CBC risk factors: age at first breast cancer diagnosis, age at menarche, parity, age at menopause if occurred at least 2 years before the first diagnosis, histology of first diagnosis, stage of first diagnosis, and chemotherapy/hormonal treatment of first diagnosis. The age cut point of 40 years was chosen to take advantage of our sample size in a younger population. To include all women, missing information on a covariate was represented by an indicator variable.60 We also conducted analyses in the subset of the WECARE Study participants screened for mutations in BRCA1, BRCA2, ATM, CHEK*1100delC, and PALB2, excluding carriers.
We created an unweighted PRS that comprised 67 SNPs previously shown to be associated with increased breast cancer risk.16 For each study participant, genotypes were determined at each of the 67 loci. An unweighted risk score was calculated as the integer count of risk alleles at each directly genotyped locus or for imputed loci, the imputed dosage (values between 0 and 2, inclusive). If the published16 minor allele odds ratio was < 1, the major allele was considered the risk allele for the PRS. Conversely, if the published16 minor allele odds ratio was > 1, the minor allele was considered the risk allele for the PRS. A PRS trend variable was constructed using the median value of each PRS quartile in the WECARE Study population52; the trend variable was included as a covariate in the subset analyses to adjust multivariable models further.
Cumulative 10-year absolute risks (ARs) of CBC according to breast cancer family history status were estimated using a previously described methodology.50,55 Briefly, prevalences and RRs were estimated directly from WECARE Study data and combined with population-based SEER*Stat software cancer incidence data for women ages 18 to 54 years diagnosed between 1985 and 2008 for comparability with women in the WECARE Study.65 All analyses were performed in SAS 9.4 statistical software (SAS Institute, Cary, NC).
RESULTS
Characteristics of the 1,521 cases and 2,212 controls included in analyses are listed in Table 1. The median age at first diagnosis was 46 years. The majority of participants were non-Hispanic white and had localized estrogen receptor– and progesterone receptor–positive first breast cancers. Among participants tested for BRCA1, BRCA2, ATM, CHEK2*1100delC, or PALB2 mutations, 130 cases (18%) and 93 controls (7%) had at least one deleterious mutation.
CBC risk of participants with a first-degree family history of breast cancer was nearly twice that for those without a family history (RR, 1.9; 95% CI, 1.6 to 2.3; Table 2). CBC risk for participants with only a second-degree family history was 40% higher than that of those without a family history (RR, 1.4; 95% CI, 1.2 to 1.7). CBC risk was highest for participants who had a first-degree relative with bilateral disease (RR, 3.4; 95% CI, 2.4 to 5.0).
Table 2.
Association Between Family History of Breast Cancer and Risk of CBC in the WECARE Study, United States and Denmark, 1985 to 2008
The association between family history and CBC risk differed by diagnosis age of the affected relative (Table 2). When the first-degree relative was younger than 40 years at diagnosis, CBC risk was more than three-fold higher (RR, 3.3; 95% CI, 2.2 to 5.1) compared with participants with no breast cancer family history. Among those with a first-degree relative diagnosed with bilateral breast cancer younger than 40 years, CBC risk was > 10-fold higher (RR, 10.3; 95% CI, 4.2 to 25.7). Results were similar, although attenuated, when the age cut point of 45 years was used (results not shown).
In analyses restricted to a subset of WECARE Study participants screened for and known to not carry any deleterious mutations in BRCA1, BRCA2, ATM, CHEK2*1100delC, or PALB2, CBC risk associated with having any affected first- or second-degree relative remained elevated (RR, 1.8; 95% CI, 1.3 to 2.4) and did not change after adjusting for PRS (Table 3). Furthermore, the association of bilateral breast cancer family history with CBC risk remained statistically significantly elevated in this subset of participants (RR, 3.7; 95% CI, 1.7 to 8.2), and adjustment for PRS had a negligible effect on risk estimates (RR, 3.4; 95% CI, 1.5 to 7.4).
Table 3.
Association of Family History of Breast Cancer and Risk of CBC in Screened Participants With No Known Deleterious Mutations in Certain Genes in the WECARE Study, United States and Denmark, 1985 to 2008
The cumulative 10-year AR of CBC for participants without a family history of breast cancer was 4.3% (95% CI, 4.1% to 4.5%; Table 4). For participants with a first-degree family history of breast cancer, the 10-year AR of CBC was 8.1% (95% CI, 6.7% to 9.8%). Risk increased further when the first-degree relative was diagnosed with breast cancer at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or if the first-degree relative was diagnosed with bilateral breast cancer (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). In addition, risk was the highest when the first-degree relative was diagnosed with bilateral breast cancer before age 40 years (10-year AR, 36.3%; 95% CI, 14.5% to 90.5%). The cumulative 10-year ARs of CBC by family history status for noncarriers of deleterious mutations in BRCA1, BRCA2, ATM, CHEK2*1100delC, or PALB2 were similar to those for all women (Table 4).
Table 4.
Cumulative Ten-Year Absolute Risk of CBC According to Family History
DISCUSSION
With the completion of WECARE II, a study of larger size, we found that a first-degree family history of breast cancer nearly doubled CBC risk, even in a subset of women screened for and known to not carry deleterious mutations in BRCA2, BRCA2, ATM, CHEK2*1100delC, or PALB2, and after adjustment for PRS. Given the larger sample size, we were able to investigate the combined effect of bilateral breast cancer and young age (< 40 years) at breast cancer diagnosis in first-degree relatives on CBC risk and report a 10-fold increased risk of developing second primary breast cancer and a 10-year absolute CBC risk of 36%. Of note, having a first-degree relative diagnosed with bilateral breast cancer conferred a 10-year absolute CBC risk of approximately 14%, as did having a first-degree relative diagnosed with breast cancer at a young age (< 40 years), which is comparable to our previously estimated 10-year absolute CBC risk of 18% for BRCA1/2 deleterious mutation carriers.55
Similar associations with family history are well-established for first primary breast cancer. In a meta-analysis of first primary breast cancer, Pharoah et al2 reported relative risks of 2.1 associated with first-degree family history of breast cancer and 1.5 associated with second-degree family history versus no family history. For women with first-degree relatives diagnosed with breast cancer before age 50 years, breast cancer risk was increased more than three-fold. A pooled analysis of 52 epidemiologic studies reported similar findings,1 with a nearly two-fold higher breast cancer risk associated with first-degree family history of breast cancer and a nearly three-fold higher risk associated with family history of early-onset breast cancer (age < 35 years). The current findings for CBC risk are consistent with the results from the few studies that reported on the association between breast cancer family history and CBC risk. In a prospective cohort study, Bernstein et al3 found that women with a first-degree relative with breast cancer had a nearly two-fold greater CBC risk than women with no relatives with breast cancer. Furthermore, among women with a first-degree relative diagnosed with breast cancer at a young age (≤ 45 years), CBC risk was nearly three-fold greater than that of women without a family history. Our findings also confirm earlier reports of increased CBC risk associated with family history of early-onset breast cancer and family history of bilateral breast cancer.5-9 To our knowledge, the current report is the first of a 10-fold increased CBC risk for women who have relatives with early-onset bilateral disease.
Previous studies have shown that germline mutations in BRCA1 and BRCA2 as well as PALB2, CHEK2, and ATM mutations are associated with risk of first breast cancer.10-15 Missense mutations in ATM have been shown to increase CBC risk in women exposed to radiation therapy, and mutations in BRCA1, BRCA2, PALB2, and CHEK2 have been shown to be associated with risk of second primary breast cancer.55,56,59,66,67 Kuchenbaecker et al68 reported rapid increases in primary breast cancer incidence in young women (until ages 30 to 40 years for BRCA1 mutation carriers and until ages 40 to 50 years for BRCA2 mutation carriers) as well as increased primary breast cancer risk for BRCA1/2 mutation carriers with a first- and second-degree family history of breast cancer. They did not report on the effect of family history on CBC risk. In the subset of WECARE Study participants screened for deleterious mutations in BRCA1, BRCA2, ATM, CHEK2*1100delC, and PALB2, the analyses that excluded mutation carriers found that a first-degree family history of breast cancer remained a statistically significant CBC risk factor. Women having a first-degree family history of bilateral breast cancer had a more than three-fold increased risk of CBC. Furthermore, these associations were negligibly affected by adjustment for PRS of common breast cancer susceptibility SNPs in this subset as well as the entire WECARE Study cohort. These findings highlight the importance of other genetic factors and/or gene-environment interactions yet to be identified.
The current study is generalizable to women younger than 55 years of age at the time of first breast cancer diagnosis. Whether the results are applicable to older women remains to be evaluated. Strengths of the study include the population-based design, the increased number of CBCs, and the detailed family histories. Because of the large numbers of CBCs, we were able to investigate in fine detail the effect of relatives’ ages at breast cancer diagnosis and age in conjunction with a family history of bilateral breast cancer. Nevertheless, the current study also had some shortcomings. Despite the large sample size, some subgroup analyses were still precluded because of small numbers. We incorporated a PRS of 67 known breast cancer risk loci into the analyses but recognize that additional loci have recently been identified.16,48,49 Other truncating mutations in CHEK2 and mutations in other genes, such as CDH1 and TP53, may be associated with CBC risk, and we did not exclude them in the current design. Although of interest, these mutations are rare, and the fraction of breast cancer attributable to them is likely low. Family history of breast cancer was based on self-report and is likely less accurate for second-degree than for first-degree relatives. Finally, only living breast cancer cases were eligible for the WECARE Study. We used cancer registry data to compare women who were eligible for the WECARE II Study and alive with women who were equally eligible except that they were deceased. (This information was unavailable for the WECARE I Study.) We observed that eligible cases who had died were diagnosed with their first breast cancer at an earlier date, at a younger age, and at a later stage compared with eligible cases who were alive. However, this observation was also true of eligible controls who had died compared with eligible controls who were alive, which suggests that it would be unlikely for this selection to bias relative estimates, such as the RRs reported in the current study. Of note, more knowledge is needed on how survival after CBC is influenced by BRCA1/2 deleterious mutation carrier status and family history of breast cancer.
In conclusion, family history of breast cancer remains a strong risk factor for CBC, even after excluding carriers of deleterious mutations in BRCA1, BRCA2, ATM, CHEK2*1100delC, or PALB2 and after adjusting for 67 common breast cancer risk variants. Family history of breast cancer is relatively easy to assess accurately and even in the absence of genetic testing, can inform the assessment of CBC risk and influence first primary breast cancer treatment decisions, such as prophylactic surgery or systemic therapy. Clinicians are urged to obtain and use detailed family histories from young women diagnosed with breast cancer to guide treatment and future screening decisions.
ACKNOWLEDGMENT
The WECARE Study Collaborative Group includes Memorial Sloan Kettering Cancer Center (Coordinating Center) investigators and staff Jonine L. Bernstein (WECARE Study principal investigator), Marinela Capanu, Xiaolin Liang, Irene Orlow, Anne S. Reiner, Mark Robson, and Meghan Woods; collaborative site investigators Leslie Bernstein, John D. Boice Jr, Jennifer D. Brooks, Patrick Concannon, David V. Conti, David Duggan, Joanne W. Elena, Robert W. Haile, Esther M. John, Julia A. Knight, Charles F. Lynch, Kathleen E. Malone, Lene Mellemkjær, Jørgen H. Olsen, Daniela Seminara, Roy Shore, Marilyn Stovall, Daniel O. Stram, Marc Tischkowitz, and Duncan C. Thomas; and collaborative site staff Kristina Blackmore, Anh T. Diep, Judy Goldstein, Irene Harris, Rikke Langballe, Cecilia O’Brien, Susan Smith, Rita Weathers, and Michele West.
Footnotes
AUTHOR CONTRIBUTIONS
Conception and design: Anne S. Reiner, Julia Sisti, Jennifer D. Brooks, Patrick Concannon, Marc Tischkowitz, Mark Robson, Daniel O. Stram, Duncan C. Thomas, Kathleen E. Malone, Leslie Bernstein, Jonine L. Bernstein
Administrative support: Meghan Woods, The WECARE Study Collaborative Group
Provision of study materials or patients: Lene Mellemkjær, Kathleen E. Malone, Leslie Bernstein, The WECARE Study Collaborative Group
Collection and assembly of data: Esther M. John, Charles F. Lynch, Jennifer D. Brooks, Lene Mellemkjær, Julia A. Knight, Patrick Concannon, Xiaolin Liang, Meghan Woods, David Duggan, Kathleen E. Malone, Leslie Bernstein, The WECARE Study Collaborative Group, Jonine L. Bernstein
Data analysis and interpretation: Anne S. Reiner, Julia Sisti, Esther M. John, Jennifer D. Brooks, Lene Mellemkjær, John D. Boice, Julia A. Knight, Marinela Capanu, David V. Conti, Roy Shore, Daniel O. Stram, Duncan C. Thomas, Jonine L. Bernstein
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women’s Environmental Cancer and Radiation Epidemiology Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Anne S. Reiner
No relationship to disclose
Julia Sisti
No relationship to disclose
Esther M. John
No relationship to disclose
Charles F. Lynch
No relationship to disclose
Jennifer D. Brooks
No relationship to disclose
Lene Mellemkjær
Employment: Novo Nordisk (I)
Stock or Other Ownership: Novo Nordisk (I), Lundbeck (I)
John D. Boice
No relationship to disclose
Julia A. Knight
No relationship to disclose
Patrick Concannon
Stock or Other Ownership: Amgen
Marinela Capanu
No relationship to disclose
Marc Tischkowitz
No relationship to disclose
Mark Robson
Honoraria: AstraZeneca
Consulting or Advisory Role: McKesson, AstraZeneca
Research Funding: AstraZeneca (Inst), AbbVie (Inst), Medivation (Inst), Myriad Genetics (Inst), InVitae (Inst)
Travel, Accommodations, Expenses: AstraZeneca
Xiaolin Liang
No relationship to disclose
Meghan Woods
No relationship to disclose
David V. Conti
No relationship to disclose
David Duggan
No relationship to disclose
Roy Shore
No relationship to disclose
Daniel O. Stram
Employment: Genomic Health (I)
Duncan C. Thomas
No relationship to disclose
Kathleen E. Malone
No relationship to disclose
Leslie Bernstein
No relationship to disclose
Jonine L. Bernstein
No relationship to disclose
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