Skip to main content

Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population



Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history.


The Women’s Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations.


Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0–1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1–1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0–9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen.


Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.


Among women with a first breast cancer, risk of a second primary tumor in the contralateral breast is greater than risk of a first primary breast cancer in the general female population, [1,2,3] and contralateral breast cancer (CBC) represents the most frequent new malignancy diagnosed among breast cancer survivors [4]. The 25-year cumulative risk of CBC in the USA is approximately 7%, [4] with some evidence that CBC incidence has recently declined [5]. However, increases in breast cancer incidence, coupled with advances in treatment and improved survival, have led to a rise in the number of breast cancer survivors at risk of CBC. Identified risk factors for CBC include young age at first breast cancer diagnosis, [2, 6] breast cancer family history, [1, 7,8,9,10] mutations in BRCA1 and BRCA2 (BRCA1/2), [11, 12] young age at menarche, [13] nulliparity, [13] and obesity [14]. We and others have shown that both chemotherapy [15, 16] and tamoxifen therapy [16, 17] are associated with reduced CBC risk, although the benefit of tamoxifen on CBC risk was limited to estrogen receptor-positive (ER+) disease in the EBCTCG meta-analysis [17]. We further demonstrated that current users of tamoxifen with longer durations of use have the largest CBC reduction, which adds further support for the recent recommendations for primary breast cancer [18].

Additionally, some features of first breast tumors may predict CBC risk. Lobular histology of the first primary tumor has been associated with higher CBC incidence in several [1, 8, 9, 19, 20] although not all studies [6, 21, 22]. Evidence of associations with other histologic parameters remains equivocal [3, 23, 24]. Women with estrogen receptor-negative (ER-) first primary tumors, particularly those diagnosed at younger ages, may be at increased risk of CBC, and appear more likely to have second tumors that are ER- and high grade, [23, 25,26,27,28,29] potentially reflecting a higher number of BRCA1 mutation carriers in this group [30, 31]. ER and progesterone receptor (PR) status, collectively referred to as hormone receptor (HR) status, is routinely evaluated to inform treatment decisions, and could potentially be used to identify women at increased CBC risk. Tumors that lack expression of HR (HR-), particularly those displaying the triple-negative phenotype, are associated with poorer clinical outcomes and presently there are fewer therapeutic options for these tumors than for HR-positive (HR+) and HER2-overexpressing tumors (HER2+) [32].

Several previous studies have examined characteristics of first breast tumors in relation to CBC risk, using cancer registry data, primarily the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Registry Program. Despite large sample sizes, these studies generally lacked detailed information on potentially important covariates including BRCA1/2 mutation carrier status, breast cancer family history, and treatment for first breast cancer [25, 26, 28, 29]. Here, we evaluate first primary breast cancer characteristics and CBC risk in a population-based case-control study of CBC cases and unilateral breast cancer (UBC) controls.


Study population

The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based case-control study in which UBC controls were individually matched to (cases) with asynchronous CBC. The study design of the first phase (WECARE I Study) has been described in detail elsewhere; [33] the second phase (WECARE II Study) employed a nearly identical approach [16]. Briefly, participants were identified through eight population-based cancer registries: six in the USA, one in Canada, and one in Denmark (Table 1). The study protocol was approved by the institutional review boards at each site and the Ethics Committee System in Denmark.

Table 1 Characteristics of cases and controls from the WECARE Study population

Cases were participants who were: (1) diagnosed between 1985 and 2008 with a first invasive breast cancer that had not spread beyond regional lymph nodes at diagnosis and a second contralateral primary breast cancer at least 1 year after the first diagnosis; (2) younger than 55 years at first diagnosis; (3) without previous or intervening cancer diagnosis except non-melanoma skin cancer or cervical carcinoma in situ; (4) alive at contact; (5) willing to provide informed consent and a biospecimen; and (6) residents of the same cancer registry reporting region for both diagnoses. Controls with an intact contralateral breast were identified using the same eligibility criteria, and individually matched to cases (1:2 in the WECARE I Study; 1:1 in the WECARE II Study) on the following criteria: diagnosis age (5-year strata), diagnosis year (4-year strata), cancer registry region, and race/ethnicity. To improve statistical efficiency, WECARE I Study cases and controls were additionally counter-matched 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.

We identified a total of 2354 CBC (cases) and 3599 UBC controls eligible for the study. Of those, 1521 patients and 2212 controls provided written informed consent, completed the interview, and provided a biospecimen.

Data collection

Study participants were interviewed by telephone using a structured questionnaire to evaluate known or suspected breast cancer risk factors, including demographics, medical history, reproductive history, breast cancer family history, hormone use, smoking and alcohol intake. Detailed data on treatment, tumor characteristics including HR status were abstracted from pathology and surgical reports, radiation oncology clinic notes, and systemic adjuvant treatment reports. Information on tumor characteristics was also obtained from SEER registry records for US participants and from the Danish Breast Cancer Cooperative Group records for Danish participants. HER2 status was available only for WECARE II Study participants. ER, PR and HER2 status were each reported as “positive” (+), “negative” (-) or “unknown”. Self-reported treatment data were used for participants with missing information in their medical records (chemotherapy, 4%; hormonal therapy, 5%).

Participants in the WECARE I Study were screened for BRCA1/2 mutations using denaturing high-performance liquid chromatography [34]. Carriers of BRCA1/2 mutations were defined based on the presence of variants known or predicted to truncate the protein including frameshifts and premature termination codons, mutations occurring within 2 bp of an intron/exon boundary, and missense substitutions known to have deleterious functional effects.

Statistical analysis

Data from the two study phases were combined for the analyses presented here. Multivariable conditional logistic regression models were fit to estimate adjusted risk ratios (RRs) and corresponding 95% confidence intervals (CIs). Models included the following known or suspected CBC risk factors: age at first breast cancer diagnosis, breast cancer family history, age at menarche, parity, menopausal status, lobular histology of first breast cancer, and treatment for first breast cancer (hormonal, radiation therapy, chemotherapy). To account for the counter-matched design of the WECARE I Study, models included a log-weight covariate. WECARE II Study participants (who were not counter-matched) were assigned an offset term of 1 [33]. During the study period, clinical guidelines for tamoxifen evolved, which is reflected in the reporting of this treatment in our study. In 1988, tamoxifen was recommended for women with lymph-node-negative breast cancer [35]. A decade later, guidelines for women with ER+ breast cancer recommended adjuvant tamoxifen for 5 years [36, 37]. We chose cut points of <5, 5–9, and ≥10 years for analysis by time since the first breast cancer diagnosis and further adjusted these estimates for tumor stage in view of changing tamoxifen guidelines during the study period. Previous work demonstrated that nearly all tumors classified as ER-/PR+ in medical records are re-classified by either immunohistochemical analysis or gene expression analysis; [38] therefore, RR estimates for first primary tumors identified as ER-/PR+ are not reported in HR status analyses. We evaluated associations of HR status of the first breast tumor with risk of ER+/PR+, ER+/PR- and ER-/PR- CBC. We examined CBC risk among 705 cases and 1398 controls who were tested for BRCA1/2 deleterious mutations, and repeated the analysis excluding BRCA1/2 mutation carriers. The association of HR status of the first breast tumor with CBC risk and subtype-specific CBC was additionally adjusted for BRCA1 deleterious mutation status in a post-hoc analysis. Likelihood ratio tests were utilized to assess heterogeneity for potential effect modifiers, including differences in all tumor characteristics and tamoxifen between the WECARE I and WECARE II Studies (all P heterogeneity by study phase ≥0.17). Analyses were conducted using SAS v9.4 (SAS Institute, Cary, NC, USA).


Our analysis includes 1521 CBC cases and 2212 UBC controls. There were 2107 participants in the WECARE I Study and 1626 participants in the WECARE II Study. Median age at first diagnosis was 46 years and median time to CBC diagnosis among cases was 6.3 years (Table 1). Overall, approximately 75% of participants were premenopausal at first diagnosis.

Lobular histology of the first breast cancer was associated with elevated CBC risk (RR = 1.3, 95% CI 1.0–1.6) (Table 2). This association was limited to non-users of tamoxifen (users RR = 1.0, 95% CI 0.7–1.4; non-users RR = 1.6, 95% CI 1.1–2.1, P heterogeneity = 0.045). Other features of the first tumor, including grade, stage, nodal involvement, and tumor size, were not associated with CBC risk.

Table 2 Association between tumor characteristics of first primary breast cancer and contralateral breast cancer risk

Women whose first primary tumor was HR- had a higher risk of CBC than women with HR+ disease (Table 2). ER- first tumor status was associated with a 30% (95% CI 1.1–1.6) increase in CBC risk compared to ER+ first tumors; similarly elevated risks were observed when comparing PR- to PR+ first breast cancers (RR = 1.2, 95% CI 1.0–1.5). When ER and PR were evaluated jointly, ER-/PR- first tumor status was associated with a higher CBC risk than ER+/PR+ status of first tumors (RR = 1.4, 95% CI 1.1–1.7). Overall results for HR status were not appreciably different in the subset of women who had not received tamoxifen for their first diagnosis (1054 cases/1425 controls; see Additional file 1). Among WECARE II Study participants who were tested for HER2 status, neither HER2 positivity (RR = 0.8, 95% CI 0.5–1.3) nor the triple-negative phenotype (ER-/PR-/HER2-) was statistically significantly associated with CBC risk (RR = 1.3, 95% CI 0.8–2.2).

Although there was no statistically significant heterogeneity, for HR- tumors, the increased CBC risk was greatest in the first 10 years following the first breast cancer diagnosis, with no association seen among women who were diagnosed with CBC more than 10 years after their first diagnosis (<5 years ER-/PR- vs. ER+/PR+ RR = 1.5, 95% CI 1.1–2.1; ≥10 years ER-/PR- vs. ER+/PR+ RR = 1.1, 95% CI 0.7–1.6) (Table 3). Similar patterns according to time since first diagnosis were observed among women who had not used tamoxifen for their first breast cancer. The associations between HR status of first tumor and CBC risk were not modified by either first-degree breast cancer family history (any family history ER-/PR- vs. ER+/PR+ RR = 1.5, 95% CI 1.1–2.3; no family history RR = 1.3, 95% CI 1.0–1.7, P heterogeneity = 0.43) or diagnosis age (<45 years ER-/PR- vs. ER+/PR+ RR = 1.4, 95% CI 1.0–1.8; ≥45 years RR = 1.3, 95% CI 1.0–1.7, P heterogeneity = 0.79).

Table 3 Association between HR status of first breast cancer and CBC risk, by time since diagnosis

Women diagnosed with an ER-/PR- first breast cancer were less likely than women with an ER+/PR+ tumor to develop ER+/PR+ CBC (RR = 0.7, 95% CI 0.5–1.0) (Table 4). In contrast, the risk of developing an ER-/PR- CBC was fivefold greater among women with ER-/PR- first breast cancer than among those with ER+/PR+ first cancer (RR = 5.4, 95% CI 3.0–9.5). There was no effect modification by age, family history, or tamoxifen therapy; elevated RRs of ER-/PR- CBC following ER-/PR- first breast cancer were also observed for women <45 years of age at first diagnosis (RR = 5.9, 95% CI 2.9–12.2), those without family history of breast cancer (RR = 5.2, 95% CI 2.8–9.7) and those who were not treated with tamoxifen (RR = 6.5, 95% CI 3.2–12.9).

Table 4 Association between hormone receptor status of first breast cancer and subtype-specific contralateral breast cancer

Among the women screened for BRCA1/2 mutations, 185 (109 cases, 76 controls) were mutation carriers. Excluding these women attenuated the increased RRs for CBC observed among all women when comparing HR+ to HR- first breast cancers, but the increased risk of ER-/PR- CBC following a diagnosis of an ER-/PR- first tumor, compared to an ER+/PR+ first tumor, persisted (all tested women RR = 7.6, 95% CI 3.0–19.5; non-carriers RR = 7.7, 95% CI 2.6–23.3) (Table 5). The findings were similar when BRCA1 deleterious mutation status was included in the multivariable model (all tested women RR = 7.6, 95% CI 3.0–19.5; all tested women adjusting for BRCA1 deleterious mutation status RR = 8.9, 95% CI 3.1–25.9). Excluding only BRCA1 carriers yielded an effect of similar magnitude for the risk of ER-/PR- CBC following an ER-/PR- first primary (results not shown).

Table 5 Association between first breast cancer HR status and subtype-specific CBC, among known BRCA1/2 mutation non-carriers


In the WECARE Study, an HR- first breast cancer was associated with greater CBC risk than an HR+ first breast cancer. In particular, having a first tumor that lacked both ER and PR expression was associated with a more than fivefold greater risk of developing a CBC with the same HR-defined phenotype than first tumors that expressed both markers. Similar patterns of association between HR- first primary tumors and overall and subtype-specific CBC risk were observed when women treated with tamoxifen were excluded, suggesting that these associations were not due to lower CBC risk following tamoxifen treatment for ER+ first tumors. A lobular versus non-lobular histologic assessment at first diagnosis conferred a 30% increased CBC risk. Other features of first breast cancers were not associated with CBC risk.

Our analysis benefits from the collection of detailed data on treatment history and potential confounders, including reproductive and family history. Many previous analyses have relied on data from cancer registries, including SEER, which records only limited covariate data and intended first course treatment. Similar to our results, the preponderance of studies indicate that HR- first breast tumors are associated with increased CBC risk. In a population-based case-control study that adjusted for treatment information available in SEER, Saltzman et al. reported that women with ER-/PR- first breast cancer were 60% more likely to be diagnosed with CBC than those with ER+/PR+ tumors, [28] a risk estimate comparable to our findings. In two of the largest and most recent US registry-based studies assessing combined HR status of first tumors and CBC risk, CBC risk was higher among [26] or limited to [25] women with HR- first tumors than among those with HR+ disease, although neither study adjusted for treatment. However, an analysis in the Stockholm Breast Cancer Registry, which included data on endocrine therapy but few other covariates, found no difference in CBC risk by ER status of the first tumor (ER+ standardized incidence ratio (SIR) = 2.30 vs. ER- SIR = 2.17) [29]. PR status was not examined.

Consistent with our findings that women with ER-/PR- first breast cancers are at particularly high risk of ER-/PR- CBC, several other studies have found high concordance between HR status of the first and second primary breast cancers [22, 27, 29, 39]. Whether the high concordance between HR status of the first and second primary breast tumors reflects an underlying genetic susceptibility or an individual’s exposure to hormonal or other risk factors is presently unknown and difficult to determine. It has been established that risk factors for first primary breast cancer vary across breast cancer subtypes defined by HR status or molecular subtypes based on distinct gene expression signatures [40,41,42]. Thus, phenotypic concordance between two primary tumors may be due, at least in part, to exposure to subtype-specific risk factors [43]. Certain genetic mutations may additionally predispose individuals to developing breast cancer subtypes. In particular, ER- tumors are prevalent among BRCA1 mutation carriers, [30, 31] which we hypothesize could explain some of the high risk of ER-/PR- CBCs following an ER-/PR- first breast cancer observed in this and in other studies. In our study, the high risk of ER-/PR- CBC following a first tumor with the same phenotype persisted after we excluded BRCA1/2 mutation carriers. BRCA1 mutation carriers also tend to develop breast cancer at a relatively young age and other studies have reported that risk of HR- CBC among those with an HR- first tumor was higher among younger women [26, 27, 39]; we did not observe differences by age in our younger population. Furthermore, risks did not appear to differ by breast cancer family history, a possible indicator of underlying genetic susceptibility. It is likely that a combination of both exogenous and endogenous factors, including genetic or molecular factors not measured here, play a role in the development of two cancers with a shared HR-defined phenotype.

Histologic identification of lobular cancer in situ and invasive first breast cancer has frequently been implicated as a risk factor for CBC. Here, we observed a statistically significant 30% increased CBC risk associated with histologic identification of a lobular first tumor, even after adjusting for treatment and other risk factors. This result is consistent with that observed in previous studies [2, 20, 43], although one large population-based study found no elevation in CBC risk comparing lobular with ductal first tumors [21]. Some older studies were conducted prior to the widespread use of endocrine therapy, while a substantial proportion of receptor-positive women in our study received tamoxifen treatment. As virtually all classic lobular tumors are ER+, [44] treatment with tamoxifen may have lowered subsequent CBC risk among women with histologic identification of lobular cancer; accordingly, we observed that histologic identification of lobular cancer was associated with significantly increased CBC risk among women who had not been treated with tamoxifen.

Our study population included women under age 55 years at diagnosis of their first primary tumor. Therefore, the results of this study are most relevant for young women with breast cancer. A limitation of our study is the lack of BRCA1/2 mutation data for WECARE II Study participants, reducing the statistical power to detect associations among non-carriers. Small numbers of ER+/PR- tumors also limited our ability to examine associations with this subtype. Additionally, HR status was evaluated by the pathology departments of treating hospitals, and was not assessed centrally using a standardized protocol. However, previous work has shown good agreement between HR status reported in cancer registries and HR status determined in a single academic reference laboratory, particularly for ER+/PR+ and ER-/PR- subtypes [45]. Additionally, misclassification of HR status is unlikely to be related to case-control status; as such, any resulting bias will likely be toward the null. We were not able to examine potential effect modification by use of aromatase inhibitors, which lower estrogen levels and have been used in the treatment of ER+ breast tumors in postmenopausal women. Given the relatively young age of participants and because most first breast cancers in our study occurred prior to the widespread use of these drugs, few women in our study population received this therapy. Last, many of the women in our study were diagnosed prior to the identification of HER2 and its incorporation into clinical practice [46]. Therefore, we lacked data on HER2 expression for a large proportion of our participants, affecting our statistical power and limiting our ability to classify tumors into categories that more closely approximate currently recognized molecular subtypes.


In summary, we observed that HR status and lobular histology of a first breast cancer are predictive of CBC risk. In particular, after adjusting for known CBC risk factors including treatment, women with an ER-/PR- first breast cancer were at a high risk of developing a second breast cancer that was also ER-/PR-. As HR status is a key factor in treatment choice, and ultimately prognosis, these results are informative for risk stratification. Notably, BRCA1 mutation carriers are known to be at high risk of HR- tumors and CBC, but these associations were also seen in BRCA1/2 non-carriers. These results suggest that HR status may be useful for informing counseling and screening strategies for CBC risk among women with a first breast cancer. Future work should focus on more refined classification of both first and subsequent primary breast cancers in order to clarify whether these tumors arise from similar etiologic pathways and to identify patients at high risk of CBC.



Base pairs


Contralateral breast cancer


Confidence interval


Estrogen receptor


Estrogen receptor negative


Estrogen receptor positive


Human epidermal growth factor receptor 2


Human epidermal growth factor receptor 2 negative


Human epidermal growth factor receptor 2 positive


Hormone receptor


Progesterone receptor


Progesterone receptor negative


Progesterone receptor positive


Risk ratio


Surveillance, Epidemiology, and End Results Registry


Unilateral breast cancer


Women’s Environmental Cancer and Radiation Epidemiology Study


  1. Bernstein JL, Thompson WD, Risch N, Holford TR. Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol. 1992;136:925–36.

    Article  CAS  PubMed  Google Scholar 

  2. Chen Y, Thompson W, Semenciw R, Mao Y. Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev. 1999;8:855–61.

    CAS  PubMed  Google Scholar 

  3. Storm HH, Jensen OM. Risk of contralateral breast cancer in Denmark: 1943-80. Br J Cancer. 1986;54:483–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Curtis RE, Ron E, Hankey BF, Hoover RN. New malignancies following breast cancer. In: Curtis RE, Ron E, Ries LAG, Hacker DG, Edwards BK, Tucker MA, Fraumeni JF Jr., editors. New malignancies among cancer survivors: SEER Cancer Registries, 1973-2000 National Cancer Institute, NIH Publ No 05-5302. Bethesda; 2006.

  5. Nichols HB, Berrington de Gonzalez A, Lacey Jr JV, Rosenberg PS, Anderson WF. Declining incidence of contralateral breast cancer in the United States from 1975 to 2006. J Clin Oncol. 2001;29:1564–9.

    Article  Google Scholar 

  6. Li CI, Malone KE, Porter PL, Daling JR. Epidemiologic and molecular risk factors for contralateral breast cancer among young women. Br J Cancer. 2003;89:513–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hemminki K, Ji J, Forsti A. Risks for familial and contralateral breast cancer interact multiplicatively and cause a high risk. Cancer Res. 2007;67:868–70.

    Article  CAS  PubMed  Google Scholar 

  8. Hom PL, Thompson WD. Risk of contralateral breast cancer: associations with factors related to initial breast cancer. Am J Epidemiol. 1988;128:309–23.

    Article  Google Scholar 

  9. Hom PL, Thompson WD, Schwartz SM. Factors associated with the risk of second primary breast cancer: an analysis of data from the Connecticut Tumor Registry. J Chronic Dis. 1987;40:1003–11.

    Article  Google Scholar 

  10. Prior P, Waterhouse JA. Incidence of bilateral tumours in a population-based series of breast-cancer patients. I. Two approaches to an epidemiologic analysis. Br J Cancer. 1978;37:620–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Graeser MK, Engel C, Rhiem K, Gadzicki D, Bick U, Kast K, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2009;27:5887–92.

    Article  PubMed  Google Scholar 

  12. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22:2328–35.

    Article  CAS  PubMed  Google Scholar 

  13. Largent JA, Capanu M, Bernstein L, Langholz B, Mellemkaer L, Malone KE, et al. Reproductive history and risk of second primary breast cancer: the WECARE study. Cancer Epidemiol Biomarkers Prev. 2007;16:906–11.

    Article  PubMed  Google Scholar 

  14. Druesne-Pecollo N, Touvier M, Barrandon E, Chan DS, Norat T, Zelek L, et al. Excess body weight and second primary cancer risk after breast cancer: a systematic review and meta-analysis of prospective studies. Breast Cancer Res Treat. 2012;135:647–54.

    Article  PubMed  Google Scholar 

  15. Bertelsen L, Bernstein L, Olsen JH, Mellemkjaer L, Haile RW, Lynch CF, et al. Effect of systematic adjuvant treatment on risk for contralateral breast cancer in the Women’s Environment, Cancer and Radiation Epidemiology Study. J Natl Cancer Inst. 2008;100:32–40.

    Article  CAS  PubMed  Google Scholar 

  16. Langballe R, Mellemkjaer L, Malone KE, Lynch CF, John EM, Knight JA, et al. Systemic therapy and risk of contralateral breast cancer in the WECARE Study. Breast Cancer Res. 2016;18:65.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Early Breast Cancer Trialists’ Collaborative Group, Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials. Lancet. 2011;78:771–84.

    Article  Google Scholar 

  18. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 2014;32(21):2255–69.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Broet P, de la Rochefordiere A, Scholl SM, Fourquet A, Mosseri V, Durand JC, et al. Contralateral breast cancer: annual incidence and risk parameters. J Clin Oncol. 1995;13:1578–83.

    Article  CAS  PubMed  Google Scholar 

  20. Ji J, Hemminki K. Risk for contralateral breast cancers in a population covered by mammography: effects of family history, age at diagnosis and histology. Breast Cancer Res Treat. 2007;105:229–36.

    Article  PubMed  Google Scholar 

  21. Gao X, Fisher SG, Emami B. Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: a population-based study. Int J Radiat Oncol Biol Phys. 2003;56:1038–45.

    Article  PubMed  Google Scholar 

  22. Swain SM, Wilson JW, Mamounas EP, Bryant J, Wickerham DL, Fisher B, et al. Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst. 2004;96:516–23.

    Article  CAS  PubMed  Google Scholar 

  23. Kollias J, Ellis IO, Elston CW, Blamey RW. Clinical and histological predictors of contralateral breast cancer. Eur J Surg Oncol. 1999;25:584–9.

    Article  CAS  PubMed  Google Scholar 

  24. Vichapat V, Gillett C, Fentiman IS, Tutt A, Holmberg L, Luchtenborg M. Risk factors for metachronous contralateral breast cancer suggest two aetiological pathways. Eur J Cancer. 2011;47:1919–27.

    Article  PubMed  Google Scholar 

  25. Bessonova L, Taylor TH, Mehta RS, Zell JA, Anton-Culver H. Risk of second breast cancer associated with hormone-receptor and HER2-neu status of the first breast cancer. Cancer Epidemiol Biomarkers Prev. 2011;20:389–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kurian AW, McClure LA, John EM, Horn-Ross PL, Ford JM, Clarke CA. Second primary breast cancer occurrence according to hormone receptor status. J Natl Cancer Inst. 2009;101:1058–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rusner C, Wolf K, Banderner-Greulich U, Stegmaier C, Holleczek B, Schubert-Fritschle G, et al. Risk of contralateral second primary breast cancer according to hormone receptor status in Germany. Breast Cancer Res. 2014;16:452.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Saltzman BS, Malone KE, McDougall JA, Daling JR, Li CL. Estrogen receptor, progesterone receptor, and HER2-neu expression in first primary breast cancers and risk of second primary contralateral breast cancer. Breast Cancer Res Treat. 2012;135:849–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sandberg ME, Hall P, Hartman M, Johansson AL, Eloranta S, Ploner A, et al. Estrogen receptor status in relation to risk of contralateral breast cancer: a population-based cohort study. PLoS One. 2012;7, e46535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Foulkes WD, Metcalfe K, Sun P, Hanna WM, Lynch HT, Ghadirian P, et al. Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res. 2004;10:2029–34.

    Article  CAS  PubMed  Google Scholar 

  31. Loman N, Johannsson O, Bendahl PO, Borg A, Ferno M, Olsson H. Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutation or unknown susceptibility genes. Cancer. 1998;83:310–9.

    Article  CAS  PubMed  Google Scholar 

  32. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–81.

    Article  PubMed  Google Scholar 

  33. Bernstein JL, Langholz B, Haile RW, Bernstein L, Thomas DC, Stovall M, et al. Study design: evaluation gene-environment interactions in the etiology of breast cancer: the WECARE study. Breast Cancer Res. 2004;6:R199–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA. 2008;299:194–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Abrams JS. Tamoxifen: Five versus ten years—is the end in sight? J Natl Cancer Inst. 2001;93:662–4.

    Article  CAS  PubMed  Google Scholar 

  36. The Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451–67.

    Article  Google Scholar 

  37. Ejlertsen B, Jensen M, Mouridsen H, Danish Breast Cancer Cooperative Group. Excess mortality in postmenopausal high-risk women who only receive adjuvant endocrine therapy for estrogen receptor positive breast cancer. Acta Oncol. 2014;53:174–85.

    Article  CAS  PubMed  Google Scholar 

  38. Hefti MM, Hu R, Knoblauch NW, Collins LC, Haibe-Kains B, Tamimi RM, et al. Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype. Breast Cancer Res. 2013;15:R68.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Huo D, Melkonian S, Rathouz PJ, Khramtsov A, Olopade OI. Concordance in histological and biological parameters between first and second primary breast cancers. Cancer. 2011;117:907–15.

    Article  PubMed  Google Scholar 

  40. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

  41. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tamimi RM, Colditz GA, Hazra A, Baer HJ, Hankinson SE, Rosner B, et al. Traditional breast cancer risk factors in relation to molecular subtypes of breast cancer. Breast Cancer Res Treat. 2012;131:159–67.

    Article  CAS  PubMed  Google Scholar 

  43. Arpino G, Weiss HL, Clark GM, Hilsenbeck SG, Osborne CK. Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen. J Clin Oncol. 2005;23:4687–94.

    Article  CAS  PubMed  Google Scholar 

  44. Arpino G, Bardou VJ, Clark GM, Elledge RM. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 2004;6:R149–56.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ma H, Wang Y, Sullivan-Halley J, Weiss L, Burkman RT, Simon MS, et al. Breast cancer receptor status: do results from a centralized pathology laboratory agree with SEER registry reports? Cancer Epidemiol Biomarkers Prev. 2009;18:2214–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:dju055.

    Article  PubMed  PubMed Central  Google Scholar 

  47. The SEER Program Code Manual, Revised Edition June 1992. National Cancer Institute, 1992

Download references


The Women’s Environmental, Cancer and Epidemiology (WECARE) Study Collaborative Group includes Memorial Sloan Kettering Cancer Center (Coordinating Center) Investigators and Staff: Jonine L. Bernstein Ph.D. (WECARE Study P.I.); Marinela Capanu Ph.D.; Xiaolin Liang M.D.; Irene Orlow Ph.D.; Anne S. Reiner M.P.H.; Mark Robson, M.D.; Meghan Woods M.P.H. Collaborative Site Investigators: Leslie Bernstein Ph.D.; John D. Boice Jr. Sc.D.; Jennifer Brooks Ph.D.; Patrick Concannon Ph.D.; Dave V. Conti Ph.D.; David Duggan Ph.D.; Joanne W. Elena Ph.D., M.P.H.; Robert W. Haile Dr.P.H.; Esther M. John Ph.D.; Julia A. Knight Ph.D.; Charles F. Lynch M.D., Ph.D.; Kathleen E. Malone Ph.D.; Lene Mellemkjær Ph.D.; Jørgen H. Olsen M.D. DMSc.; Daniela Seminara Ph.D. M.P.H.; Roy E. Shore Ph.D., Dr.P.H.; Marilyn Stovall Ph.D.; Daniel O. Stram Ph.D.; Marc Tischkowitz M.D., Ph.D.; Duncan C. Thomas Ph.D. Collaborative Site Staff: Kristina Blackmore M.Sc.; Anh T. Diep; Judy Goldstein; Irene Harris B.S., C.M.D.; Rikke Langballe M.P.H.; Cecilia O’Brien; Susan Smith M.P.H.; Rita Weathers M.S.; Michele West Ph.D.


The work was funded by the US National Institutes of Health (CA129639, CA083178, CA097397, CA114236, CA008748). The funding sources had no role in the design, in the collection, analysis, or interpretation of the data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. The authors thank the WECARE Study participants.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author (ASR) on reasonable request. The data are not publicly available due to them containing information that could compromise research participant privacy and consent.

Author information

Authors and Affiliations




JLB, LB, and KEM designed the study. MW provided administrative support. CFL, EM, LB, JAK, LM, and KEM provided study materials or patients. CFL, EM, JDB, LB, JAK, PC, LM, MW, KEM, XL, and JLB collected and assembled the data. ASR, JSS, LH, LB, LM, MT, RWH, RS, MM, and JLB analyzed the data and interpreted the results. All authors participated in manuscript writing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Anne S. Reiner.

Ethics declarations

Ethics approval and consent to participate

All participants gave written informed consent before enrollment, and the study protocols were approved by the institutional review boards at the University of Iowa (IRB-01), Fred Hutchinson Cancer Research Center, Cancer Prevention Institute of California, University of Southern California, Beckman Research Institute of the City of Hope, University of California at Irvine, Mount Sinai Hospital, Danish Cancer Society and Memorial Sloan Kettering Cancer Center, and by the Committee for the Protection of Human Subjects of the State of California and the ethical committee system in Denmark.

Consent for publication

Not applicable.

Competing interests

Patrick Concannon owns stock in Amgen; Lene Mellemkjaer has an immediate family member who owns stock in Novo Nordisk and stock in Lundbeck and has an immediate family member employed at Novo Nordisk.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Additional file

Additional file 1: Table S1.

Association between first breast cancer HR status and CBC, among women not receiving tamoxifen for first diagnosis. In the WECARE Study population of women who had not received tamoxifen for their first breast cancer diagnosis, having an ER-negative first breast cancer or a PR-negative first breast cancer statistically significantly increased the risk of CBC. (DOCX 19 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reiner, A.S., Lynch, C.F., Sisti, J.S. et al. Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population. Breast Cancer Res 19, 83 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: