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Originally published as JCO Early Release 10.1200/JCO.2007.14.3081 on February 4 2008 © 2008 American Society of Clinical Oncology. Oral Contraceptives, Postmenopausal Hormones, and Risk of Asynchronous Bilateral Breast Cancer: The WECARE Study Group
From the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, University of Iowa, Iowa City, IA; Epidemiology Division, Department of Medicine, University of California, Irvine, CA; Department of Radiation Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark Corresponding author: Leslie Bernstein, PhD, City of Hope Comprehensive Cancer Center, 1500 East Durate Rd, Bldg 173, Durate, CA 91010; e-mail: Ibernstein{at}coh.org
Purpose To investigate whether oral contraceptive (OC) use and postmenopausal hormones (PMH) are associated with an increased risk of developing asynchronous bilateral breast cancer among women diagnosed with breast cancer younger than 55 years. Patients and Methods The WECARE (Women's Environment, Cancer, and Radiation Epidemiology) study is a population-based, multicenter, case-control study of 708 women with asynchronous bilateral breast cancer and 1,395 women with unilateral breast cancer. Risk factor information collected during a telephone interview focused on exposures before and after the first breast cancer diagnosis. Treatment and tumor characteristics were abstracted from medical records. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% CIs. Results OC use before the first breast cancer diagnosis was not associated with risk of asynchronous bilateral breast cancer (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after breast cancer diagnosis was also not significantly associated with risk (RR = 1.56; 95% CI, 0.71 to 3.45). Risk did not increase with longer duration of use or among women who had begun using OCs at a younger age. No evidence of an increased risk of asynchronous bilateral breast cancer was observed with PMH use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after breast cancer diagnosis (RR = 1.10; 95% CI, 0.67 to 1.77). Neither duration nor type of PMH were associated with risk. Age at and time since first breast cancer diagnosis did not substantially affect these results. Conclusion This study provides no strong evidence that OC or PMH use increases the risk of a second cancer in the contralateral breast.
Many premenopausal women diagnosed with breast cancer will either maintain regular menstrual cycles or regain ovarian function after treatment. A personal history of breast cancer is currently a noted contraindication for the use of many oral contraceptives (OCs).1 At least four studies2-5 have found no evidence of an increased risk of contralateral breast cancer among women who used OCs. The Women's Contraceptive and Reproductive Experiences (CARE) study reported no association of OC use with risk of first breast cancer6; whereas the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) found a modest increased risk associated with recent OC use.7 Women with breast cancer who undergo therapies beyond surgical intervention, including chemotherapy and hormonal-based therapy, often experience reduced estrogen levels. Postmenopausal hormone therapy (PMH) can be used to relieve menopausal symptoms, but has been associated with an increased risk of first breast cancer, especially combination estrogen-progestin therapy (EPT).8-11 Current guidelines for healthy women recommend avoiding combination PMH for any reason other than to relieve severe menopausal symptoms uncontrolled by other treatments.12 For women with a history of breast cancer, PMH is contraindicated. Two randomized clinical trials investigated the use of PMH in breast cancer survivors, and although the HABITS (Hormonal Replacement Therapy After Breast Cancer—Is It Safe?) study showed a significant increased risk of recurrence and was terminated early,13 a trial in Sweden found no association.14 Several observational studies have also shown no increased risk of tumor recurrence or increased mortality associated with PMH use among breast cancer survivors.15-17 In addition, two observational studies examined the relationship between PMH and risk of contralateral breast cancer2,4; neither demonstrated a significant association. Women with a personal history of breast cancer may consider using OCs for contraception and PMH for relief of menopausal symptoms18 because they lack other effective alternatives; therefore, further study is needed. In this population-based case-control study, we examine the impact of OC and PMH use before and after a diagnosis of breast cancer on risk of a second cancer in the contralateral breast.
Study Population The WECARE (Women's Environmental Cancer and Radiation Epidemiology) study is a multicenter, population-based case-control study that recruited women with asynchronous bilateral breast cancer (cases) and women with unilateral breast cancer (controls).19 All participants were identified from four population-based tumor registries in the United States (covering Iowa, Orange/San Diego and Los Angeles counties in California, and three counties surrounding Seattle, Washington) and one covering Denmark. Women were eligible to be cases if they (1) were diagnosed between January 1, 1985, and December 31, 2001, with an invasive breast cancer that did not spread beyond the regional lymph nodes at diagnosis and a second in situ or invasive breast cancer diagnosed in the contralateral breast at least 1 year after the first breast cancer diagnosis (reference date) (2); resided in the same study reporting area for both diagnoses (3); had no previous or intervening cancer diagnosis except squamous or basal cell skin cancer or cervical carcinoma in situ (4); were alive at the time of contact and able to provide informed consent to complete the interview and blood draw; and (5) were younger than 55 years at the time of the first breast cancer diagnosis. Two controls were individually matched to each case on year of birth, year of diagnosis, registry region at reference date, and race, and were counter-matched on registry-reported radiation exposure. Counter-matching on radiation therapy was employed for statistical efficiency purposes related to the study's primary goal of assessing genetic factors underlying the effects of radiation on breast cancer risk and is described in detail elsewhere.19 All controls met the following eligibility criteria: (1) diagnosed since January 1, 1985, with invasive breast cancer that did not spread beyond the regional lymph nodes at diagnosis, while residing in one of the study reporting areas; (2) no diagnosis of any other cancer (except squamous or basal cell skin carcinoma or in situ cervical cancer) before their breast cancer diagnosis or at the reference date (defined as the date of first diagnosis plus the elapsed time between their matched case's two diagnoses); (3) alive at time of contact and able to provide informed consent to complete the interview and blood draw; and (4) no prophylactic mastectomy of the contralateral breast before or within the interval from first diagnosis to reference date. We identified 998 cases and 2,112 controls who were eligible for inclusion in this study. Interviews and blood draws were completed with 708 cases and 1,399 controls. Reasons for nonparticipation included physician refusal (0.5% cases, 1% controls), patient refusal of interview (27% cases, 31% controls), and patient blood draw refusal (3% cases, 3% controls). We constructed 694 triplets where, per the counter-matched design, two members of each triplet received radiation treatment for their first breast cancer, according to cancer registry records. Among 11 case-control pairs, eight sets were discordant on radiation exposure, and three were concordant on exposure. We were unable to match controls to three cases, so they were excluded.
Data Collection Medical records, pathology reports, and hospital charts, in addition to self-reported data, were used to collect detailed treatment information (chemotherapy, hormonal therapy, radiation therapy). Information on tumor characteristics (including location in the breast, stage at diagnosis, estrogen-receptor [ER] and progesterone-receptor [PR] status, and histology) was collected from medical records and cancer registries for both the first and second primaries. For ER and PR, we used data from medical records if available. Agreement between medical and registry records was high. The study protocol was approved by the institutional review boards at each study site in the United States and by the ethical committee system in Denmark.
Statistical Methods
In the multivariable analyses, we included known breast cancer risk factors. to determine the relationship between age at first and last use of OCs or PMH, we restricted the analysis to women who had reached the age of the last use category. Adjusted linear trend test P values were obtained by including in the multivariable models variables that assigned ordinal values to the different categories. Analyses were stratified on time since first breast cancer diagnosis (< 5 v
Patient Characteristics Asynchronous bilateral breast cancer cases and unilateral breast cancer controls were well matched on age, diagnosis year, registry region, and race, and counter-matched on radiation treatment (Table 1). Cases and controls did not differ on age at reference date or time at risk. Cases were more likely to have a family history of breast cancer, an age of menarche younger than 13 years, and fewer children than controls. Cases and controls did not differ on either BMI or menopausal status at first diagnosis or at reference date. Cases were more likely to have been diagnosed with a localized first breast cancer than controls. Controls were more likely to receive hormonal-based therapy and chemotherapy.
Association Between OC Use and Asynchronous Bilateral Breast Cancer OC use at any time before the woman's reference date was not associated with risk of asynchronous bilateral breast cancer (relative risk [RR] = 0.88; 95% CI, 0.67 to 1.15) (Table 2). OC use before a woman's first breast cancer diagnosis was not significantly associated with risk of asynchronous bilateral breast cancer in analyses adjusted for use after a first diagnosis (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after first diagnosis was also not associated with risk after adjustment for OC use before first diagnosis (RR = 1.56; 95% CI, 0.71 to 3.45), although the prevalence of such use was low. Longer duration of OC use was not associated with risk. Women who stopped using OCs after their first breast cancer diagnosis (RR = 1.61; 95% CI, 0.56 to 4.60) and current users at reference date (RR = 1.30; 95% CI, 0.37 to 4.58) were at a nonsignificant increased risk. As expected, women who used OCs after diagnosis were younger than those who did not (mean age, 39.3 ± 7.0 v 45.6 ± 6.2 years; P < .001) and were more likely to be pre- or perimenopausal compared to nonusers (97.3% v 65.9%; P < .001), but did not differ from nonusers in terms of mean duration of time at-risk (4.9 ± 5.0 v 4.1 ± 5.0 years).
Neither age at first use (Table 2) nor age at last use (data not shown) was associated with risk of asynchronous bilateral breast cancer. Years of use before age 30 and before first full-term pregnancy were also not associated with risk (data not shown). We observed no significant differences in the risk estimates for ever-users and never users of OCs by latency, age at onset, BMI, menopausal status, or hormone-receptor status (data not shown).
Association Between PMH Use and Asynchronous Bilateral Breast Cancer
We did not observe a statistically significant increased risk of asynchronous bilateral breast cancer with ever-use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after (RR = 1.10; 95% CI, 0.67 to 1.77) the woman's first breast cancer diagnosis. The majority of women who took PMH after their diagnoses were postmenopausal (84.1%) or going through the menopause (11.2%). Age at first diagnosis did not differ between women who used PMH after their diagnoses of breast cancer and those who did not (45.4 ± 6.3 v 47.3 ± 5.1 years); however, we observed a statistically significant difference in the time at-risk between users and nonusers (6.4 ± 3.2 v 5.0 ± 3.1 years). When we examined duration of use before and after diagnosis, we found no significant associations. Women who stopped using PMH more than 5 years before first breast cancer (RR = 1.75; 95% CI, 0.95 to 3.21) or after a diagnosis of breast cancer (RR = 1.54; 95% CI, 0.77 to 3.10) were not at a significantly increased risk compared to never users.
Results from this large, population-based, case-control study provide little evidence that use of either OC or PMH substantially increases the risk of asynchronous bilateral breast cancer. To our knowledge, ours is the first study to examine OC and PMH effects in terms of duration and age of use, as well as use before and after a diagnosis of breast cancer. Our results showed that OC use after diagnosis was associated with a modest nonsignificant increased risk. Most of the 37 women who used OCs after diagnosis were premenopausal, and their duration of use was short. We found little indication that PMH use before or after a breast cancer diagnosis substantially increased risk of asynchronous bilateral breast cancer. We also found no indication of an increased risk associated with duration of use, age at use, or type of PMH. Women in this study were relatively young at diagnosis; therefore, initiation of PMH use was likely close to menopause and for relief of symptoms. Furthermore, fewer than half of women taking PMH were exclusive EPT users. The Women's Health Initiative study8 suggests that PMH (particularly, EPT) use may increase the risk of first breast cancer among older women who use PMH long after menopause. We did not observe any evidence that latency, age at onset, BMI, menopausal status or hormone-receptor status modified the associations between OCs or PMH and risk of asynchronous bilateral breast cancer. Four previously published studies investigating OC use and risk of contralateral breast cancer also found no evidence to support an association.2-5 Two population-based cohort studies showed that risk of second breast cancer was not associated with OCs.3,4 A third population-based study among women diagnosed younger than age 45 found no duration of use effect when comparing women with at least 10 years of use and those with less than 10 years of use with never-users.5 Further, a small hospital-based case-control study showed no association between any use of OCs and risk of contralateral breast cancer.2 Despite differences in design, all studies, including the present study, suggest that OC use is unlikely to be associated with a strong increased risk of a subsequent contralateral breast primary. This finding agrees with results from the Women's CARE study of first breast cancer showing no increase in risk with current or former OC use among women aged 35 to 64 years.6 The CGHFBC, which pooled data from a large number of studies conducted in the 1980s and earlier, found a modest increase in risk of a first breast cancer with current and recent OC use.7 In the CGHFBC, the majority of OC use was at a higher estrogen dose than is currently used. Two other population-based studies have investigated the relationship between PMH and risk of subsequent contralateral breast cancer, with results that were similar to ours. Trentham-Dietz4 found no association for ever or recent use compared with never use. Horn2 compared ever versus never use for estrogen-only therapy and found no association. The role of PMH has been more widely investigated in first breast cancer. Evidence exists supporting an association of PMH, particularly combined EPT, with a modest increase in breast cancer risk.9-11 The CGHFBC found a strong duration response effect, showing that the relative risk of breast cancer increased significantly with each year of PMH use.10 A meta-analysis focusing on the EPT-specific results from the CGHFBC data confirmed a significant increase in breast cancer risk.11 Results from the Women's Health Initiative trial8 and Million Women Study9 also support these findings. When we examined duration and type of PMH, we observed no increase in risk with years of use or exclusive EPT use. We also did not observe a significant difference in results by BMI. Previous studies of first breast cancer have shown that the PMH-breast cancer association is limited to slender women.22 PMH was more strongly associated with hormone-responsive breast cancer,23 but our data showed no evidence of effect modification by hormone-receptor status of the first breast cancer. Two clinical trials investigating PMH use in breast cancer survivors showed discordant results. The HABITS trial, with a median follow-up of 2.1 years, found that the risk for breast cancer recurrence was significantly higher among patients who received PMH than among patients receiving no treatment (hazard ratio [HR] = 3.3; 95% CI, 1.5 to 7.4). In contrast, a Swedish randomized trial with a median follow-up of 4.1 years, found no association between risk of recurrence and PMH use (HR = 0.82; 95% CI, 0.35 to 1.95). These studies differ in important ways. The HABITS trial had higher proportions of EPT users and lymph node-positive disease and a lower proportion of Tamoxifen users than the Swedish trial.13,14 Observational studies also showed no significant associations between PMH use and tumor recurrence or mortality among breast cancer survivors.15-17 Several important limitations should be considered when interpreting our study results. We required that all of our cases and controls be alive at recruitment to obtain a blood sample. To limit this potential survival bias, controls were individually matched to cases on age and year of first breast cancer diagnosis. Further, we restricted study eligibility to women whose breast cancer had not spread beyond regional lymph nodes at first diagnosis. Our study also did not exclude carriers of BRCA1/2 mutations, nor did we analyze the results according to the molecular classification of breast tumors.24 It is possible that OC/PMH use may be more relevant to certain subtypes of breast cancer, as suggested by studies of first breast cancer in carriers.25,26 We were also unable to validate information on use of PMH and OC, or investigate differences in OC formulations. In addition, exposure prevalences were low in some analyses. Study strengths include the careful matching of cases to controls and the abstraction of medical records to confirm a cancer-free interval for controls. In addition, by limiting initial breast cancer diagnoses to localized and regional disease and specifying a minimum interval of 1 year between the first and second diagnoses of the cases, we limited the potential for misclassification of metastases as second primaries. This study has avoided biases associated with use of high-risk or selected populations by ascertaining cases and controls via multiple population-based cancer registries, which provides broader generalizability of the findings. These findings have important clinical implications for women with breast cancer. Although current clinical guidelines do not recommend that women with a history of breast cancer use OCs or PMH, results from this large observational study, combined with those from other observational studies and from clinical trials, suggest that use of these exogenous hormone preparations does not increase the risk of second breast primaries.
The author(s) indicated no potential conflicts of interest.
Conception and design: Jane C. Figueiredo, Leslie Bernstein, Kathleen E. Malone, Charles F. Lynch, Hoda Anton-Culver, Marilyn Stovall, Robert W. Haile, Jonine L. Bernstein Financial support: Leslie Bernstein, Kathleen E. Malone, Charles F. Lynch, Hoda Anton-Culver, Marilyn Stovall, Robert W. Haile, Jonine L. Bernstein Administrative support: Leslie Bernstein, Jonine L. Bernstein Provision of study materials or patients: Leslie Bernstein, Kathleen E. Malone, Charles F. Lynch, Hoda Anton-Culver, Marilyn Stovall, Robert W. Haile, Jonine L. Bernstein Collection and assembly of data: Jane C. Figueiredo, Leslie Bernstein, Marinela Capanu, Kathleen E. Malone, Charles F. Lynch, Marilyn Stovall, Lisbeth Bertelsen, Robert W. Haile, Jonine L. Bernstein Data analysis and interpretation: Jane C. Figueiredo, Leslie Bernstein, Marinela Capanu, Kathleen E. Malone, Charles F. Lynch, Robert W. Haile, Jonine L. Bernstein Manuscript writing: Jane C. Figueiredo, Leslie Bernstein, Marinela Capanu, Kathleen E. Malone, Charles F. Lynch, Hoda Anton-Culver, Marilyn Stovall, Lisbeth Bertelsen, Robert W. Haile, Jonine L. Bernstein Final approval of manuscript: Jane C. Figueiredo, Leslie Bernstein, Marinela Capanu, Kathleen E. Malone, Charles F. Lynch, Hoda Anton-Culver, Marilyn Stovall, Lisbeth Bertelsen, Robert W. Haile, Jonine L. Bernstein
The WECARE Study Collaborative Group Principal Investigator: Jonine L. Bernstein, PhD; Coinvestigators named on grant: Hoda Anton-Culver, PhD, Colin Begg., PhD, Leslie Bernstein, PhD, John Boice, Jr., PhD, Anne-Lise Børresen-Dale, PhD, Marinela Capanu, PhD, Patrick Concannon, PhD, Richard A. Gatti, PhD, Robert W. Haile, DrPH, Bryan M. Langholz, PhD, Charles F. Lynch, M.D., PhD, Kathleen E. Malone, PhD, Jørgen H. Olsen, M.D., DMSc., Barry Rosenstein, PhD, Roy E. Shore, PhD, DrPH, Marilyn Stovall, PhD, Duncan C. Thomas, PhD, W. Douglas Thompson, PhD. Coordinating Center: Memorial Sloan-Kettering Cancer Center (New York, NY)—Jonine L. Bernstein, PhD (WECARE Study principal investigator), Xiaolin Liang, MD, MS (informatics specialist), Abigail Wolitzer, MSPH (project director); National Cancer Institute (Bethesda, MD)—Daniela Seminara, PhD, MPH (program officer). Data Collection Centers: University of Southern California (Los Angeles, CA)—Leslie Bernstein, PhD (principal investigator), Laura Donnelly-Allen (project manager); Danish Cancer Society (Copenhagen, Denmark)—Jørgen H. Olsen, MD, DMSc (principal investigator), Lene Mellemkjær, PhD, MSc (project manager); University of Iowa (Iowa City, IA)—Charles F. Lynch, MD, PhD (principal investigator), Jeanne DeWall, MA (project manager); Fred Hutchinson Cancer Research Center (Seattle, WA)—Kathleen E. Malone, PhD (principal investigator), Noemi Epstein (project manager); University of California at Irvine (Irvine, CA)—Hoda Anton-Culver, PhD (principal investigator), Joan Largent, PhD, MPH (project manager). Radiation Measurement: The University of Texas M.D. Anderson Cancer Center (Houston, TX)—Marilyn Stovall, PhD (principal investigator), Susan Smith, M.P.H. (quality assurance dosimetry supervisor); New York University (New York, NY)—Roy E. Shore, PhD, DrPH (epidemiologist); International Epidemiology Institute (Rockville, MD) and Vanderbilt University (Nashville, TN)—John D. Boice Jr., Sc.D. (consultant). Biostatistics Core: University of Southern California (Los Angeles, CA)—Bryan M. Langholz, PhD, Duncan C. Thomas, PhD; Memorial Sloan-Kettering Cancer Center (New York, NY) Colin Begg, PhD, Marinela Capanu, PhD; University of Southern Maine (Portland, ME) W. Douglas Thompson, PhD (principal investigator). External Advisor: Stanford University (Palo Alto, CA)—Alice Whittemore, PhD.
published online ahead of print at www.jco.org on February 4, 2008. Supported by National Institutes of Health Grants No. U01-CA83178, R01-CA97397, and R01-CA42949; and a post-PhD Research Fellowship from the National Cancer Institute of Canada (#017602; J.C.F.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. US Food and Drug Administration: Medical product safety information. http://www.fda.gov/medwatch/SAFETY/2005/safety.htm 2. Horn PL, Thompson WD: Risk of contralateral breast cancer: Associations with histologic, clinical, and therapeutic factors. Cancer 62:412-424, 1988[CrossRef][Medline] 3. Bernstein JL, Thompson WD, Risch N, et al: Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 136:925-936, 1992 4. Trentham-Dietz A, Newcomb PA, Nichols HB, et al: Breast cancer risk factors and second primary malignancies among women with breast cancer. Breast Cancer Res Treat 105:195-207, 2007[CrossRef][Medline] 5. Li CI, Malone KE, Porter PL, et al: Epidemiologic and molecular risk factors for contralateral breast cancer among young women. Br J Cancer 89:513-518, 2003[CrossRef][Medline] 6. Marchbanks PA, McDonald JA, Wilson HG, et al: Oral contraceptives and the risk of breast cancer. N Engl J Med 346:2025-2032, 2002 7. Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies: Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 347:1713-1727, 1996[CrossRef][Medline] 8. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 9. Beral V: Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419-427, 2003[CrossRef][Medline] 10. 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] 11. Lee SA, Ross RK, Pike MC: An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br J Cancer 92:2049-2058, 2005[CrossRef][Medline] 12. Solomon CG, Dluhy RG: Rethinking postmenopausal hormone therapy. N Engl J Med 348:579-580, 2003 13. Holmberg L, Anderson H: HABITS (Hormonal Replacement Therapy After Breast Cancer—Is It Safe?), a randomised comparison: Trial stopped. Lancet 363:453-455, 2004[CrossRef][Medline] 14. von Schoultz E, Rutqvist LE: Menopausal hormone therapy after breast cancer: The Stockholm randomized trial. J Natl Cancer Inst 97:533-535, 2005 15. Powles TJ, Hickish T, Casey S, et al: Hormone replacement after breast cancer. Lancet 342:60-61, 1993[Medline] 16. DiSaia PJ, Grosen EA, Kurosaki T, et al: Hormone replacement therapy in breast cancer survivors: A cohort study. Am J Obstet Gynecol 174:1494-1498, 1996[Medline] 17. O'Meara ES, Rossing MA, Daling JR, et al: Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 93:754-762, 2001 18. Xydakis AM, Sakkas EG, Mastorakos G: Hormone replacement therapy in breast cancer survivors. Ann N Y Acad Sci 1092:349-360, 2006[CrossRef][Medline] 19. Bernstein JL, Langholz B, Haile RW, et al: Study design: Evaluating gene-environment interactions in the etiology of breast cancer—The WECARE Study. Breast Cancer Res 6:R199-214, 2004[CrossRef][Medline] 20. Langholz B: Counter-matching, in Armitage P, Colton T (eds): Encyclopedia of Biostatistics (ed 2). New York, NY, John Wiley, 2005, pp 1248-1254 21. Huberman M, Langholz B: Application of the missing-indicator method in matched case-control studies with incomplete data. Am J Epidemiol 150:1340-1345, 1999 22. Wu A, Pearce CL, Spicer DV, et al: Body weight, menopausal hormone therapy, and risk of breast cancer, in Lobo RA (ed): Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. New York, Raven Press Ltd, 2007 23. Rosenberg LU, Einarsdottir K, Friman EI, et al: Risk factors for hormone receptor-defined breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 15:2482-2488, 2006 24. Sørlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 25. Narod SA, Dube MP, Klijn J, et al: Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94:1773-1779, 2002 26. Haile RW, Thomas DC, McGuire V, et al: BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 15:1863-1870, 2006 Submitted September 4, 2007; accepted November 29, 2007.
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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
5 years), age at first breast cancer (< 45 v 
