Abstract
Post-menopausal hormone therapy with estrogen plus progestin is consistently reported to be associated with an increased risk of invasive breast cancer. However, findings on an association between hormone use and ductal carcinoma in situ of the breast (DCIS), a possible precursor lesion of invasive breast cancer, are sparse and inconsistent. Women’s Health Initiative data were used to assess the effects of hormone therapy on the risk of DCIS in two clinical trials of hormone therapy (16,276 women enrolled in the trial of daily conjugated equine estrogens plus medroxyprogesterone acetate (CEE + MPA) vs placebo; 10,187 women enrolled in the trial of CEE-alone vs placebo). The effects of hormone therapy on DCIS in clinical trial participants were assessed during the intervention, post-intervention, and entire followup periods, and in the observational study (OS; 30,421 CEE + MPA users and non-users and 18,657 CEE-alone users and non-users who met eligibility criteria similar to the clinical trial). Compared to placebo, CEE + MPA was non-significantly associated with higher risk of DCIS over approximate average of 11 years of follow-up (HR = 1.23; 95 % CI: 0.91–1.64). No statistical difference was detected between intervention and post-intervention phases (p = 0.32). Corresponding OS results supported an increased risk for DCIS in CEE + MPA users compared to women who were non-users (HR = 1.65; 95 % CI: 1.25–2.19) after adjusting for potential confounders. There was no clear association between CEE-alone use and risk of DCIS. CEE-alone trial data showed that the risk of DCIS was non-significantly lower in the treatment than in the placebo group, while analysis of the corresponding OS showed a non-significantly higher risk of DCIS in the CEE-alone users than non-users. Our analysis suggests that combined estrogen plus progestin use in post-menopausal women may increase risk of DCIS. Whether estrogen-alone use is associated with DCIS requires further investigation.
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References
Virnig BA, Tuttle TM, Shamliyan T, Kane RL (2011) Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. doi:10.1093/jnci/djp482
SEER (2007) SEER cancer statistics review, 1975–2004, National Cancer Institute, Bethesda http://seer.cancer.gov/csr/1975_2004/. Accessed 15 May 2011
Pinder SE (2010) Ductal carcinoma in situ (DCIS): pathological features, differential diagnosis, prognostic factors and specimen evaluation. Mod Pathol 23(Suppl 2):S8–S13. doi:10.1038/modpathol.2010.40
Anon A (1997) 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 (vol 350, p 1047, 1997). Lancet 350(9089):1484
Beral V (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362(9382):419–427
Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 289(24):3243–3253. doi:10.1001/jama.289.24.3243
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333
Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, Chlebowski RT, Gass M, LaCroix A, Manson JE, Prentice RL, Rossouw J, Stefanick ML (2008) Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 299(9):1036–1045. doi:10.1001/jama.299.9.1036
Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chlebowski RT (2006) Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295(14):1647–1657. doi:10.1001/jama.295.14.1647
LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J, Investigators W (2011) Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy a randomized controlled trial. JAMA 305(13):1305–1314
Reeves GK, Beral V, Green J, Gathani T, Bull D (2006) Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 7(11):910–918. doi:10.1016/S1470-2045(06)70911-1
Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN (1994) Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes Control 5(6):491–500
Trentham-Dietz A, Newcomb PA, Storer BE, Remington PL (2000) Risk factors for carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 9(7):697–703
Longnecker MP, Bernstein L, Paganini-Hill A, Enger SM, Ross RK (1996) Risk factors for in situ breast cancer. Cancer Epidemiol Biomarkers Prev 5(12):961–965
Gapstur SM, Morrow M, Sellers TA (1999) Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women’s Health Study. JAMA 281(22):2091–2097
Claus EB, Stowe M, Carter D (2001) Breast carcinoma in situ: risk factors and screening patterns. J Natl Cancer Inst 93(23):1811–1817
Phillips LS, Millikan RC, Schroeder JC, Barnholtz-Sloan JS, Levine BJ (2009) Reproductive and hormonal risk factors for ductal carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 18(5):1507–1514. doi:10.1158/1055-9965.EPI-08-0967
Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA (1995) Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 274(2):137–142
Henrich JB, Kornguth PJ, Viscoli CM, Horwitz RI (1998) Postmenopausal estrogen use and invasive versus in situ breast cancer risk. J Clin Epidemiol 51(12):1277–1283
Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group (1998). Control Clin Trials 19(1):61–109
Hays J, Hunt JR, Hubbell FA, Anderson GL, Limacher M, Allen C, Rossouw JE (2003) The Women’s Health Initiative recruitment methods and results. Ann Epidemiol 13(9 Suppl):S18–S77
Jackson RD, LaCroix AZ, Cauley JA, McGowan J (2003) The Women’s Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 13(9 Suppl):S98–S106
Langer RD, White E, Lewis CE, Kotchen JM, Hendrix SL, Trevisan M (2003) The Women’s Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 13(9 Suppl):S107–S121
Ritenbaugh C, Patterson RE, Chlebowski RT, Caan B, Fels-Tinker L, Howard B, Ockene J (2003) The Women’s Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 13(9 Suppl):S87–S97
Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR (2003) The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 13(9 Suppl):S78–S86
Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Pettinger M, Hendrix SL, Hubbell FA, Kooperberg C, Kuller LH, Lane DS, McTiernan A, Jo O’Sullivan M, Rossouw JE, Anderson GL (2008) Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 167(10):1207–1216. doi:10.1093/aje/kwn044
Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Langer RD, Pettinger M, Hendrix SL, Hubbell FA, Kooperberg C, Kuller LH, Lane DS, McTiernan A, O’Sullivan MJ, Rossouw JE, Anderson GL (2008) Conjugated equine estrogens and breast cancer risk in the Women’s Health Initiative clinical trial and observational study. Am J Epidemiol 167(12):1407–1415. doi:10.1093/aje/kwn090
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291(14):1701–1712. doi:10.1001/jama.291.14.1701
Hendrix SL, Wassertheil-Smoller S, Johnson KC, Howard BV, Kooperberg C, Rossouw JE, Trevisan M, Aragaki A, Baird AE, Bray PF, Buring JE, Criqui MH, Herrington D, Lynch JK, Rapp SR, Torner J (2006) Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation 113(20):2425–2434
Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, Mulvihill JJ (1989) Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81(24):1879–1886
Kerlikowske K, Miglioretti DL, Ballard-Barbash R, Weaver DL, Buist DS, Barlow WE, Cutter G, Geller BM, Yankaskas B, Taplin SH, Carney PA (2003) Prognostic characteristics of breast cancer among postmenopausal hormone users in a screened population. J Clin Oncol 21(23):4314–4321. doi:10.1200/JCO.2003.05.151
Chlebowski RT, Kuller LH, Prentice RL, Stefanick ML, Manson JE, Gass M, Aragaki AK, Ockene JK, Lane DS, Sarto GE, Rajkovic A, Schenken R, Hendrix SL, Ravdin PM, Rohan TE, Yasmeen S, Anderson G (2009) Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 360(6):573–587. doi:10.1056/NEJMoa0807684
2010 Top 200 branded drugs by total prescriptions (2012) http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727256/article.pdf. Accessed 18 Dec 2012
Anderson GL, Chlebowski RT, Aragaki AK, Kuller LH, Manson JE, Gass M, Bluhm E, Connelly S, Hubbell FA, Lane D, Martin L, Ockene J, Rohan T, Schenken R, Wactawski-Wende J (2012) Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 13(5):476–486. doi:10.1016/S1470-2045(12)70075-X
Barnes NL, Ooi JL, Yarnold JR, Bundred NJ (2012) Ductal carcinoma in situ of the breast. BMJ 344:e797. doi:10.1136/bmj.e797
StatBite (2010) Relative survival and incidence rates: ductal carcinoma in situ. J Natl Cancer Inst 102(1):8. doi:10.1093/jnci/djp492
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The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.
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A short list of WHI investigators is given in an Appendix.
Appendix: Short list of WHI investigators
Appendix: Short list of WHI investigators
Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller.
Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA).
Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles Kooperberg; (Medical Research Labs, Highland Heights, KY) Evan Stein; (University of California at San Francisco, San Francisco, CA) Steven Cummings.
Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller; (Baylor College of Medicine, Houston, TX) Haleh Sangi-Haghpeykar; (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (Brown University, Providence, RI) Charles B. Eaton; (Emory University, Atlanta, GA) Lawrence S. Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley Beresford; (George Washington University Medical Center, Washington, DC) Lisa Martin; (Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center, Torrance, CA) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR) Erin LeBlanc; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn; (Rush Medical Center, Chicago, IL) Henry Black; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, AL) Cora E. Lewis; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of California at Davis, Sacramento, CA) John Robbins; (University of California at Irvine, CA) F. Allan Hubbell; (University of California at Los Angeles, Los Angeles, CA) Lauren Nathan; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer; (University of Cincinnati, Cincinnati, OH) Margery Gass; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Hawaii, Honolulu, HI) J. David Curb; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser; (University of Miami, Miami, FL) Mary Jo O’Sullivan; (University of Minnesota, Minneapolis, MN) Karen Margolis; (University of Nevada, Reno, NV) Robert Brunner; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (University of Tennessee Health Science Center, Memphis, TN) Karen C. Johnson; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski; (University of Wisconsin, Madison, WI) Gloria E. Sarto; (Wake Forest University School of Medicine, Winston-Salem, NC) Mara Vitolins; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Michael S. Simon.
Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker.
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Luo, J., Cochrane, B.B., Wactawski-Wende, J. et al. Effects of menopausal hormone therapy on ductal carcinoma in situ of the breast. Breast Cancer Res Treat 137, 915–925 (2013). https://doi.org/10.1007/s10549-012-2402-0
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DOI: https://doi.org/10.1007/s10549-012-2402-0