Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes
- 544 Downloads
We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy.
This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case–control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses’ Health Study, Nurses’ Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy.
Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11–25% OR 2.50, 95% CI 1.94–3.22 vs. OR 2.03, 95% CI 1.70–2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41–0.70 vs. OR 0.71, 95% CI 0.59–0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11–25% OR 3.24, 95% CI 1.75–6.00 vs. OR 1.93, 95% CI 1.25–2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21–0.85 vs. OR 0.56, 95% CI 0.35–0.89, p-heterogeneity = 0.01), even though the interaction was not significant.
Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.
KeywordsBreast density Breast cancer subtypes Tumor aggressiveness Postmenopausal hormone therapy
This study was supported by the National Institutes of Health (Grant Numbers CA140286 to C. M.V. and K.K., CA087969 to R.M.T., UM1 CA176726 to W.W., UM1 CA186107 to M.S.), Mayo Clinic Specialized Program of Research Excellence (SPORE) in Breast Cancer (Grant Number P50 CA116201 to M.P.G. and J.N.I.), Mayo Clinic Cancer Center, and Breast Cancer Research Foundation. We would like to thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
Compliance with ethical standards
This study was approved by the Institutional Review Boards at the Mayo Clinic, Brigham and Women’s Hospital, and the University of California, San Francisco. Informed consent was obtained or implied by return of questionnaires (NHS, NHSII).
Conflict of interest
The authors declare that they have no conflict of interest.
- 5.Boyd NF, Byng JW, Jong RA, Fishell EK, Little LE, Miller AB, Lockwood GA, Tritchler DL, Yaffe MJ (1995) Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 87(9):670–675CrossRefPubMedGoogle Scholar
- 8.Aitken Z, McCormack VA, Highnam RP, Martin L, Gunasekara A, Melnichouk O, Mawdsley G, Peressotti C, Yaffe M, Boyd NF, dos Santos Silva I (2010) Screen-film mammographic density and breast cancer risk: a comparison of the volumetric standard mammogram form and the interactive threshold measurement methods. Cancer Epidemiol Biomark Prev 19(2):418–428CrossRefGoogle Scholar
- 10.Ursin G, Ma H, Wu AH, Bernstein L, Salane M, Parisky YR, Astrahan M, Siozon CC, Pike MC (2003) Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomark Prev 12(4):332–338Google Scholar
- 14.Pettersson A, Graff RE, Ursin G, Santos Silva ID, McCormack V, Baglietto L, Vachon C, Bakker MF, Giles GG, Chia KS, Czene K, Eriksson L, Hall P, Hartman M, Warren RM, Hislop G, Chiarelli AM, Hopper JL, Krishnan K, Li J, Li Q, Pagano I, Rosner BA, Wong CS, Scott C, Stone J, Maskarinec G, Boyd NF, van Gils CH, Tamimi RM (2014) Mammographic density phenotypes and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 106(5):dju078CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Bertrand KA, Tamimi RM, Scott CG, Jensen MR, Pankratz V, Visscher D, Norman A, Couch F, Shepherd J, Fan B, Chen YY, Ma L, Beck AH, Cummings SR, Kerlikowske K, Vachon CM (2013) Mammographic density and risk of breast cancer by age and tumor characteristics. Breast Cancer Res 15(6):R104CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J, Richardson AL, Schnitt SJ, Schmitt FC, Tan P-H, Tse GM, Badve S, Ellis IO (2010) Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res 12(4):1–12CrossRefGoogle Scholar
- 26.NCCN clinical practice guidelines in oncology: breast cancer. V 1.2016. National Comprehensive Cancer Network. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 15 Dec 2015
- 28.Olson JE, Sellers TA, Scott CG, Schueler BA, Brandt KR, Serie DJ, Jensen MR, Wu FF, Morton MJ, Heine JJ, Couch FJ, Pankratz VS, Vachon CM (2012) The influence of mammogram acquisition on the mammographic density and breast cancer association in the Mayo Mammography Health Study cohort. Breast Cancer Res 14(6):R147CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Kerlikowske K, Carney PA, Geller B, Mandelson MT, Taplin SH, Malvin K, Ernster V, Urban N, Cutter G, Rosenberg R, Ballard-Barbash R (2000) Performance of screening mammography among women with and without a first-degree relative with breast cancer. Ann Intern Med 133(11):855–863CrossRefPubMedGoogle Scholar
- 34.Ziv E, Tice J, Smith-Bindman R, Shepherd J, Cummings S, Kerlikowske K (2004) Mammographic density and estrogen receptor status of breast cancer. Cancer Epidemiol Biomark Prev 13(12):2090–2095Google Scholar
- 44.Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Porter GJR, Evans AJ, Cornford EJ, Burrell HC, James JJ, Lee AHS, Chakrabarti J (2007) Influence of mammographic parenchymal pattern in screening-detected and interval invasive breast cancers on pathologic features, mammographic features, and patient survival. Am J Roentgenol 188(3):676–683CrossRefGoogle Scholar
- 54.Greene F (2002) American Cancer Society, American Joint Committee on Cancer. AJCC cancer staging manual. Springer, New YorkGoogle Scholar
- 55.Mook S, Schmidt MK, Rutgers EJ, van de Velde AO, Visser O, Rutgers SM, Armstrong N, van’t Veer LJ, Ravdin PM (2009) Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: a hospital-based retrospective cohort study. Lancet Oncol 10(11):1070–1076CrossRefPubMedGoogle Scholar
- 57.Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, Van de Vijver MJ, Bergh J, Piccart M, Delorenzi M (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 98(4):262–272CrossRefPubMedGoogle Scholar
- 58.Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, Lindahl T, Pawitan Y, Hall P, Nordgren H, Wong JEL, Liu ET, Bergh J, Kuznetsov VA, Miller LD (2006) Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Can Res 66(21):10292–10301CrossRefGoogle Scholar