Does Mirena use Increase Peri-menopausal Breast Cancer Development? Maccabi Health Services (MHS) Perspective and Recent Danish Study Nava Siegelmann Danieli, Itzhak Katzir, Janet Vesterman Landes, Yaakov Segal, Rachel Bachar, Hadas Rotem Rabinovich, Martin Bialik, Josef Azury, Avi Porath, Yosef Lomnicky 1
Maccabi Study: Background o Post-menopausal breast cancer risk is associated with combined progestin-estrogen exposure o Mirena is an intrauterine device with sustained 5 year release of Levenogestrel o Mirena is included in National Health Basket since 2001 for women aged 45 with heavy menstrual bleeding o Peri-menopausal women tend to reduce endogenous progestin level, raising the question of whether exogenous progestin may increase breast cancer risk 2
Objectives o To assess breast cancer risk in Peri-menopausal women as a function of Mirena exposure o To define tumor characteristics 3
Methods: Population o MHS data base holds electronic data for 2 million beneficiaries o Cases were women aged 40-50 years during the years 2003-2013, breast cancer free at time of inclusion (plus 6 months), who purchased Mirena o Controls: for every case we identified next 2 women aged +/- 2 years who did not purchase Mirena o Participants did not use other female hormones (OC, Fertility drugs, HRT) within 5 years prior to inclusion, and up to 11/2015 o Women exposed to preventive Tamoxifen were excluded 4
Methods: Tumor Features o Breast cancer diagnosed up to 11/2015 was linked to MHS cancer registry o Tumors stratified to Invasive and in-situ o Invasive tumors were sub-divided by systemic treatment approach including: o Hormonal therapy o Chemotherapy o Anti-Her2 approach o Combinations of the above o None 5
Methods: Statistics o Group comparison: Chi-square /Fisher, Mann-Whitney, Log-rank o Time to Event: Kaplan-Meier curves o Statistically significant : 2-sided P<0.05 6
Results o Women aged 40-50 years during 1/2003-12/2013-338,184 o Purchased Mirena - 17,667 o Purchased Mirena and fulfilled study criteria - 13,354 7
Cohort Characteristic (N = 40,678) Cases Controls P Value N = 13,354 N = 27,324 Age at study entry, years Median Mean (SD) 43.9 44.1 (2.6) 45.1 44.9 (2.8) <0.0001 Wilcoxon rank sum test Age category, n (%) 40-45 46-50 67% 33% 54% 46% <0.0001 Chi-square Follow up (median and range) 6.5 years (0.5-13) 9.6 years (0.5-13) <0.0001 Wilcoxon rank sum test 8 8
Breast Cancer Risk
Invasive Breast Cancer Risk 10
5-Year Estimate for Breast Cancer Risk * 11
Invasive breast cancers features occurring within 5 years 12
Summary o No increase in overall breast cancer risk associated with Mirena use in Peri-menopausal women o In sub-group of women aged 40-45 years, increase risk for invasive breast tumors was noted, significant but minimal o Tumor features: more TN (and less Her2+) tumors in Mirena users o Strengths: Israeli cohort, no other hormonal exposure o Limitations: retrospective analysis 13
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The Danish Sex Hormone Registry Study: sub-group of women aged 15-49 years o 1.8 million women aged 15-49 years by Jan 1995 o Followed till December 2012 for a median duration of 10.8 years o Exclusion criteria: prior breast cancer, VTE, fertility medications o Outcome: Cancer, Cardiac events o Herein: association between hormonal contraception and invasive breast cancer (BC) occurrence o Population: 7.8 million years (MY) non-users, 4.3 MY former users, 7.3 MY current/recent users (Mirena users 0.5 MY) 15
Median age varied between groups 16
Major findings o Invasive BC risk increased with prolonged exposure to hormonal contraception: 1.09 with 1 year to 1.38 with 10 years of exposure o After hormonal contraceptive discontinued, risk diminished within 1 year if total exposure was up to 5 years 17
Relative Risk of Breast Cancer 18
Major Differences Between Studies Danish Israeli Size 1.8 M 40K Patient Age (years) 15-49 40-50 Follow up duration Median 11 Years Adjusted to 5 Years Users/non users 3:2 1:2 Breast tumor Hormonal contraception Excluded Invasive (at study entry) Multiple Prior Fertility meds, VTE Invasive + DCIS (6 months past entry) Mirena Median age - Mirena 40 years 44 years Prior OC, Fertility meds, HRT Tamoxifen 19
Outcome Danish Israeli Invasive BC Risk 1.21 1.26 (age 40-45) Total BC Risk Not-evaluated Similar Time to BC 1 st year? 5 th year Adjusted Multiple factors: Age Gynecological factors Level of education Calendar year Family history Age 20
Conclusions o The Israeli study showed no overall increased breast cancer risk with Mirena use (peri- menpuasal, followed to 5 years) o Sub-group of Israeli women aged 40-45 years with slight but significant increased invasive BC risk of 1.26 o In the Danish Study of 0.5 million years for Mirena use, median age of 40 years and median follow-up of 11 years, RR 1.21 (adjusted to numerous factors) 21
Avital Bareket-Samish Ph.D. Bioinsight LTD Bayer for supporting medical writing 22