Breast Cancer Risk categories: Objectives 1. Breast cancer risk 2. - PDF document

9/13/2019 Hormone Management 101: • Consulting: Bayer, BioSyent, Duchesnay, Merck, Pfizer, Teva Disclosures Orals vs Transdermals • Speaker: AbbVie, Allergan, Amgen, Bayer, Merck, Pfizer, Searchlight Denise Black, MD, FRCSC • To review the published data and recommendations exploring the differences between oral and transdermal estrogens in the following Breast Cancer Risk categories: Objectives 1. Breast cancer risk 2. CVD risk or benefit 3. Venous thromboembolic risk 1

9/13/2019 • Recent data from a large meta analysis, in women using estrogen only preparations, shows Breast Cancer Cardiovascular NO DIFFERENCE in breast cancer risk dependent on route of administration Risk: Orals vs • RR 1.33 (CI 1.27 ‐ 1.38) for oral preparations, RR Disease Risk Transdermals 1.35 (CI 1.25 ‐ 2.46) for transdermals • Limitations: data does not discriminate for dosing CVD Risk/Benefit: Orals vs Transdermals • Many studies have suggested CVD benefit with MHT: Nurse’s Health Study, WHI in women age 50 ‐ 59, WHI CAC sub ‐ • Issue of primary prevention of CVD study, DOPS, ELITE, Finnish Database Endothelial with MHT is difficult to “prove”: Study, PEPI cells Smooth-muscle cells CVD • Large epidemiological studies will • All of these studies have used oral likely never be undertaken again Estrogen estrogens Risk/Benefits: • The MOA partly due to enzymatic • KEEPS recent release: oral CEE slowed alterations (MMP), endothelial Orals vs epicardial fat deposition, while changes (PG, NO, ILGF) and these are Transdermals difficult to elucidate and quantify transdermal estradiol increased paracardial fat deposition and increased • The anatomic model (great for imaging male model of CVD) of Rapid Effects progression of coronary artery calcium Long-Term Effects limited usefulness in young women deposits 1 Without alteration of Related to alteration gene expression of gene expression 1. El Khoudary et al, J Am Heart Assoc. 2019;8:e012763 Adapted from Mendelsohn et al, N Engl J Med. 1993;340:1801 ‐ 1811 2

9/13/2019 CVD Risks ‐‐ Stroke: Orals vs Transdermals • A Cochrane sub ‐ group analysis, looking at Venous data from the WHI and DOPs, and restricting analysis to women who initiated MHT less than 10 years from menopause Thromboembolic did not demonstrate an increased risk of stroke: RR 1.37 (CI 0.88 ‐ 2.34) 1 • The Renoux case ‐ controlled study Risk purporting less stroke with Td administration did not adequately compare bioequivalent estrogen doses: 50 ug Td was compared with up to 2 mg oral estradiol 2 • Recent RCTs in women age 50 ‐ 59 using lower dose orals did not demonstrate any increase in stroke risk 1. Boardman et al, The Cochrane Library 2015, Issue 3 2. Renoux et al, BMJ 2010;340:c2519 Hazard Ratios of Idiopathic VTE by Route of HT—E3N Trial Venous Thromboembolic Risk: Orals vs Transdermals Hazard Ratios (95% Confidence Intervals) Cases Person ‐ Years Treatment n=549 811,643 Multivariable Age ‐ Adjusted Adjusted* Never use 181 291,399 1 [reference] 1 [reference] • First was the ESTHER Study—a case Past use 66 100,943 1.0 (0.7 ‐ 1.3) 1.1 (0.8 ‐ 1.5) control study Current use of oral estrogens 81 93,211 1.5 (0.9 ‐ 2.3) 1.7 (1.1 ‐ 2.8) • Numbers were small (total of 62 Current use of transdermal estrogens 174 268,481 1.1 (0.7 ‐ 1.6) 1.1 (0.8 ‐ 1.8) cases were MHT users) No progestogen use 26 46,163 ‐‐ ‐‐ Current use of micronized progesterone 47 87,959 0.9 (0.6 ‐ 1.4) 0.9 (0.6 ‐ 1.5) • Average age was 62 Current use of pregnane derivatives 91 125,804 1.3 (0.8 ‐ 1.9) 1.3 (0.9 ‐ 2.0) • Not controlled for endometrial Current use of norpregnane derivatives 69 78,855 1.7 (1.1 ‐ 2.6) 1.8 (1.2 ‐ 2.7) protection agent Current use of nortestosterone derivatives 22 22,911 1.4 (0.8 ‐ 2.5) 1.4 (0.7 ‐ 2.4) Current use of other treatment 30 47,693 1.0 (0.7 ‐ 1.5) 1.1 (0.7 ‐ 1.8) • Stratification of dosing incorrect Unknown 17 9,916 2.0 (0.5 ‐ 3.9) 2.0 (0.5 ‐ 3.9) * Adjusted for age, body ‐ mass index, parity, education level, and time ‐ period. P for homogeneity between current use of oral estrogens vs. current use of transdermal estrogens is significant ( P = 0.01). P for homogeneity between progesterone subgroups is significant ( P < 0.01). Canonico M, et al. Arterioscler Thromb Vasc Biol 2010;30(2):340 ‐ 5. 3

9/13/2019 • KEEPS (n=727 over 48 months): This is the only RCT that pits an oral and a transdermal head ‐ to ‐ head, using relatively • SMART Trials (n=1585 over 24 months): bioequivalent doses of estrogen and the no increase in VTE risk seen with use of same endometrial protective agent oral CE/BZA (0.45/20) compared to (micronized progesterone). Results: One Recent RCTs Recent RCTs placebo 1 VTE in transdermal group, one in placebo group, none in oral on VTE on VTE • REPLENISH (n=415 over 52 weeks): no • ELITE (n=271 over 5+ years): no cases of VTEs seen in 415 subjects in oral VTE seen. Low dose oral estradiol (1 mg) estradiol 1mg/MP 100 mg group, none in and micronized progesterone were used. placebo 2 KEEPS: Harman SM, Black DM et al, Ann Intern Med. 2014;161:249 ‐ 260 • ELITE: Hodis HN, Mack WJ et al, N Engl J Med 2016;374:1221 ‐ 1231 • • Compared to standard dose oral HT, lower dose • Two nested case ‐ control studies involving over 450,000 oral as well as lower dose transdermal therapy women age 40 ‐ 79 has less effect on risk of stroke (RCT data • Stratified for age, co ‐ morbidities, dose and route of lacking) VTE Risk: administration of estrogen, as well as endometrial • Compared to standard dose oral HT, protective agent QResearch transdermal HT as well as lower doses of oral • Results: VTE risk with oral estrogens was dependent What do the or transdermal HT have less effect on VTE risk upon dose and endometrial protective agent: low dose and CRPD (RCT data lacking) oral estradiol, when combined with dydrogesterone, did guidelines say? not result in increased VTE risk, irrespective of age group • Micronized progesterone may be less Study or BMI. Overall odds ratio was 1.12 (CI 0.90 ‐ 1.40) thrombogenic than progestins • Tibolone showed no increased VTE risk • Older women, obese women, or those with • Transdermal estrogens did not increase risk, independent elevated TG or liver issues may consider lower of dose or endometrial protective agent doses of transdermal preparations 2017 Position Statement of the North American Menopause Society, Menopause Vol 24, No. 7, 2017 4

9/13/2019 Why is this important? • This allows healthy, younger, low risk women the option of the product that meets her specific needs (individualization of therapy) • Combined oral preparations with choice of endometrial protective agent allows customization for convenience, side effect profile, potential other benefits such as neutral effect on breast density, breast cancer risk, and specific QOL parameters, including amenorrhea • Women with additional risk (VTE, CVD) should Thank you opt for a transdermal estrogen preparation, with micronized progesterone for endometrial protection 5