Breast Cancer Risk in Patients Using Hormonal Contraception

Breast Cancer Risk in Patients Using Hormonal Contraception Bradley L. Smith, Pharm.D. Smith.bradley1@mayo.edu Pharmacy Ground Rounds Mayo Clinic Rochester April 3 rd, 2018 2017 MFMER slide-1

Presentation Objectives Explain hormonal effects on breast cancer cell proliferation Describe the pharmacology of hormonal contraceptives Discuss evidence-based risks of breast cancer associated with hormonal contraceptive use 2017 MFMER slide-2

Explain hormonal effects on breast cancer cell proliferation 2017 MFMER slide-3

Female Sex Hormone Production Hypothalamus Negative Feedback Positive Feedback GnRH Anterior Pituitary FSH/LH Negative Feedback Positive Feedback Ovaries Ovulation and Secondary Sex Characteristics Estrogen & Progesterone GnRH: Gonadotropin-releasing hormone FSH: Follicle-stimulating hormone LH: Luteinizing hormone Gibson M. Time. 2015 2017 MFMER slide-4

LH LDL LDL LH AC ATP camp Cholesterol Pregnenolone Progesterone Androgens Cholesterol Pregnenolone Progesterone Androgens ATP Aromatase AC camp Theca Cell LDL: Low-density lipoprotein LH: Luteinizing hormone FSH: Follicle-stimulating hormone AC: Adenyl cyclase Estrogens ATP: Adenosine Triphosphate camp: Cyclic Adenosine Monophosphate Granulosa Cell FSH 2017 MFMER slide-5

Female Sex Hormone Production Hypothalamus Negative Feedback Positive Feedback GnRH Anterior Pituitary FSH/LH Negative Feedback Positive Feedback Ovaries Ovulation and Secondary Sex Characteristics Estrogen & Progesterone GnRH: Gonadotropin-releasing hormone FSH: Follicle-stimulating hormone LH: Luteinizing hormone 2017 MFMER slide-6

Estrogen and Progesterone Receptors Estrogen Receptors (ER) Estrogen Receptor Alpha (ERα) Uterus, prostate, ovarian theca cells, breast, liver Estrogen Receptor Beta (ERβ) Prostate, testes, ovarian granulosa cells, bone, brain Increase progesterone receptor expression Progesterone Receptors (PR) Three types: A, B, C Equally expressed in tissues Downregulate expression of estrogen receptors Lee HR, et al. Lab Anim Res. 2012; 28(2): 71-76 Diep CH, et al. J Mol Endocrinol. 2015; 54(2): R31-R53 2017 MFMER slide-7

Estrogen HSP90 ER ER ER Gene Expression and Cell Proliferation ER ERE ER DNA Cytoplasm Nucleus ER: Estrogen Receptor ERE: Estrogen Response Element HSP90: Heat Shock Protein 90 Begam AJ, et al. Bioorganic Chemistry. 2017; 71: 257-274 2017 MFMER slide-8

Estrogen HSP90 ER ER ER Gene Expression and Cell Proliferation TF ER ER TF DNA Cytoplasm Nucleus ER: Estrogen Receptor TF: Transcription Factors HSP90: Heat Shock Protein 90 Begam AJ, et al. Bioorganic Chemistry. 2017; 71: 257-274 2017 MFMER slide-9

Estrogen ER ER ER Gene Expression and Cell Proliferation ER ERE ER DNA Cytoplasm Nucleus ER: Estrogen Receptor ERE: Estrogen Response Element Begam AJ, et al. Bioorganic Chemistry. 2017; 71: 257-274 2017 MFMER slide-10

Which receptor is most likely to play a role in breast cancer incidence? A. Progesterone Receptor A (PR-A) B. Estrogen Receptor Beta (ERβ) C. Progesterone Receptor C (PR-C) D. Estrogen Receptor Alpha (ERα) 2017 MFMER slide-11

Describe the pharmacology of hormonal contraceptives 2017 MFMER slide-12

Hormonal Contraception Brief History 1873 Comstock Act 1965 Griswold v CT 1976 Mammogram 1972 Eisenstadt v Baird 1957/1960 Enovid 1988 Low dose CT: Connecticut Gibson M. Time. 2015 2017 MFMER slide-13

Hormonal Contraception Estrogen Progesterone Decrease LH and FSH Inhibit FSH surge release Prevent follicular Thicken cervical mucus development Alter tubular peristalsis Decrease endometrial receptivity Amy JJ, et al. BMJ. 2009; 339: b2895 2017 MFMER slide-14

Therapeutic Estrogen Drug Estradiol Ethinyl estradiol Comments Main biological estrogen in premenopausal women Commonly used in postmenopausal women Semi-synthetic Commonly used in oral contraceptives CH 3 OH CH 3 OH C CH HO Estradiol HO Ethinyl Estradiol 2017 MFMER slide-15

Therapeutic Progesterone Inc. AR activity Inc. PR potency Pregnanes Estranes Gonanes Progesterone Norethindrone Norgestrel H 3 C OAc CH AcO Drospirenone Medroxyprogesterone acetate Ethynodiol diacetate Norgestimate PR: Progesterone Receptor AR: Androgen Receptor 2017 MFMER slide-16

Hormonal Contraception Methods Method % of women aged % of 15-44 contraceptive use Oral 16.0 25.9 Intrauterine Device 6.4 10.3 Injectable 2.8 4.5 Vaginal Ring 1.2 2.0 Implant 0.8 1.3 Patch 0.4 0.6 Daniels K, et al. National Health Statistics Report. 2014 Curtis K, et al. MMWR Recomm Rep. 2016 2017 MFMER slide-17

Which of the following statements is true? A. Increased progesterone receptor activity has demonstrated increased risk of breast cancer B. Drospirenone has increased androgen receptor activity over norgestimate C. Hydrolization of ethinyl estradiol increases the bioavailability 2017 MFMER slide-18

Discuss evidence-based risks of breast cancer associated with hormonal contraceptive use 2017 MFMER slide-19

Breast Cancer Risk Current Age 10-year probability 1 in: 20 0.1% 1,567 30 0.5% 220 40 1.5% 68 50 2.3% 43 60 3.4% 29 70 3.9% 25 Lifetime risk 12.4% 8 Breast Cancer Facts and Figures 2017-2018 2017 MFMER slide-20

A Case-Control Study of Menopausal Estrogen Therapy and Breast Cancer Design Case-control study (n = 393) Population Baseline Demographics Data Collection Methods Breast cancer diagnosed between October 1, 1971 to July 1, 1977 Aged 50 to 74 at diagnosis No previous history of breast cancer Post-menopausal White Affluent Average age = 72 years Patient interviews Medical charts Pharmacy records Ross RK, et al. JAMA. 1980;243:1635-1639 2017 MFMER slide-21

A Case-Control Study of Menopausal Estrogen Therapy and Breast Cancer Ovaries Intact Total Milligram Accumulated Dose 0 1-1,499 1,500 Unknown Ever p-value Cases 50 21 28 2 51 Controls 103 56 23 5 84 Risk Ratio 1.0 0.9 2.5 1.4 0.02 Ovaries Removed Cases 13 6 7 0 13 Control 29 15 21 1 37 Risk Ratio 1.0 0.9 0.7 0.8 NS All Cases 64 28 37 2 67 Control 134 73 48 7 128 Risk Ratio 1.0 0.8 1.9 1.1 0.03 Ross RK, et al. JAMA. 1980;243:1635-1639 2017 MFMER slide-22

Hormonal Contraception in the 80s and 90s Early studies raised the question of breast cancer risk Most research in the 80s suggested little or no risk Approval for use in acne in 1997 Malone KE. National Academy Press. 1991 Ortho Tri-cyclen Package Insert. 1997 2017 MFMER slide-23

Oral Contraceptives and the Risk of Breast Cancer Case-control study Cases (n = 4575) Controls ( n = 4682) Inclusion Aged 35 to 64 years Invasive breast cancer diagnosed 1994 to 1998 Case Subjects Control Subjects Odds Ratio (95% CI) No use 1032 980 1.0 Any use 3497 3658 0.9 (0.8-1.0) Current use 200 172 1.0 (0.8-1.3) Former use 3289 2481 0.9 (0.8-1.0)* *CI was rounded to 1.0 but not contain 1.0 Marchbanks PA, et al. NEJM. 2002;346:2025-32 2017 MFMER slide-24

Oral Contraceptives and the Risk of Breast Cancer High estrogen dose Case Subjects Control Subjects Odds Ratio (95% CI) Any use 1082 1265 0.8 (0.7-0.9) Current use 7 10 0.7 (0.2-1.8) Former use 1074 1255 0.8 (0.7-0.9) Low estrogen dose Any use 1460 1560 0.9 (0.8-1.0) Current use 183 160 1.0 (0.8-1.3) Former use 1267 1398 0.9 (0.8-1.0) Marchbanks PA, et al. NEJM. 2002;346:2025-32 2017 MFMER slide-25

Oral Contraceptives and the Risk of Breast Cancer Estrane progestins Case Subjects Control Subjects Odds Ratio (95% CI) Any use 2439 2598 0.9 (0.8-1.0) Gonane progestins Any use 649 678 1.0 (0.8-1.2) Marchbanks PA, et al. NEJM. 2002;346:2025-32 2017 MFMER slide-26

Oral Contraceptive Use as a Risk Factor for Premenopausal Breast Cancer Design Mata-analysis of Case-control studies (n = 34) Inclusion Exclusion Exposure Measures Conducted in 1980 or later Included premenopausal women or women under 50 years of age Subjects developed breast cancer prior to 1980 Inclusion of postmenopausal women Ever use of OC Ever use of OC by ever parous women Ever use of OC before and after FFTP Use of OC for 4 years before FFTP Ever use of OC by nulliparous women Use of OC for 4 years by nulliparous women OC: Oral Contraceptive FFTP: First full-term pregnancy Kahlenborn C, et al. Mayo Clin Proc. 2006;31(10):1290-1302 2017 MFMER slide-27

Oral Contraceptive Use as a Risk Factor for Premenopausal Breast Cancer Ever use of OC (n = 37) Ever use of OC by ever parous women (n = 14) Ever use of OC before FFTP (n = 23) Ever use of OC after FFTP (n = 14) Use of OC for 4 years before FFTP (n = 10) Ever use of OC by nulliparous women (n = 12) Use of OC for 4 years by nulliparous women (n = 8) Odds Ratio (95% CI) p-value 1.19 (1.09-1.29) 9.5 x 10-5 1.29 (1.2-1.4) 8.4 x 10-11 1.44 (1.28-1.62) 8.1 x 10-10 1.15 (1.06-1.26) 0.0015 1.52 (1.26-1.82) 1.0 x 10-5 1.24 (0.92-1.67) 0.17 1.29 (0.85-1.96) 0.24 OC: Oral Contraceptive FFTP: First full-term pregnancy Kahlenborn C, et al. Mayo Clin Proc. 2006;31(10):1290-1302 2017 MFMER slide-28

Contemporary Hormonal Contraception and the Risk of Breast Cancer Design Prospective cohort study (n = 1,797,932) Population Aged 15 to 49 years on January 1, 1995 and turned 15 years before December 31, 2012 Exclusion Cancer (except nonmelanoma skin cancer) Venous thromboembolism Treatment for infertility Study Groups Never user Previous user (discontinuation > 6 months) Current or recent user (discontinuation 6 months) Mørch LS, et al. NEJM. 2017;377:2228-39 2017 MFMER slide-29

Contemporary Hormonal Contraception and the Risk of Breast Cancer No. of personyears No. Breast CA events Adjusted Relative Risk (95% CI) Never user 7,815,180 5,955 1.00 (reference) Previous user 4,348,722 2,883 1.08 (1.03-1.13) Current or recent user 7,308,437 2,679 1.20 (1.14-1.26)* *Increase of 13 events per 100,000 person-years Duration of use <1 year since recent use Relative Risk (95% CI) 1 to <5 years since recent use 5 to 10 years since recent use <1 year 0.96 (0.78-1.19) 0.96 (0.85-1.09) 1.01 (0.88-1.15) 1 to <5 years 1.04 (0.88-1.23) 1.06 (0.96-1.18) 1.07 (0.94-1.20) 5 to 10 years 1.33 (1.11-1.59) 1.16 (1.02-1.33) 1.30 (1.06-1.58) >10 years 1.52 (1.17-1.98) 1.16 (0.89-1.49) N/A CA: Cancer Mørch LS, et al. NEJM. 2017;377:2228-39 2017 MFMER slide-30

Contemporary Hormonal Contraception and the Risk of Breast Cancer No. of personyears Non-oral Combined Hormonal Contraception No. Breast CA events Adjusted Relative Risk (95% CI) Patch 10,842 2 0.85 (0.21-3.41) Vaginal Ring 791,313 20 0.97 (0.62-1.50) Non-oral Progestin-only Hormonal Contraception Implant 42,217 9 0.93 (0.48-1.79) LNG intrauterine system 503,441 571 1.21 (1.11-1.33) Medroxyprogesterone acetate depot 19,308 5 0.95 (0.40-2.29) CA: Cancer LNG: Levonorgestrel Mørch LS, et al. NEJM. 2017;377:2228-39 2017 MFMER slide-31

ACOG Practice Advisory Decreased risk of ovarian, endometrial, and colon cancers Overall cancer risk may be slightly lower in users compared to nonusers Decreased maternal mortality rate 26.4 deaths per 100,000 United States women in 2015 Breastfeeding, exercise, limited alcohol intake can lower breast cancer risk Many nonhormonal contraceptive options exist ACOG: American College of Obstetricians and Gynecologists ACOG. 2017 2017 MFMER slide-32

Which of the following is likely to be at the highest risk of developing breast cancer? A. 36 yo with 2 children starting hormonal contraception for the first time B. 28 yo using a patch for hormonal contraception C. 33 yo first-time pregnant woman having used hormonal contraception for 20 years D. 22 year old woman using a copper IUD to prevent contraception 2017 MFMER slide-33

Conclusion Data inconsistent Shared decision making Nonhormonal contraceptive methods 2017 MFMER slide-34

Questions & Discussion smith.bradley1@mayo.edu 2017 MFMER slide-35