Is postmenopause hormone therapy acceptable in view of breast ...

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  • One out of ten women will develop breast cancer sometime in their life
  • Although breast cancer is very frequent, its prognosis is very favorable
  • Public health policy with respect to breast cancer is of very high importance
  • For longer than ten years we know that long term HT is associated with a small but significant breast cancer risk.
  • In the time of individualization of HT, we would like to know 1) what characteristics of our regimen influence breast cancer risk and 2) what does this risk mean in real life
  • Regimens containing NETA were associated with higher risk of breast cancer, while dydrogesterone did not associate with significant risk
  • Let’s compare HT related risk with other risk factors of breast cancer. It’s far more risky if you are obese…
  • Is postmenopause hormone therapy acceptable in view of breast ...

    1. 1. Endocrinologist Ass. Professor of Gynecological Endocrinology University of Athens, Greece Irene Lambrinoudaki Is postmenopausal hormone therapy acceptable in view of breast cancer risk?
    2. 2. National Institutes of Health, http://seer.cancer.gov , accessed April 2010 <ul><li>The most frequent cancer in women </li></ul><ul><li>Incidence: 124 cases / 100,000 women/years </li></ul><ul><li>Lifetime risk: 12.1% </li></ul><ul><li>Risk between 50 and 60 years: 2.4% </li></ul>Breast cancer
    3. 3. Breast cancer has a favorable prognosis 10-year survival rate: 80% National Institutes of Health, http://seer.cancer.gov , accessed April 2010
    4. 4. Breast cancer: High incidence + favorable prognosis = high prevalence National Institutes of Health, http://seer.cancer.gov , accessed April 2010
    5. 5. Meta-analysis (51 studies ) 1.35 1 NHS EPT 1.32 2 WHI EPT 1.26 3 WHI EPT 1.24 4 MWS EPT/ET 1.66 5 1 . Lancet 1997;350:1047 2 . Chen WY et al, Ann Intern Med 2002;137:798 3. Writing Group for WHI, JAMA 2002;288:321 Study RR Hormone therapy is associated with a small but significant risk of breast cancer 4. Chlebowski et al, JAMA 2003;289:3243 5. Beral V, Lancet 2003;362:419-27
    6. 6. Characteristics of HT regimen and breast cancer risk A. Characteristics of HT regimen B. Real impact of risk (attributable risk) 1. Estrogen monotherapy versus combined EPT 2. Duration of use 3. Mode (sequential versus continuous) 4. Route (oral versus transdermal) 5. Dose 6. Type of estrogen 7. Type of progestin
    7. 7. 1. Estrogen monotherapy is associated with lower risk compared to combined EPT therapy Shah NR, Wong T Expert Opin Pharmacother. 2006;7(18):2455-63. E EPT
    8. 8. 1. Estrogen monotherapy versus combined EPT therapy <ul><li>EPIC study: prospective observational study </li></ul><ul><li>10 European countries </li></ul><ul><li>134,000 women </li></ul><ul><li>Mean follow-up: 8.6 years </li></ul>Bakken K et al, Int J Cancer 2010
    9. 9. 2. Breast cancer risk increases with duration of HT use EPIC Study, Bakken K et al, Int J Cancer 2010
    10. 10. WHI Study: women with no prior exposure to HT had no increased risk of breast cancer Anderson GL, Maturitas 2006;55:103
    11. 11. 3. Continuous regimens may be associated with higher risk compared to sequential regimens EPIC Study, Bakken K et al, Int J Cancer 2010 The cumulative exposure to progestin is lower with the sequential regimens Lyytinen H et al, Int J Cancer 2010 <ul><li>Finnish case-control study </li></ul><ul><li>10,000 cases and 30,000 controls aged 50-62 </li></ul>
    12. 12. 4. The route of HT does not modify the risk of breast cancer Oral HT Transdermal HT Lyytinen H et al, Int J Cancer 2010 RR RR Cases controls Cases controls Bakken K et al, Int J Cancer 2010 EPIC study: oral versus transdermal RR 1.13 (NS)
    13. 13. 5. Dose of estrogen in HT and breast cancer risk <ul><li>No RCT on the effect of different HT doses on breast cancer risk </li></ul><ul><li>Lower estrogen doses have less impact on breast density 1 </li></ul><ul><li>Breast density is a surrogate marker of breast cancer </li></ul>Martin LJ et al, Maturitas 2009;64:20-26 Stuedal A Climacteric 2009;12:248-58 Grady D Menopause 2007;14:391-6
    14. 14. Identical HT regimens differing only in E2 dose are associated with different increases in breast density Christodoulakos G, Lambrinoudaki I, Vourtsi A et al, Maturitas 2006;54:78
    15. 15. 6. The type of estrogen in HT does not influence breast cancer risk <ul><li>No RCT directly comparing CEE to E2 </li></ul><ul><li>EPIC study: </li></ul>Bakken K et al, Int J Cancer 2010 compound RR of breast cancer estradiol 1.08 – 1.61 CEE 1.16 – 2.18 RR CEE versus E2: 1.15 NS
    16. 16. <ul><li>E3N Study (French component of EPIC) </li></ul><ul><li>80,391 postmenopausal teachers in France </li></ul><ul><li>Mean follow-up: 8.1 years </li></ul>Fournier A et al, J Clin Oncol 2008;26:1260 7. The type of progestin may modify breast cancer risk
    17. 17. 7. The type of progestin may modify breast cancer risk <ul><li>All Finnish women > 50 years (221,551 women) </li></ul><ul><li>Follow – up 1994 – 2005 </li></ul><ul><li>6,211 incident cases of breast cancer </li></ul>Lyytinen H et al, Obstet Gynecol 2009;113:65
    18. 18. B. HT and absolute risk of breast cancer Among 50-year old women not on HT , 11 out of 100 0 will develop breast cancer until the age of 55 http://seer.cancer.gov
    19. 19. B. HT and absolute risk of breast cancer <ul><li>Baseline 5-year absolute risk : 1.1 % </li></ul><ul><li>HT related RR: 1.26 (WHI) </li></ul>5-year risk of breast cancer attributable to HT: 3 women in 1000 Among 50-year old women who use HT (CEE/MPA) for 5 years , 14 out of 100 0 will develop breast cancer until the age of 55
    20. 20. Risk factors of breast cancer: comparative assessment <ul><li>Risk factors </li></ul><ul><li>ΒΜΙ (>29,7 Kg/m2 ) 1.26-2.52 </li></ul><ul><li>alcohol ( 20 g / day x 5 years ) 1.28 </li></ul><ul><li>Hormone Therapy ( EPT / WHI) 1. 26 </li></ul><ul><li>1 st delivery > 30 years 1. 5 </li></ul><ul><li>Family history of breast cancer 1. 5 </li></ul><ul><li>Benign breast disease - breast biopsy 1.6-2.8 </li></ul><ul><li>Increased breast density 2.0-4.0 </li></ul>RR Shah NR, Exp Opin Pharmacotherapy 2006;7(18):2455-63 Pichard C et al, Maturitas 2008;60:19-30
    21. 21. Mammographic patterns according to BI-RADS system I II III IV < 25% dense > 75% dense 51-75% dense 25-50% dense RR 1.0 2.03 2.95 4.03 Cummings SR, J Natl Cancer Institute 2009;101:384-389
    22. 22. Bluming AZ et al, Cancer J 2009;15:93-104
    23. 23. Is postmenopausal hormone therapy acceptable in view of breast cancer risk?
    24. 24. expectations Osteoporosis prevention Cardiovascular disease prevention WHI <ul><li>Osteoporosis prevention </li></ul><ul><li>Increase of stroke risk </li></ul><ul><li>Increase of CHD risk in older women </li></ul><ul><li>Increase of VTE risk </li></ul><ul><li>Increase of breast cancer risk </li></ul>Pre-WHI era: HT to every postmenopausal woman however...
    25. 25. Individualization of HT <ul><li>Patient selection </li></ul><ul><li>Timing of initiation </li></ul><ul><li>Duration of use </li></ul><ul><li>Regimen selection </li></ul><ul><li>Maximal efficacy </li></ul><ul><li>No clinically relevant risks </li></ul>Quality of life, osteoporosis prevention, CHD prevention Breast cancer, stroke, VTE <ul><li>Estrogen dose </li></ul><ul><li>Progestin type </li></ul><ul><li>Mode of delivery </li></ul><ul><li>Route of delivery </li></ul>Post -WHI era…
    26. 26. Patient classification Menopause Clinic 1. Premature ovarian failure (<4 0 ) , early menopause (<45) 2. Symptomatic women, normal age at menopause 3. Asymptomatic women, normal age at menopause <ul><li>Osteoporosis prevention </li></ul><ul><li>CVD prevention </li></ul><ul><li>Gynecologic cancer prevention </li></ul>
    27. 27. Pal, Lubna et al, Menopause 2008; 15(6):1086-1094. Premature ovarian dysfunction is associated with high bone turnover before the establishment of amenorrhea
    28. 28. Premature ovarian failure and osteoporosis risk Luborsky JL et al, Hum Reprod 2002
    29. 29. Premature ovarian failure is a strong risk factor for ischemic heart disease Incidence (per 1,000 women) Age (years) Kannel W, et al. Ann Intern Med. 1976;85:447-52 .
    30. 30. Premature ovarian failure Early menopause HT is indicated as “replacement” therapy <ul><li>CVD prevention </li></ul><ul><li>Osteoporosis prevention </li></ul><ul><li>Quality of life </li></ul><ul><li>Breast cancer </li></ul><ul><li>Stroke, VTE </li></ul><ul><li>Low incidence in ages < 45 </li></ul><ul><li>WHI results NOT extendable to this age group </li></ul>Panay N et al, Best Pract Res Clin Obstet Gynaeco l 2008 1 Nelson L, N Engl J Med 2009
    31. 31. Symptomatic women at their fifties 2
    32. 32. Climacteric symptomatology <ul><li>Vasomotor </li></ul><ul><li>Psychosomatic </li></ul><ul><li>Sexual / urogenital </li></ul><ul><li>Hot flashes </li></ul><ul><li>Night sweats </li></ul><ul><li>Vaginal dryness </li></ul><ul><li>Painful intercourse </li></ul><ul><li>Loss of libido </li></ul><ul><li>Recurrent urogenital infections </li></ul><ul><li>Sleep disturbances </li></ul><ul><li>Fatigue, diminshed well-being </li></ul><ul><li>Loss of interest in life </li></ul><ul><li>Mood swings, irritability </li></ul><ul><li>Headaches, arthralgias </li></ul>
    33. 33. Duration of vasomotor symptoms in middle-aged women: a longitudinal study. Col, Nananda et al, Menopause 2009; 16(3):453-457. Hot flashes last longer than we thought… <ul><li>50% of women have hot flashes > 4 years </li></ul><ul><li>23% of women still have hot flashes after 13 years </li></ul>
    34. 34. <ul><li>Quality of life </li></ul><ul><li>prevention of urogenital atrophy </li></ul><ul><li>Prevention of osteoporosis </li></ul><ul><li>Prevention of CHD </li></ul><ul><li>Breast cancer </li></ul><ul><li>VTE / Stroke </li></ul><ul><li>CHD </li></ul>?? Individual benefit / risk ratio HT in the symptomatic postmenopausal woman risk benefit
    35. 35. <ul><li>Symptom severity </li></ul><ul><li>Osteoporosis risk </li></ul><ul><li>Cardiovascular risk </li></ul><ul><li>Breast cancer risk </li></ul><ul><li>BMD </li></ul><ul><li>personal of family history of Fx </li></ul><ul><li>BMI </li></ul><ul><li>corticosteroid use </li></ul><ul><li>Smoking </li></ul><ul><li>Calcium intake, exercise </li></ul>Martin KA, Manson J, JCEM Dec 2008; 93:4576 Assessing the individual risk / benefit ratio <ul><li>Age </li></ul><ul><li>Years since menopause </li></ul><ul><li>BMI, WHI </li></ul><ul><li>Smoking </li></ul><ul><li>Hypertension </li></ul><ul><li>Diabetes </li></ul><ul><li>Personal or fam. history of VTE </li></ul>Kanis JA et al, Osteoporosis Int 2008; 19:399
    36. 36. Individual breast cancer risk assessment <ul><li>Age, age at menarche and menopause </li></ul><ul><li>BMI, adult weight gain </li></ul><ul><li>Family history of breast cancer (1 st degree relative) </li></ul><ul><li>Benign breast disease requiring FNA or biopsy </li></ul><ul><li>Previous hormone therapy </li></ul><ul><li>Nulliparity / 1 st delivery > 30years </li></ul><ul><li>Daily alcohol intake </li></ul><ul><li>Breast density </li></ul>Vogel VG et al, Menopause 2008; 15(4 Suppl):782 Santen RJ et al, Endocr Relat Cancer. 2007 Jun;14(2):169-87
    37. 37. Individual breast cancer risk assessment US National Institutes of Health, www.cancer.gov accessed April 2010 Patient 5-year risk: 1.2% Average 5-year risk: 1.4% National Cancer Institute breast cancer risk assessment tool <ul><li>Breast density: </li></ul><ul><li>BI-RADS II </li></ul><ul><li>BMI: 27 </li></ul><ul><li>Menopause: 51 </li></ul>Risk factor patient age 52 menarche 12 1 st delivery 27 1 st degree relative with breast cancer NO Breast biopsy NO Race white
    38. 38. <ul><li>Quality of life </li></ul><ul><li>Urogenital atrophy prevention </li></ul><ul><li>Osteoporosis prevention </li></ul><ul><li>CHD prevention </li></ul><ul><li>Breast cancer </li></ul>benefit risk <ul><li>Lowest effective E dose </li></ul><ul><li>Progestin selection </li></ul><ul><li>Follow-up: assess need of HT annually </li></ul>
    39. 39. Individual breast cancer risk assessment US National Institutes of Health, www.cancer.gov accessed April 2010 Patient 5-year risk: 2.5% Average 5-year risk: 1.4% US National Cancer Institute breast cancer risk assessment tool <ul><li>Breast density: </li></ul><ul><li>BI-RADS III </li></ul><ul><li>BMI: 27 </li></ul><ul><li>Menopause: 51 </li></ul>Risk factor patient age 52 menarche 12 1 st delivery 34 1 st degree relative with breast cancer YES Breast biopsy YES No of biopsies 1 Atypical hyperplasia NO Race white
    40. 40. <ul><li>Quality of life </li></ul><ul><li>prevention of urogenital atrophy </li></ul><ul><li>Prevention of osteoporosis </li></ul><ul><li>Prevention of CHD </li></ul><ul><li>Breast cancer </li></ul>?? risk benefit
    41. 41. Summary <ul><li>Hormone therapy is associated with a small, but statistically significant increase in breast cancer risk </li></ul><ul><li>The risk is more apparent with continuous combined HT regimens </li></ul><ul><li>The risk increases with duration of use </li></ul><ul><li>The risk may differ by the progestin in the HT regimen </li></ul><ul><li>The absolute risk is small and in most cases has minor clinical relevance </li></ul><ul><li>HT is acceptable , provided a thorough assessment of individual risk is performed in each woman </li></ul>
    42. 42. … . see you in Athens in 2012

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