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La terapia ormonale sostitutiva: sostituire che cosa? Catania, 26 ottobre 2006

La terapia ormonale sostitutiva: sostituire che cosa? Catania, 26 ottobre 2006. Terapia ormonale sostitutiva e rischio oncologico. Prof. A.Gadducci Dipartimento di Medicina della Riproduzione, Divisione di Ginecologia e Ostetricia, Sezione Interna di Ginecologia Oncologica, Università di Pisa.

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La terapia ormonale sostitutiva: sostituire che cosa? Catania, 26 ottobre 2006

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  1. La terapia ormonale sostitutiva: sostituire che cosa? Catania, 26 ottobre 2006 Terapia ormonale sostitutiva e rischio oncologico Prof. A.Gadducci Dipartimento di Medicina della Riproduzione, Divisione di Ginecologia e Ostetricia, Sezione Interna di Ginecologia Oncologica, Università di Pisa

  2. La terapia ormonale sostitutiva: sostituire che cosa? Terapia ormonale sostitutiva e rischio oncologico • Breast cancer • Endometrial cancer • Ovarian cancer

  3. Estrogens and breast cancer Estrogens may: • stimulate cell proliferation and increase the numbers of errors occuring during DNA replication • cause DNA damage via their genotoxic metabolites produced during oxidation reactions • induce expression/activation of h-TERT, growth factors, matrix metalloproteinases and VEGF

  4. IGF-I and breast cancer Estrogens Insulin TGF- EGF Antiestrogens Glucocorticoids TGF-ß StimulateInhibit IGF-secretion

  5. IGF-I and breast cancer • Breast cancer patients show elevated plasma IGF-I • IGF-I serum levels increases with tumor size • IGF-I levels higher in women with cancer recurrence • Survival probability greater in patients with plasma • IGF-I levels < 120 ng/ml Vadgama et al, (Oncology 1999)

  6. Thymidine labeling index in normal breast epithelium during different phases of the menstrual cycle authors weeks of menstrual cycle 1 2 3 4 Meyer (1977) 0.17% 0.17% 0.79% 0.79% Anderson (1989) 0.51% 0.37% 0.78% 1.25% Williams (1991) 1.8% 1.5% 3.4% 3.6%

  7. Progestins and breast cancer cell mitosis T- 47D and MCF-7 breast cancer cell lines Progestins induced an initial increase in the number of S-phase cells, but 12h later a reduction occurred so that after 24h the percentage of cells in S-phase was lower than baseline and was maintained at 96h Clarke and Sutherland, 1996; Musgrove et al, 1991

  8. A re-analysis:Collaborative Group on Hormonal Factors in Breast Cancer (Lancet 1997) • Collaborative combined re-analysis • More rigorous than a standard meta-analysis • 51 studies world-wide • 51.000 cases / 108000 controls • no statistical evidence of variation in the results across the studies • 80% of users had taken oestrogens alone, and there was no evidence of variation according to type of HRT preparation

  9. The risk increased with increasing duration of use (+ 2.3%/year) roughly equivalent to the increase associated with delaying menopause by a year The effects of HRT on breast cancer disappeared 5 years after ceasing use A re-analysis:Collaborative Group on Hormonal Factors in Breast Cancer (Lancet 1997)

  10. Breast cancer cases in 1000 women aged 50 over the next 20 years non HRT users 45 HRT 5 yrs 47 HRT 10 yrs 51 HRT 15 yrs 57 Collaborative group on Hormonal Factors in Breast cancer, Lancet, 1997

  11. Obesity and breast cancer risk in postmenopausal women Conversion androgens estrogens SHBG levels • Breast cancer risk increases from the basal individual risk by 2.3% for each use of ERT, but this increase seems to be almost entirely limited to lean women • Overweight postmenopausal women alredy have achieved the maximun hormone-related risk to their endogenous production of estrogens

  12. Cythocrome P450 gene polymorfism, HRT and BC risk • In a case-control study (1521 BC cases and 1498 controls), CYP1B1 gene polymorfism did not influence overall BC risk. • However, women who had taken HRT for > 4 yrs and carried a particular CYP1B1 genotype (CYP1B1*3/*3) had a RR of BC of 2.0 (95% CI 1.1-3.5) compared with long-term HRT users without this genotype From Rylander-Rudqvist, 2003

  13. (1.0-1.5) (1.0-1.6) (1.0-1.5) (1.0-1.3) (0.5-1.6) RR of breastcancer 716/196666 805/179401 162/29564 11/3048 130/24757 101/17428 No use E-P(?) E P E-P E and E-P Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk (all data) Modified from Schairer et al, JAMA 2000; 283: 485-491

  14. (CI 1.07-1.45) (CI 1.02-1.18) (CI 0.97-1.15) (CI 1.13-1.68) (CI 0.88-1.35) Effects of Hormonal Replacement Therapy on Breast Cancer Risk: Estrogen Versus Estrogen Plus Progestin over 5 yrs Hormone Replacement Therapy: HRT Estrogen replacement therapy: ERT Estrogen progestin replacement therapy: EPRT Continuous combined replacement therapy: CCRT Sequential estrogen + progestin therapy: SEPRT From Ross RK et al, 2000

  15. Risks and benefits of estrogen plus progestin in healthy postmenopausal women (Women’s Health Initiative [WHI] randomized controlled trial) 16.608 postmenopausal women aged 50-79 with an intact uterus were randomized by 40 US centers in 1993-1998 Randomization Placebo CE 0.625 mg/die+MPA 2.5 mg/die 2002

  16. Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI) After a median 5.2 follow-up HR ( 95% CI) Coronary heart disease 1.29 (1.02-1.63) Stroke 1.41 (1.07-1.85) Pulmonary embolism 2.13 (1.39-3.25) Breast cancer 1.26 (1.00-1.59) Colorectal cancer 0.63 (0.43-0.92) Endometrial cancer 0.83 (0.47-1.47) Hip fracture 0.66 (0.45-0.98) Death due other causes 0.92 (0.74-1.14)

  17. Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI) Absolute excess risks per 10.000 person-years attributable to E+P • 7 more coronary heart disease events • 8 more strokes • 8 more pulmonary embolisms • 8 more invasive breast cacers • 6 fewer colorectal cancers • 5 fewer hip fractures 2002

  18. WHI trial: Critical questions • 26% of women were current or past hormone users and 1/3 of them for > 5 years. • The risk for breast cancer was increased only in those women previously treated with hormones. • In never users before entering the study, the HR for breast cancer was 1.06 after 5.2 years of HRT. • MPA is a very potent down regulator of the estrogen receptor. • HRT is a collective name, but not all types of HRT are the same.

  19. Effects of CE in postmenopausal women with hysterectomy: WHI randomised controlled trial 10.739 postmenopausal women aged 50-79 with prior hysterectomy randomized by 40 US centers Randomization Placebo CE 0.625 mg/die 2004

  20. Risks and benefits of CE in postmenopausal women with hysterectomy (WHI trial) After a median 6.8 follow-up HR ( 95% CI) Coronary heart disease 0.91 (0.75-1.12) Stroke 1.39 (1.10-1.77) Pulmonary embolism 1.34 (0.87-2.06) Breast cancer 0.77 (0.59-1.01) Colorectal cancer 1.08 (0.75-1.55) Hip fracture 0.61 (0.41-0.91) 2004

  21. Million Women Study 1.084.110 UK women aged 50-64 years with an intact uterus were recruited breast cancer RR (95% CI) Current HRT use 1.66 (1.58-1.75) Estrogen alone 1.30 (1.22-1.38) Estrogen/progestin 2.00 (1.91-2.09) Tibolone 1.45 (1.25-1.67) Beral 2003

  22. Million Women Study breast cancer RR (95% CI) Never users of HRT 1.00 (0.96-1.04) Past users of HRT < 1 year 0.94 (0.84-1.05) 1-4 years 1.01 (0.92-1.12) 5-9 years 1.14 (1.00-1.30) >10 years 1.05 (0.84-1.30) Beral 2003

  23. Million Women Study breast cancer RR (95% CI) Current use of estrogen-progestin combinations < 1 year 1.45 (1.19-1.78) 1-4 years 1.74 (1.60-1.89) 5-9 years 2.17 (2.03-2.33) >10 years 2.31 (2.08-2.56) Beral 2003

  24. Million Women Study Duration use < 5 years Duration use > 5 yearsRR (95% CI) RR (95% CI) Sequential 1.77 (1.59-1.97) 2.12 (1.95-2.30) Continous 1.57 (1.37-1.79) 2.40 (2.15-2.67) Beral 2003

  25. Million Women Study breast cancer RR (95% CI) Current use estrogen alone < 1 year 0.81 (0.55-1.20) 1-4 years 1.25 (1.10-1.41) 5-9 years 1.32 (1.20-1.46) >10 years 1.37 (1.22-1.54) Beral 2003

  26. Breast cancerrisk and HRT with progestins other MPA Cohort study including 3175 women (mean follow-up= 8.9 years) 83% of them received TTS estradiol + progestin other than MPA RR (95% CI) 0.98 0.65-1.5 Cohort study including 54548 women (mean follow-up= 5.8 years) RR 95% CI estrogen alone 1.1 0.8-1.6 estrogen + synthetic progestin 1.4 1.2-1.7 estrogen + micronized progesterone 0.9 0.7-1.2 De Lignieres 2002 Fournier 2004

  27. La terapia ormonale sostitutiva: sostituire che cosa? Terapia ormonale sostitutiva e rischio oncologico • Breast cancer • Endometrial cancer • Ovarian cancer

  28. Endometrial carcinoma Type-1 Type-2 Histology Endometrioid Non endometrioid OriginAtypical hyperplasia Intraepithelial carcinoma Endocrine Estrogen-dependent Estrogen- statusindependent P53-status Wild-type Mutated Prognosis Good Poor

  29. 5-year survival in EC by histotype pts (n) 5-year survival HR (95%CI) Endometrioid 6231 81.2% reference Adenosquamous 317 76.1% 1.1 (0.9-1.4) Mucinous 74 76.2% 0.9 (0.6-1.5) Serous 335 48.4% 1.7 (1.4-2.0) Clear cell 185 59.7% 1.6 (1.2-2.0) 25th Volume Annual Report, 2003

  30. Postmenopausal endogenous estrogens and risk of EC Variables cases controls RR (95% CI) p value E1 (pg/ml) <20 10 83 1.0 20-28 19 79 2.1 (0.9-4.8) >28 27 56 3.9 (1.8-8.7) < 0.001 SHBG (nMol/L) <44.3 26 67 1.0 44.3-64.418 74 0.6 (0. 3-1.2) >64.4 13 80 0.39 (0.18-0.84) 0.01 From Zeleniuch-Jacquotte, 2001

  31. Postmenopausal endogenous estrogens and risk of EC Variables cases controls RR (95% CI) p value E2 (pg/ml) <6 14 77 1.0 6-8 16 80 1.1 (0.52-2.4) >8 27 61 2.4 (1.1-4.9) 0.02 Free E2 (%) <1.10 13 78 1.0 1.10-1.2813 84 1.1 (0. 44-2.4) >1.28 31 60 3.5 (1.6-7.5) < 0.001 From Zeleniuch-Jacquotte, 2001

  32. Insuline like growth factor (IGF) in endometrium • IGF are predominantly synthetized by the stromal cells • IGF expression is up- regulated by estrogens • IGF- receptors are up- regulated by progesterone

  33. Insuline-like growth factor binding protein (IGF-BP) mRNA in the endometrium IGF-BP 1 high expression in late secretory phase IGF- BP 2 no cyclic change IGF- BP 4 no cyclic change IGF- BP 5 no cyclic change IGF- BP 6 high expression in late secretory and early proliferative phase From Rutanen et al, 1994

  34. IGFBP-1 expression and endometrial cancer Hyperinsulinemia Progesterone absence • Obesity • Hypertension • Early stages of non- • Insulin dependent diabetes • Anovulatory cycle • Postmenopause IGFBP-1 expression unopposed stimulation of endometrial cells by IGF uncontrolled cell proliferation

  35. HRT and EC risk: A meta-analysis Study selection: 30 studies with adequate controls and risk estimates RR 95% CI Unopposed estrogen users 2.3 2.1-2.5 Duration of use < 1 years 1.4 1.0-0.8 1-5 years 2.8 2.3-3.5 5-10 years 5.9 4.7-7.5 10 years 9.5 7.4-12.3 Regimen Intermittent and cyclic 3.0 2.4-3.8 Continuous 2.9 2.2-3.8 From Grady et al. 1995

  36. HRT and EC risk: A meta-analysis RR 95% CI Type of estrogen Conjugated 2.5 2.1-2.9 Synthetic 1.3 1.1-1.6 Dose of conjugated estrogen (mg) 0.3 3.9 1.6-9.5 0.625 3.4 2.0-5.6 >1.25 5.8 4.5-7.5 Time since last use (years) <1 4.1 2.9-5.7 1.4 3.7 2.5-5.5 >5 2.3 1.8-3.1 From Grady et al. 1995

  37. Incidence of hyperplasia in HRT users: Relationship with the length of progestin use Length of progestin use Incidence of hyperplasia 7 days 4 % 10 days 2 % 12 days 0 % Whitehead and Fraser, 1987

  38. Postmenopausal Estrogen/ Progestin Interventions (PEPI ) trial From Writing Group for the PEPI trial , 1996 Hyperplasia pts simple complex atypical % % % Placebo 119 0.8 0.8 0.8 CE 0.625 mg/day 119 27.7 22.7 11.8 CE +MPA 10 mg for 12 days 118 3.4 1.7 0 CE +MPA 2.5 mg /day 120 0.8 0 0 CE +MP 200 mg for 12 days 120 4.2 0 0.8

  39. Antiestrogenic activity of progestins • Down-regulation of ER • Enhanced conversion of estradiol to estrone • Down-regulation of bcl-2 expression • Suppression of estrogen-induced expression of VEGF • Stimulation of IGF-BG • Inhibition of the estrogen-induced activation of hTERT expression

  40. Postmenopausal estrogen plus progestin use and risk of EC RR 95% CI Gambrell 1980 cohort 0.2 0.1-0.6 Persson 1989 cohort 0.2 0.1-0.6 Voigt 1991 case-control 1.6 0.6-3.9 Jick 1993 case-control 1.9 0.9-3.8 Brinton 1993 case-control 1.8 0.6-4.9 Grady 1995 meta-analysis cohort 0.4 0.2-0.6 Grady 1995 meta-analysis case-control 1.8 1.1-3.1 WHI 2002 randomized trial 0.83 0.47-1.47 MWS 2005 cohort 0.71 0.56-0.9 Strom 2006 case-control 0.8 0.6-1-1

  41. Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI) After a median 5.2 follow-up HR ( 95% CI) Coronary heart disease 1.29 (1.02-1.63) Stroke 1.41 (1.07-1.85) Pulmonary embolism 2.13 (1.39-3.25) Breast cancer 1.26 (1.00-1.59) Colorectal cancer 0.63 (0.43-0.92) Endometrial cancer 0.83 (0.47-1.47) Hip fracture 0.66 (0.45-0.98) Death due other causes 0.92 (0.74-1.14)

  42. Risk of endometrial cancer by days/ month progestin used Cases Controls N N OR (95% CI) Never used 270 593 1.0 Progestin added 25 26 3.1 (1.7-5.7) < 10 days/mo. Progestin added 25 64 1.3 (0.8-2.2) 10-21 days/mo. Beresford et al. Lancet 1997

  43. Case-control study of HRT and EC US population-based case-control study: 511 EC cases aged 50-79 yrs 1412 random-digit-dialing controls OR (95% CI) ERT > 3 yrs 3.4 (1.4-8.3) HRT any duration 0.8 (0.6-1.1) HRT > 3 yrs vs ERT > 3 yrs 0.2 (0.1-0.6) Strom, 2006

  44. ccHRT and EC: RR (95% CI) ERT scHRT ccHRT Pike, 1997 2.2 (1.9-2.5) 1.9 (1.3-2.7) 1.1 (0.8-1.4) 1.1 (0.8-1.4) Weiderpass, 1999 6.2 (3.1-12.6) 2.9 (1.8-4.6) 0.2 (0.1-0.8) Hill, 2000 0.6 (0.3-1.3)

  45. La terapia ormonale sostitutiva: sostituire che cosa? Terapia ormonale sostitutiva e rischio oncologico • Breast cancer • Endometrial cancer • Ovarian cancer

  46. HRT and risk of EOC INCREASED INCIDENCE NO YES La Vecchia 1982 Cramer 1983 Smith 1984 Booth 1989 Wu 1988 Kaufman 1989 Hartge 1988 Whittemore 1993 Purdie 1999 Rodriquez 1995 Hempling 1997 Negri 1999 Coughlin 2000 Riman 2002 Sit 2002 Lacey 2002

  47. HRT and EOC : Re-analysis of 4 European Studies 2 studies conducted in Greece 1 in Italya total of 1470 EOC and 1 in UK3271 hospital records RR of EOC among HRT users: 1.71 (95% CI 1.30-2.25) Negri et al. 1999

  48. Cancer incidence and mortality in women receiving HRT Population study: cohort of 22.597 Swedish Women. 2230 incident cancer and 848 cancer deaths after 13 years of follow-up SiteIncidence O E RR 95% CI Breast 634 643 1.0 0.9-1.1 Endometrium 261 147 1.8 1.6-2.0 Ovary 131 141 0.9 0.8-1.1 Colon 153 175 0.9 0.7-1.0 Liver and biliary tract 43 73 0.6 0.4-0.8 Melanoma 60 68 0.9 0.7-1.1 Other skin 43 46 0.9 0.7-1.3

  49. HRT and risk of EOC 491 pts with EOC , 741 women as controls RR among HRT users: O.85 (95% CI= 0.6-1.2) duration EOC controls Odds ratio (y) 470 70595%CI None 391 (83.2%) 581 (82.4%) 1.0 <5 54 (11.5%) 74 (10.5%) 0.8 (0.5-1.2) 5-9 16 ( 3.4%) 28 ( 4.0%) 0.6 (0.3-1.1) >10 9 ( 1.9%) 22 ( 3.1%) 0.6 (0.3-1.4) Hempling 1997

  50. Risks and benefits of estrogen plus progestin in healthy postmenopausal women (WHI) After a median 5.2 follow-up HR ( 95% CI) Coronary heart disease 1.29 (1.02-1.63) Stroke 1.41 (1.07-1.85) Pulmonary embolism 2.13 (1.39-3.25) Breast cancer 1.26 (1.00-1.59) Colorectal cancer 0.63 (0.43-0.92) Endometrial cancer 0.83 (0.47-1.47) Hip fracture 0.66 (0.45-0.98) Ovarian cancer 1.58 (0.77-3.24)

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