1. Postmenopausal Hormone Therapy and Breast Cancer PHT : an Initiator or Promoter/Cofactor ? Semih Kaleli Cerrahpaşa Medical Faculty Department of Obstetrics and Gynecolgy

2. Collaborative Group Study on PHT and Breast Cancer Prospective studies RR Prospective studies RR Canada NBSS 1.01 Canada NBSS 1.01 Schairer NIH 0.97 Schairer NIH 0.97 Nurses’ Health 1.20 Nurses’ Health 1.20 Netherlands’ Cohort 0.98 Netherlands’ Cohort 0.98 Iowa Women’s Health 1.20 Iowa Women’s Health 1.20 Other 0.62 Other 0.62 All Prospective 1.09 All Prospective 1.09 Collaborative Group Study

3. Case-Population Controlled RR Brinton 1.09 Brinton 1.09 CASH 1.20 CASH 1.20 Histop 1.15 Histop 1.15 Bain 1.33 Bain 1.33 Ewertz 1.35 Ewertz 1.35 Long Island 1.49 Long Island 1.49 4 state study 1.17 4 state study 1.17 Yang/Gallagher 1.29 Yang/Gallagher 1.29 Stanford 0.75 Stanford 0.75 Other 0.96 Other 0.96 All Case-Population Controlled 1.15 All Case-Population Controlled 1.15 Collaborative Group Study Collaborative Group Study on PHT and Breast Cancer

4. Case-Hospital Controlled RR Morabia 1.41 Morabia 1.41 Vessey 1.21 Vessey 1.21 La Vecchia 1.67 La Vecchia 1.67 Katsouyanni 1.16 Katsouyanni 1.16 Franceschi 1.37 Franceschi 1.37 Other 1.03 Other 1.03 All Case-hospital controlled 1.27 All Case-hospital controlled 1.27 All studies 1.14 All studies 1.14 Collaborative Group Study Collaborative Group Study on PHT and Breast Cancer

5. Postmenopausal HT- Breast Cancer Risk The Effect of PHT Duration PHT case/control RR 0 12467/23568 1.00 0-1 1154/2546 1.09 1-4 1660/3999 1.05 5-9 813/1912 1.19 10-14 386/867 1.09 > 15 337/587 1.58 Collaborative Group Study

6. Tumor PHT+/PHT- RR Local Tm. 1387/4104 1.00 Axillary LN 940/2827 0.82 Distant Metas. 98/312 0.54 PHT- Stage of Breast Cancer Collaborative Group Study

7. WHI Study Aim: CVD, breast cancer, colorectal cancer and osteoporotic fracture risk Aim: CVD, breast cancer, colorectal cancer and osteoporotic fracture risk Age 50-80 yrs (64.500+100.000 women) Age 50-80 yrs (64.500+100.000 women) Most expensive NIH study (628 million USD) Most expensive NIH study (628 million USD) 1. Diet 1. Diet 2. PHT 2. PHT 3. Calcium-VitD 3. Calcium-VitD 40 center, started 1993-1998, ended 2007 40 center, started 1993-1998, ended 2007 2002’ EP Arm stopped and 2004’ E Arm stopped 2002’ EP Arm stopped and 2004’ E Arm stopped

8. WHI-EP Arm Result EP Placebo OR Nominal/Adjusted CI Follow-up 62.2 (16.1) 61.2 (15.0) CVH 164 (0.37) 122 (0.30) 1.29 1.02-1.63/0.85-1.97 Stroke 127 (0.29) 85 (0.21) 1.41 1.07-1.85/0.86-2.39 VTE 151 (0.34) 67 (0.16) 2.11 1.58-2.82/1.26-3.55 Breast Ca 166 (0.38) 124 (0.30) 1.26 1.00-1.59/0.83-1.92 End. Ca 22 (0.05) 25 (0.06) 0.83 0.47-1.47/0.29-2.32 Colon Ca 45 (0.10) 67 (0.16) 0.63 0.43-0.92/0.32-1.24 Coxa fr. 44 (0.10) 62 (0.15) 0.66 0.45-0.98/0.33-1.33 Vertebral fr. 41 (0.09) 60 (0.15) 0.66 0.44-0.98/0.32-1.34 Global Index 751 (0.09) 623 (1.51) 1.15 1.03-1.28/0.95-1.39

9. WHI-EP Arm Total Breast Ca Invasive Breast Ca in situ Breast Ca

10. WHI-Estrogen Arm Total Breast Ca Invasive Breast Ca in situ Breast Ca JAMA. 2006 Apr 12;295(14):1647-57

11. Lancet 2003; 362: 419–27 MWS EP Use – Breast Cancer Risk

12. MWS Estrogen Use – Breast Cancer Risk Lancet 2003; 362: 419–27

13. EP Use – Breast Cancer Risk Schairer et al. JAMA, 2000 29 center, multidisciplinary cohort 29 center, multidisciplinary cohort 46335 postmenopausal women 46335 postmenopausal women 2082 breast ca. 2082 breast ca. ET RR 1.2, EPT RR 1.4 ET RR 1.2, EPT RR 1.4 ET after 8 yrs, EPT after 4 yrs RR increase ET after 8 yrs, EPT after 4 yrs RR increase ET RR increase 0.01/yr (general) ET RR increase 0.01/yr (general) RR increase 0.03/yr (BMI<24.4) RR increase 0.03/yr (BMI<24.4) EPT RR increase 0.08/yıl (general) EPT RR increase 0.08/yıl (general) RR increase 0.12/yıl (BMI<24.4) RR increase 0.12/yıl (BMI<24.4)

14. Danish Nurse Cohort PHT - Breast Cancer Risk Int. J. Cancer: 109, 721–727 (2004)

15. Hormone Type Hormone RR (% 95 GA) Hormone RR (% 95 GA) Estrogen Estrogen MWS CE 1.29 (1.16-1.43) Estradiol 1.24 (1.12-1.37) Estradiol 1.24 (1.12-1.37) Progestin Progestin MWS C21 (MPA) 2.14 (1.18-3.87) DNC C19 (NETA,LNG) 2.14 (1.68-2.72) Collins JA. Human Reproduction Update, Vol.11, No.6 pp. 545–560, 2005

16. Hormone Dose Hormone Dose RR Hormone Dose RR Estrogen Estrogen MWS CE < 0.625 mg 1.27 (1.11-1.45) WHS SE < 1 mg E2 CE > 0.625 mg 1.25 (1.00-1.56) CE > 0.625 mg 1.25 (1.00-1.56) SE > 1 mg E2 SE > 1 mg E2 Progestin Progestin WHS MPA < 5 1.54 (1.12-2.11) p:0.37 5-9 1.30 (0.86-1.98) 5-9 1.30 (0.86-1.98) 10 1.13 (0.76-1.68) 10 1.13 (0.76-1.68) Collins JA. Human Reproduction Update, Vol.11, No.6 pp. 545–560, 2005

17. Hormon Route of Administration Route RR (CI 95 %) Route RR (CI 95 %) Oral 1.32 (1.21-1.45) p:0.27 Transdermal 1.24 (1.11-1.39) Implant 1.65 (1.26-2.16) Collins JA. Human Reproduction Update, Vol.11, No.6 pp. 545–560, 2005

18. Progestin Use MWS’03 Seq. 1.49 (1.16-1.90) WHS’02 Cont. 1.87 (1.46-2.40) DNC’04 Chen’02 p=0.13 Weiss’02 (1 case extra/yr in cont. fashion) Li’03 Collins JA. Human Reproduction Update, Vol.11, No.6 pp. 545–560, 2005

19. Prior PHT Use – Breast Cancer Risk WHI 1.20 (0.94-1.53) WHI 1.20 (0.94-1.53) MWS 1.01 (0.95-1.08) MWS 1.01 (0.95-1.08) DCH 1.33 (0.82-2.16) DCH 1.33 (0.82-2.16) DNC 1.16 (0.76-1.77) DNC 1.16 (0.76-1.77) Li 1.00 (0.60-1.80) Li 1.00 (0.60-1.80) Collins-metaanalysis 1.02 (0.96-1.08)

20. Mammography window Breast tumor Cell No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years 10¹² 1 Premammography Preclinical Clinical 1 mm1 cm2.5 cm Modified from Wertheimer 1986’

21. Tumor Doubling Time Adenocarcinomas 50-150 days Adenocarcinomas 50-150 days Some embriyonal tumors 20-40 days Some embriyonal tumors 20-40 days

22. If it is assumed that an exponential growth occurs early in the malignancy and tumor starts from a single cell, If it is assumed that an exponential growth occurs early in the malignancy and tumor starts from a single cell, 20-tumor doublings require for the tumor mass to reach 1-mm 20-tumor doublings require for the tumor mass to reach 1-mm 30 tumor doublings get the tumor mass up to 1 cm 30 tumor doublings get the tumor mass up to 1 cm Some embryonal tumors and lymphomas have shortest doubling times such as 20-40 days Some embryonal tumors and lymphomas have shortest doubling times such as 20-40 days However, adenocancers have relatively longer doubling times that usually range from 50 to 150 days However, adenocancers have relatively longer doubling times that usually range from 50 to 150 days Breast cancers are supposed to have approximately 100 days of tumor doubling. Therefore, breast cancers that initiated after an PHT, needs app. 3000 days (8.2 years) to be able to reach to clinically palpable phase Breast cancers are supposed to have approximately 100 days of tumor doubling. Therefore, breast cancers that initiated after an PHT, needs app. 3000 days (8.2 years) to be able to reach to clinically palpable phase Also, premammographic phase needs at least 5 years past to be able to detect a breast carcinomas Also, premammographic phase needs at least 5 years past to be able to detect a breast carcinomas

23. Tumor Volume Doubling Time of Primary Breast Cancer Age at geometric mean Age at geometric mean diagnosis in days 68 % range diagnosis in days 68 % range (yr) (95 % Conf. limits) (yr) (95 % Conf. limits) < 50 80 (44-147) 24-273 < 50 80 (44-147) 24-273 50-70 157 (121-204) 46-533 50-70 157 (121-204) 46-533 > 70 188 (120-195) 55-640 > 70 188 (120-195) 55-640 Peer PGM. Cancer 1993;71~3547-51

24. Tumor Doubling Time in Hereditary Breast Cancer Tilanus-Linthorst MMA. EJC 41;1610,2005 ▼ carriers ▼ non-carriers

25. Breast tumor Cell No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years 10¹² 1 Premammography Preclinical Clinical 1 cm2.5 cm Wertheimer 1986 MWS WHI DNC HERS II NCI-Schairer

26. Invasive Breast Cancer Greater than 2 cm Diagnosed During PHT study HT never user ever user study HT never user ever user n/N % n/N % n/N % n/N % BCDPP E 56/165 (34 %) 44/112 (35 %) BCDPP E 56/165 (34 %) 44/112 (35 %) EP 56/165 (34 %) 4/31 (15 %) EP 56/165 (34 %) 4/31 (15 %) DCS PHT 55/131 (42 %) 75/209 (36 %) DCS PHT 55/131 (42 %) 75/209 (36 %) WHI E 18/133 (14 %) 13/104 (23 %) WHI E 18/133 (14 %) 13/104 (23 %) EP 22/150 (15 %) 42/199 (21 %) EP 22/150 (15 %) 42/199 (21 %) MWS PHT all breast cancers diagnosed at an MWS PHT all breast cancers diagnosed at an average of 1.2 years average of 1.2 years

27. Tjonneland A et al. Cancer 2004;100:2328–37

28. Receptor Status of Breast Cancer Cases Diagnosed During PHT Tjonneland A et al. Cancer 2004;100:2328–37

29. Changes of Proliferation Markers in Breast Cancer Developed During PHT Prasad. Cancer 2003;98:2539–46 !

30. Holmberg L. THE LANCET Vol 363 February 7, 2004 HABITS Study: New Tm in Breast Cancer Patients During PHT

31. Prevelance of Occult Breast Cancer in Healthy Women Age Group BC Age Group BC 20-54 21 % Breast Cancer 20-54 21 % Breast Cancer 18 % in situ BC 18 % in situ BC 14 % DCIS 14 % DCIS 4 % LCIS 4 % LCIS 1 % DCIS+LCIS 1 % DCIS+LCIS 40-50 39 % BC 40-50 39 % BC Nielsen M et al. Br J Cancer 1987;56:814–819

32. By the time that the slowest growing breast tumor has become 2 cm, there are many more invasive tumors in the population as well as undiscovered DCIS

33. Summary Postmenopausal EP use slightly increases the breast cancer risk after 4-5 years. Postmenopausal EP use slightly increases the breast cancer risk after 4-5 years. Postmenopausal estrogen-only HT is safe at least 7-8 years Postmenopausal estrogen-only HT is safe at least 7-8 years Prior HT does not change the current risk of breast cancer attributable to PHT Prior HT does not change the current risk of breast cancer attributable to PHT Acceleration/promotion of preexisting/undiscovered breast tumors by PHT is not certain but it is possible Acceleration/promotion of preexisting/undiscovered breast tumors by PHT is not certain but it is possible

34. Screen detected and interval breast cancer during PHT Norwegian breast cancer screening program Hofvind S et al. Int J Cancer 2006;118,3112–3117

35. EP Use and Mammographic Density in Postmenopausal Women: WHI Study density change EP (%) Placebo (%) density change EP (%) Placebo (%) Year 1-baseline 6.0 -0.9 Year 1-baseline 6.0 -0.9 (4.6:7.5) (-1.5:-0.2) (4.6:7.5) (-1.5:-0.2) Year 2-baseline 4.9 -0.8 Year 2-baseline 4.9 -0.8 (3.6:6.3) (-1.6:-0.1) (3.6:6.3) (-1.6:-0.1) McTiernan A et al. J Natl Cancer 2005;1366-76

36. Value of the Breast Imaging Techniques n=429,000, 43 facilities, 2351 BC cases Screening Computer-aided Screening Computer-aided mammography mammography mammography mammography Specificity 90.2 87.2 < 0.001 Specificity 90.2 87.2 < 0.001 Sensitivity 80.4 84.0 = 0.32 Sensitivity 80.4 84.0 = 0.32 Recall rate 10.1 13.2 < 0.001 Recall rate 10.1 13.2 < 0.001 PPV 4.1 3.2 = 0.01 PPV 4.1 3.2 = 0.01 25-50 % of cases of BC are identified retrospectively on the previous annual screening mammography 25-50 % of cases of BC are identified retrospectively on the previous annual screening mammography Fenton JJ et al. N Engl J Med 2007;356:1399-09