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

Postmenopausal Hormone Postmenopausal Hormone Therapy and Breast Therapy and Breast

CancerCancer

PHT : an Initiator or PHT : an Initiator or Promoter/Cofactor ?Promoter/Cofactor ?

Semih KaleliSemih Kaleli

Cerrahpaşa Medical FacultyCerrahpaşa Medical Faculty

Department of Obstetrics and GynecolgyDepartment of Obstetrics and Gynecolgy

Collaborative Group Study on PHT and Collaborative Group Study on PHT and Breast CancerBreast Cancer

Prospective studies RRProspective studies RR Canada NBSS 1.01Canada NBSS 1.01 Schairer Schairer NIHNIH 0.97 0.97 NurseNursess’ Health ’ Health 1.201.20 Netherlands’ Cohort 0.98 Netherlands’ Cohort 0.98 Iowa Iowa WomenWomen’s Health 1.20’s Health 1.20 Other 0.62Other 0.62 All Prospective 1.09All Prospective 1.09

Collaborative Group Study

Case-Population ControlledCase-Population Controlled RR RR Brinton 1.09Brinton 1.09 CASH 1.20CASH 1.20 Histop 1.15Histop 1.15 Bain 1.33Bain 1.33 Ewertz 1.35Ewertz 1.35 Long Island 1.49Long Island 1.49 4 state study 1.174 state study 1.17 Yang/Gallagher 1.29Yang/Gallagher 1.29 Stanford 0.75Stanford 0.75 Other 0.96Other 0.96 All Case-Population Controlled 1.15All Case-Population Controlled 1.15



Case-Hospital Controlled RRCase-Hospital Controlled RR Morabia 1.41Morabia 1.41 Vessey 1.21Vessey 1.21 La Vecchia 1.67La Vecchia 1.67 Katsouyanni 1.16Katsouyanni 1.16 Franceschi 1.37Franceschi 1.37 Other 1.03Other 1.03 All Case-hospital controlled 1.2All Case-hospital controlled 1.277

All studies 1.14All studies 1.14



Postmenopausal HT- Breast Cancer RiskPostmenopausal HT- Breast Cancer RiskThe Effect of PHT DurationThe Effect of PHT Duration

PHT case/control RRPHT case/control RR

0 12467/23568 1.000 12467/23568 1.00

0-1 1154/2546 1.090-1 1154/2546 1.09

1-4 1660/3999 1.051-4 1660/3999 1.05

5-9 813/1912 5-9 813/1912 1.191.19

10-14 386/867 1.0910-14 386/867 1.09

>> 15 337/587 15 337/587 1.581.58


Tumor PHT+/PHT- RRTumor PHT+/PHT- RR

Local Tm. 1387/4104 1.00Local Tm. 1387/4104 1.00

Axillary LN 940/2827 0.82Axillary LN 940/2827 0.82

Distant Metas. 98/312 0.54Distant Metas. 98/312 0.54

PHT- Stage of Breast CancerPHT- Stage of Breast Cancer


WHI StudyWHI Study

AimAim: CVD, breast cancer, colorectal cancer and : CVD, breast cancer, colorectal cancer and osteoporotic fracture riskosteoporotic 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. Diet1. Diet 2. PHT2. PHT 3. Calcium-VitD3. Calcium-VitD 40 center, started 1993-1998, ended 200740 center, started 1993-1998, ended 2007 2002’ EP Arm stopped and 2004’ E Arm stopped2002’ EP Arm stopped and 2004’ E Arm stopped

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

WHI-EP ArmWHI-EP Arm

Total Breast Ca Invasive Breast Ca in situ Breast CaTotal Breast Ca Invasive Breast Ca in situ Breast Ca

WHI-Estrogen ArmWHI-Estrogen ArmTotal Breast Ca Invasive Breast Ca in situ Breast CaTotal Breast Ca Invasive Breast Ca in situ Breast Ca

JAMA. 2006 Apr 12;295(14):1647-57

Lancet 2003; 362: 419–27

MWSMWSEP Use – Breast Cancer RiskEP Use – Breast Cancer Risk

MWSMWSEstrogen Use – Breast Cancer RiskEstrogen Use – Breast Cancer Risk

Lancet 2003; 362: 419–27

EP Use – Breast Cancer Risk EP Use – Breast Cancer Risk Schairer et al. JAMA, 2000Schairer et al. JAMA, 2000

29 center, multidisciplinary cohort29 center, multidisciplinary cohort 46335 postmenopausal women46335 postmenopausal women 2082 breast ca. 2082 breast ca. ET RR 1.2, EPT RR ET RR 1.2, EPT RR 1.41.4 ET after 8 yrs, EPT after 4 yrs RR increaseET after 8 yrs, EPT after 4 yrs RR increase ET RR increase ET RR increase 0.01/yr0.01/yr (general) (general) RR increase RR increase 0.03/yr0.03/yr (BMI (BMI<<24.4) 24.4) EPT RR increase EPT RR increase 0.08/yıl0.08/yıl (general) (general) RR increase RR increase 0.12/yıl0.12/yıl (BMI (BMI<<24.4)24.4)

Danish Nurse CohortDanish Nurse CohortPHT - Breast Cancer RiskPHT - Breast Cancer Risk

Int. J. Cancer: 109, 721–727 (2004)

Hormone TypeHormone Type

Hormone RR (% 95 GA) Hormone RR (% 95 GA)

EstrogenEstrogenMWS CE 1.29 (1.16-1.43)MWS CE 1.29 (1.16-1.43) Estradiol 1.24 (1.12-1.37)Estradiol 1.24 (1.12-1.37)

ProgestinProgestinMWS C21 (MPA) 2.14 (1.18-3.87)MWS C21 (MPA) 2.14 (1.18-3.87)DNC C19 (NETA,LNG) 2.14 (1.68-2.72)DNC C19 (NETA,LNG) 2.14 (1.68-2.72)

Collins JA. Human Reproduction Update, Vol.11, No.6 pp. 545–560, 2005

Hormone DoseHormone Dose

Hormone Dose RR Hormone Dose RR

EstrogenEstrogenMWS CE < 0.625 mg 1.27 (1.11-1.45) MWS CE < 0.625 mg 1.27 (1.11-1.45) WHS SE < 1 mg E2 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 ProgestinProgestinWHS MPA < 5 1.54 (1.12-2.11) WHS MPA < 5 1.54 (1.12-2.11) p:0.37p: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)


Hormon Route of AdministrationHormon Route of Administration

Route RR (CI 95 %)Route RR (CI 95 %)

Oral 1.32 (1.21-1.45) Oral 1.32 (1.21-1.45) p:0.27p:0.27

Transdermal 1.24 (1.11-1.39)Transdermal 1.24 (1.11-1.39)

Implant 1.65 (1.26-2.16)Implant 1.65 (1.26-2.16)


Progestin UseProgestin Use

MWS’03 MWS’03 Seq. 1.49 (1.16-Seq. 1.49 (1.16-1.90)1.90)

WHS’02 WHS’02 Cont. 1.87 (1.46-Cont. 1.87 (1.46-2.40)2.40)

DNC’04DNC’04

Chen’02 Chen’02 p=0.13p=0.13

Weiss’02 (1 case extra/yr in cont. Weiss’02 (1 case extra/yr in cont. fashion)fashion)

Li’03Li’03 Collins JA. Human Reproduction Update, Vol.11, No.6 pp. 545–560, 2005

Prior PHT Use – Breast Cancer RiskPrior 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)Collins-metaanalysis 1.02 (0.96-1.08)

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 mm 1 cm 2.5 cm

Modified from Wertheimer 1986’

Tumor Doubling TimeTumor Doubling Time

Adenocarcinomas 50-150 daysAdenocarcinomas 50-150 days

Some embriyonal tumors 20-40 daysSome embriyonal tumors 20-40 days

If it is assumed that an exponential growth occurs early in the If it is assumed that an exponential growth occurs early in the malignancy and tumor starts from a single cell, malignancy and tumor starts from a single cell,

20-tumor doublings require for the tumor mass to reach 1-mm20-tumor doublings require for the tumor mass to reach 1-mm 30 tumor doublings get the tumor mass up to 1 cm30 tumor doublings get the tumor mass up to 1 cm Some embryonal tumors and lymphomas have shortest Some embryonal tumors and lymphomas have shortest

doubling times such as 20-40 daysdoubling times such as 20-40 days However, adenocancers have relatively longer doubling times However, adenocancers have relatively longer doubling times

that usually range from 50 to 150 daysthat usually range from 50 to 150 days Breast cancers are supposed to have approximately 100 days Breast cancers are supposed to have approximately 100 days

of tumor doubling. Therefore, breast cancers that initiated of tumor doubling. Therefore, breast cancers that initiated after an PHT, needs app. 3000 days (8.2 years) to be able to after an PHT, needs app. 3000 days (8.2 years) to be able to reach to clinically palpable phasereach to clinically palpable phase

Also, premammographic phase needs at least 5 years past to Also, premammographic phase needs at least 5 years past to be able to detect a breast carcinomas be able to detect a breast carcinomas

Tumor Volume Doubling Time of Tumor Volume Doubling Time of Primary Breast Cancer Primary Breast Cancer

Age at geometric mean Age at geometric mean

diagnosis in days 68 % rangediagnosis 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) 46-53350-70 157 (121-204) 46-533

> 70 188 (120-195) 55-640> 70 188 (120-195) 55-640

Peer PGM. Cancer 1993;71~3547-51

Tumor Doubling Time in Hereditary Tumor Doubling Time in Hereditary Breast CancerBreast Cancer

Tilanus-Linthorst MMA. EJC 41;1610,2005

▼ carriers▼ non-carriers

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 cm 2.5 cm

Wertheimer 1986

MWS

WHI

DNC

HERS II

NCI-Schairer

Invasive Breast Cancer Greater than 2 cm Invasive Breast Cancer Greater than 2 cm Diagnosed During PHTDiagnosed During PHT

study HT never user study HT never user ever userever user

n/N % n/N % n/N %n/N %

BCDPP E 56/165 (34 %) BCDPP E 56/165 (34 %) 44/112 (35 %)44/112 (35 %)

EP 56/165 (34 %) EP 56/165 (34 %) 4/31 (15 %)4/31 (15 %) DCS PHT 55/131 (42 %) DCS PHT 55/131 (42 %) 75/209 (36 %)75/209 (36 %) WHI E 18/133 (14 %) WHI E 18/133 (14 %) 13/104 (23 %)13/104 (23 %)

EP 22/150 (15 %) EP 22/150 (15 %) 42/199 (21 %)42/199 (21 %) MWS PHT all breast cancers diagnosed at anMWS PHT all breast cancers diagnosed at an

average of 1.2 yearsaverage of 1.2 years

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

Receptor Status of Breast Cancer Receptor Status of Breast Cancer Cases Diagnosed During PHTCases Diagnosed During PHT

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

Changes of Proliferation Markers in Changes of Proliferation Markers in Breast Cancer Developed During PHTBreast Cancer Developed During PHT

Prasad. Cancer 2003;98:2539–46

!

Holmberg L. THE LANCET • Vol 363 • February 7, 2004

HABITS Study: New Tm in Breast HABITS Study: New Tm in Breast Cancer Patients During PHTCancer Patients During PHT

Prevelance of Occult Breast Cancer in Prevelance of Occult Breast Cancer in Healthy WomenHealthy Women

Age Group BC Age Group BC

20-54 21 % Breast Cancer 20-54 21 % Breast Cancer 18 % in situ BC18 % in situ BC 14 % DCIS14 % DCIS 4 % LCIS4 % LCIS 1 % DCIS+LCIS1 % DCIS+LCIS 40-50 39 % BC40-50 39 % BC

Nielsen M et al. Br J Cancer 1987;56:814–819

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

SummarySummary

Postmenopausal EP use slightly increases the Postmenopausal EP use slightly increases the breast cancer risk after 4-5 years. breast cancer risk after 4-5 years.

Postmenopausal estrogen-only HT is safe at Postmenopausal estrogen-only HT is safe at least 7-8 yearsleast 7-8 years

Prior HT does not change the current risk of Prior HT does not change the current risk of breast cancer attributable to PHTbreast cancer attributable to PHT

Acceleration/promotion of Acceleration/promotion of preexisting/undiscovered breast tumors by PHT preexisting/undiscovered breast tumors by PHT is not certain but it is possibleis not certain but it is possible

Screen detected and interval breast cancer during PHT

Norwegian breast cancer screening program

Hofvind S et al. Int J Cancer 2006;118,3112–3117

EP Use and Mammographic DensityEP Use and Mammographic Densityin Postmenopausal Women:in Postmenopausal Women:

WHI Study 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 -0.8Year 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

Value of the Breast Imaging Value of the Breast Imaging TechniquesTechniques

n=429,000, 43 facilities, 2351 BC casesn=429,000, 43 facilities, 2351 BC cases

Screening Computer-aidedScreening Computer-aided

mammography mammography mammography mammography

Specificity 90.2 87.2 < 0.001Specificity 90.2 87.2 < 0.001 Sensitivity 80.4 84.0 = 0.32Sensitivity 80.4 84.0 = 0.32 Recall rate 10.1 13.2 < 0.001Recall rate 10.1 13.2 < 0.001 PPV 4.1 3.2 = 0.01PPV 4.1 3.2 = 0.01

25-50 % of cases of BC are identified retrospectively on 25-50 % of cases of BC are identified retrospectively on the previous annual screening mammographythe previous annual screening mammography

Fenton JJ et al. N Engl J Med 2007;356:1399-09

Documents

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