Endometrial andEndometrial andother cancersother cancers

David W. Sturdee

Endometrial cancerEndometrial cancerHysterectomy specimen showing

cancer invading myometriumfollowing unopposed estrogen therapy for 15 years

Endometrial cancer world-wideEndometrial cancer world-wideWorld age-standardized incidence and mortality rates

(selected)North America

Western EuropeNorthern EuropeSouthern Europe

Eastern EuropeAustralia/New Zealand

South AmericaWestern Africa

Central AmericaSouth-Eastern Asia

Southern AfricaEastern Africa

Eastern AsiaMiddle Africa

Northern AfricaSouth-Central Asia

Western Africa

0 4 8 12 16 20 24

Rate per 100,000 females

IncidenceMortality

Ferley J, et al. IARC Cancer Base No. 5, version 2.0, 2004

Endometrial histology in peri- and Endometrial histology in peri- and postmenopausal women without symptomspostmenopausal women without symptoms

Atrophic 37346.9

Proliferative 13316.7

Secretory 546.8

HyperplasiaAll 415.2Cystic 313.9Simple 91.1Adenomatous 10.1

Cellular atypia 40.5

Cancer 10.1

Insufficient tissue 19524.5

Archer D, et al. Am J Obstet Gynecol 1991;165:317–22

Histology n %

Unopposed estrogenUnopposed estrogenand endometrial cancerand endometrial cancer

Smith 1975 4.5

Ziel 1975 5.6–7.6

Mack 1976 8

Antunes 1979 6–15

Jick 1979 10

Hammond 1979 3.8

Weiderpass 1999 6.2

Year Risk ratio

Unopposed estrogenUnopposed estrogenand endometrial hyperplasiaand endometrial hyperplasia

PEPI trial 62% at 36 months

Placebo 2% at 36 months

Other studies:OR = 5.4 (1.4–20.9) for 6 months 16.0 (9.3–27.5) for 36 months

Lethaby A, et al. In The Cochrane Library, Issue 4, 2004 (ISSN 1464-780X)

HRT in postmenopausal women:HRT in postmenopausal women:endometrial hyperplasia and irregular bleedingendometrial hyperplasia and irregular bleeding

(Cochrane Review)(Cochrane Review)

• Unopposed estrogen significantly increases hyperplasia

• Oral progestogen reduces rate of hyperplasia

• Suggestion that continuous therapy over long duration is more protective from hyperplasia

• Hyperplasia is more likely when progestogen is given every 3 months

Lethaby A, et al. In The Cochrane Library, Issue 4, 2004 (ISSN 1464-780X)

30 randomized controlled trials were suitable for review

HT: the addition of progestogenHT: the addition of progestogen

• For at least 10 days in each cycle to prevent endometrial hyperplasia and carcinoma

• In sequential regimens to imitate the ovarian cycle and to promote a regular and predictable bleed

Complex endometrial hyperplasiaComplex endometrial hyperplasia

Atypical endometrial hyperplasiaAtypical endometrial hyperplasia

Malignant potentialMalignant potentialof endometrial hyperplasiaof endometrial hyperplasia

• Simple 1–3% over 15 years

• Complex 3–4% over 13 years

• Atypical 25% over 11 years

Norris HJ, et al. Clin Obstet Gynaecol 1986;13:725–38 Deligdisch L, Cohen CJ. Cancer 1985;56:1452–5

Never used HRT 387 (87.3) 685 (89.0) 1.0

Current users:Progestogen 10–21 days per month

6–59 months 12 (3.1) 48 (6.2) 0.7 (0.4–1.4)> 60 months 12 (3.1) 15 (1.9) 2.7 (1.2–6.0)

Endometrial cancer and duration of Endometrial cancer and duration of sequential estrogen/progestogen HRTsequential estrogen/progestogen HRT

Duration of HRT Cases (%) Controls (%) Odds ratio

Beresford SA, et al. Lancet 1997;349:458–61

HRT and risk ofHRT and risk ofendometrial cancerendometrial cancer

OR (95% CI)OR (95% CI)

Duration Sequential E + P

< 5 years 1.5 (1.0–2.2)

> 5 years 2.9 (1.8–4.6)

Per year 1.1 (1.06–1.15)

Weiderpass E, et al. J Natl Cancer Inst 1999;911:1131–7

Period-free therapyPeriod-free therapy

• Same benefits as sequential

• No cycle

• Period-free

• Atrophic endometrium

Continuous combined therapy: estrogen + low-dose progestogen every day (CCEPT) or tibolone

Normal 226 119Simple 9 1Complex 2 0Atypical 1 0Cancer 0 0Total 238 120

PEPI study:PEPI study:endometrial hyperplasia at 3 yearsendometrial hyperplasia at 3 years

Histology CEE + MPA CEE + MPA or MP (cyclic) (continuous)

CEE, conjugated equine estrogen 0.625 mg/day; MPA, medroxyprogesterone acetate 2.5 mg; MP, micronized progesterone 200 mg; Cyclic, MPA or MP × 12 days

The Writing Group for the PEPI Trial. JAMA 1996;275:370–5

Endometrial histology during Endometrial histology during sequential and after changing to sequential and after changing to

continuous combined therapycontinuous combined therapy(estradiol 2 mg + norethisterone acetate 1 mg daily for 9 months)(estradiol 2 mg + norethisterone acetate 1 mg daily for 9 months)

Unassessable 18.0 37.3

Inactive/atrophic 7.6 30.0

Proliferative 15.1 2.3

Secretory 47.4 26.2

Complex hyperplasia 5.5 0.0

Sturdee DW, et al. BJOG 2000;107:1392–400

* Including 42 with previous complex hyperplasia

CSEPT (%) CCEPT (%)(n = 1192) (n = 823)*

< 5 years 1.5 (1.0–2.2) 0.8 (0.5–1.3)

> 5 years 2.9 (1.8–4.6) 0.2 (0.1–0.8)

Per year 1.1 (1.06–1.15) 0.86 (0.77–0.97)

Duration Sequential Continuous E + P combined

HT and risk of endometrial cancerHT and risk of endometrial cancerOR (95% CI)OR (95% CI)

Weiderpass E, et al. J Natl Cancer Inst 1999;911:1131–7

WHI study: gynecological cancers WHI study: gynecological cancers (annualized %)(annualized %)

Outcome CEE + MPA Placebo Hazard 95% CIratio

n 8506 8102

Duration (months) 67.8 66.8

Ovary 20 (0.04) 12 (0.03) 1.58 0.77–3.24

Endometrium 27 (0.06) 31 (0.07) 0.81 0.48–1.36

Endometrioid (%) 14 (51.9) 17 (54.8)Cervix 8 (0.02) 5 (0.01) 1.44 0.47–4.42

Anderson GL, et al. JAMA 2003;290:1739–48

Progestogen in HTProgestogen in HT

• Only needed to protect the endometrium

• Other effects, e.g. on breast, lipids

• Premenstrual syndrome-type side-effects

• Logical to give direct to the endometrium by intrauterine system

MLS 10 µg LNG/dayMLS 10 µg LNG/day Mirena 20 µg LNG/dayMirena 20 µg LNG/day

Intrauterine application of progestins Intrauterine application of progestins in hormone replacement therapyin hormone replacement therapy

• Since 1991, 16 studies of intrauterine levonorgestrel in combination with different types and routes of estrogen (n = 809)

• Duration 6 months – 5 years

• IUS + oral CEE and E2, patch, gel and implant

• New 10 µg system: 3 studies for 1–2 years

• All 0% hyperplasia

Riphagen FE. Climacteric 2000;3:199–21

“Confirms endometrial safety for this application”

Endometrial and breast cancerEndometrial and breast cancerin the Million Women Studyin the Million Women Study

Standardized incidence rates/1000 women/5 yearsStandardized incidence rates/1000 women/5 years

CCEPT CSEPT Tibolone E only Never use

CCEPT, combined continuous estrogen and progestogen therapy; CSEPT, combined sequential estrogen and progestogen therapy

Million Women Study Collaborators. Lancet 2005;365:1543–51

Breast 30 28 19 18 13

Endometrial 2 3 6 5 3

Total 32 31 25 23 16

THEBESTHEBESTTibolone ibolone HHistology of the istology of the EEndometriumndometrium

and and BBreast reast EEndpoint ndpoint SStudytudy

•Multicenter world-wide

• Tibolone 1.25 and 2.5 mg vs. CEE/MPA 0.625/2.5 mg (Prempro)

• 24 months

• 3240/3000 subjects (1:1:2 randomization)

• Endometrial histology – hyperplasia and cancer

• Endometrial thickness, bleeding, breast pain, health-related quality of life

THEBESTHEBES

Livial Prempro 2.5

* 1 endometrial stromal sarcoma

Archer DF, et al. J Clin Endocrinol Metab 2007;92:911–18

n 1598 1626

Women-years 2402 2415

Endometrial hyperplasia 0 2 (0.1%)

Endometrial cancer 0 0*

Polyps at 1 year 33 (2.6%) 40 (3.1%)

Polyps at 2 years 24 (2.5%) 25 (2.5%)

Estimated cumulative additional cancers Estimated cumulative additional cancers over 10 years HT per 1000 womenover 10 years HT per 1000 women

Unopposed Combined estrogen E + P

Breast cancer 5 19

Endometrial cancer 10 0

Million Woman Study collaborators. Lancet 2003;362:419–27

Million Women StudyMillion Women Study

Breast cancerBreast cancerand hormone therapyand hormone therapy

“…little advantage to using estrogen/progestogen in preference to estrogen-only HRT for women who still have a uterus”

Million Women Study collaborators. Lancet 2003;362:419–27

Million Women StudyMillion Women Study

Is combined Is combined estrogen/progestogen therapy estrogen/progestogen therapy

worth the risk?worth the risk?• Combined estrogen/progestogen therapy

associated with four-fold greater risk of breast cancer than unopposed estrogen therapy

• Risk of endometrial cancer from unopposed estrogen therapy much less

• After cessation of unopposed estrogen, risk of endometrial cancer persists for many years

• Other implications of unopposed estrogen

• Against perceived wisdom over last 25 years

• Hysterectomy rate

Raloxifene: endometrial healthRaloxifene: endometrial health

• Uterine bleeding– no difference from placebo

• Endometrial thickness by transvaginal ultrasound scan– no difference from placebo

• Endometrial biopsy– no stimulation of atrophic endometrium

Cummings S, et al. JAMA 1999;281:2189–97

Impact of recent reportsImpact of recent reportsand regulatory authoritiesand regulatory authorities

• Lowest dose for shortest time

• Lower dose regimens being produced

• Is there a threshold dose/circulating level of estrogen at which symptoms can be relieved and bone spared without causing endometrial stimulation?

• Is there a similar threshold for progestogen at which the endometrium will still be protected without affecting breast tissue?

Women’s HOPE, Women’s Health, Osteoporosis, Progestin, Estrogen; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate

Endometrial hyperplasia rates afterEndometrial hyperplasia rates after1 and 2 years of low-dose E + P1 and 2 years of low-dose E + P

Women’s HOPE Study

0

5

10

15

20

25

30

Hyp

erp

lasi

a ra

te (

%)

0.625 mg 0.625/2.5 mg

0.45 mg 0.45/2.5 mg

0.45/1.5 mg

0.3 mg 0.3/1.5 mg

Placebo

CEE CEE/MPA

0.000.000.000.000.000.00

Year 1

Year 2

Pickar JH, et al. Fertil Steril 2003;80:1234–40

Unopposed ultra-low-dose Unopposed ultra-low-dose transdermal estradioltransdermal estradiol

• 417 postmenopausal women (60–80 years)mean 67 ± 5

years

• Randomly assigned to placebo or transdermal 14 µg/day for 2 years

• Baseline serum E2 = 4.8 pg/ml

• On treatment E2 = 8.6 pg/ml

Johnson SR, et al. Obstet Gynecol 2005;105:779–87

Unopposed ultra-low-dose Unopposed ultra-low-dose transdermal estradioltransdermal estradiol

Endometrial effects:

• Proliferation 8.5% vs 1.1% p = 0.6

• Bleeding 12.4% vs 8.6% p = 0.3

• Atypical hyperplasia × 1

• Adenosarcoma × 1

Johnson SR, et al. Obstet Gynecol 2005;105:779–87

Conclusions:

• “This therapy apparently causes little or no endometrial stimulation”

HT and endometrial safetyHT and endometrial safety

• Endometrial cancer still a risk for postmenopausal women taking HT

• Duration of progestogen important

• Change to CCEPT for long-term endometrial health

• ? Ultra-low-dose combination or unopposed estrogen

Hormone therapyHormone therapyand ovarian cancerand ovarian cancer

David W. Sturdee

Ovarian cancer: backgroundOvarian cancer: background

• Ovarian cancer is the second leading cause of death from gynecologic cancers1

• Ovarian cancer is usually diagnosed in its advanced stage

• An estimated one woman in 70 will develop ovarian cancer in her lifetime, and one in 100 will die from the disease2

•Median age of diagnosis is 63 years2

1American Cancer Society. Cancer Facts and Figures 2003. Available at: www.cancer.org/docroot/STT/stt_0.asp.

2Schneider HPG. Maturitas 2002;43:S35–52

Centers for Disease ControlCenters for Disease Controlmeta-analysis: ovarian cancer and HRTmeta-analysis: ovarian cancer and HRT

Relative risk (95% CI)

European/Australian Case-Control Studies

Hospital/Clinic ControlsBooth et al, 1998La Vecchia et al, 1982Parazzini et al, 1994

Polchronopolou et al, 1993Tzonou et al, 1984

Community ControlsPurdie et al, 1995

US/Canadian Case-Control Studies

Hospital/Clinic ControlsAnnegers et al, 1979Hartge et al, 1988Hempling et al, 1997Hildreth et al, 1981Kaufman et al, 1989

Community ControlsCramer et al, 1983Lee et al, 1986Risch, 1996Weiss et al, 1982

0.4 0.6 1.0 1.4 1.8 2.22.6 3.0 4.0 5.0

Schneider HPG. Maturitas 2002;43:S35–S52. ©2002 Elsevier Ireland, Ltd. Used with permission

Ovarian cancer risk with HTOvarian cancer risk with HTNationwide case-control trial: SwedenNationwide case-control trial: Sweden

655 cases and 3899 controls, 1993–1995655 cases and 3899 controls, 1993–1995Odds ratio compared to never usersOdds ratio compared to never users

Riman T, et al. J Natl Cancer Inst 2002;94:497–504

Use E alone CSEPTCCEPT

Ever 1.43 1.54 1.02(1.02–2.0) (1.15–2.05) (0.73–

1.43)

10 years 2.4 2.1 1.8(1.03–4.46) (NS) (NS)

Lacey JV Jr, et al. JAMA 2002;288:334–41

Effect of HT on ovarian cancer riskEffect of HT on ovarian cancer riskNational Cancer Institute, NIH, USANational Cancer Institute, NIH, USA

Follow-up of 44,241 postmenopausal women, mean age Follow-up of 44,241 postmenopausal women, mean age 56.6 years; 329 developed ovarian cancer56.6 years; 329 developed ovarian cancer

0.1 1 10

Non-user

E alone, 4 years

E alone, 4–9 years

E alone, 10–19 years

E alone, 20 years

E + P, 2 years

E + P, 2 years

Relative hazard (95% CI)

WHI study: gynecological cancers WHI study: gynecological cancers (annualized %)(annualized %)

CEE + Hazard 95% Outcome MPA Placebo ratio nCI

n 8506 8102

Duration (months) 67.8 66.8

Ovary 20 (0.04) 12 (0.03) 1.58 0.77–3.24

Endometrium 27 (0.06) 31 (0.07) 0.81 0.48–1.36

Cervix 8 (0.02) 5 (0.01) 1.44 0.47–4.42

Anderson GL, et al. JAMA 2003;290:1739–48

Ovarian cancerOvarian cancerand hormone replacement therapyand hormone replacement therapy

in the Million Women Studyin the Million Women Study

• Current users incidence RR = 1.20 (1.09–1.32)

• Current users mortality RR = 1.23 (1.09–1.38)

• Increased with duration of use

• Past users at no increased risk

Million Women Study collaborators. Lancet 2007;369:1703–10

One extra case of ovarian cancerfor every 2500 users

One extra death from ovarian cancerin every 3300 users

Hormone therapyHormone therapyand colorectal cancerand colorectal cancer

David W. Sturdee

Colorectal cancerColorectal cancer

• Third most common cancer in US women, and third most common cause of cancer death in women

• A woman’s lifetime risk of developing colorectal cancer is 5.5%, with 91% of cases occurring after age 50 years

• Colon 72%, rectal 28%

• 5-year survival for women with colorectal cancer is 63%

American Cancer Society. Cancer Facts and Figures 2005 Available at: www.cancer.org/docroot/STT/stt_0.asp

HT use and HT use and risk of colorectal cancerrisk of colorectal cancer

*Statistic refers to colon cancer risk only†Multivariate risk analysis‡Risk assessment adjusted for age only§Meta-analysis includes 2 studies of colorectal cancer mortality

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Relative risk (95% CI)

Jacobs et al, 1994*†

Newcomb and Storer, 1995*†

Folsom et al, 1995*†

Troisi et al, 1997‡

Kampman et al, 1997†

Grodstein et al, 1998†

Paganini-Hill, 1999‡

Hully et al, 2002†

Chlebowski et al, 2004†

Meta-analysis: Nanda et al, 1999*†

Meta-analysis: Grodstein et al, 1999‡§

Chlebowski RT, et al. N Engl J Med 2004;350:991–1004

0.000

0.005

0.010

0.015

0 1 2 3 4 5 6 7

Time (years)

Cu

mu

lati

ve

ha

zard

fo

r c

olo

rec

tal c

an

ce

r

WHI results: effect of HTWHI results: effect of HTon risk of colorectal canceron risk of colorectal cancer

Kaplan-Meier estimateHR = 0.5695% nCI = 0.38–0.8195% aCI = 0.33–0.94 Placebo

E+P

Colorectal cancer:Colorectal cancer:absolute risk after 5 years of E + Pabsolute risk after 5 years of E + P

• A 50-year-old woman has approximately a 0.5% chance of developing colorectal cancer by age 60 years1– This translates to an absolute risk of 5.0 cases

per 1000 women

• WHI reported HR for colorectal cancer of 0.56 after 5 years of E + P use = 44% decrease in risk2– This translates to an absolute risk of 2.8 cases

per 1000 users

1Feuer EJ, Wun LM. Available at: http://srab.cancer.gov/devcan/canques.html2Chlebowski RT, et al. N Engl J Med 2004;350:991–1004

Mortality outcomes for colorectal Mortality outcomes for colorectal cancer patients: ever-users of HTcancer patients: ever-users of HT

Relative risk (95% CI)

0.5 1.0 102.0

Calle et al, 1995

Sturgeon et al, 1995

Persson et al, 1996

Meta-analysis: Nanda et al, 1999

Gastric and esophageal cancersGastric and esophageal cancers

• Unexplained male predominance

• Nested case–control study from UK GP Research Database

• 313 women with gastric cancers

• 299 women with esophageal cancers

• 3191 randomly selected matched controls

• 1,619,563 person-years follow-up

Lindblad M, et al. Br J Cancer 2006;94:136–41

Gastric and esophageal cancersGastric and esophageal cancers

HRT users

Lindblad M, et al. Br J Cancer 2006;94:136–41

Gastric cancers (all) 0.48 0.29–0.79

Gastric non-cardia 0.34 0.14–0.78

Gastric cardia 0.68 0.23–2.01

Esophageal 1.17 0.41–3.32

Odds ratio 95% CI

Effect of HRT Effect of HRT on risk of endometrialon risk of endometrial

and cancers other than breastand cancers other than breast

Conclusions:

• Estrogen alone and combined therapy with progestogen can affect the risk of endometrial and colorectal cancers in postmenopausal women but the data on ovarian and gastric cancer risks are less certain

IMS, 2007

AcknowledgementAcknowledgement

Some of these slides have been adaptedfrom those provided by the

Council on Hormone Education