Cancer Associated With HRT

8/3/2019 Cancer Associated With HRT

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HRT & Endometrial cancer


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Overview

Oestrogen only RCT Increase the risk of endometrial hyperplasia

Besides, the longer the duration and the higher the dose of oestrogen onlyRCT, the higher of the risk of endometrial hyperplasia

Endometrial hyperplasia can progress to endometrial carcinoma withatypical type is the highest followed by complex and simple hyperplasia

Oestrogen & progestrogen HRT: Progestrogen is protective to endometrial hyperplasia

Endometrial cancer was not increased with up to 5 years of use, but withmore than 5 years of use.

Progestogens will reduce the risk of endometrial hyperplasia and carcinoma,but the duration of progestogen in each cycle is important and should be forat least 10 days.

Continuous combined therapy had protective effect not only inpreventing hyperplasia but also in the correction of pre-existinghyperplasia.


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Endometrial hyperplasia & oestrogen

Writing Group for the PEPI Trial. Effects of hormone replacement

therapy on endometrial histology in postmenopausal women. The

Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.

JAMA 1996; 275: 370375.

Study population: 596 postmenopausal women receiving 0.625 mg CEE

or placebo over 36 months

Type of study: RCT (randomized to placebo)

Results:

Simple hyperplasia Complex hyperplasia Atypical hyperplasia

HRT Placebo HRT Placebo HRT Placebo

27.7% 0.8% 22.7% 0.8% 11.7% 0.7% P


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Duration of HRT & endometrial

hyperplasia

Lethaby A, Suckling J, Barlow DH et al. Hormone

replacement therapy in postmenopausal women:

endometrial hyperplasia and irregular bleeding.

Cochrane Database Syst Rev 2004; (3).CD000402.

30 randomized controlled trials

Results

6 months of unopposed oestrogen: OR 5.4 (95% CI1.4

20.9)

36 months of unopposed oestrogen: OR16.0 (95% CI 9.3

27.5)


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Dose & endometrial cancer

Pickar JH, Yeh IT, Wheeler JE et al. Endometrial effects of lower doses of

conjugated equine estrogens and medroxyprogesterone acetate: 2-year

substudy results. Fertil Steril 2003; 80: 12341240.

Results

Weiderpass E. Risk of endometrial cancer following estrogen replacement

with and without progestins. J Nat Cancer Inst 1999; 91: 11311137.

There is no evidence that use of the weaker ostrogen oestriol, either

vaginally or orally, has any less effect on the risk of endometrial

hyperplasia.

Dosage of CEE 0.3 mg 0.4 mg 0.625 mg

1 year 0% 7% 10%

2 year 3% 15% 27%


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Stopping HRT ???

Paganini-Hill A, Ross RK & Henderson BE.

Endometrial cancer and patterns of use of estrogen

replacement therapy: a cohort study. Br J Cancer

1989; 59: 445447. the risk of endometrial cancer remains increased for

many years after stopping oestrogen therapy.

Even after 15 years or more without therapy, there is

still a significantly increased risk of 5.8 (95% CI 2.0

17)


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Endometrial hyperplasia; risk of

progression to endometrial cancer

Reference Simple Complex Atypical

Wentz 26.7 88.9

Sherman 19.8 57.1

Kurman 1.1 3.4 29Norris 2 52

Kurman RJ, Kaminski P & Norris H. The behaviour of endometrial hyperplasia. A long

term study of untreated hyperplasia in 170 patients. Cancer 1985; 56: 403412.

Wentz WB. Progestin therapy in endometrial hyperplasia.Obstet Gynecol 1974; 2:362367.Sherman AI. Precursors of endometrial cancer. Isr J Med Sci 1978; 14: 370378.

Norris HJ, Connor MP & Kurman RJ. Preinvasive lesions of the endometrium. Clin

Obstet Gynaecol 1986; 13: 725738.


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Furthermore, in hysterectomy specimens performedafter a biopsy or curettage with a diagnosis ofatypical hyperplasia, co-existing endometrial

adenocarcinoma is found in 4050% of cases.

Edris F, Vilos GA, Al-Mubarak A et al. Resectoscopic surgery may bean alternative to hysterectomy in high risk women with atypicalendometrial hyperplasia. J Minim Invasive Gynecol 2007; 14: 68

73.

Shutter J &Wright TC. Prevalence of underlying adenocarcinoma inwomen with atypical endometrial hyperplasia. Int J Gynecol Pathol2005; 24: 313318.


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Oestrogen & progestrogen HRT &

endometrial hyperplasia

Sturdee DW, Ulrich LG, Barlow DH et al. Theendometrial response to sequential and continuouscombined oestrogenprogestogen replacement therapy.Br J Obstet Gynaecol 2000; 107: 13921400. 1192 women who were taking standard sequential

regimens of HRT for a mean of 3.29 years (median 2.56years, 5th95th centile 0.778.49 years) had endometrialaspiration biopsies taken by Pipelle during the progestogenphase of the cycle.

Results: 47.4% had a secretory endometrium

5.5% had complex hyperplasia

0.7% atypical hyperplasia


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Combined HRT & endometrial

carcinoma

Reference > 5 years > 5 years

Beresford JAA Not increase RR 2.5 (95% CI 1.15.5).

Weiderpass E OR 1.5 (95% CI 1.02.2), OR 2.9 (95% CI 1.84.6).

Beresford JAA, Weiss NS

, Voigt LF et al. Risk of endometrial cancer in relation touse of estrogen combined with cyclic progestogen therapy in postmenopausal

women. Lancet 1997; 349: 458461.

Weiderpass E. Risk of endometrial cancer following estrogen replacement withand without progestins. J Nat Cancer Inst 1999; 91: 11311137.


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Pukkala E, Tulenheimo-Silfvast A & Leminem A.Incidence of cancer among women using long versusmonthly cyclical HRT, Finland 19941997. CancerCauses Control 2001; 12: 111115. long-cycle HRT was associated with a higher RR of

endometrial pathology than monthly-cycle HRT, with astandardized incidence ratio (SIR) for the quarterly cycle of2.0 (95% CI 1.62.6), compared with a SIR for the monthlycycle of 1.3 (95% CI 1.11.6).

Therefore, progestogens will reduce the risk of endometrialhyperplasia and carcinoma, but the duration ofprogestogen in each cycle is important and should be for atleast 10 days.


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Continuous combined therapy

Wells M, Ulrich LG, Sturdee DW et al. Effect onendometrium of long term treatment with continuouscombined estrogen/progestogen replacement therapy:follow up study. BMJ 2002; 325: 239242.

prospective study of women taking CCT followed 534postmenopausal women for a mean of 4.4 years (range 1.15.9).

There were no cases of endometrial hyperplasia or malignancy,and 69% of women had an endometrium classified as atrophic orunassessable.

Furthermore, in 42 women who had previously been taking

sequential HRT before the study, and who were found to havecomplex endometrial hyperplasia, all of these cases reverted tonormal results on histological examination after just 9 months oftreatment, and this was maintained with continuation of the studyup to 5 years.


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Lethaby A, Suckling J, Barlow DH et al. Hormone replacementtherapy in postmenopausal women: endometrial hyperplasia andirregular bleeding. Cochrane Database Syst Rev 2004; (3).CD000402. endometrial hyperplasia is less likely with CCT than with sequential

regimen with an OR of 0.3 (95% CI 0.10.97)

Writing Group for the PEPI Trial. Effects of hormone replacementtherapy on endometrial histology in postmenopausal women. ThePostmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA1996; 275: 370375. there were no cases of complex hyperplasia in women on CCT after 3

years compared with 1.7% of 118 women treated with sequential HRTand 0.8% of different types and routes of oestrogen.


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HRT & Cervical cancer


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Anderson GL, Judd HL, Kaunitz AM et al. Effects of estrogenplus progestin on gynaecologic cancers and associateddiagnostic procedures: the Womens Health Initiativerandomised trial. JAMA 2003; 290: 17391748.

women without hysterectomy aged 5079 years were randomizedto receive either CEE 0.625 mg with MPA 2.5 mg daily (n = 8506)or placebo (n = 8102) for a mean follow-up of 5.6 years.

The incidence of cervical cancer did not differ significantly betweenthe treated and placebo groups (hazard ratio = 1.4, 95% (CI 0.5

4.4) Limitation:

The study was too short

Limited statistical power to conclude that there is no effect of HRT incervical carcinogenesis


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Conclusion

Although HRT reverses many characteristics of

epithelial atrophy after the menopause, it does not

seem to play a significant role in cervical

carcinogenesis.


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HRT and Ovarian cancer


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American Cancer Society Cancer

Prevention Study

based on mortality data of 224 307 woman-years foundan RR of 1.7 (95% CI 1.12.8).

A 14-year follow-up of this study confirmed these findingswith: RR of 1.5 (95% CI 1.22.0) for ever use

RR of 2.2 (95% CI 1.53.2) for use of 10 years or more.

Among former users, the RR decreased with time since last use.

Rodriguez C, Calle EE, Coates RJ et al. Estrogen replacement therapy andfatal ovarian cancer. Am J Epidemiol 1995; 141: 828835.

Rodriguez C, Patel AV, Calle EE et al. Estrogen replacement therapy andovarian cancer mortality in a large prospective study of US women.JAMA 2001; 285: 14601465.


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Million Women Study Collaborators. Ovarian cancer and

hormone replacement therapy in the Million Women study. Lancet

2007; 369: 17031710.

an observational study of 948 576 postmenopausalwomen who were taking part in the NHSBSP

identified 2273 incident ovarian cancers and 1591 deathsfrom this malignancy.

For current users of HRT, the incidence of ovarian cancerincreased with increasing duration of use, but did notdiffer significantly by type of preparation used, its

constituents or mode of administration. Over 5 years, the Standardized Incidence Ratio, SIRs for

ovarian cancer in current use 2.6 (95% CI 2.42.9) per 1000

never users 2.2 (95% CI 2.12.3) per 1000


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From these data, the authors calculated that there

would be one extra ovarian cancer in approximately

2500 users and one extra ovarian cancer death in

approximately 3300 users. The risks associated with HRT also varied significant

according to tumour histology

epithelial tumours 1.53 (95% CI 1.311.79)

serous 0.72 (95% CI 0.521.0),

Mucinous 1.05 (95% CI 0.771.43)

Endometrioid or clear cell tumours 0.77 (95% CI 0.481.23)


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Anderson GL, Judd HL, Kaunitz AM et al. Effects of

estrogen plus progestin on gynaecologic cancers

and associated diagnostic procedures: the Womens

Health Initiative randomised trial. JAMA 2003; 290:17391748.

8506 women aged 5079 years treated with

combined CEE 0.625 mg with 2.5 mg MPA daily, and

8102 untreated women.

Result: a non-significant RR of 1.58 (95% CI 0.773.24)


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Oestrogen only HRT vs Combined HRT

Rossing MA, Cushing-Haugen KL, Wicklund KG et al. Menopausalhormone therapy and risk of epithelial ovarian cancer. CancerEpidemiol Biomarkers Prev 2007; 16: 25482556.

In a population-based study in Washington, USA, 812 women with ovariancancer and 1313 controls were interviewed about the use of HRT and othercharacteristics.

The risk of epithelial ovarian cancer was increased among Current users or OR 1.6, 95% CI 1.12.5

recent (within the last 3 years) users of unopposed oestrogen for 5 or more yearsOR 1.8, 95% CI 0.83.7

Little increase was noted among users who discontinued use in the moredistant past (OR 1.2, 95% CI 0.62.6).

However, no increase in risk was noted among women who used combinedoestrogen and progestogen therapy regardless of duration (OR 1.1, 95%CI 0.81.5)


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HRT AND BREAST CANCER


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Placebo controlled WHI confirmed that addition of

oral continuous progestogen was responsible for

increase risk of breast ca

Combined HRT (1.24, 1.01-1.54)

Unopposed HRT (0.77, 0.57-1.06)


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Association between LNG-IUS (Mirena)

with breast cancer risk

Cohort of 79women with early stage of breast ca

Overall no increase of recurrence (hazard ratio 1.86,

95% CI 0.8-4.0)

Increase recurrence in women used before and after

diagnosis (hazard ratio 3.39, 95% CI 1.01-11.35)

Risk unaffected those who used after diagnosis(hazard ratio 1.48, 95% CI 0.62-3.49)


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Unopposed estrogen

Risk of breast ca with hx of benign breast biopsy

-no biopsy (0.57, 0.41-0.78)

-one prior biopsy (1.6, 0.82-3.74)-two or more (2.54, 0.73-8.86)

Breast ca risk with family history-no affected relatives (0.68, 0.5-0.78)

-one or more first degree relatives (1.75, 0.95-3.22)


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Colorectal Cancer

Protective effect of estrogen

13 case-control studies:

8 showed a significant protective effect,

4 showed a neutral effect

1 suggested an increased risk.

8 large cohort studies:

6 showed a significant protective effect2 showed a neutral effect.


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2 large randomized clinical trials

WHI 43 invasive colorectal cancer cases in CEE and MPA group

72 in placebo group

Risk reduction confined to local disease, not regional or

metastatic disease

unopposed estrogen: no difference in the risk for colorectal

cancer compared with the placebo group

Heart and Estrogen/Progestin Replacement Study

(HERS)

11 cases of colon cancer in HRT group

16 in placebo


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Protective Mechanism?

Undefined

Possibilities:

inhibitory effect of oestrogen on cellular proliferation

Women with a high-risk profile for the development

of colon cancer could be advised to use HRT as a

chemopreventive agent


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Gallbladder Cancer

Oral estrogen cause change in content of bile,decrease in bile acids, increase cholesterolsaturation favours gallstone formation

2 randomized double-blind placebo controlled-trials Both oral CEE alone and CEE combined with MPA

associated with greater likelihood for cholecystectomywhile receiving therapy

1 case control study Increased risk of gallbladder cancer for ever used HRT

Risk increase with longer duration of use

Transdermal route less likely to affect gallbladder


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Melanoma

Not associated with ever being pregnant, age at

first pregnancy, ever use of oral contraceptives or

current use of replacement oestrogen therapy.

Neither exogenous nor endogenous hormonescontribute significantly to an increased risk of

melanoma


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Lung Cancer

1 case control

Reduced risk with HRT use

effects were similar with unopposed oestrogen or

combined oestrogen and progestogen therapy, but thestatistically relevant decrease was only seen in current

smokers


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Esophageal & Gastric Ca

Male predominance = estrogen protective?

1 case control study

>50% reduced risk of gastric adenocarcinoma among

HRT users compared with non-users

no association between HRT and oesophageal

adenocarcinoma


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Summary

Increased Risk Protective No Association

Breast Endometrial Melanoma

Ovarian Colorectal Esophageal

Cervical Lung

Gallbladder Gastric


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Practice point


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Breast cancer risk is not increased with short-term use (3 years forcombined HRT, up to 5 years for unopposed oestrogen)

For longer term use, the degree of increase in breast cancer risk willbe dependent on an individuals baseline breast cancer risk

Women with a high-risk benign breast condition or a family historyhave greater absolute risk; it is essential to communicate this whencounselling women and, in doing so, acknowledge that uncertaintystill prevails

There is no indication for additional mammographic screening forwomen using HRT; this will only generate unnecessary additionalconcern where none should exist


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Decisions regarding any intervention for symptom relief in breastcancer survivors should be made jointly with the patient, theirspecialist and gynaecology-endocrine specialists

There is a paucity of clinical evidence evaluating efficacy, toxicityand the potential for antagonism of concurrently prescribed breastcancer therapy with the use of HRT alternatives for vasomotorsymptom control in breast cancer survivors.

HRT may still have a role in subgroups of women treated for breast

cancer, but the current clinical climate is so HRT adverse that trialsare unlikely to be implemented successfully in the near future


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Unopposed oestrogen should only be given to women following hysterectomy

Very occasionally, women who have severe progestogen intolerance may besuitable for unopposed oestrogen. They will need regular endometrialassessment by ultrasound and, if evidence of thickening, an endometrial biopsy

Endometrial cancer is still a risk for postmenopausal women taking HRT

Sequential HRT regimens are suitable for the short-term relief of menopausalsymptoms, but for long-term use, a change to CCT is advisable for endometrial

protection and also better patient satisfaction with the loss of monthlywithdrawal bleeds

The development of ultra-low-dose combinations may be even more acceptablefor long-term use because of the reduced endometrial simulation and bleeding


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Reference

Jo Marsden, David Sturdee; Cancer Issues; Best

Practice & Research Clinical Obstetrics and

Gynaecology 23 (2009) 87107

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Cancer Associated With HRT

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