Benign and Hyperplastic Endometrial Changes Associated With Tamoxifen Use

ABSTRACT: For nearly 20 years, tamoxifenhas been successfully used in the management of breast cancer. Tamoxifenis a mixed estrogen agonist/antagonist that has a proliferative effecton the endometrium. The drug has been associated with a higher percentageof endometrial polyps and hyperplasia than in control patients as wellas a slightly increased risk of endometrial cancer. Although patients needto undergo annual gynecologic exams and abnormal vaginal bleeding needsto be aggressively followed up, the utility of routine gynecologic screeningof tamoxifen patients has not been established and requires further study.Transvaginal sonography is a useful tool for detecting endometrial proliferation;however, an appropriate cut-off point for further intervention must beestablished. A cut-off point that is too low for abnormal endometrial thicknesswould result in a large number of unnecessary endometrial biopsies. Routineoffice endometrial biopsy needs further study as a screening method forbreast cancer patients on tamoxifen. [ONCOLOGY 11(Suppl 1):35-37, 1997]

Introduction

Tamoxifen (Nolvadex) is currently the first-line endocrine therapy forbreast cancer. Approved by the Food and Drug Administration (FDA) in 1978,tamoxifen was initially used for the management of advanced breast cancerand later approved for adjuvant therapy. Currently, it is under study inchemoprevention trials in healthy women at high risk for breast cancer.Although tamoxifen acts against breast cancer primarily as an antiestrogen,the agent also possesses partial estrogen agonist activity. This lattereffect has been associated with improvements in bone mineral density andlipid profiles in postmenopausal women taking the drug but also with aproliferative effect on the endometrium. As tamoxifen has been associatedwith a slightly increased risk of endometrial cancer (about two cases per1000 patients per year), further research needs to be done to uncover therole of tamoxifen in the etiology of endometrial cancer. The purpose ofthis article is to review the benign and hyperplastic endometrial changesobserved in women on tamoxifen.

Endometrial Polypsand Hyperplasia

A number of investigators have documented an association between tamoxifenand benign endometrial changes such as polyps and hyperplasia (Table1).[1-6] These conditions have been attributed to the estrogenic activityof tamoxifen. A review by Assikis et al[7] estimated that tamoxifen patientshad a threefold increase in endometrial proliferation and polyps and atenfold increase in endometrial hyperplasia compared with controls. Althoughthe incidence of these endometrial changes is high, the chance of theseconditions progressing to endometrial cancer is low; only atypical hyperplasia,an uncommon finding, has a significant (27%) risk of progression to cancer.Moreover, tamoxifen has not been shown to aggravate preexisting endometrialpathology after 18 months of follow-up in asymptomatic postmenopausal breastcancer patients.[8]

Studies evaluating the relationship between tamoxifen and endometrialpathology are fraught with problems. In most cases, these studies werenot designed to assess this association and many lack a control group.Breast cancer patients inherently have an age-dependent increase in endometrialcancer risk, and their risk for benign endometrial changes has not beenevaluated. Tamoxifen itself produces gynecologic symptoms that lead toincreased intervention, and thus a detection bias may result. Moreover,other risk factors such as hormone replacement therapy have not been welldocumented in these studies.

Controlled Clinical Studies

Lahti et al[1] evaluated endometrial changes in 103 postmenopausal breastcancer patients using transvaginal sonography, hysteroscopy, and endometrialcurettage. Fifty-one patients had received tamoxifen (20-40 mg/day) fora median of 30 months, whereas the remaining patients did not receive anyhormonal treatment. Patients in the two groups were matched with respectto age, parity, time since menopause, body mass index, and concomitantmedical conditions.

Tamoxifen-treated patients had a significantly greater mean endometrialthickness (10.4 mm vs 4.2 mm) and a larger uterine volume on sonographythan controls. There was also a higher incidence of endometrial polyps(36% vs 10%) as well as uterine fibroids in the tamoxifen group. Endometrialhyperplasia was observed in two tamoxifen patients, and endometrial cancerwas diagnosed in one tamoxifen patient and two control patients.

Gibson et al[4] conducted a retrospective review of the results of dilatationand curettage (D&C) in 240 breast cancer patients, 75 of whom had beentreated with tamoxifen (20 mg/day; mean treatment duration of 26 months).The overall results in tamoxifen-treated patients were polyps in 13%, hyperplasiain 1.3%, and carcinoma in 8%. Patients were stratified as symptomatic orasymptomatic on the basis of abnormal bleeding. In symptomatic patients,the frequency of endometrial polyps was 15% in the tamoxifen group and13% in the control group; the incidence of endometrial hyperplasia was2% and 4%, respectively; and the rate of endometrial cancer was 11% inboth groups. In asymptomatic patients, the rates of these conditions fortamoxifen patients and controls, respectively, were 9% and 5% for endometrialpolyps and 0% and 4% for endometrial hyperplasia, with no cases of endometrialcarcinoma. The 11% incidence of endo- metrial cancer reported in this studyfor symptomatic women is similar to that seen in women with postmenopausalbleeding in the general population.

The effect of tamoxifen on the uterus and ovaries has been studied ina cohort of 111 postmenopausal women participating in the Pilot BreastCancer Prevention Trial at the Royal Marsden Hospital.[5] Endometrial evaluationconsisted of endovaginal sonography with color Doppler imaging, followedby endometrial biopsy. Tamoxifen (20 mg/day) was administered to 61 patientsfor a median of 22 months, while the remaining 50 women received placebofor a median of 24 months. Eight patients in each group were also on estrogenreplacement therapy. Patients were not stratified as to the presence ofuterine fibroids.

Compared with the control group, tamoxifen patients had a significantlylarger uterine volume, a lower impedance to blood flow in uterine arteries,and a significantly greater mean endometrial diameter (9.1 mm vs 4.8 mm).Endometrial biopsy revealed atypical hyperplasia in 10 tamoxifen patientsas well as endometrial polyps in five tamoxifen patients and one controlpatient. There were no cases of endometrial cancer.

The Role of EndometrialScreening

Most gynecologic oncologists do not recommend routine endometrial screeningin tamoxifen patients at this time; however, many gynecologists are performingsonograms and endometrial biopsies every six months. These pro- cedureslead to an increase in D&C and hysterectomy rates. Although this levelof testing may provide an increased level of psychological comfort, theultimate goal of screening--decreasing mortality--is achieved for onlya very small number of patients. Since most endometrial cancers presentwith abnormal bleeding, they tend to be detected early even without specialscreening. Patients need to be advised to see their gynecologist for annualexams and to immediately report any symptoms that resemble bleeding.

Cost of Routine Screening

The annual average risk of endometrial cancer in tamoxifen patientsis low (two per 1000 patients), with a mortality rate of about 15%, thesame as in patients not treated with tamoxifen. Approximately 500,000 womenin the United States are currently receiving tamoxifen, 30% of whom willhave already undergone a hysterectomy. Of 406,000 tamoxifen patients (withintact uteri) who would have to be screened, 802 cancers would be detectedand 120 endometrial cancer deaths would be prevented. If the cost of oneendometrial biopsy per year is $300 (excluding ultrasound), the total costof screening would be $121 million per year to save 120 lives--about onemillion dollars to prevent each death.

Ultrasound vs EndometrialSampling

Clearly more research needs to be done to evaluate the role of differentscreening methods. Although sonography is relatively noninvasive, it mayresult in a large number of unnecessary follow-up procedures. Tamoxifenpatients have increased endometrial thickness on ultrasound; if the abnormalcut-off point was set at five mm, about half of patients would undergoneedless endometrial sampling. A more appropriate cut-off point may beeight mm, which was found to be 100% predictive of abnormal findings inone study.[5]

The preliminary results of a prospective endometrial screening studywere reported at the 1995 Annual Meeting of the American Society of ClinicalOncology.[6] One hundred one evaluable tamoxifen patients underwent a totalof 296 biopsies using a Pipelle device over a median surveillance timeof 16.2 months. There were four abnormal biopsies (two complex hyperplasias,one atypical hyperplasia, and one abnormal histiocyte count). These wereconfirmed with fractional D&C. In addition, there were six cases ofpersistent bleeding despite normal biopsy; the results of D&C revealedpolyps in three cases, pseudodecidualization in one case, and no pathologyin two cases. Three patients underwent hysterectomy due to atypical hyperplasia,high-grade leiomyosarcoma, and complex hyperplasia with extensive mucinouschange.

The authors concluded that office endometrial biopsy can be a usefulscreening tool in up to 95% of breast cancer patients on tamoxifen. Theremaining 5% represents the proportion of women with a stenotic cervixwho are unable to undergo the procedure. Long-term follow-up will be requiredto determine the value of this screening method.

Conclusion

Clearly, tamoxifen does appear to exert an estrogenic effect on theendometrium, resulting in endometrial proliferation and an increase inbenign endometrial pathology, such as polyps and hyperplasia. Moreover,an increase in the hyperdiploid fraction in endometrial biopsies--a markerfor endometrial proliferation--has been associated with the duration oftamoxifen use.[9]

The risk of any of these endometrial changes progressing to endometrialcarcinoma, however, appears to be very low. Only one of these endometrialchanges, atypical hyperplasia, bears a significant risk of progressionto cancer, and this type of hyperplasia is uncommon.

It is clear that any abnormal vaginal bleeding needs to be aggressivelyinvestigated, regardless of whether the patient is taking tamoxifen, becauseof the link between this symptom and endometrial cancer. Routine endometrialscreening of tamoxifen patients is not recommended outside of clinicaltrials. There appears to be a possible role for transvaginal sonography;however, a cut-off point for abnormal endometrial thickness needs to becarefully chosen. If all patients with endometrial thickness more thanfive mm were subjected to endometrial biopsy, about half of these procedureswould be unnecessary. A more appropriate cut-off point might be more thaneight mm, as this was 100% predictive of discovering atypical hyperplasiaor endometrial polyps in one study. The role of routine office endometrialbiopsy for breast cancer patients on tamoxifen needs to be evaluated inlong-term studies.

References:

1. Lahti E, Blanco G, Kauppila A, et al: Endometrial changes in postmenopausalbreast cancer patients receiving tamoxifen. Obstet Gynecol 81:660-664,1993.

2. Corley D, Rowe J, Curtis MT, et al: Postmenopausal bleeding fromunusual endometrial polyps in women on chronic tamoxifen therapy. ObstetGynecol 79:111-116, 1992.

3. Gal D, Kopel S, Bashevkin M, et al: Oncologic potential of tamoxifenon endometria of postmenopausal women with breast cancer: Preliminary report.Gynecol Oncol 42:120-123, 1991.

4. Gibson LE, Barakat RR, Venkatraman ES, et al: Endometrial pathologyat dilatation and curettage in breast cancer patients: Comparison of tamoxifenusers and nonusers. Cancer J Sci Am 2:35-38, 1995.

5. Kedar RP, Bourne TH, Powles TJ, et al: Effects of tamoxifen on uterusand ovaries of postmenopausal women in a randomised breast cancer preventiontrial. Lancet 343:1318-1321, 1994.

6. Barakat RR, Gilewski TA, Saigo PE, et al: The effect of adjuvanttamoxifen on the endometrium in women with breast cancer: an interim analysisof a prospective study [abstract]. Proc Am Soc Clin Oncol 779, 1995.

7. Assikis VJ and Jordan VC: Gynecologic effects of tamoxifen and theassociation with endometrial carcinoma. Int J Gynecol Obstet 49:241-257,1995.

8. Cohen I, Tepper R, Rosen DJD, et al: Continuous tamoxifen treatmentin asymptomatic postmenopausal breast cancer patients does not cause aggravationof endometrial pathologies. Gynecol Oncol 55:138-143, 1994.

9. Decensi A, Fontana V, Bruno S, et al: Effect of tamoxifen on endometrialproliferation. J Clin Oncol 14:434-440, 1996.