Tamoxifen (Nolvadex) is currently the first-line endocrine therapy for
breast cancer. Approved by the Food and Drug Administration (FDA) in 1978,
tamoxifen was initially used for the management of advanced breast cancer
and later approved for adjuvant therapy. Currently, it is under study in
chemoprevention 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 latter
effect has been associated with improvements in bone mineral density and
lipid profiles in postmenopausal women taking the drug but also with a
proliferative effect on the endometrium. As tamoxifen has been associated
with a slightly increased risk of endometrial cancer (about two cases per
1000 patients per year), further research needs to be done to uncover the
role of tamoxifen in the etiology of endometrial cancer. The purpose of
this article is to review the benign and hyperplastic endometrial changes
observed in women on tamoxifen.
A number of investigators have documented an association between tamoxifen
and benign endometrial changes such as polyps and hyperplasia (Table
1).[1-6] These conditions have been attributed to the estrogenic activity
of tamoxifen. A review by Assikis et al estimated that tamoxifen patients
had a threefold increase in endometrial proliferation and polyps and a
tenfold increase in endometrial hyperplasia compared with controls. Although
the incidence of these endometrial changes is high, the chance of these
conditions 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 endometrial
pathology after 18 months of follow-up in asymptomatic postmenopausal breast
Studies evaluating the relationship between tamoxifen and endometrial
pathology are fraught with problems. In most cases, these studies were
not designed to assess this association and many lack a control group.
Breast cancer patients inherently have an age-dependent increase in endometrial
cancer risk, and their risk for benign endometrial changes has not been
evaluated. Tamoxifen itself produces gynecologic symptoms that lead to
increased intervention, and thus a detection bias may result. Moreover,
other risk factors such as hormone replacement therapy have not been well
documented in these studies.
Lahti et al evaluated endometrial changes in 103 postmenopausal breast
cancer patients using transvaginal sonography, hysteroscopy, and endometrial
curettage. Fifty-one patients had received tamoxifen (20-40 mg/day) for
a median of 30 months, whereas the remaining patients did not receive any
hormonal treatment. Patients in the two groups were matched with respect
to age, parity, time since menopause, body mass index, and concomitant
Tamoxifen-treated patients had a significantly greater mean endometrial
thickness (10.4 mm vs 4.2 mm) and a larger uterine volume on sonography
than controls. There was also a higher incidence of endometrial polyps
(36% vs 10%) as well as uterine fibroids in the tamoxifen group. Endometrial
hyperplasia was observed in two tamoxifen patients, and endometrial cancer
was diagnosed in one tamoxifen patient and two control patients.
Gibson et al conducted a retrospective review of the results of dilatation
and curettage (D&C) in 240 breast cancer patients, 75 of whom had been
treated with tamoxifen (20 mg/day; mean treatment duration of 26 months).
The overall results in tamoxifen-treated patients were polyps in 13%, hyperplasia
in 1.3%, and carcinoma in 8%. Patients were stratified as symptomatic or
asymptomatic on the basis of abnormal bleeding. In symptomatic patients,
the frequency of endometrial polyps was 15% in the tamoxifen group and
13% in the control group; the incidence of endometrial hyperplasia was
2% and 4%, respectively; and the rate of endometrial cancer was 11% in
both groups. In asymptomatic patients, the rates of these conditions for
tamoxifen patients and controls, respectively, were 9% and 5% for endometrial
polyps and 0% and 4% for endometrial hyperplasia, with no cases of endometrial
carcinoma. The 11% incidence of endo- metrial cancer reported in this study
for symptomatic women is similar to that seen in women with postmenopausal
bleeding in the general population.
The effect of tamoxifen on the uterus and ovaries has been studied in
a cohort of 111 postmenopausal women participating in the Pilot Breast
Cancer Prevention Trial at the Royal Marsden Hospital. Endometrial evaluation
consisted of endovaginal sonography with color Doppler imaging, followed
by endometrial biopsy. Tamoxifen (20 mg/day) was administered to 61 patients
for a median of 22 months, while the remaining 50 women received placebo
for a median of 24 months. Eight patients in each group were also on estrogen
replacement therapy. Patients were not stratified as to the presence of
Compared with the control group, tamoxifen patients had a significantly
larger 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 patients
as well as endometrial polyps in five tamoxifen patients and one control
patient. There were no cases of endometrial cancer.
Most gynecologic oncologists do not recommend routine endometrial screening
in tamoxifen patients at this time; however, many gynecologists are performing
sonograms and endometrial biopsies every six months. These pro- cedures
lead to an increase in D&C and hysterectomy rates. Although this level
of testing may provide an increased level of psychological comfort, the
ultimate goal of screening--decreasing mortality--is achieved for only
a very small number of patients. Since most endometrial cancers present
with abnormal bleeding, they tend to be detected early even without special
screening. Patients need to be advised to see their gynecologist for annual
exams and to immediately report any symptoms that resemble bleeding.
The annual average risk of endometrial cancer in tamoxifen patients
is low (two per 1000 patients), with a mortality rate of about 15%, the
same as in patients not treated with tamoxifen. Approximately 500,000 women
in the United States are currently receiving tamoxifen, 30% of whom will
have already undergone a hysterectomy. Of 406,000 tamoxifen patients (with
intact uteri) who would have to be screened, 802 cancers would be detected
and 120 endometrial cancer deaths would be prevented. If the cost of one
endometrial biopsy per year is $300 (excluding ultrasound), the total cost
of screening would be $121 million per year to save 120 lives--about one
million dollars to prevent each death.
Clearly more research needs to be done to evaluate the role of different
screening methods. Although sonography is relatively noninvasive, it may
result in a large number of unnecessary follow-up procedures. Tamoxifen
patients have increased endometrial thickness on ultrasound; if the abnormal
cut-off point was set at five mm, about half of patients would undergo
needless endometrial sampling. A more appropriate cut-off point may be
eight mm, which was found to be 100% predictive of abnormal findings in
The preliminary results of a prospective endometrial screening study
were reported at the 1995 Annual Meeting of the American Society of Clinical
Oncology. One hundred one evaluable tamoxifen patients underwent a total
of 296 biopsies using a Pipelle device over a median surveillance time
of 16.2 months. There were four abnormal biopsies (two complex hyperplasias,
one atypical hyperplasia, and one abnormal histiocyte count). These were
confirmed with fractional D&C. In addition, there were six cases of
persistent bleeding despite normal biopsy; the results of D&C revealed
polyps in three cases, pseudodecidualization in one case, and no pathology
in two cases. Three patients underwent hysterectomy due to atypical hyperplasia,
high-grade leiomyosarcoma, and complex hyperplasia with extensive mucinous
The authors concluded that office endometrial biopsy can be a useful
screening tool in up to 95% of breast cancer patients on tamoxifen. The
remaining 5% represents the proportion of women with a stenotic cervix
who are unable to undergo the procedure. Long-term follow-up will be required
to determine the value of this screening method.
Clearly, tamoxifen does appear to exert an estrogenic effect on the
endometrium, resulting in endometrial proliferation and an increase in
benign endometrial pathology, such as polyps and hyperplasia. Moreover,
an increase in the hyperdiploid fraction in endometrial biopsies--a marker
for endometrial proliferation--has been associated with the duration of
The risk of any of these endometrial changes progressing to endometrial
carcinoma, however, appears to be very low. Only one of these endometrial
changes, atypical hyperplasia, bears a significant risk of progression
to cancer, and this type of hyperplasia is uncommon.
It is clear that any abnormal vaginal bleeding needs to be aggressively
investigated, regardless of whether the patient is taking tamoxifen, because
of the link between this symptom and endometrial cancer. Routine endometrial
screening of tamoxifen patients is not recommended outside of clinical
trials. There appears to be a possible role for transvaginal sonography;
however, a cut-off point for abnormal endometrial thickness needs to be
carefully chosen. If all patients with endometrial thickness more than
five mm were subjected to endometrial biopsy, about half of these procedures
would be unnecessary. A more appropriate cut-off point might be more than
eight mm, as this was 100% predictive of discovering atypical hyperplasia
or endometrial polyps in one study. The role of routine office endometrial
biopsy for breast cancer patients on tamoxifen needs to be evaluated in
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3. Gal D, Kopel S, Bashevkin M, et al: Oncologic potential of tamoxifen
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