Uterine side effects of treatment with tamoxifen

European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 235–240

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Original Article

Uterine side effects of treatment with tamoxifen ´ a , *, Pedro Lafuente b , Roberto Matorras c , Jose´ M. Usandizaga a Daniel Andıa a

b

Department of Obstetrics and Gynecology, Basurto Hospital, Bilbao, Spain Department of Preventive Medicine, University of the Basque Country, Bilbao, Spain c Department of Obstetrics and Gynecology, Cruces Hospital, Vizcaya, Spain Accepted 7 December 2000

Abstract Objective: To assess a causal the relationship between endometrial lesions and tamoxifen therapy in patients with breast cancer. Design: Prospective longitudinal study and cross-sectional study. Setting: Cancer prevention unit at Basurto Hospital, Bilbao. Population and methods: Three populations of breast cancer were studied: 43 before the beginning of tamoxifen; 78 after 5–72 months of tamoxifen, and 34 before tamoxifen and after 12–24 months of tamoxifen treatment (PAIRED GROUP). All of them were systematically studied with CO 2 diagnostic hysteroscopy and endometrial biopsy by the same clinician. Results: Before tamoxifen, the following endometrial lesions were detected: endometrial polyps 9.3%; endometrial cysts 16.3%; synechiae 11.6%. In the paired group the ingestion of tamoxifen shows a direct causal effect with a significant increase in endometrial polyps (11.8% vs. 29.4%; OR513; CI57.9–18.1), in endometrial cysts (17.7% vs. 55.9%; OR57.5; CI55.9–9.1) and in synechiae (14.7% vs. 35.5%; OR58; CI54.7–11.3). In the group under tamoxifen for 5–72 months, one endometrial carcinoma was detected. Conclusions: Breast cancer patients have a number of endometrial lesions before undergoing any hormonal therapy. Tamoxifen significantly increased benign endometrial lesions, usually after less than one year of treatment. No cases of endometrial carcinoma was found in our series of 34 patients with 1–2 years of tamoxifen treatment, and 1 / 78 in patients with 5–72 months of tamoxifen.  2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Breast cancer; Endometrial; Hysteroscopy; Tamoxifen

1. Introduction Greater life expectancy has led to breast cancer becoming an ever more common disease, especially in developed countries. In our particular environment it is the malignant tumour most frequently diagnosed in women [1]. As a result, a number of studies have been carried out in the search for more effective treatments. Hormonotherapy, and more specifically tamoxifen, forms one of the pillars of breast cancer therapy. This drug is of proven efficacy both in reducing recurrences and in increasing global survival [2,3]. Extensive prospective studies have shown that the ingestion of tamoxifen increases disease-free survival [4],

*Corresponding author. Tel.: 134-94-442-4994 / 94-400-6000. ´ E-mail address: [email protected] (D. Andıa).

a fact demonstrated by joint studies involving more than 75,000 women [5]. An improvement in lipid profile [6,7] and a protective effect on the bones [8,9] are among the benefits noted. However, as is the case with all medication, its use is not without side effects, the most important being those associated with gynecologic pathology. The ingestion of tamoxifen has been linked with the appearance of endometrial cancer. Since the first episodes were described in 1985 [10], numerous cases have been published, many being descriptions of clinical cases having no relation with either control cases or studies prior to treatment [11–37]. There are some studies with control cases in which breast cancer patients under treatment with tamoxifen had a relative risk of endometrial cancer with respect to untreated patients of between 1.3 [95% CI50.7–2.4] [32] and 7.5 [95% CI51.7–32.7] [33].

0301-2115 / 00 / $ – see front matter  2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00291-2

´ et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 235 – 240 D. Andıa

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As regards the relationship with benign pathology, various studies using heterogeneous methodology show a high frequency of endometrial lesions [13,14,20,30,31,38– 46]. We do not know, however, if these changes in the uterus are due to the fact that both mammary and endometrial pathologies appear in women with a certain endogenous hormonal profile and thus common risk factors, or to the ingestion of tamoxifen. This study was carried out in an attempt to resolve this problem. It makes use of hysteroscopy with endometrial biopsy, demonstrably the most suitable technique for assessment of the uterine cavity [47].

2. Methods Our study involved three population groups. The first consisted of 43 asynptomatic women operated on for breast cancer at our Hospital during the period 1994–95. After being informed of the study and its subsequent follow-up, they underwent diagnostic hysteroscopy and endometrial biopsy prior to coadjuvant treatment. Their evaluation consisted of the working group WITHOUT tamoxifen. They were called again 12–24 months later for a new control. Of these 43 initial patients, 34 received treatment, decided by the clinical oncology, at a dose of 20 mg / day and constituted the PAIRED group of the study, consisting of the same 34 women evaluated before and after treatment. The study was blinded and the hysteroscopist (always the same person) did not know about the treatment (time). Of the initial group of 43 women, 7 were premenopausic women with estrogen and progesterone receptors negative and were excluded as being considered unsuitable for endocrinotherapy, one because she did not tolerate it and

one due to the appearance of metastasis, which pointed to second line endocrinotherapy. These decisions were considered by the clinical oncology. The third population of the study was composed of 78 women under treatment with tamoxifen for a period of between 5 and 72 months, and who had been sent to the consulting room for a check-up as they were asymptomatic. These comprised the group WITH tamoxifen (Informed consent and Institutional Board approval were obtained). The characteristics of these populations are described under Table 1. The material used was that typically employed for gynecological explorations. The hysteroscopy equipment consisted of a Hamou I microhysteroscope (Ref. 26156-B STORZ, Tuttlingen, Germany) of 4 mm diameter and length 25 cm. The diagnostic sleeve presents a diameter of 5.2 mm and has a channel for CO 2 entry, regulated by a Hamou ‘‘microhysteroflator’’ (Ref. 26-021-HB STORZ, Tuttlingen, Germany) which controls CO 2 flow and the pressure in the uterine cavity. The equipment is carried by a trolley with shelves, and is complemented by a cold height source, videocamera for filming and recording, monitor and video. Prominent among the images observed are polyps, of peduncular or sessile nature, glandular or fibrous; cysts, which appear as formations with surface vascularization, mucous content, transparent under transillumination, and normally located on an atrophic endometrium; synechiae may present as thin, flexible adherences or as dense, fibrous structures. Endometrial biopsy were obtained with Novak canula biopsy after the hysteroscopy, guiding the canula to the lesion. We have considered as insufficient material those instances where there is not enough endometrial material for histologic study, fragments of superficial endometrium

Table 1 Population characteristics a Group without TX* (n543) Age median (S.D.)1 Pregnancies median (S.D.)1 Weight (kg) median (S.D.)1 Height (m) median (S.D.)1 Postmenopausal Premenopausal Most common surgery Most common histologic variety N (1) Estrogen receptors (1) Progesterone receptors (1) Chemotherapy Radiotherapy a

* Tamoxifen;

1

54.21 2 63.59 1.59 67.4% 32.6% Madden 56.1% Ductal infiltrate 75.6% 37.2% 44.7% 42.1% 53.8% 62.5%

Standard Deviation (S.D.).

Group with TX* (n578) (10.86) (1.59) (8.43) (0.06)

56.08 2.01 66.79 1.59 75.6% 24.4% Madden 46.4% Ductal infiltrate 83.6% 32.1% 50.7% 47.8% 59.2% 67.1%

Paired group (n534) (10.38) (1.51) (9.54) (0.06)

54.41 1.91 63.80 1.59 70.6% 29.4% Madden 54.5% Ductal infiltrate 75.8% 32.3% 48.4% 45.2% 45.5% 54.5%

(10.53) (1.52) (7.00) (0.07)

´ et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 235 – 240 D. Andıa

not being taken into account. Hormonal receptors were determined by immunofluorescence if breast tissue was sent fresh, or by immunohistochemistry if the piece was sent in formol. As regards statistical treatment, x 2 was used to measure the odds ratio (OR) for matched data, with a confidence interval of 95% (95% CI). Unmatched data were measured using Mantel-Haenszel x 2 , and Fisher exact test in the case of small samples. Relative Risk (RR) with 95% CI was employed to determine the frequency of exposed compared to non-exposed.

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Table 2 Hysteroscopic findings before and after treatment with tamoxifen Initial N Polyps Cysts Synechiae

4 6 5

% 11.8 17.7 14.7

After treatment N

%

10 19 12

29.4 55.9 35.3

P

OR

CI

0.03 0.002 0.004

13 7.5 8

7.9–18.1 5.9–9.1 4.7–11.3

limit of statistical significance (P50.06) with OR54.6 and CI of 0.98–6.79. 3. Results

3.1. Group without tamoxifen Composed of 43 women operated on for breast cancer and studied before beginning coadjuvant treatment. The hysteroscopic findings showed polyps in 4 patients (9.3%), endometrial cysts in 7 (16.3%) and synechiae in 5 (11.6%). The results of the endometrial biopsies revealed atrophic endometrium in 3 cases (7%), proliferative endometrium in 4 cases (9.3%), secretory endometrium in 5 cases (11.6%) and insufficient material in 22 cases (51.2%). 9 cases (20.9%) are mature endometrium but with functioning alterations.

3.2. Paired group Composed of the same women, studied before and after treatment. After treatment with tamoxifen the patients showed an increase in endometrial polyps, 29.4% as opposed to the initial 11.8%. Statistically, this represents a significant difference (P50.03, McNemar test55.04), with OR 13 and CI of 7.9–18.1. The increase in polyps was produced as much at the expense of single polyps (5.9% vs. 14.7%) as in patients with 2 polyps (0% vs. 2.9%) and as in those with multiple polyps (5.9% vs. 11.8%). A higher frequency of endometrial cysts was noted in post-tamoxifen patients: 55.9% compared to 17.7% in the same women before treatment, these differences being of statistical significance (P50.002, McNemar test59.19) with OR57.5 and CI of 5.9–9.1. We observed synechiae in 5 patients before treatment (14.7%) and in 12 (35.3%) after treatment (P50.04, McNemar test54.69), giving an OR58 and CI54.7–11.3. These results are detailed in Table 2. The results of endometrial biopsies after treatment with tamoxifen showed a number of non-functioning endometria, 82.4% in comparison with the initial 61.8%, which from the statistical viewpoint produces differences at the

3.3. Group with tamoxifen Composed of 78 asymptomatic women under treatment with tamoxifen for varying periods. They have been subdivided into three groups according to treatment time: from 5 to 12 months (n526) (Group I); from 13 to 24 months (n537) (Group II), and over 24 months (n515) (Group III). There were no significant differences in the various hysteroscopic anomalies in relation with treatment time (Table 3). Neither did the results of the histologic study vary with treatment time. In the group of women under treatment for one year or less, endometrial biopsy results revealed atrophy in 12%, proliferative endometrium in 4%, secretory in 4% and insufficient material in 72%. 8% are mature endometrium with functioning alterations. On analyzing the group under treatment for between one and two years, we found 17.1% with endometrial atrophy, 5.7% with proliferative endometrium, 5.7% with secretory endometrium and 65.7% where the material obtained was regarded as insufficient. 5.7% are mature endometrium with functioning alterations. The group of women treated for over two years showed atrophic endometrium in 14.3%, secretory in 14.3% and 64.3% where the material obtained was insufficient. 7.1% are mature endometrium with functioning alterations. The results according to other clinical variables showed how there was a tendency close to statistical significance in respect of a lower frequency of synechiae when estrogen receptors were positive (14.7%) than when they were negative (41.7%) (P50.07) (RR52.83, CI50.99–8.10). Table 3 Hysteroscopic changes and time of treatment with tamoxifen. Absence of significant differences % Months of treatment

Endometrial polyps Endometrial cysts Synechiae

5–12 (n526)

13–24 (n537)

25–60 (n513)

19.2 57.7 34.6

27 51.4 21.6

26.7 66.7 20

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´ et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 235 – 240 D. Andıa

Table 4 Endometrial changes in women treated with tamoxifen according to menopausal state and to receptor positivity for estrogens and progesterone in the breast %a

Polyps Cysts * 1 Synechiae †

Estrog. r. (1) (n534)

Estrog. r. (2) (n512)

Progest. r. (1) (n532)

Progest. r. (2) (n514)

Premenopause (n519)

Postmenopause (n559)

23.5 50 14.7

16.7 75 41.7

21.9 46.9 15.6

21.4 78.6 35.7

26.3 26.3 21.1

23.7 66.1 28.8

* P50.048, (1) progesterona receptors vs. (2) progesterone receptors, (RR51.68; CI51.06–2.65); 1 P50.03, Premenopausal state vs. Postmenopausal state, (RR52.51; CI51.16–5.45); † P50.07, (1) estrogen receptors vs. (2) estrogen receptors, (RR52.83; CI50.99–8.10). a

The frequency of endometrial cysts among women with positive progesterone receptors was 46.9% compared to 78.6% when the receptors were negative. Such differences were statistically significant (P50.048, x 2 53.90) (RR5 1.68, CI51.06–2.65). Endometrial cysts were significantly more common in postmenopausal (66.1%) as compared to premenopausal women (26.3%) (P50.03, x 2 59.13) (RR52.51, CI5 1.16–5.45). The remaining parameters analyzed had no significant influence on hysteroscopic changes (Table 4). In this group of 78 women a carcinoma of the endometrium was found in a patient who, after 5 years of treatment with tamoxifen, was given (under protocol) a hysteroscopy and endometrial biopsy with Novak cannula, the result proving negative. Given that it was a vascularized endometrial polyp and that the patient experienced bleeding during the exploration, a surgical hysteroscopy to remove the polyp was proposed. The anatomicalpathological study reponed a lesion at the end of the polyp compatible with grade I adenocarcinoma of the endometrium. The rest of the resected polyp and endometrium were reported negative.

4. Discussion The use of tamoxifen in treating breast cancer is universally recognised, and while in 1993 it was calculated that there were some 4.5 million [48] women under tamoxifen treatment, by 1997 this figure had risen to more than 7 million [49]. As is the case with all medication, tamoxifen is not without side effects, chiefly those produced in the endometrium. We initially studied 43 women with breast cancer, who had undergone surgical treatment but who had been evaluated prior to any complementary treatment (radiotherapy, hormonotherapy or chemotherapy). In this way we have a group with ‘‘pure breast cancer’’ in which we were able to observe the endometrial condition. It is worthy of note that a high frequency of hysteroscopal changes was observed in these women: polyps (9.3%); cysts (16.3%) and synechiae (11.6%). As the directed biopsies were negatives, these lesions remained untreated. From our work it was not possible to clarify whether these

changes are attributable to the particular endocrine environment or other factors associated with breast cancer, or whether they correspond to habitual findings in the general population. As far as we know, asymptomatic hysteroscopic series of patients in this age group do not exist. The influence of tamoxifen on endometrial maturation has been demonstrated in a study in which endometrial samples from patients treated with this medication are processed for histologic assessment and flow cytometry with DNA. The hyperploid fraction, index of the proliferation of diploid histograms, changes depending on the duration of tamoxifen treatment [50]. Although some authors have found varying degrees of hyperplasia [51], it seems that the action of tamoxifen on the endometrium is somewhat more complex than a simple estrogen effect producing hyperplasia [52]. Our findings point to an evolution in the results of endometrial biopsies and in the hysteroscopic observation of endometrial maturation towards atrophy of the endometrium. This was observed within a short time of beginning treatment, since the women who had been treated for one year or less showed 12% atrophic endometria and 72% insufficient material in the endometrial biopsy results. Study of the PAIRED group revealed a tendency to endometrial atrophy, reducing functioning endometria and increasing endometrial atrophy as well as insufficient materials. When we looked at premenopausal women in isolation, the tendency to endometrial atrophy rose from 30% to 60%, this being insignificant from a statistical viewpoint. There are studies with no control group [20] or controlled studies of reduced casuistry [14,44] in which endometrial polyps have been found in 25–39% of cases. In one controlled study with 51 cases and 52 controls, the presence of endometrial polyps was noted in 36% of cases and 10% of controls [30]. In a recent longitudinal study, ‘‘tamoxifen-like’’ lesions (glandulacystic atrophy) were observed in 49.1% and polyps in 40.3% of women treated with tamoxifen [37]. Our own study produced a remarkable increase in the frequency of endometrial lesions in the paired group after tamoxifen therapy. As histeroscopy is a non invasive procedure and directed biopsy with Novak Cannula is a

´ et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 92 (2000) 235 – 240 D. Andıa

non aggressive method of biopsy, there is very little probability of an association between the primary procedures, histeroscopy and biopsy, and uterine synechiae which were observed in the second histeroscopy. We found a significant increase in endometrial cysts in the case of postmenopausal women and when progesterone receptors were negative. It has recently been observed that the incidence of atypical lesions after tamoxifen treatment was greater in women with changes described as endometrial polyps prior to treatment [53]. It has been suggested that the etiology of endometrial lesions produced by tamoxifen may be related to the drug’s regulation of certain genes associated with the endometrium, genes which are different to those controlled by estrogen, and among which may be insulin-like growth factor-1 and insulin-like growth factor binding protein-1 [54]. The fact that a longer exposure time of tamoxifen did not increase the number of endometrial lesions introduces some doubt about the biological plausibility of the causal relationship between tamoxifen and these lesions. Perhaps the lesion develop soon after the start of treatment and do not increase in number afterwards. There are two clinical implications in respect of endometrial polyps. In the first place, they may produce bleeding, necessitating numerous examinations and gynaecological explorations [55]. Secondly, there is the risk of endometrial polyps becoming malignant, and a figure of 10% for postmenopausal women has been suggested [56]. In our paired casuistry we did not find any cases of cancer of the endometrium, nor pre-malign endometrial lesions. The frequency which may be expected after 1–2 years of treatment would be less than 3% (,1 / 34). However, we did find one instance of cancer of the endometrium among the 78 women who were under treatment for a variable period (between 5 and 72 months); this is a frequency of 1.3%. These results are in agreement with the report by Fisher et al., in which a 5-year accumulative rate of endometrial carcinoma of 6.3% was found. In the literature, the RR for endometrial cancer in tamoxifen-treated women with breast cancer ranges from 0.6 [34] to 7.5 [33]. Tamoxifen treated women who develop amenorrhea [57], and women with endometrial lesions before starting tamoxifen therapy [53] may be at special risk of developing endometrial cancer. We may conclude that there are a number of benign endometrial lesions among breast cancer patients even before tamoxifen treatment, and that there is a very significant increase in such lesions after even less than one year of treatment. The lesions are usually asymptomatic. In our series, the only case of endometrial cancer occurred in the only case with endometrial bleeding. Since endometrial biopsies and transvaginal ultrasonography are of no use in these patients [58], the recommendable frequency of outpatient hysteroscopic studies on breast patients being

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treated with tamoxifen remains to be ascertained. Perhaps one check up after one year treatment with tamoxifen would be enough for those whom at first check up would be diagnosed to be without polyps. It should be mandatory where there is bleeding.

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