- Email: [email protected]
Uterine side effects of tamoxifen: a need for systematic pretreatment screening
Uterine Side Effects of Tamoxifen: A Need for Systematic Pretreatment Screening MARTINE BERLkRE, MD, ALAIN JACQUES DONNEZ, MD, PhD
CHARLES, MD, CHRISTINE
Objective: To determine the effect of tamoxifen on the endometrium in postmenopausal women with breast cancer and to try to identify, by pretreatment screening, subjects at higher risk of developing endometrial cancer. Methods: Between January 1993 and January 1996, 264 postmenopausal women with breast cancer were studied prospectively with pelvic ultrasonography. Outpatient hysteroscopy and endometrial biopsy were done if ultrasound abnormalities were detected. Initial endometrial evaluation was done before treatment with tamoxifen was started, 20 mg daily, and annually thereafter. Attention was focused on endometrial lesions and, especially, endometrial hyperplasia, which was defined according to World Health Organization classification. Endometrial hyperplasia was subdivided into two broad categories: hyperplasia without cytological atypia and hyperplasia with cytological atypia. Adenocarcinoma in situ was defined as a well-differentiated endometrial carcinoma confined to the endometrial mucosa without myometrial invasion. Results: Forty-six women (17.4%) had asymptomatic endometrial lesions diagnosed before starting tamoxifen, and two of these were atypical lesions. Patients with initial lesions and those without initial lesions were followed separately. At 3 years of follow-up, the incidence of atypical lesions was significantly higher in women with lesions initially than in those without (three lesions among nine women versus one lesion among 51 women, P = .0091. Conclusion: It appears that a group of high-risk subjects can be defined on the basis of endometrial evaluation before tamoxifen therapy; these women should be followed carefully because of the high incidence of severe atypical lesions. (Obstet Gynecol 1998;91:40-4. 0 1998 by The American College of Obstetricians and Gynecologists.)
Tamoxifen appears to increase the risk of endometrial cancer.‘” According to Rose,4 the likelihood of developing endometrial cancer is low, varying from 12 cases per 100,000 women at 40 years of age to 84 cases per From Hospital,
40
the Departments of Gynecology and Pathology, Catholic University of Louvain, Brussels, Belgi~m~.
0029-7844/98/$19.00 PI1 SOO29-7844(97)00591-7
St Luc’s
GALANT,
MD, AND
100,000 women at 60 years of age. Fisher et al3 reported a relative risk of tamoxifen-induced endometrial cancer two to three times greater than that seen in women with breast cancer not treated with tamoxifen. Rutqvist et al’ and Fornander et al,” report a sixfold excess risk of endometrial carcinoma in women treated with tamoxifen in comparison with controls. Tamoxifen has an estrogenic agonistic effect on the human uterus.3,5,6 Although evidence points to the involvement of estrogens in the growth of endometrial cancer, the molecular mechanisms underlying the uterotrophic activity of tamoxifen have not been established clearly. Experiments performed on rats have demonstrated overexpression of oncogenes, which may contribute to the uterine toxicity associated with chronic tamoxifen treatment.7 It remains unknown whether genotoxicity observed with tamoxifen in the rat also can be seen in humans.8 Tamoxifen has become standard therapy for metastatic disease, and adjuvant therapy for nodepositive and node-negative postmenopausal patients.” It is now being studied as a preventive agent in women at high risk of breast cancer.’ Tamoxifen’s side effects should be evaluated carefully before its extensive use as preventive treatment. Although its benefits also have been demonstrated in premenopausal patients with breast cancer, its use remains problematic because of gynecologic side effects.” The purposes of this prospective study were to determine the effect of tamoxifen on the endometrium in postmenopausal women with breast cancer and to try to identify subjects at higher risk of developing endometrial cancer on the basis of gynecologic pretreatment screening.
Materials and Methods Between January 1993 and January 1996,264 postmenopausal women with histologically documented breast cancer who were to receive tamoxifen as adjuvant
Obstetrics
& Gynecology
Table 1.
Patient
Characteristics
Characteristic Age (y) Weight (kg) Average parity Age at menopause Previous hormonal Diabetes Hypertension Demographic deviation).
Without lesions (n = 218)
With lesions (n = 46)
62.7 (27.1) 73.2 (?11.9) 1.6 (range O-4) 53.6 (14.3) 25/215 (11.6%) None None
63.6 (27.2) 71.3 (?12.1) 1.8 (range O-5) 53.8 (24.2) 5/46 (10.9%) None None
(y) therapy
characteristics
are expressed
as mean
(Z
standard
therapy (20 mg daily for 5 years) were included in a prospective study. Subjects with prior hysterectomy were excluded, and all eligible patients seen during the 3 years were enrolled. All subjects were considered free of metastatic lesions at the time breast cancer was diagnosed, and all were eligible for the study after locoregional treatment (surgery with or without adjuvant radiotherapy). Two hundred twenty women had a minimum follow-up of 1 year; 140, a follow-up of 2 years, and 60, a follow-up of 3 years. No patients were lost to follow-up. Patient characteristics are listed in Table 1. Our initial evaluation included gynecologic examination, Papanicolaou smear evaluation, and endovaginal ultrasonography (vaginal probe 6 MHZ, model PVF 621 VT, Toshiba SSH 140A, Toshiba Europe, Brussels, Belgium). We defined an abnormal endometrial thickness as greater than 4 mm, in accordance with a previous rep0rt.l’ In women with abnormal transvaginal sonography, an outpatient hysteroscopy was done along with an endometrial biopsy. After the initial evaluation, women were reviewed every year. A complete physical examination, with a gynecologic examination, a Papanicolaou smear, and a vaginal sonography, was done. In the caseof an abnormal ultrasound, an outpatient hysteroscopy was carried out with an endometrial biopsy (the ultrasound criteria were the same as those described for the pretreatment evaluation). This gynecologic follow-up was associated with an oncologic follow-up (blood test, chest x-ray, and mammography). The diagnosis of endometrial hyperplasia was based on Kurman and Norris.12 Endometrial hyperplasia was subdivided into two broad categories: hyperplasia without cytological atypia and hyperplasia with cytological atypia (atypical hyperplasia). These proliferative lesions were classified further into simple or complex according to the extent of glandular complexity and crowding. Adenocarcinoma in situ was defined as a well-differentiated endometrial carcinoma confined to
VOL.
91,
NO.
1, JANUARY
1998
the endometrial mucosa, without myometrial infiltration.13 Depending on the pathology observed, two types of surgical treatments were used: 1) hysteroscopic resection or hysteroscopic myomectomy in the caseof benign lesions or 2) laparoscopy-assisted vaginal hysterectomy and adnexectomy in casesof hyperplasia with atypia or adenocarcinoma. The 2 test and Fisher exact test were used to compare the incidence of lesions in the two groups at each point in time. Statistical significance was established at P < .05. Because the duration of follow-up varied, data also were expressed in personyears.
Results Before starting tamoxifen therapy, all 264 women were asymptomatic. On the basis of the initial screening, two subgroups of women were distinguished: women without initial lesions (n = 218) and women with initial lesions (n = 46) (Table 2). Thus, the prevalence of asymptomatic baseline endometrial lesions was 17.4%. Among the 46 asymptomatic women with abnormal sonography and abnormal hysteroscopy before tamoxifen, two atypical lesions were observed: one case of atypical hyperplasia and another of endometrial adenocarcinoma in situ. Hysterectomy and bilateral salpingooophorectomy (BSO) were carried out in both women, who are still alive and currently free of any metastatic lesions. Among the other 44 women, the lesions observed most frequently were endometrial polyps (n = 34; 77%) (Table 3). Submucosal myomas and simple hyperplasia (without atypia) with adenomyosis were observed in seven and three women, respectively. All the women were treated with polyp resection followed by either endometrial resection, myomectomy, or endometrial resection. The two groups of women were followed separately in precisely the same way. There were no deaths after surgical procedures. At 1 year, 220 women were evaluated: 185 in the group without initial lesions and 35 in the group with initial lesions. The percentages of intrauterine lesions were 3.8% and 8.6Y~respectively, which was not signif-
Table 2.
Patient
Follow-up lesions
Initial
rz
Benign
Atypical
II
Benign
218 185 120 51
7 (3.8%) I1 (9.2%:) 5 (9.8%) 23
-
46 35 20 9
44 3 3 1 51
Without
Treatment (year)
n
0 1 2 3
264 220 140 60 Total
Berlibe
initial
et al
0 0 1 1
Uterine
Effects
lesions
of Tamoxifen
(treated) Atypical 2 0 1 3 6
41
3. Lesions Found at Follow-up
Table
Without
Treatment
(year)
initial
lesions
Initial
Benign 7
1
Atypical
Benign
1 myoma
2 endometrial
polyps 2 hyperplasia
11
Atypical
1 myoma
3
6 endometrial 2
lesions
polyps 2 endometrial
4
without atypia and adenomyosis
1 endometrial
polyps
PO’YP CCIS)
1 myoma 9 endometrial 3
polyps 2 myomas
6
1 polyp and complex hyperplasia with
4
1 endometrial
3 endometrial polyps: -1 CIS -2
PO’YP
atypia
hyperplasia with atypia 3 endometrial polYPs CIS
= in situ
adenocarcinoma
icantly different (P = ,421). No atypical lesions were observed in either group. One hundred forty women were evaluated at 2 years: 120 in the group without initial lesions and 20 in the group with initial lesions. The percentage of intrauterine lesions was higher in the group with lesions (20%) than in the group without lesions (9.2%) but without statistical significance (P = .289). In the group with initial lesions, one atypical lesion (an adenocarcinoma in situ within a polyp) was observed, and hysterectomy and BSO were carried out. This woman with recurrent lesions had an endometrial polyp diagnosed before tamoxifen treatment and had been treated by polypectomy and endometrial resection before tamoxifen treatment. Sixty women had 3 years of follow-up, 51 in the group without initial lesions and nine in the group with initial lesions. The number of lesions (with and without atypia) was significantly (P = .034) higher in the group with initial lesions (four lesions among nine subjects) compared with the group without lesions (six lesions
Table
4. Data Expressed in Person-years and Incidence Rate Without Personyears
Total (n = 264 patients)
578
680 person-years The number The number The number
42
among 51 subjects). The incidence of benign intrauterine lesions was very similar (one lesion among nine women versus five benign lesions among 51 women), but the incidence of atypical lesions was different. Three atypical lesions were observed in the group with initial lesions,but only one atypical lesion was observed in the group of women without initial lesions. Even though the number of women was small and the follow-up short, Fisher exact test showed that the incidence of atypical lesions was significantly higher in the group with initial lesions than in the group without initial lesions (P = .009). None of the women who developed atypical lesions had diabetes or hypertension. During the entire follow-up period, four cases of atypical lesionswere observed in the group with lesions initially: two casesof adenocarcinoma in situ and two of hyperplasia with atypia. These diagnoses represent recurrent lesions, endometrial polyps having been completely resected before starting tamoxifen. Because the duration of follow-up varied, data also were expressed in person-years, and the incidence rate was noted in
Berlihe
of lesions of benign of atypical
et al
(benign lesions lesions
Uterine
initial
With
lesions
Benign lesions
Atypical lesions
23 (4%)
1 (0.2%)
and atypical) is significantly higher in the group is not significantly different in the two groups is significantly higher in the group with initial
Efects
of Tamoxifen
Personyears 102
initial
lesions
Benign lesions
Atypical lesions
7 (6.9%)
4 (3.9%)
with initial lesions than in that without initial lesions (P = .Oll). (P = ,296). lesions than in that without initial lesions U’ < .OOl).
Obstetrics
6 Gynecology
each group for benign and atypical lesions (Table 4). The findings of the statistical analysis were the same as those observed at 3 years of follow-up. Many benign asymptomatic intrauterine lesions also were diagnosed by routine vaginal ultrasonography and hysteroscopy. In the group without initial lesions, 24 lesions were diagnosed during the 3 years of followup: seven (29.2%) were symptomatic, and 17 (70.8%‘) were asymptomatic. In the group with lesions, 11 lesions were observed during the 3 years of follow-up: three (27.3%) were symptomatic, and eight (72.7%) were asymptomatic. Currently, two women in the group without lesions have developed metastatic lesions and have had to change their hormonal therapy after 3 years of follow-up.
Discussion In our unpublished retrospective study of 140 women with histologically documented breast cancer receiving tamoxifen who underwent gynecologic examination and monitoring of uterine abnormalities by endovaginal ultrasonography and outpatient hysteroscopy, 35 (25%) had endometrial polyps and seven (5%) had atypical lesions (either atypical hyperplasia or adenocarcinoma in situ). This relatively high prevalence of atypical changes and the distribution of the different types of pathologic lesions do not differ from the findings of published reports.‘“-l7 However, no conclusions could be drawn, not only because the study was retrospective, but also because, as in other studies2z3 reported in the literature, no data concerning the initial endometrial status were available. Even in most of the prospective studies’,3 reported so far, no information concerning baseline endometrial conditions is available, so that bias is a possibility. This is why we decided to initiate a prospective study in which each woman served as her own control, with the uterine cavity evaluated before tamoxifen therapy. Only two prospective studies’s,‘9 also have analyzed the baseline endometrial status of their subjects. In the study by Neven et a1,18hysteroscopy and biopsy were performed on 16 women before the initiation of and during adjuvant tamoxifen therapy. At the start, all women had diagnoses of atrophic endometrium. At the time of the second biopsy (6-36 months of tamoxifen therapy), seven women were diagnosed with proliferative endometrium, four had developed endometrial polyps, and one woman was found to have an endometrial adenocarcinoma. In the study by Gal et a1,1912 of 19 women underwent biopsy before initiating tamoxifen treatment, and 11 had repeated biopsies during treatment. All initial biopsies were normal, but three women developed endometrial abnormalities: hyper-
VOL.
91, NO.
1, JANUARY
1998
plasia without atypia, one complex hyperplasia without atypia, and one complex hyperplasia with atypical changes. In contrast to these reports,“,” we observed a high prevalence of baseline abnormalities in asymptomatic women with breast cancer (46 of the 264 women, 17.4%). Most of these lesions (n = 34) were endometrial polyps. This difference may be explained partially by the small number of women involved in the studies by Neven et al’* and Gal et a1.19In our prospective study, we separated clearly the women without initial intrauterine lesions from those with initial intrauterine lesions before starting tamoxifen. However, it must be noted that although all the women were asymptomatic, one had endometrial adenocarcinoma and another hyperplasia with atypia. This highlights the importance of the evaluation of the uterine cavity before starting tamoxifen, in order not to attribute prior abnormalities to tamoxifen treatment. After 3 years, the incidence of benign endometrial lesions was similar (9.8% compared with 11.1%) in both groups, but a significantly higher incidence of hyperplasia with atypia and adenocarcinoma was observed in the group in which initial lesions were diagnosed before tamoxifen treatment was initiated. The severity of lesions (atypical changes) increased with the time of exposure to tamoxifen. In the subgroup with initial lesions, the number of patients with 3 years of follow-up is currently small. Nevertheless, at this time, the incidence of atypical changes is high in this group and is significantly higher than in the group without initial lesions. Because of their initial lesions, these patients may be more sensitive to the carcinogenic effect of tamoxifen. However, the two cases of endometrial carcinoma diagnosed after tamoxifen treatment in our study were well-differentiated, in contrast with other studies20,21 that report high-grade or unusual types of carcinoma, such as clear cell carcinoma, Miillerian tumors, or leiomyosarcomas in tamoxifen-treated women. These reports20J21 were retrospective and did not mention initial endometrial status before starting tamoxifen. Thus, we have identified prospectively a group of women at high risk of developing endometrial cancer with tamoxifen treatment. Until now, no group of women taking tamoxifen has been identified clearly as being at greater risk of developing endometrial cancer. Our findings and the high percentage of asymptomatic lesions (mentioned in the other two prospective studies) i8,19 support the need for regular endometrial surveillance of tamoxifen-treated women even in the absence of symptoms. This is in contrast to the ACOG’s recommendation to investigate symptomatic women only.22 The best method of follow-up is yet to be defined.22
Berli&re
et al
Uterine Effects of Tamoxifen
43
Preventive medicine is costly, and a complete follow-up program for all women treated with tamoxifen may not be cost-effective. Identification of high-risk women before initiation of tamoxifen therapy should be considered. These women need close monitoring, and the optimal surgical treatment of their baseline endometrial lesions should be studied further.
References
Blaustein’s
pathology
of the female
genital
tract.
4th ed. New
York:
14.
Springer Verlag, 1994:439-86. Cohen I, Altaras MM, Beyth Y, Weed JC. Gynecologic tumors in tamoxifen treated women with breast cancer. Obstet Gynecol
15.
1994;81:158-9. Cohen I, Rosen et al. Endometrial
16.
DJD, Shapiro J, Cordoba changes in postmenopausal
M, Gilboa S, Altaras women treated
tamoxifen for breast cancer. Br J Obstet-Gynaecol Neven I’, De Muylder X, Van Belle Y, Campo Tamoxifen and the uterus: Women given this assessment. BMJ 1994;309:1313-4.
MM, with
1993;100:567-70. R, Vanderick G. drug need careful
1. Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Nat1 Cancer Inst
17. Nuovo MA, Muovo GJ, MC Caffey RM, Leviner V, Barron B, Winkler B. Endometrial polyps in postmenopausal patients receiving tamoxifen. Int J Gynecol Path01 1989;8:125-31. 18. Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder E.
1995;87:645-51. 2. Fisher B, Costantino JP, Redmond Cronin WN. Endometrial cancer
Hysteroscopic follow-up during tamoxifen Gynecol Reprod Biol 1990;35:235-8. 19. Gal D, Kopel S, Basheukin M, Lebowicz
patients; findings from Bowel Project (NSABI’) 3. Fornander T, Rutqvist
CK, Fisher in tamoxifen
ER, Wickerham treated breast
DL, cancer
the National Surgical Adjuvant Breast B 14. J Nat1 Cancer Inst 1994;86:527-37. LE, Cedermark B, Glas U, Mattson
and
treatment. J, Lev
Eur J Obstet R, Tancer
L.
Silfversward C, et al. Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1989;1:117-20. 4. Rose PG. Endometrial carcinoma. N Engl J Med 1996;335:640-9.
20.
Oncogenic potential of tamoxifen on endometria of postmenopausal women with breast cancer. Preliminary report. Gynecol Oncol 1991;42:120-3. Sasco AJ, Raffi F, Satge D, Goburdhun J, Fallou HB, Leduc B.
5. Fried1 A, Jordan about tamoxifen 1994;1:27-39.
21.
Endometrial miillerian carcinosarcoma after cessation of tamoxifen therapy for breast cancer. Int J Gynaecol Obstet 1995;48:307-10. Magriples U, Naftolin F, Schartz PC, Carcangiu ML. High-grade
6. Jordan breast 7. Nephen
VC. Molecular cancer. Breast KP, Polek
oncogene Endocrinology 8. Carmichael Phillips trium. 9. Powles
VC. What do we know in the human uterus.
and what don’t Breast Cancer
we know Res Treat
mechanisms of antioestrogen Cancer Res Treat 1994;31:41-52. TC, Khan SA. Tamoxifen-induced
expression persists 1996;137:219-24. PL, Ugwumadu
in uterine AH,
Neven
action
I’, Hewer
AJ, Poon
VA,
GK,
endomeTreleovan
J, et al. The Royal Marsden Hospital pilot tamoxifen chemoprevention trials. Breast Cancer Res Treat 1994;3:73-82. 10. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal cytotoxic or immune therapy. 133 randomised trials involving 31000 recurrences and 24000 11
12
13
44
deaths
among
75000
women.
Lancet
treated with tamoxifen. J Ultrasound Med 1993;5:275-80. Kurman RJ, Norris HJ. Endometrial hyperplasia and related cellular changes. In: Kurman RJ, ed. Blaustein’s pathology of the female tract. 4th ed. New York: RJ, Norris HJ. Endometrial
Bedike
et al
Cancer
carcinoma in tamoxifen-treated 1993;11:485-90. Neven P, Jordan VC, Vergote of tamoxifen and endometrial
breast
cancer
patients.
I. A realistic carcinogenesis.
clinical Eur
J
1996;32:1464-76.
Address reprint requests to: Martine BerliPre, MD Department of Gynecology St Luc’s Hospital Avenue Hippocrate 10-B-2200 Brussels Belgium
1992;339:1-15,71-85.
Cohen I, Rosen D, Tepper R, Cordoba M, Shapira Y, Altaras M, et al. Ultrasonographic evaluation of the endometrium and correlation with endometrial sampling in postmenopausal patients
genital Kurman
endometrial J Clin Oncol 22. Assikis VJ, perspective
epithelium.
in human Tidy
in
proto-
endometrial
DH. Lack of genotoxicity of tamoxifen Cancer Res 1996;56:1475-9. TJ, Jones AL, Ashley SE, O’Brien MER,
A,
Springer Verlag, 1994:411-37. carcinoma. In: Kurman
Uterine Efects of Tumoxifen
RJ, ed.
ReceivedMay 27, 1997. in revised form September Accepted October 10, 1997. Received
Copyright Gynecologists.
0
1998 by Published
The American by Elsevier
29, 1997.
College of Science Inc.
Obstetricians
and
Obstetrics & Gynecology
CHARLES, MD, CHRISTINE
Objective: To determine the effect of tamoxifen on the endometrium in postmenopausal women with breast cancer and to try to identify, by pretreatment screening, subjects at higher risk of developing endometrial cancer. Methods: Between January 1993 and January 1996, 264 postmenopausal women with breast cancer were studied prospectively with pelvic ultrasonography. Outpatient hysteroscopy and endometrial biopsy were done if ultrasound abnormalities were detected. Initial endometrial evaluation was done before treatment with tamoxifen was started, 20 mg daily, and annually thereafter. Attention was focused on endometrial lesions and, especially, endometrial hyperplasia, which was defined according to World Health Organization classification. Endometrial hyperplasia was subdivided into two broad categories: hyperplasia without cytological atypia and hyperplasia with cytological atypia. Adenocarcinoma in situ was defined as a well-differentiated endometrial carcinoma confined to the endometrial mucosa without myometrial invasion. Results: Forty-six women (17.4%) had asymptomatic endometrial lesions diagnosed before starting tamoxifen, and two of these were atypical lesions. Patients with initial lesions and those without initial lesions were followed separately. At 3 years of follow-up, the incidence of atypical lesions was significantly higher in women with lesions initially than in those without (three lesions among nine women versus one lesion among 51 women, P = .0091. Conclusion: It appears that a group of high-risk subjects can be defined on the basis of endometrial evaluation before tamoxifen therapy; these women should be followed carefully because of the high incidence of severe atypical lesions. (Obstet Gynecol 1998;91:40-4. 0 1998 by The American College of Obstetricians and Gynecologists.)
Tamoxifen appears to increase the risk of endometrial cancer.‘” According to Rose,4 the likelihood of developing endometrial cancer is low, varying from 12 cases per 100,000 women at 40 years of age to 84 cases per From Hospital,
40
the Departments of Gynecology and Pathology, Catholic University of Louvain, Brussels, Belgi~m~.
0029-7844/98/$19.00 PI1 SOO29-7844(97)00591-7
St Luc’s
GALANT,
MD, AND
100,000 women at 60 years of age. Fisher et al3 reported a relative risk of tamoxifen-induced endometrial cancer two to three times greater than that seen in women with breast cancer not treated with tamoxifen. Rutqvist et al’ and Fornander et al,” report a sixfold excess risk of endometrial carcinoma in women treated with tamoxifen in comparison with controls. Tamoxifen has an estrogenic agonistic effect on the human uterus.3,5,6 Although evidence points to the involvement of estrogens in the growth of endometrial cancer, the molecular mechanisms underlying the uterotrophic activity of tamoxifen have not been established clearly. Experiments performed on rats have demonstrated overexpression of oncogenes, which may contribute to the uterine toxicity associated with chronic tamoxifen treatment.7 It remains unknown whether genotoxicity observed with tamoxifen in the rat also can be seen in humans.8 Tamoxifen has become standard therapy for metastatic disease, and adjuvant therapy for nodepositive and node-negative postmenopausal patients.” It is now being studied as a preventive agent in women at high risk of breast cancer.’ Tamoxifen’s side effects should be evaluated carefully before its extensive use as preventive treatment. Although its benefits also have been demonstrated in premenopausal patients with breast cancer, its use remains problematic because of gynecologic side effects.” The purposes of this prospective study were to determine the effect of tamoxifen on the endometrium in postmenopausal women with breast cancer and to try to identify subjects at higher risk of developing endometrial cancer on the basis of gynecologic pretreatment screening.
Materials and Methods Between January 1993 and January 1996,264 postmenopausal women with histologically documented breast cancer who were to receive tamoxifen as adjuvant
Obstetrics
& Gynecology
Table 1.
Patient
Characteristics
Characteristic Age (y) Weight (kg) Average parity Age at menopause Previous hormonal Diabetes Hypertension Demographic deviation).
Without lesions (n = 218)
With lesions (n = 46)
62.7 (27.1) 73.2 (?11.9) 1.6 (range O-4) 53.6 (14.3) 25/215 (11.6%) None None
63.6 (27.2) 71.3 (?12.1) 1.8 (range O-5) 53.8 (24.2) 5/46 (10.9%) None None
(y) therapy
characteristics
are expressed
as mean
(Z
standard
therapy (20 mg daily for 5 years) were included in a prospective study. Subjects with prior hysterectomy were excluded, and all eligible patients seen during the 3 years were enrolled. All subjects were considered free of metastatic lesions at the time breast cancer was diagnosed, and all were eligible for the study after locoregional treatment (surgery with or without adjuvant radiotherapy). Two hundred twenty women had a minimum follow-up of 1 year; 140, a follow-up of 2 years, and 60, a follow-up of 3 years. No patients were lost to follow-up. Patient characteristics are listed in Table 1. Our initial evaluation included gynecologic examination, Papanicolaou smear evaluation, and endovaginal ultrasonography (vaginal probe 6 MHZ, model PVF 621 VT, Toshiba SSH 140A, Toshiba Europe, Brussels, Belgium). We defined an abnormal endometrial thickness as greater than 4 mm, in accordance with a previous rep0rt.l’ In women with abnormal transvaginal sonography, an outpatient hysteroscopy was done along with an endometrial biopsy. After the initial evaluation, women were reviewed every year. A complete physical examination, with a gynecologic examination, a Papanicolaou smear, and a vaginal sonography, was done. In the caseof an abnormal ultrasound, an outpatient hysteroscopy was carried out with an endometrial biopsy (the ultrasound criteria were the same as those described for the pretreatment evaluation). This gynecologic follow-up was associated with an oncologic follow-up (blood test, chest x-ray, and mammography). The diagnosis of endometrial hyperplasia was based on Kurman and Norris.12 Endometrial hyperplasia was subdivided into two broad categories: hyperplasia without cytological atypia and hyperplasia with cytological atypia (atypical hyperplasia). These proliferative lesions were classified further into simple or complex according to the extent of glandular complexity and crowding. Adenocarcinoma in situ was defined as a well-differentiated endometrial carcinoma confined to
VOL.
91,
NO.
1, JANUARY
1998
the endometrial mucosa, without myometrial infiltration.13 Depending on the pathology observed, two types of surgical treatments were used: 1) hysteroscopic resection or hysteroscopic myomectomy in the caseof benign lesions or 2) laparoscopy-assisted vaginal hysterectomy and adnexectomy in casesof hyperplasia with atypia or adenocarcinoma. The 2 test and Fisher exact test were used to compare the incidence of lesions in the two groups at each point in time. Statistical significance was established at P < .05. Because the duration of follow-up varied, data also were expressed in personyears.
Results Before starting tamoxifen therapy, all 264 women were asymptomatic. On the basis of the initial screening, two subgroups of women were distinguished: women without initial lesions (n = 218) and women with initial lesions (n = 46) (Table 2). Thus, the prevalence of asymptomatic baseline endometrial lesions was 17.4%. Among the 46 asymptomatic women with abnormal sonography and abnormal hysteroscopy before tamoxifen, two atypical lesions were observed: one case of atypical hyperplasia and another of endometrial adenocarcinoma in situ. Hysterectomy and bilateral salpingooophorectomy (BSO) were carried out in both women, who are still alive and currently free of any metastatic lesions. Among the other 44 women, the lesions observed most frequently were endometrial polyps (n = 34; 77%) (Table 3). Submucosal myomas and simple hyperplasia (without atypia) with adenomyosis were observed in seven and three women, respectively. All the women were treated with polyp resection followed by either endometrial resection, myomectomy, or endometrial resection. The two groups of women were followed separately in precisely the same way. There were no deaths after surgical procedures. At 1 year, 220 women were evaluated: 185 in the group without initial lesions and 35 in the group with initial lesions. The percentages of intrauterine lesions were 3.8% and 8.6Y~respectively, which was not signif-
Table 2.
Patient
Follow-up lesions
Initial
rz
Benign
Atypical
II
Benign
218 185 120 51
7 (3.8%) I1 (9.2%:) 5 (9.8%) 23
-
46 35 20 9
44 3 3 1 51
Without
Treatment (year)
n
0 1 2 3
264 220 140 60 Total
Berlibe
initial
et al
0 0 1 1
Uterine
Effects
lesions
of Tamoxifen
(treated) Atypical 2 0 1 3 6
41
3. Lesions Found at Follow-up
Table
Without
Treatment
(year)
initial
lesions
Initial
Benign 7
1
Atypical
Benign
1 myoma
2 endometrial
polyps 2 hyperplasia
11
Atypical
1 myoma
3
6 endometrial 2
lesions
polyps 2 endometrial
4
without atypia and adenomyosis
1 endometrial
polyps
PO’YP CCIS)
1 myoma 9 endometrial 3
polyps 2 myomas
6
1 polyp and complex hyperplasia with
4
1 endometrial
3 endometrial polyps: -1 CIS -2
PO’YP
atypia
hyperplasia with atypia 3 endometrial polYPs CIS
= in situ
adenocarcinoma
icantly different (P = ,421). No atypical lesions were observed in either group. One hundred forty women were evaluated at 2 years: 120 in the group without initial lesions and 20 in the group with initial lesions. The percentage of intrauterine lesions was higher in the group with lesions (20%) than in the group without lesions (9.2%) but without statistical significance (P = .289). In the group with initial lesions, one atypical lesion (an adenocarcinoma in situ within a polyp) was observed, and hysterectomy and BSO were carried out. This woman with recurrent lesions had an endometrial polyp diagnosed before tamoxifen treatment and had been treated by polypectomy and endometrial resection before tamoxifen treatment. Sixty women had 3 years of follow-up, 51 in the group without initial lesions and nine in the group with initial lesions. The number of lesions (with and without atypia) was significantly (P = .034) higher in the group with initial lesions (four lesions among nine subjects) compared with the group without lesions (six lesions
Table
4. Data Expressed in Person-years and Incidence Rate Without Personyears
Total (n = 264 patients)
578
680 person-years The number The number The number
42
among 51 subjects). The incidence of benign intrauterine lesions was very similar (one lesion among nine women versus five benign lesions among 51 women), but the incidence of atypical lesions was different. Three atypical lesions were observed in the group with initial lesions,but only one atypical lesion was observed in the group of women without initial lesions. Even though the number of women was small and the follow-up short, Fisher exact test showed that the incidence of atypical lesions was significantly higher in the group with initial lesions than in the group without initial lesions (P = .009). None of the women who developed atypical lesions had diabetes or hypertension. During the entire follow-up period, four cases of atypical lesionswere observed in the group with lesions initially: two casesof adenocarcinoma in situ and two of hyperplasia with atypia. These diagnoses represent recurrent lesions, endometrial polyps having been completely resected before starting tamoxifen. Because the duration of follow-up varied, data also were expressed in person-years, and the incidence rate was noted in
Berlihe
of lesions of benign of atypical
et al
(benign lesions lesions
Uterine
initial
With
lesions
Benign lesions
Atypical lesions
23 (4%)
1 (0.2%)
and atypical) is significantly higher in the group is not significantly different in the two groups is significantly higher in the group with initial
Efects
of Tamoxifen
Personyears 102
initial
lesions
Benign lesions
Atypical lesions
7 (6.9%)
4 (3.9%)
with initial lesions than in that without initial lesions (P = .Oll). (P = ,296). lesions than in that without initial lesions U’ < .OOl).
Obstetrics
6 Gynecology
each group for benign and atypical lesions (Table 4). The findings of the statistical analysis were the same as those observed at 3 years of follow-up. Many benign asymptomatic intrauterine lesions also were diagnosed by routine vaginal ultrasonography and hysteroscopy. In the group without initial lesions, 24 lesions were diagnosed during the 3 years of followup: seven (29.2%) were symptomatic, and 17 (70.8%‘) were asymptomatic. In the group with lesions, 11 lesions were observed during the 3 years of follow-up: three (27.3%) were symptomatic, and eight (72.7%) were asymptomatic. Currently, two women in the group without lesions have developed metastatic lesions and have had to change their hormonal therapy after 3 years of follow-up.
Discussion In our unpublished retrospective study of 140 women with histologically documented breast cancer receiving tamoxifen who underwent gynecologic examination and monitoring of uterine abnormalities by endovaginal ultrasonography and outpatient hysteroscopy, 35 (25%) had endometrial polyps and seven (5%) had atypical lesions (either atypical hyperplasia or adenocarcinoma in situ). This relatively high prevalence of atypical changes and the distribution of the different types of pathologic lesions do not differ from the findings of published reports.‘“-l7 However, no conclusions could be drawn, not only because the study was retrospective, but also because, as in other studies2z3 reported in the literature, no data concerning the initial endometrial status were available. Even in most of the prospective studies’,3 reported so far, no information concerning baseline endometrial conditions is available, so that bias is a possibility. This is why we decided to initiate a prospective study in which each woman served as her own control, with the uterine cavity evaluated before tamoxifen therapy. Only two prospective studies’s,‘9 also have analyzed the baseline endometrial status of their subjects. In the study by Neven et a1,18hysteroscopy and biopsy were performed on 16 women before the initiation of and during adjuvant tamoxifen therapy. At the start, all women had diagnoses of atrophic endometrium. At the time of the second biopsy (6-36 months of tamoxifen therapy), seven women were diagnosed with proliferative endometrium, four had developed endometrial polyps, and one woman was found to have an endometrial adenocarcinoma. In the study by Gal et a1,1912 of 19 women underwent biopsy before initiating tamoxifen treatment, and 11 had repeated biopsies during treatment. All initial biopsies were normal, but three women developed endometrial abnormalities: hyper-
VOL.
91, NO.
1, JANUARY
1998
plasia without atypia, one complex hyperplasia without atypia, and one complex hyperplasia with atypical changes. In contrast to these reports,“,” we observed a high prevalence of baseline abnormalities in asymptomatic women with breast cancer (46 of the 264 women, 17.4%). Most of these lesions (n = 34) were endometrial polyps. This difference may be explained partially by the small number of women involved in the studies by Neven et al’* and Gal et a1.19In our prospective study, we separated clearly the women without initial intrauterine lesions from those with initial intrauterine lesions before starting tamoxifen. However, it must be noted that although all the women were asymptomatic, one had endometrial adenocarcinoma and another hyperplasia with atypia. This highlights the importance of the evaluation of the uterine cavity before starting tamoxifen, in order not to attribute prior abnormalities to tamoxifen treatment. After 3 years, the incidence of benign endometrial lesions was similar (9.8% compared with 11.1%) in both groups, but a significantly higher incidence of hyperplasia with atypia and adenocarcinoma was observed in the group in which initial lesions were diagnosed before tamoxifen treatment was initiated. The severity of lesions (atypical changes) increased with the time of exposure to tamoxifen. In the subgroup with initial lesions, the number of patients with 3 years of follow-up is currently small. Nevertheless, at this time, the incidence of atypical changes is high in this group and is significantly higher than in the group without initial lesions. Because of their initial lesions, these patients may be more sensitive to the carcinogenic effect of tamoxifen. However, the two cases of endometrial carcinoma diagnosed after tamoxifen treatment in our study were well-differentiated, in contrast with other studies20,21 that report high-grade or unusual types of carcinoma, such as clear cell carcinoma, Miillerian tumors, or leiomyosarcomas in tamoxifen-treated women. These reports20J21 were retrospective and did not mention initial endometrial status before starting tamoxifen. Thus, we have identified prospectively a group of women at high risk of developing endometrial cancer with tamoxifen treatment. Until now, no group of women taking tamoxifen has been identified clearly as being at greater risk of developing endometrial cancer. Our findings and the high percentage of asymptomatic lesions (mentioned in the other two prospective studies) i8,19 support the need for regular endometrial surveillance of tamoxifen-treated women even in the absence of symptoms. This is in contrast to the ACOG’s recommendation to investigate symptomatic women only.22 The best method of follow-up is yet to be defined.22
Berli&re
et al
Uterine Effects of Tamoxifen
43
Preventive medicine is costly, and a complete follow-up program for all women treated with tamoxifen may not be cost-effective. Identification of high-risk women before initiation of tamoxifen therapy should be considered. These women need close monitoring, and the optimal surgical treatment of their baseline endometrial lesions should be studied further.
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Copyright Gynecologists.
0
1998 by Published
The American by Elsevier
29, 1997.
College of Science Inc.
Obstetricians
and
Obstetrics & Gynecology