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© 1999 American Society for Clinical Oncology
Screening for Endometrial Cancer in the Patient Receiving Tamoxifen for Breast CancerDepartment of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY APPROXIMATELY 80,000 OF the 182,000 women diagnosed annually with breast cancer in the United States will be started on tamoxifen as part of their treatment. Although the expected annual risk of developing endometrial cancer while taking tamoxifen is approximately two per 1,000 patients, as defined by the National Surgical Adjuvant Breast and Bowel Project B-14 trial,1 many patients worry a great deal about developing a second cancer. Clinicians who care for these patients sense this anxiety, and in an effort to help, they subject their patients to screening procedures in an attempt to detect endometrial cancers earlier and thereby improve their outcome. Although the chance of detecting endometrial cancer is very low, the patient may benefit from the reassurance that a negative test provides. To date, however, there is no evidence that any form of screening for endometrial cancer in tamoxifen-treated patients will accomplish this.
Transvaginal sonography may provide a noninvasive means of screening the endometrium in tamoxifen-treated breast cancer patients by evaluating endometrial thickening, which may be indicative of pathology. There is, however, no clear definition of an abnormal endometrial stripe. As reported by Lahti et al,2 if a cutoff of Care must be taken, however, not to overinterpret the ultrasonographic findings of the endometrium in tamoxifen-treated patients. Goldstein4 reported five postmenopausal tamoxifen-treated patients who on routine surveillance with vaginal probe ultrasonography were described as having heterogeneous, bizarre-appearing endometria with multiple sonolucent areas suggestive of a polyp. Because of concerns regarding tamoxifen use and endometrial neoplasia, the first patient was referred for a curettage and hysteroscopy. Minimal tissue was obtained and hysteroscopic evaluation revealed a smooth atrophic endometrium. When the abnormal sonographic appearance persisted, the patient underwent a sonohysterogram, which involves the instillation of 3 to 10 mL of saline at the time of sonography. The fluid enhancement revealed that the changes originally interpreted as endometrial were actually subendometrial in origin. Four additional patients with similar abnormal sonographic findings were actually found to have subendometrial abnormalities on sonohysterogram. In evaluations of hysterectomy specimens, it has been noted that these findings actually represent areas of adenomyomatous-like changes in the myometrium. In this issue of the Journal of Clinical Oncology, Love et al5 highlight the pitfalls of screening for endometrial abnormalities using transvaginal sonography in this population. They report on the sonographic endometrial characteristics of 357 asymptomatic patients treated with tamoxifen for a mean period of 66 months, compared with 130 control patients who did not use tamoxifen. Clearly, women receiving tamoxifen had a greater mean endometrial thickness (7.3 mm v 2.5 mm), which correlated with increasing duration of tamoxifen use. With a cutoff for abnormal endometrial thickness of greater than 6 mm, 41% of the tamoxifen-treated group met this criteria, compared with none of the controls. Office hysteroscopy was performed successfully in 134 of 145 of these women, while the remaining 10 underwent a dilatation and curettage (D&C). Atrophic endometrium was noted in 61, giving a false-positive rate of 46%. The remaining patients all had benign features to account for the thickened endometrial stripe. Not all patients, however, had histologic sampling of the endometrium, and one does have to rely to some extent on the hysteroscopic interpretation of the endometrium by the authors. Furthermore, the evaluations were done at a single time point for each patient, and no information is available regarding the prospective evaluation of the endometrium in these patients. Nevertheless, this study looks at a large group of patients treated with tamoxifen for a mean period of 66 months and confirms the poor predictive value of transvaginal sonographic measurement of endometrial stripe thickness for detecting endometrial cancer. Perhaps most importantly, the current study reported that no cancers were detected in this group of asymptomatic patients. During the study period, the authors did note one case of endometrial hyperplasia and one carcinoma, both of which occurred in women referred for evaluation of abnormal bleeding. This confirms the findings of Gibson et al,6 who noted that all cases of endometrial carcinoma detected by D&C in tamoxifen-treated breast cancer patients presented with abnormal bleeding. Another frequently used method of screening the endometrium in this group of patients is the office endometrial biopsy. Barakat et al7 presented the results of a prospective endometrial screening study in tamoxifen-treated breast cancer patients at the 35th annual meeting of the American Society of Clinical Oncology (May 15-18, 1999, Atlanta, GA). One hundred fifty-nine patients with a mean age of 51 years were prospectively entered onto a study where patients underwent endometrial biopsies every 6 months for 2 years and then once a year for an additional 3 years. Eight patients (5%) could not undergo the biopsy procedure because of a stenotic cervix. One hundred eleven patients considered assessable underwent a total of 635 endometrial biopsies (mean, 5.8 per patient) over a median time period of 36 months. Screening led to an increase in operative procedures, with 14 patients (12.6%) requiring a D&C for abnormal biopsy findings. Three patients underwent hysterectomy. The first underwent a hysterectomy for a pelvic mass after 15 months of tamoxifen treatment; final pathology revealed a high-grade leiomyosarcoma. The second patient underwent hysterectomy for complex hyperplasia with extensive mucinous change after 12 months of tamoxifen treatment. One additional patient required a hysterectomy for a large symptomatic endometrial polyp after 48 months of tamoxifen treatment. Although three patients required hysterectomy, only one had pathology detected by endometrial biopsy, and this patient had complex hyperplasia only. The reported rate of progression of this condition to cancer is less than 3%, so it is unclear whether screening benefitted this patient as well. The authors concluded that although office endometrial biopsies can be used to monitor the endometrium in the majority (95%) of breast cancer patients receiving tamoxifen, their utility in terms of cancer screening seems limited. What, if any, recommendations then can be made regarding the need for screening for endometrial cancer in breast cancer patients receiving tamoxifen? The ultimate goal of any cancer-screening program is to detect disease at an earlier stage, when it is more curable. Since tamoxifen-associated endometrial cancers seem to have a similar stage, grade, and histology as endometrial cancers occurring in the general population,8 their prognosis is generally good and early detection will probably not improve outcome significantly. Furthermore, a small number of tamoxifen-treated breast cancer patients could be expected to benefit from screening for endometrial cancer. Since the annual risk of endometrial cancer is two per 1,000 in this population, and approximately 15% of these cancers will result in the patient's death,8 annual screening could potentially decrease mortality in only 0.002 x 0.15 = 0.0003, or 0.03%, of all tamoxifen-treated patients. Since approximately 80,000 women begin tamoxifen treatment annually, the cost to undertake screening for endometrial cancer in this population may be prohibitively high. Breast cancer patients receiving tamoxifen are anxious about developing a second cancer. Rather than feed into this anxiety by ordering a battery of screening tests with unproven efficacy, clinicians should educate their patients regarding the actual risk and outcome of endometrial cancers that develop during tamoxifen treatment. These patients should be instructed to alert their physician about any sign of abnormal vaginal bleeding, including spotting or abnormal vaginal discharge. All women with breast cancer, whether or not they are receiving tamoxifen, should undergo an annual gynecologic evaluation. Endometrial sampling with or without a transvaginal sonogram should be reserved for patients with any sign of abnormal vaginal bleeding. REFERENCES
1.
Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86:527-537, 1994 2. Lahti E, Blanco G, Kauppila A, et al: Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen. Obstet Gynecol 81:660-664, 1993[Medline] 3. Kedar RP, Bourne TH, Powles TJ, et al: Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial. Lancet 343:1318-1321, 1994[Medline] 4. Goldstein SR: Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 170:447-451, 1994[Medline]
5.
Love CDB, Muir BB, Scringeour JB, et al: Investigation of endometrial abnormalities in asymptomatic women treated with tamoxifen and an evaluation of the role of endometrial screening. J Clin Oncol 17:2050-2054, 1999 6. Gibson LE, Barakat RR, Venkatraman ES, et al: Endometrial pathology at dilatation and curettage in breast cancer patients: Comparison of tamoxifen users and nonusers. Cancer J Sci Am 2:35-38, 1995 7. Barakat RR, Gilewski TA, Almadrones L, et al: The effect of adjuvant tamoxifen (T) on the endometrium in women with breast cancer: A prospective study. Proc Am Soc Clin Oncol 18:358a, 1999 (abstr 1381) 8. Barakat RR, Wong G, Curtin JP, et al: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 55:164-168, 1994[Medline]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5 mm was used to define an abnormal endometrial echo, 22 patients (51.2%) had no abnormal endometrial pathology. Kedar et al
