Summary
Recently, Rye et al. [1] investigated the association of the use of tamoxifen with the risk of endometrial cancer and other uterine diseases in premenopausal women with breast cancer (BC). For this the authors carried out a nationwide, population-based, retrospective longitudinal cohort study with an 18-year study period using data obtained from the Korean National Health Insurance Service. Premenopausal women aged 20 to 50 years with BC diagnoses between January 2003 and December 2018 were included, with data analysis being performed from April to December 2021. Tamoxifen treatment was the main exposure variable and outcomes included: the incidence of uterine diseases, including endometrial cancer (EC), endometrial hyperplasia (EH), endometrial polyps (EP), and other uterine cancers. The incidence of uterine diseases was compared between tamoxifen users and non-users. A total 78,320 female participants were included (mean age 42.1), 34,637 (44.2%) were tamoxifen users and 43,683 (55.8%) were non-users. During the mean follow-up 6.13 years, among tamoxifen users the incidence of newly diagnosed EP, EH, EC and uterine cancers was 20.13, 13.49, 2.01 and 0.45 cases per 1,000 person-years, respectively. The risk of EC was higher in the tamoxifen group than in the control group after adjusting for age, body mass index, history of diabetes, and other co-variates. The authors conclude that premenopausal Korean women with BC who received tamoxifen as adjuvant hormone therapy, as compared to those who did not, had a significantly increased risk of studied uterine diseases, suggesting that clinicians should consider this risk in premenopausal women.
Commentary
Many studies have reported an increased risk of uterine disease, such as EC, among postmenopausal tamoxifen users; however, this association in premenopausal women with BC remains controversial. Tamoxifen is the first clinically available SERM (selective estrogen receptor modulator). Actually, clomiphene citrate is a SERM but not usually included in that category. Tamoxifen was discovered in 1966 and approved in the United States for BC adjuvant therapy in 1978. Worldwide it is the most frequently prescribed anti-cancer drug which has led to an increase overall survival and disease-free survival in women with estrogen receptor positive BC.
On the basis of the Breast Cancer Prevention Trial (BCPT) of the National Surgical Adjuvant Breast and Bowel Project [2], tamoxifen was approved for BC chemo prevention in women at high risk for BC. This trial enrolled women who, using the Gail Model, had a risk of 1.6% of developing invasive BC in the following five years, or had a history of lobular carcinoma in situ (LCIS), or were over 60 years of age. The trial involved 13,388 women over the age of 35. It was stopped early because the data safety monitoring board felt it was unethical to continue a trial in light of a 49% reduction in invasive BC when comparing those treated with tamoxifen to those assigned to the placebo group (p-value was <0.00001). They could not allow the trial to continue with such a high-risk group of women taking placebo in light of the highly significant efficacy. In this trial, in terms of endometrial cancer, participants who received tamoxifen had a 2.53 times greater risk of developing an invasive EC (95% CI 1.35-4.97) than did women who received placebo. This calculates to an average annual rate per 1,000 participants of 2.30 in the tamoxifen group and 0.91 in the placebo group. The increased risk was predominantly in women 50 years of age or older. The RR of women aged 49 years or younger was 1.21 (95% CI 0.41-3.60), whereas it was 4.01 (95% CI 1.70-10.90) in women aged 50 years or older. However, one must remember that these were women at risk for BC but not already diagnosed with BC.
In the present commented retrospective longitudinal cohort study, premenopausal Korean women with BC who received tamoxifen as adjuvant hormone therapy presented a significantly increased risk of EC compared with those who were not treated. Important to mention is the fact that the study was of Korean women, thus, it may or may not be extrapolated to all women. In addition, the BCPT was a randomized, placebo controlled, prospective trial. The current study was retrospective, albeit a large study.
A more important distinction (and possible explanation) is that in the BCPT those women did not have BC while in the current Korean study the women did. Clearly, we would expect that women with BC would have a greater underlying risk of EC than women simply at risk for BC. I do believe that in patients with BC, tamoxifen’s ability to cause endometrial neoplasia is real and clinicians should be aware. However, data still seems to indicate that in premenopausal patients without BC this is not the same.
Finally, we have the work of Berliere et al. [3] involving 575 patients with newly diagnosed BC that were followed up for five years. Prior to tamoxifen therapy, all women underwent transvaginal ultrasound, and if an endometrial echo was > 4 millimeters, hysteroscopic evaluation was performed. In such cases, 16.6% had EP prior to tamoxifen therapy. In that group with no initial polyps (something I refer to as “squeaky clean”), 12.9% developed benign polyps and 0.7% developed atypical hyperplasia through 5 years. This is presumably in line with what the background “noise” for such a group might be. However, in the group that had an initial polyp removed and then went on tamoxifen therapy, 17.6% developed polyps and 11.7% developed atypical hyperplasia. This represents an 18-fold increase over the group with no initial polyps. As a result, in 2006, The American College of Obstetricians and Gynecologists [4] issued the following opinion, “emerging evidence suggests the presence of high- and low-risk groups based on the presence or absence of benign endometrial polyps before tamoxifen therapy. Thus, there may be a role for pretreatment screening of postmenopausal women with transvaginal ultrasound and sonohysterography when needed… before initiation of tamoxifen therapy.” Utilization of such pretreatment screening would allow triage of patients about to embark on tamoxifen therapy into two distinct groups: a low-risk group with no initial polyp versus a high-risk group with a benign polyp removed prior to tamoxifen therapy. Unfortunately, in my community, this information has not been widely disseminated, and is only utilized sporadically.
Steven R. Goldstein, MD, CCD, NCMP, FAGCOG, FRCOG (H)
Professor of Obstetrics and Gynecology,
New York University, Grossman School of Medicine,
New York, New York, USA
Immediate Past President of IMS
References
- Ryu KJ, Kim MS, Lee JY, et al. Risk of Endometrial Polyps, Hyperplasia, Carcinoma, and Uterine Cancer After Tamoxifen Treatment in Premenopausal Women With Breast Cancer. JAMA Netw Open. 2022;5(11):e2243951.
https://pubmed.ncbi.nlm.nih.gov/36441547/ - Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371-1388.
https://pubmed.ncbi.nlm.nih.gov/9747868/ - Berlière M, Radikov G, Galant C, Piette P, Marbaix E, Donnez J. Identification of women at high risk of developing endometrial cancer on tamoxifen. Eur J Cancer. 2000;36 Suppl 4:S35-36.
https://pubmed.ncbi.nlm.nih.gov/11056310/ - Committee Opinion No. 601: Tamoxifen and uterine cancer. Obstet Gynecol. 2014;123(6):1394-1397.
https://pubmed.ncbi.nlm.nih.gov/24848920/
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