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:e2243951.
EXPERT COMMENTARY
Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.
Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,1 physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.
A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.2
Details of the study
The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.2 The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.
The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).
Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.
Study strengths and limitations
A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.
Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.
Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.
Continue to: Methodological concerns...