While extended adjuvant tamoxifen therapy has been found to improve breast cancer-free survival rates in premenopausal women with estrogen-receptor positive breast cancer, new research suggests that may not be without risk. A meta-analysis of four randomized controlled trials (RCTs) shows that using the drug for 10 years rather than 5 significantly raises the likelihood that a woman will get endometrial cancer.
The researchers performed two systematic literature searches with the primary aim of the first search to identify risk of endometrial malignancy in the setting of extended tamoxifen therapy. The primary goal of the second search was to identify the efficacy of routine endometrial surveillance in all patients receiving tamoxifen.
The endometrial malignancy studies were winnowed down to four RCTs, which included 21,361 patients, of whom 7652 (35.8%) received extended therapy. Three of the studies (ATLAS, aTTom, NSABP B-14) compared extended adjuvant tamoxifen therapy with standard (5-year) therapy with or without placebo. The fourth study (Scottish) compared indefinite tamoxifen therapy at a 10-year interval with 5 years of treatment.
Studies on endometrial surveillance were also winnowed down, from 301 to four studies that met the inclusion criteria. The researchers use the Newcastle-Ottawa quality assessment scale to determine the quality of each eligible study. Points were awarded for patient selection (maximum 4 points), comparability of cohorts (maximum 2 points), and outcome assessment (maximum 3 points). Studies were eligible for inclusion if they were prospective original studies published in English, that reported on the identification of endometrial abnormalities and malignancy in patients who received tamoxifen during endometrial surveillance. However, quality assessment was poor due to the heterogeneity in study designs, endpoints, and surveillance methods. Only one of the studies compared endometrial surveillance methods in women receiving tamoxifen against a cohort not receiving tamoxifen.
The results of the endometrial malignancy analysis illustrated that risk of developing endometrial malignancy was significantly higher in patients undergoing extended therapy than those who received therapy for 5 years and carried an absolute risk from 1.5% to 3.2% (RR 2.29, 95% CI, 1.60 – 3.28). In NSABP B-14 study, the risk ratio was 6.84, but 21 of 24 endometrial cancers were International Federation of Gynecology and Obstetrics (FIGO) stage 1 with good to moderate histological grade when diagnosed. The ATLAS study found extended therapy was associated with a twofold increase in 15-year endometrial cancer risk almost exclusively in postmenopausal women. The other two included studies had similar results (aTTom [RR 2.28, 1.61 – 3.22] and Scottish [RR 3.42, 0.72 – 16.22]).
The authors note several limitations to their analysis. Several patient-related factors, such as family history and obesity, were not addressed in the studies and may have acted as confounding variables. Their analysis of endometrial surveillance was made difficult due to the lack of uniformity between the studies that matched their inclusion criteria. However, they believe their findings on the increased risk of endometrial cancer and extended tamoxifen therapy warrant increased endometrial screening in breast cancer patients who have taken the therapy for over 5 years. Ultimately, more research is necessary to determine the best types of surveillance and surveillance frequency.