Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial

Abstract

PURPOSE The addition of ovarian function suppression (OFS) for 5 years to tamoxifen (TAM) for treatment of premenopausal patients with breast cancer after completion of chemotherapy has beneficial effects on disease-free survival (DFS). This study evaluated the efficacy of adding 2 years of OFS to TAM in patients with hormone receptor–positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. PATIENTS AND METHODS We enrolled 1,483 premenopausal women (age ≤ 45 years) with estrogen receptor–positive breast cancer treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment on the basis of follicular-stimulating hormone levels and vaginal bleeding history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomly assigned to complete 5 years of TAM alone (TAM-only) group or 5 years of TAM with OFS for 2 years that involved monthly goserelin administration (TAM + OFS) group. DFS was defined from the time of enrollment to the time of the first event. RESULTS A total of 1,293 patients were randomly assigned, and 1,282 patients were eligible for analysis. The estimated 5-year DFS rate was 91.1% in the TAM + OFS group and 87.5% in the TAM-only group (hazard ratio, 0.69; 95% CI, 0.48 to 0.97; P = .033). The estimated 5-year overall survival rate was 99.4% in the TAM + OFS group and 97.8% in the TAM-only group (hazard ratio, 0.31; 95% CI, 0.10 to 0.94; P = .029). CONCLUSION The addition of 2 years of OFS to TAM significantly improved DFS compared with TAM alone in patients who remained premenopausal or resumed ovarian function after chemotherapy.

CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients

“…The significantly higher RFS event rates associated with high intratumoral CYP27A1 expression in patients < 55 years (pre-and perimenopausal) presenting with ER+ tumors during the first 5 years after BC diagnosis in BC-blood is intriguing since the logical expectation is that high 27HC should display antagonistic properties under estrogenic conditions and therefore be protective in premenopausal patients, a premise which was verified in our previous study [39] reporting a significant improved RFS and OS for younger patients (< 50 years old) presenting with high compared with low CYP27A1 mRNA in their tumors. Several studies have reported the benefit of suppressing ovarian function in premenopausal patients receiving endocrine therapies [48][49][50], and it is also well established that chemotherapy treatment can induce a postmenopausal physiological state in some premenopausal patients [51,52]. The more generous prescription of chemotherapy in BC-blood and the higher likelihood that ovarian function suppressants may have been prescribed for patients in BC-blood given the more recent recruitment of patients into this cohort may to some extent explain the observed inverse association between high CYP27A1 and survival among the younger patients in this cohort.…”

Current State of the Art in the Adjuvant Systemic Treatment of Premenopausal Patients With Early Breast Cancer

“…57,59,60 While negative results emerged from the E-3193 INT-0142 study, probably due to the small sample size and the low-risk population included, 59 an improvement in terms of DFS and OS by adding OFS to tamoxifen was observed in both the ASTRRA and SOFT studies. 58,61 In the ASTRRA trial, a total of 1289 premenopausal patients with hormone receptor-positive breast cancer were randomly allocated to receive tamoxifen alone for 5 years or tamoxifen for 5 years plus OFS for 2 years. 58 Median age was 39 years and 53% of the patients had nodal involvement.…”

“…58,61 In the ASTRRA trial, a total of 1289 premenopausal patients with hormone receptor-positive breast cancer were randomly allocated to receive tamoxifen alone for 5 years or tamoxifen for 5 years plus OFS for 2 years. 58 Median age was 39 years and 53% of the patients had nodal involvement. All patients in this study were previously exposed to adjuvant or neoadjuvant chemotherapy and had to have a recovery of ovarian function within 2 years after the end of cytotoxic treatment for being eligible to the trial.…”

“…60 An improvement in DFS (HR: 0.69; 95% CI: 0.48-0.97) and OS (HR: 0.31; 95% CI: 0.10-0.94) was observed for patients that received tamoxifen plus OFS. 58 The SOFT study was a 3-arm trial that randomized 3066 premenopausal women with hormone receptor-positive early breast cancer to tamoxifen alone, OFS plus tamoxifen, or OFS plus exemestane. 57 Median age was 43 years; approximately 35% of patients had nodal involvement and about 53% were previously exposed to chemotherapy.…”

Is the extension of adjuvant hormone therapy for breast cancer justified?

“…Таким образом, пременопаузальные женщины с HR-позитивным/HER2-негативным РМЖ высокого риска по клинико-патомофрологическим характеристикам могут достичь от 10 до 15% абсолютного улучшения 8-летней безметастатической выживаемости благодаря адъювантной гормонотерапии эксеместаном + OFS в сравнении с терапией тамоксифеном + OFS или одним тамоксифеном [1,2,12].…”