Abstract GS4-03: Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial
Authors: Fleming G , Francis PA , Láng I , Ciruelos EM , Bellet M , Bonnefoi HR , Climent MA , Pavesi L , Burstein HJ , Martino S , Davidson NE , Geyer CE , Walley BA , Coleman RE , Kerbrat P , Buchholz S , Ingle JN , Rabaglio-Poretti M , Colleoni M , Regan MM 
Published: February 2018

Abstract
Background: The primary results of SOFT at 5.6 years median follow-up found adding OFS to T did not provide a significant benefit in the overall study population of premenopausal women with HR+ BC (Francis et al, NEJM 2015). For those women at sufficient risk for recurrence to warrant adjuvant chemotherapy (CT) and who remained premenopausal, the addition of OFS improved disease outcomes. Follow-up was immature for overall survival (OS). We report a planned update with visit cut-off of 31Dec16 after 8 yrs median follow-up.
Methods: SOFT randomized premenopausal women with HR+ BC from Nov 2003 to Jan 2011 to 5 yrs of T vs T+OFS vs Exemestane(E)+OFS. OFS was by choice of GnRH agonist triptorelin, oophorectomy or ovarian irradiation. SOFT was stratified by the use of prior CT; 47% received no CT and 53% remained premenopausal after prior CT, determined by premenopausal estradiol level within 8 months of CT completion. The primary endpoint was invasive disease-free survival (DFS; randomization until invasive local, regional, distant recurrence or contralateral breast; invasive second malignancy; death). Secondary endpoints included invasive breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI) and OS. NCT00066690.
Results: DFS for patients assigned T+OFS (n=1015) was significantly improved over T (n=1018; HR=0.76 [95%CI 0.62-0.93]) and 8yr DFS was 83.2% vs 78.9%, respectively; BCFI and DRFI results were supportive (see Table). Hazard ratios for these 3 endpoints showed no heterogeneity by use of prior CT. For patients with prior CT, 8yr DFS was 76.7% with T+OFS vs 71.4% with T (Δ=5.3%); in those without CT, 8yr DFS was 90.6% vs 87.4% (Δ=3.2%). E+OFS (n=1014) improved outcomes relative to T (Table); 8yr DFS for E+OFS was 85.9% (80.4% with use of prior CT and 92.5% for those without CT). OS was improved with T+OFS vs T (8yr OS 93.3% vs 91.5%). 8yr OS was 92.1% with E+OFS. 201/225 deaths occurred in women with prior CT. For women without CT there have been 10, 5 and 9 deaths in the T+OFS, T and E+OFS groups (total n=1419), respectively, only half of these deaths after breast cancer event.
N. EventsHazard Ratio (95% CI)Endpoint(3 arms)T+OFS vs TE+OFS vs TDFS5180.76 (0.62-0.93) P=0.0090.65 (0.53-0.81)BCFI4370.76 (0.61-0.95)0.64 (0.51-0.81)DRFI3060.86 (0.66-1.13)0.73 (0.55-0.96)OS2250.67 (0.48-0.92)0.85 (0.62-1.15)
Overall toxicity was worse with T+ OFS than with T, including 32% vs 25% grade 3+ targeted AEs. Early cessation of tamoxifen occurred for 19% assigned T+OFS and 22% of women assigned T; the cumulative incidence of early cessation of triptorelin on the T+OFS arm was 23% by 4yrs. Early cessation of exemestane occurred for 28% and of triptorelin for 21% by 4yrs on the E+OFS arm.
Conclusions: With additional follow-up to a median of 8yrs, SOFT further supports the value of OFS for some premenopausal women. Follow-up continues, which will further clarify the safety and the benefit of OFS for late recurrence and overall survival. Oncologists appear to be able to select a low risk group (no chemotherapy) for whom treatment escalation is unlikely to improve survival.
Citation Format: Fleming G, Francis PA, Láng I, Ciruelos EM, Bellet M, Bonnefoi HR, Climent MA, Pavesi L, Burstein HJ, Martino S, Davidson NE, Geyer Jr CE, Walley BA, Coleman RE, Kerbrat P, Buchholz S, Ingle JN, Rabaglio-Poretti M, Colleoni M, Regan MM. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Update of the SOFT trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-03.