Background
Suppression of Ovarian Function Trial (SOFT). Phase III RCT of 3,066 premenopausal women with HR+ early breast cancer, evaluating whether adding ovarian function suppression (OFS) to adjuvant endocrine therapy, and whether exemestane+OFS vs tamoxifen+OFS, improves outcomes.
Interventions and follow up
Arm A: Tamoxifen 20mg daily
Arm B: Tamoxifen 20mg daily + ovarian function suppression (OFS)
Arm C: Exemestane 25mg daily + OFS
OFS achieved by GnRH agonist triptorelin 3.75mg IM q28d, bilateral oophorectomy, or bilateral ovarian irradiation.
Primary endpoint: DFS (tamoxifen+OFS vs tamoxifen)
mFollow up: 67mo (~5.5yr)
Arm B: Tamoxifen 20mg daily + ovarian function suppression (OFS)
Arm C: Exemestane 25mg daily + OFS
OFS achieved by GnRH agonist triptorelin 3.75mg IM q28d, bilateral oophorectomy, or bilateral ovarian irradiation.
Primary endpoint: DFS (tamoxifen+OFS vs tamoxifen)
mFollow up: 67mo (~5.5yr)
Results
5-yr DFS, TAM vs TAM+OFS: 84.7% vs 86.6% (HR 0.83, 95%CI 0.66-1.04, P=.10).
5-yr DFS, exemestane+OFS: 89.0% (HR 0.68, 95%CI 0.53-0.86 vs TAM).
5-yr freedom from breast cancer, TAM vs TAM+OFS: 86.4% vs 88.4% (HR 0.81, 95%CI 0.63-1.00, P=.09; multivariable HR 0.75, 95%CI 0.59-0.96, P=.02).
5-yr freedom from breast cancer, exemestane+OFS: 90.9% (HR 0.63, 95%CI 0.49-0.83).
Chemotherapy subgroup (higher-risk): larger absolute benefit from adding OFS, most pronounced in women <35yr.
OS: no significant overall difference at this follow-up.
5-yr DFS, exemestane+OFS: 89.0% (HR 0.68, 95%CI 0.53-0.86 vs TAM).
5-yr freedom from breast cancer, TAM vs TAM+OFS: 86.4% vs 88.4% (HR 0.81, 95%CI 0.63-1.00, P=.09; multivariable HR 0.75, 95%CI 0.59-0.96, P=.02).
5-yr freedom from breast cancer, exemestane+OFS: 90.9% (HR 0.63, 95%CI 0.49-0.83).
Chemotherapy subgroup (higher-risk): larger absolute benefit from adding OFS, most pronounced in women <35yr.
OS: no significant overall difference at this follow-up.
Adverse events
Vasomotor/menopausal: hot flashes, sweating, vaginal dryness, decreased libido, more frequent in OFS arms.
Musculoskeletal/bone: osteoporosis and arthralgia more common with exemestane+OFS.
Psychiatric: depression more frequent with OFS.
Overall: grade 3-4 AEs ~31% (exemestane+OFS), ~32% (TAM+OFS), ~24% (TAM); menopausal symptoms reduced quality of life.
Musculoskeletal/bone: osteoporosis and arthralgia more common with exemestane+OFS.
Psychiatric: depression more frequent with OFS.
Overall: grade 3-4 AEs ~31% (exemestane+OFS), ~32% (TAM+OFS), ~24% (TAM); menopausal symptoms reduced quality of life.
Conclusions
Adding OFS to tamoxifen did not significantly improve DFS overall, but provided meaningful benefit in higher-risk women (those warranting chemotherapy, especially age <35yr). Exemestane+OFS further reduced recurrence. OFS is not warranted for low-risk patients not requiring chemotherapy.
Key Limitations
Primary DFS comparison did not reach significance overall; benefit driven by subgroup analyses (hypothesis-generating). Heterogeneous risk population; relatively short 5.5yr follow-up for an HR+ disease with late recurrences. OFS achieved by different methods.
Clinical Context
Combined SOFT/TEXT analyses support OFS plus an aromatase inhibitor (or tamoxifen) for higher-risk premenopausal HR+ disease. ASCO and ESMO guidelines endorse OFS for premenopausal women at sufficient recurrence risk. Longer follow-up (SOFT/TEXT 12-yr) confirms durable DFS and emerging OS benefit with exemestane+OFS.
References
Francis PA et al, NEJM, 2015; PMID: 25495490
Francis PA et al, NEJM, 2018 (SOFT/TEXT 8-yr update); PMID: 29863451
Francis PA et al, NEJM, 2018 (SOFT/TEXT 8-yr update); PMID: 29863451