Final outcomes of the SOFT and TEXT phase III trials in premenopausal hormone receptor-positive early breast cancer☆

Francis P.A.; Pagani O.; Fleming G.F.; Walley B.; Colleoni M.; Rubovszky G.; Tondini C.; Ciruelos E.M.; Gomez H.L.; Bonnefoi H.R.; Burstein H.J.; Chini C.; Puglisi F.; Spazzapan S.; Bernardo A.; Climent M.A.; Bellet M.; Ruhstaller T.; Bermejo B.; Chia S.K.L.; Martino S.; Geyer C.E.; Goetz M.P.; Ingle J.N.; Stearns V.; Davidson N.E.; Le Du F.; Müller B.; Coleman R.E.; Loibl S.; Winer E.P.; Ruepp B.; Loi S.; Láng I.; Coates A.S.; Gelber R.D.; Goldhirsch A.; Regan M.M.; Colleoni M.; Loi S.; Hiltbrunner A.; Allemann S.; Gasca A.; Kammler R.; Maibach R.; Rabaglio-Poretti M.; Roschitzki H.; Roux S.; Schroeder J.; Regan M.; Bouzan C.; Gelber R.; Giobbie-Hurder A.; Huang H.; Price K.; Shaw H.; Blacher L.; Blackwell M.; Greco M.; Mora de Karausch A.; Narayanan D.; Polizzi D.; Scott K.; Starkweather R.; Viale G.; Arrigoni L.; Benini E.; Dell’Orto P.; Russo L.; Bernhard J.; Ribi K.; Piccart-Gebhart M.; Cameron D.; El-Abed S.; Abrams J.; Korde L.; Mooney M.; Zujewski J.A.; Winer E.; Savoie J.; Francis P.; Fleming G.; Pagani O.; Regan M.; Bonnefoi L.; Colleoni M.; De Meulemeester L.; Ciruelos E.; Coates A.; El-Abed S.; Gelber R.; Hiltbrunner A.; Roschitzki-Voser H.; Kammler R.; Loi S.; Loibl S.; Shaw H.; Stearns V.; Torrisi R.; Viale G.; Badger H.; Laycock I.; Dempsey A.; Stewart J.; Kannourakis G.; Underhill C.; Chan A.; van der Westhuizen A.; Forbes J.; Davis A.; Beith J.; Briscoe K.; Beale P.; Sullivan A.; Power J.; Gauden S.; Byard I.; Moylan E.; Della-Fiorentina S.; Livshin E.; Bonaventura A.; Chua S.; Chirgwin J.; Boyle F.; White M.; Hawson G.; Bochner M.; Gill P.G.; Nottage M.; McCarthy N.; Colosimo M.; Boadle D.; Lowenthal R.; Baron-Hay S.; Vasey P.; Lynch J.; Kiberu A.; Buck M.; Tsoi D.; Ng S.; Snyder R.; Dear R.; Epstein R.; Dalley D.; Srivastav R.; Abdi E.; Chipman M.; Wilson S.; Harvey V.; Gardner K.; Fitzharris B.; Campbell I.; Villanova Biazús J.; Torres R.; Torres S.; Letzkus J.; Barajas O.; Rojas H.; Bravo M.E.; Cardemil B.; Solé S.; Láng I.; Spazzapan S.; Graiff C.; Tondini C.; Clerico M.; Fabrizio A.; Mattioli R.; Visini M.; Gianni L.; Gomez H.L.; Vorobiof D.; Karlsson P.; Loden B.; Bergh J.; Malmström P.; Nissborg A.; Zaman K.; Rabaglio M.; Ruhstaller T.; von Moos R.; Rochlitz C.; Rauch D.; Buser K.; Gabriel N.; Rageth C.; Schoenenberger A.; Popescu R.; Caspar C.; Senn H.J.; Muñoz M.; Bellet M.; Ciruelos E.; Márquez R.; Catalán J.G.; Aramendia J.M.; Climent M.A.; Perelló A.; López R.; Morales S.; Virizuela J.A.; Bermejo B.; Martínez Jáñez N.; Melé M.; de la Haba J.R.; Negrin; Saura S.; Pérez Segura C.; Jassem J.; Neskovic-Konstantinovic Z.; Marreaud S.; Bogaerts J.; Vandebroek A.; Berliere M.; Jerusalem G.; Mitine C.; Henry S.; Dirix L.; Ziad E.A.; Moldovan C.; Dalenc F.; Jouannaud C.; Bachelot T.; Bonnefoi H.; Desmoulins I.; Brain E.; Pierga J.Y.; de la Motte Rouge T.; Venat-Bouvet L.; Delecroix V.; Fignon A.; Saghatchian M.; Fried G.; Sonke S.; Meerum Terwogt J.; Kroep J.; Moreira A.; Ortmann O.; Reißmüller K.; Kleine-Tebbe A.; Tessen H.W.; Thomssen C.; Beckmann M.W.; Hahn A.; Tomé O.; Bauerfeind I.; Solbach C.; Stauder H.; Grogan L.; McCaffrey J.; Keane M.; O’Reilly S.; Walshe J.; Coleman R.; Bliss J.; Kernaghan S.; Atkins N.; Mazdai G.; Makris A.; Cole D.; Churn M.; Ines H.; Todd R.; Smith I.E.; Joji J.; Perren T.; Chittalia A.; Ramachanara P.; Winer E.; Carey L.; Partridge A.; Ingle J.; Davidson N.; O’Regan R.; Gluck S.; Pritchard K.; Whelan T.; Gelmon K.; Webster M.; Geyer C.E., Jr.; Wolmark N.; Mamounas E.P.; Swain S.M.; Hortobagyi G.; Martino S.; Gralow J.; Scott A.; McCarthy J.; Kennecke H.; Robidoux A.; Roy J.; Prady C.; Kumar V.; Dent S.F.; Vergidis D.; Lopez P.G.; Tozer R.G.; Potvin K.R.; Grenier D.; Tonkin K.S.; Ellard S.; Pansegrau G.K.; Salim M.; Anderson J.E.; Diasio R.; Ganz P.A.; Russel C.A.; Kroener J.F.; Parker B.A.; Ganey J.T.; Fehrenbacher L.; Irwin D.H.; Javeed M.; Anderson I.C.; Wapnir I.L.; Polikoff J.A.; Al-Jazayrly G.; Medgyesy D.; Pajon E.R.; Elias A.D.; Drucker B.J.; Frank C.; Tepler I.; Jagathambal K.; Brandt D.S.; Isaacs C.; Aggarwal A.; Barr F.; Schwartz M.A.; Lilenbaum R.C.; O’Regan R.M.; Lebos H.C.; Seay T.E.; Keaton M.R.; Taylor M.A.; Bate W.W.; Holm C.; Albain K.S.; Cobleigh M.A.; Kindler H.L.; Nora R.E.; Wade J.L.; Kozloff M.F.; Rowland K.M.; Walling R.; Miller K.D.; Ansari R.H.; Dakhil S.R.; Mills G.M.; Erban J.K.; Burstein H.J.; Wolff A.C.; Watkins S.P.; Hwang L.C.; Segal H.M.; Inhorn R.C.; Zakalik D.; Schott A.F.; Morris R.T.; Hurtubise M.R.; Schneider D.J.; Dalton R.J.; Ingle J.N.; Flynn P.J.; Naughton M.J.; Goodwin J.W.; Lyss A.P.; Marchello B.T.; Shea T.C.; Hopkins J.O.; Wall J.G.; Hertzel D.J.; Dentchev T.; Weckstein D.; Kaufman P.A.; Catcher C.; Michaelson R.A.; Biggs D.D.; Toppmeyer D.L.; Klein P.; Hudis C.A.; Leonard J.; Odaimi M.; Pellegrino C.M.; Budman D.R.; Kalavar M.R.; Levine G.; Bloomfield C.D.; Budd G.T.; Silverman P.; Gross H.M.; Schaefer P.L.; Tirumali N.R.; Brufsky A.M.; Gottlieb R.J.; Domchek S.M.; Goldstein L.J.; Luginbuhl W.E.; Reilly R.E.; Andrews W.G.; Hyzinski M.; Sikov W.M.; Dizon D.S.; Mazurczak M.A.; Schlabach L.L.; Mullins B.A.; Strauss J.F.; Green M.C.; Elledge R.M.; Unzeitig G.W.; Burdette-Radoux S.; Rivkin S.E.; Lanier K.S.; Stewart J.A.; Saphner T.J.; Nambudiri G.S.; Tria Tirona M.R.B.; Rennie L.; Tindal D.; Redfern A.; Koczwara B.; Hill J.; Sardelic F.; Goldstein D.; Gombos A.; Barbeaux A.; Salmon J.P.; Neven P.; Azim H.; Parmar V.; Puglisi F.; Bernardo A.; Pinotti G.; Di Leo A.; Simoncini E.; Santoro A.; Gomez H.; Skof E.; Linderholm B.; Pagani O.; Loibl S.; Augustin D.; Lorenz-Salehi F.; Rody A.; Earl H.; Hughes-Davies L.; McAdam K.; Goetz M.; Pritchard K.I.; White J.; Gapski J.A.; Sami A.; Whitlock P.; Roy J.A.; Hamm C.; Freimann J.H.; Mortimer J.E.; Rugo H.S.; Ryan C.J.; Tannenbaum S.; Van Echo D.C.; Perez E.; Wender D.B.; Walters T.A.; Merkel D.E.; Zaren H.A.; Rose C.G.; Ansari R.H.; Ansari R.H.; Nattam S.R.; Ansari R.H.; Vogel S.J.; McIntyre A.P.; Burstein H.J.; Burstein H.J.; Burstein H.J.; Burstein H.J.; Krag K.J.; Burstein H.J.; Hendricks C.B.; Rak Tkaczuk K.H.; Riseberg D.A.; Flynn P.J.; Flynn P.J.; Flynn P.J.; Schneider D.J.; Flynn P.J.; Naughton M.J.; Stephenson W.T.; Feldmann J.E.; Messino M.J.; Hetzel D.J.; Wos E.J.; Sen K.; Reed E.C.; Bonnem E.M.; Blom D.H.; Entmacher M.S.; Tiersten A.D.; Pellegrino M.; Levine E.G.; Schmotzer J.A.; Padula G.D.A.; Rivkin S.E.; Rivkin S.E.; Gautam U.; Hart R.D.; Abraham J. · Annals of Oncology (2026) · DOI: 10.1016/j.annonc.2026.05.704

Resumen

Background: The Suppression of Ovarian Function Trial (SOFT) found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. A combined analysis of SOFT and TEXT showed a significant reduction in distant recurrence with E+OFS versus T+OFS. We now report final 15-year outcomes. Patients and methods: Premenopausal women with hormone receptor-positive early breast cancer were enrolled, with 3047 in SOFT and 2660 in TEXT intention-to-treat populations. SOFT randomized to 5 years of T versus T+OFS versus E+OFS. TEXT randomized to 5 years of T+OFS versus E+OFS. Chemotherapy was optional, before SOFT entry with subsequent premenopausal oestradiol or concurrent with OFS in TEXT. Endpoints included disease-free survival, breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), and overall survival (OS). Additionally, 15-year Kaplan–Meier estimates, hazard ratios (HRs), and 95% confidence intervals (CIs) are reported. Results: In SOFT, escalating endocrine therapy (ET) continued to reduce recurrence with 15-year BCFI of 78.6% for E+OFS, 75.7% for T+OFS, and 72.1% for T (T+OFS versus T: HR 0.82, 95% CI, 0.69-0.98, P = 0.03). In the SOFT no-chemotherapy cohort, OFS reduced breast cancer events at 15 years, while DRFI and OS remained high regardless of ET assignment. After prior chemotherapy for HER2-negative tumors (n = 1257), the 15-year OS rate in SOFT was 81.0% with E+OFS, 77.1% with T+OFS and 76.8% with tamoxifen alone. In women under age 35 years with HER2-negative tumors (n = 241), the 15-year OS rate was 82.5% with E+OFS, 77.9% with T+OFS, and 68.1% with tamoxifen. In combined SOFT and TEXT analysis, among those with HER2-negative tumors (n = 4035), E+OFS versus T+OFS reduced distant recurrence (HR 0.75, 95% CI 0.63-0.90), with a smaller reduction in deaths (HR 0.89, 95% CI 0.74-1.06), with absolute survival benefits largest with high-risk features, particularly young age or high-grade tumors. Conclusion: Meaningful OS benefit in hormone receptor-positive, HER2-negative breast cancer from adjuvant exemestane and/or OFS compared with tamoxifen alone is limited to high-risk premenopausal subgroups. Tamoxifen-based ET may not result in optimal outcomes in premenopausal high-grade HER2-negative tumors.