Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor–positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2–negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.

INTRODUCTION

Very young women with estrogen receptor–positive early breast cancer are at heightened risk for recurrence.¹ Premenopausal women who develop amenorrhea after chemotherapy for estrogen receptor–positive tumors have a lower risk of recurrence.² The Suppression of Ovarian Function Trial (SOFT) aimed to assess the benefit from adding ovarian function suppression (OFS) to adjuvant tamoxifen, and to understand the role of combining an aromatase inhibitor (AI) with OFS in premenopausal women. Those who received prior chemotherapy were required to have a premenopausal estradiol level.

The results after 5 years did not show a significant improvement in disease-free survival (DFS) from the addition of OFS to tamoxifen, although improved outcomes were observed with OFS in women who remained premenopausal after chemotherapy.³ Guidelines subsequently recommended OFS in premenopausal women at higher risk of recurrence, including those younger than 35 years.^4,5 The results after 8 years reported significant improvements in disease-free survival and overall survival (OS) from the addition of OFS to adjuvant tamoxifen, while exemestane plus OFS resulted in further reduction in recurrence.⁶ Subsequent analyses focused on clinical-pathologic features associated with larger absolute benefit from intensification of adjuvant endocrine therapy.^7,8 We now report 12-year outcomes.

PATIENTS AND METHODS

The design and conduct of SOFT have been described previously.³ Premenopausal women were randomly assigned 1:1:1 to 5 years of adjuvant tamoxifen, tamoxifen plus OFS, or exemestane plus OFS, stratified according to prior use of chemotherapy and lymph node status. Women who received prior (neo)adjuvant chemotherapy were enrolled within 8 months after completing chemotherapy, after a premenopausal estradiol level was documented.

The primary end point was DFS. Secondary end points included breast cancer–free interval, distant recurrence-free interval (DRFI), and OS. Using an intention-to-treat approach, stratified proportional-hazards regression estimated hazard ratios (HRs) and 95% CIs for the two pairwise comparisons with tamoxifen alone, over the entire follow-up period and in time intervals from 0 to 5 years and ≥ 5 years (Data Supplement, online only). The database lock was May 2021.

RESULTS

The overall intention-to-treat analysis population was 3,047 women (Table 1; Data Supplement). The median age was 40 years in the cohort who were premenopausal after prior chemotherapy (53.4%), and 46 years in the no-chemotherapy cohort. Most patients (84.9%) had human epidermal growth factor receptor 2 (HER2)–negative tumors.

TABLE 1.

Characteristics of Patients Enrolled in SOFT, Overall and According to Cohort Defined by Receipt or Nonreceipt of Prior Chemotherapy

Overall Survival

After 12 years of median follow-up, death was reported in 332 patients, including 14 deaths without any cancer event (Data Supplement). OS was improved in patients assigned tamoxifen plus OFS compared with tamoxifen (HR, 0.78; 95% CI, 0.60 to 1.01; Fig 1A). The 12-year OS was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS (HR, 0.80; 95% CI, 0.62 to 1.04 v tamoxifen). Compared with patients assigned tamoxifen, patients assigned tamoxifen plus OFS showed a greater early mortality reduction in the first 5 years, while those assigned exemestane plus OFS showed a later emergence of improved survival (Fig 1A; Data Supplement).

FIG 1.

Outcomes after median follow-up of 12 years. Kaplan-Meier estimates of (A) OS, (B) DRFI, and (C) DFS with 5- and 12-year event-free percentages according to treatment assignment in the overall intention-to-treat population and (D) OS in the subgroup of patients with HER2-negative tumors who received prior chemotherapy. Stratified HRs with 95% CIs are reported. In addition, numbers of events, pyfu, and HRs are provided for time intervals of 0-5 years and ≥ 5 years since random assignment. DFS, disease-free survival; DRFI, distant recurrence-free interval; E, exemestane; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; OFS, ovarian function suppression; OS, overall survival; pyfu, patient-years of follow-up; T, tamoxifen.

In the no-chemotherapy cohort, there were 52 deaths, with 29 subsequent to breast cancer recurrence, and 12-year OS exceeded 95% in all three treatment groups (Data Supplement). In the prior chemotherapy cohort, 92% of deaths followed breast cancer recurrence (Data Supplement). Larger absolute improvements in 12-year OS of 4.7% (95% CI, –0.3 to 9.8) and 4.0% (95% CI, –1.0 to 9.1) were seen in the chemotherapy cohort in patients assigned OFS with either tamoxifen or exemestane, respectively (Data Supplement). Meaningful absolute improvements in 12-year OS in those assigned OFS were evident in subgroups associated with higher-risk clinical-pathologic features, including prior neoadjuvant chemotherapy, age under 35 years, and grade 3 tumors (Fig 2). In patients with grade 3 tumors (n = 642), 12-year OS was 76.4% with tamoxifen alone, 80.8% with tamoxifen plus OFS, and 84.0% with exemestane plus OFS.

FIG 2.

Kaplan-Meier estimates of 12-year OS (95% CIs) in subgroups, according to treatment assignment, in the overall intention-to-treat population and in the subgroup with HER2-negative tumors. Adj, adjuvant; D/Pts, numbers of deaths and patients in the subgroup; E, exemestane; HER2, human epidermal growth factor receptor 2; neoadj, neoadjuvant; OFS, ovarian function suppression; OS, overall survival; pN, pathologic lymph node status; T, tamoxifen.

Other End Points

Compared with tamoxifen, distant recurrences were fewer with tamoxifen plus OFS, and further reduced with exemestane plus OFS (Fig 1B). There remained very high rates of freedom from distant recurrence in the no-chemotherapy cohort, with 12-year DRFI in this cohort of 95.8% with tamoxifen, 95.9% with tamoxifen plus OFS, and 97.7% with exemestane plus OFS (Data Supplement). In the prior chemotherapy cohort, 12-year DRFI was 75.1% with tamoxifen, 77.7% with tamoxifen plus OFS, and 79.6% with exemestane plus OFS.

After a median follow-up of 12 years, there continued to be a significant improvement in DFS with tamoxifen plus OFS compared with tamoxifen (HR, 0.82; 95% CI, 0.69 to 0.98; P = .03; Fig 1C). The 12-year DFS was 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS (HR, 0.69; 95% CI, 0.57 to 0.83 v tamoxifen). The 12-year breast cancer–free interval in women younger than 35 years was 57.0% with tamoxifen and 71.6% with tamoxifen plus OFS (Data Supplement).

Outcomes in the HER2-Negative Subgroup

Among the predominant subgroup with HER2-negative tumors, the 12-year OS was 87.7% with tamoxifen, 88.8% with tamoxifen plus OFS, and 90.9% with exemestane plus OFS (Data Supplement), and among those in the prior chemotherapy cohort was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS (Fig 1D; Data Supplement). There continued to be heterogeneity of treatment effect in subgroups defined by HER2 status that suggested greater benefit from the addition of OFS to tamoxifen in HER2-positive tumors (Data Supplement).

DISCUSSION

After 12 years, SOFT shows a sustained significant reduction in the risk of recurrence with the addition of OFS to adjuvant tamoxifen. Further reduction of recurrence was observed with exemestane plus OFS. Moreover, a benefit in OS with exemestane plus OFS, that was not evident in the first 5 years, emerged in subsequent years (Fig 1). Patients who did not receive chemotherapy and were assigned tamoxifen alone continue to have very high rates of freedom from distant recurrence and OS, although distant recurrences have continued to occur.

The ASTRRA trial reported significantly improved 5-year DFS (absolute improvement 3.6%) with the addition of 2 years OFS to tamoxifen in women with persisting or recovering ovarian function after chemotherapy.⁹ In the SOFT prior chemotherapy cohort, absolute improvements in 12-year OS of at least 4% are now seen with OFS with either tamoxifen or exemestane. In those who received chemotherapy for HER2-negative tumors, there were absolute improvements in 12-year OS of 2.3% with tamoxifen plus OFS and 5.6% with exemestane plus OFS, compared with tamoxifen.

Although overall SOFT did not enroll particularly high-risk patients, there are high-risk subgroups. More than half of the patients who received neoadjuvant chemotherapy experienced recurrence when assigned tamoxifen alone (Data Supplement). Maximal endocrine therapy with 5 years of an AI plus OFS provided an effective strategy to meaningfully reduce recurrence and improve survival, compared with tamoxifen, in premenopausal women after neoadjuvant chemotherapy for luminal breast cancer. Almost one in four patients with grade 3 tumors assigned tamoxifen have died. Premenopausal patients with high-grade HER2-negative tumors should be considered for maximal adjuvant endocrine therapy (AI plus OFS) rather than tamoxifen with or without OFS (Fig 2).

In the under 35 age group, an absolute improvement of > 7% in 12-year OS was seen for patients assigned to receive OFS (Fig 2). Premature surgical menopause is associated with increased mortality in population studies,^10,11 but currently there is no indication of excess noncancer deaths in patients assigned 5 years of OFS in SOFT, notwithstanding quality-of-life effects.¹²

Annual follow-up for SOFT continues until 2025. The pattern of treatment effects over time, with the later emergence of survival benefit with exemestane plus OFS compared with tamoxifen, underscores the need for prolonged follow-up in hormone receptor–positive breast cancer trials.

ACKNOWLEDGMENT

We thank the patients, clinicians, trial staff, and pathologists who participated in the SOFT clinical trials; the International Breast Cancer Study Group (IBCSG), the Breast International Group (BIG), BIG cooperative groups, and the US National Cancer Institute National Clinical Trials Network (NCI NCTN) for their collaboration; and Dr Larry Norton and Dr Jeffrey Abrams for supporting the international collaboration between the IBCSG, BIG, and the US NCI NCTN through the breast cancer committee of Alliance for Clinical Trials in Oncology. SOFT conduct was supported by Pfizer; Pfizer and Ipsen provided the study drugs. Lists of the investigators in SOFT and members of the International Breast Cancer Study Group can be found in the Appendix (online only).

APPENDIX

Steering Committee: P. Francis (Chair, SOFT Co-Chair), G. Fleming (SOFT Co-Chair), O. Pagani (TEXT Co-Chair), B. Walley (TEXT Co-Chair), M. Regan (Trial Statistician), S. Loi, M. Colleoni, L. Blacher, H. Bonnefoi, L. De Meulemeester, E. Ciruelos, A. Coates, S. El-Abed, R. Gelber, A. Hiltbrunner, H. Roschitzki-Voser, R. Kammler, S. Loibl, B. Ruepp, H. Shaw, V. Stearns, R. Torrisi, G. Viale, K. DeMontille (Pfizer), J. Amauri Soares (Ipsen)

IBCSG Scientific Committee: M. Colleoni (Chair), S. Loi (Co-Chair)

IBCSG Scientific Executive Committee (until June 30, 2021): M. Colleoni, A. Di Leo, F. Boyle, G. Jerusalem, S. Loi, M.M. Regan, G. Viale

ETOP IBCSG Partners Foundation Board (effective from 01 July 2021): R Stahel (President), S. Aebi, P. Baas, M. Colleoni, R. Gelber, S. Loi, K. McGregor, S. Peters, S. Popat, R. Rosell

ETOP IBCSG Partners Foundation Coordinating Center, Bern, Switzerland: A. Hiltbrunner (Director), A. Gasca, R. Kammler, R. Maibach, M. Rabaglio-Poretti, H. Roschitzki, S. Roux, B. Ruepp, J. Schroeder

IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA: M. Regan (Director), C. Bouzan, R. Gelber, A. Giobbie-Hurder, H. Huang, K. Price

IBCSG Data Management Center, Frontier Science & Technology Research Foundation, Amherst, NY: L. Blacher (Director), H. Shaw (Lead Trial Coordinator), M. Blackwell, M. Greco, A. Mora de Karausch, D. Narayanan, K. Scott, R. Starkweather

IBCSG Central Pathology Office, European Institute of Oncology, Division of Pathology, Milan, Italy: G. Viale (Director), S. Andrighetto, O. Biasi, P. Dell’Orto, L. Russo

ETOP IBCSG Partners Foundation Quality of Life Office, Bern, Switzerland: J. Bernhard, K. Ribi

Breast International Group (BIG), Brussels, Belgium: M. Piccart-Gebhart, D. Cameron, S. El- Abed,

US National Cancer Institute: J. Abrams, L. Korde, M. Mooney, J.A. Zujewski

Alliance (CALGB) Pathology Coordinating Office, Alliance Biorepository at Ohio State, Ohio State University, Columbus, OH: W. Frankel, L. McCart, R. Jewell, D. Rohrer

Dana-Farber Cancer Institute, Boston, MA (US FDA IND): E. Winer, J. Savoie

Pfizer Study Support: K. DeMontille, S. Salem, S. Simon

Ipsen Study Support: J. Amauri Soares, F. Baton

Participating Centers and Principal Investigators

Centers with accrual of more than one patient

SOFT

BREAST INTERNATIONAL GROUP (BIG)

International Breast Cancer Study Group (a division of ETOP IBCSG Partners FOUNDATION)

Breast Cancer Trials Australia and New Zealand (BCT-ANZ), Australia; P. Francis, I. Laycock

Austin Health, Heidelberg, Victoria; J. Stewart

Ballarat Oncology and Haematology Services, Wendouree, Victoria; G. Kannourakis

Border Medical Oncology, Wodonga, Victoria; C. Underhill

Box Hill Hospital, Box Hill, Victoria; J. Chirgwin

Calvary Mater Newcastle, Waratah, New South Wales; A. van der Westhuizen

Canberra Hospital, The, Garran, Australian Capital Territory; N. Gorddard

Chris O'Brien Lifehouse, The, Canperdown, New South Wales; J Beith

Coffs Harbour Health Campus, Coffs Harbour, New South Wales; K. Briscoe

Concord Repatriation General Hospital, Concord, New South Wales; P. Beale

Launceston General Hospital, Launceston, Tasmania; S. Gauden

Liverpool Hospital, Liverpool, New South Wales; E. Moylan

Macarthur Cancer Therapy Center, Campbelltown, New South Wales; S. Della-Fiorentina

Manning Rural Referral Hospital, Taree, New South Wales; E. Livshin

Maroondah Hospital, Ringwood East, Victoria; J. Chirgwin

Mater Hospital, The, North Sydney, New South Wales; F. Boyle

Monash Medical Center, East Bentleigh, Victoria; M. White

Nambour Hospital, Nambour, Queensland; G. Hawson

Peter MacCallum Cancer Center, East Melbourne, Victoria; P.A. Francis

Riverina Cancer Care Center, Wagga Wagga, New South Wales; J. Hill

Royal Adelaide Hospital, Adelaide, South Australia; M. Bochner

Royal Brisbane and Women's Hospital, Herston, Queensland; M. Nottage

Royal Hobart Hospital, Hobart, Tasmania; I. Byard

Royal North Shore Hospital, St Leonards, New South Wales; S. Baron-Hay

St Andrews Toowoomba Hospital, Toowoomba, Queensland; P. Vasey

St George Hospital, Kogarah, New South Wales; J. Lynch

St John of God Hospital, Bunbury, Western Australia; A. Kiberu

St John of God Hospital, Subiaco, Western Australia; D. Tsoi

St Vincent's Hospital, Fitzroy, Victoria; R. Snyder

St Vincent's Hospital, Darlinghurst, New South Wales; R. Dear

Tweed Hospital, The, Tweed Heads, New South Wales; E. Abdi

Victorian Breast and Oncology Care, Melbourne, Victoria; M. Chipman

Breast Cancer Trials Australia and New Zealand (BCT-ANZ), New Zealand

Auckland City Hospital, Auckland; S. Wilson

Christchurch Hospital, Christchurch; K. Gardner

Palmerston North Hospital, Palmerston North; R. Isaacs

Waikato Hospital, Hamilton; I. Campbell

Brazil

Hospital de Clinicas de Porto Alegre, Porto Alegre; J. Villanova Biazús

Grupo Oncológico Corporativo Chileno de Investigación (GOCCHI), Chile; B. Muller

Instituto Nacional del Cancer, Santiago; R. Torres

Hospital San Juan de Dios, Santiago; S. Torres

Hospital San Borja Arriaran, Santiago; J. Letzkus

Hospital Clinico de la Universidad de Chile, Santiago; O. Barajas

Hospital Dr Sotero Del Rio, Santiago; H. Rojas

Centro De Patologia Mamaria, Santiago; M.E. Bravo

Hospital Base de Valdivia, Valdivia; B. Cardemil

Instituto De Radiomedicina, Vitacura; S. Solé

Hungary

National Institute of Oncology, Budapest; I. Láng

India

Tata Memorial Hospital, Mumbai; V. Parmar

Italy

Centro di Riferimento Oncologico, Aviano; S. Spazzapan

Azienda Sanitaria di Bolzano, Bolzano; C. Graiff

Ospedali Riuniti di Bergamo, Bergamo; C. Tondini

Ospedale degli Infermi, Biella; M. Clerico

Unita Operativa de Medicina Oncologica, Ospedale Ramazzini, Carpi; A. Fabrizio

Oncologia Medica Fano Italy, Fano; R. Mattioli

Ospedale Civile di Lecco, Lecco; M. Visini

Fondazione Salvatore Maugeri, Pavia; A. Bernardo

Ospedale degli Infermi, Rimini; L. Gianni

Ospedale di Circolo e Fondazione Macchi, Varese; G. Pinotti

Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine, Udine; F. Puglisi

Peru

Instituto de Enfermedades Neoplásicas, Lima; H.L. Gomez

South Africa

Sandton Oncology Center, Johannesburg; D. Vorobiof

Sweden

Sahlgrenska University Hospital, Gothenburg; P. Karlsson

Central Hospital Karlstad, Karlstad; B. Loden

Karolinska University Hospital, Stockholm; J. Bergh

Lund University Hospital, Lund; P. Malmström

Skaraborg Hospital Skovde, Skovde; A. Nissborg

Southern Elfsborg Hospital Boras, Boras; P. Karlsson

Swiss Association for Clinical Cancer Research (SAKK), Switzerland

Center Hospitalier Universitaire Vaudois, Lausanne; K. Zaman

Inselspital, Berne; M. Rabaglio

Kantonsspital St Gallen, St Gallen; T. Ruhstaller

Rätisches Kantonos-/Regionalspital, Chur; R. von Moos

Kantonsspital Basel, Basel; C. Rochlitz

Onkologiezentrum Thun-Berner Oberland, Thun; D. Rauch

Oncocare Engeried, Bern; K. Buser

Zürich Frauenklinik, Zürich; N. Gabriel

Brust-Zentrum Zurich, Zurich; C. Rageth

Kantonsspital Aarau (AG), Aarau; A. Schoenenberger

Tumor Zentrum Hirslanden Klinik, Aarau; R. Popescu

Kantonsspital Baden, Baden; C. Caspar

Tumor und Brustzentrum Zetup St Gallen, St Gallen; H.J. Senn

SOLTI, Spain; E. CIRUELOS

Hospital Clínic i Provincial de Barcelona, Barcelona; M. Muñoz

Hospital Universitari Vall D' Hebron, Barcelona; M. Bellet

Hospital Universitario 12 de Octubre, Madrid; E. Ciruelos

Centro Oncológico MD Anderson, Madrid; R. Márquez

Hospital Son Llàtzer, Palma de Mallorca; J. G. Catalán

Clinica Univ. De Navarra, Pamplona; J. M. Aramendia

Instituto Valenciano de Oncología, Valencia; M.A. Climent

Hospital Son Espases (Palma de Mallorca), Palma de Mallorca; A. Perelló

Complejo Hospitalario Universitario de Santiago De Compostela, Santiago de Compostela; R. López

H.U. Arnau de Vilanova, Lleida; S. Morales

Hospital Universitario Virgen Macarena, Sevilla; J.A. Virizuela

Hospital Clínico Universitario de Valencia, Valencia; B. Bermejo

Hospital Ramón Y Cajal, Madrid; N. Martínez Jáñez

Hospital Sant Joan de Reus, Reus; M. Melé

Hospital Reina Sofía De Córdoba, Córdoba; J.R. de la Haba

Complejo Hospitalario Universitario De Gran Canaria Dr Negrín, Las Palmas de Gran Canaria; Negrín; S. Saura

Hospital Sant Pau i Santa Tecla, Tecla; C. Pérez Segura

Central and East European Oncology Group (CEEOG); J. Jassem

Poland

Medical University of Gdansk, Gdansk, Poland; J. Jassem

Serbia

Institute of Oncology & Radiology of Serbia, Belgrade, Serbia; Z. Neskovic-Konstantinovic

European Organisation for Research and Treatment of Cancer (EORTC); S. Marreaud, J. Bogaerts

Belgium

ZNA Middelheim, Antwerpen; A. Vandebroek

Cliniques Universitaires St-Luc UCL, Brussels; M. Berliere

U.Z. Gasthuisberg, Leuven; P. Neven

Center Hospitalier Universitarie Sart Tilman, Liège; G. Jerusalem

Hopital De Jolimont, Haine St Paul; C. Mitine

Clinique Sainte Elisabeth, Namur; S. Henry

Algemeen Ziekenhuis Sint-Augustinus, Wilrijk; L. Dirix

Center Hospitalier Etterbeek Ixelles, Brussels; El Ali Ziad

France

Center Henri Becquerel, Rouen; C. Moldovan

Institut Claudius Regaud, Toulouse; F. Dalenc

Institut Jean Godinot, Reims; C. Jouannaud Center Leon Berard, Lyon; T. Bachelot

Institut Bergonie, Bordeaux; H. Bonnefoi

Center Georges Francois-Leclerc, Dijon; I. Desmoulins

Center Rene Huguenin, Saint-Cloud; E. Brain

Institut Curie, Paris; J.Y. Pierga

Center Eugene Marquis, Rennes; T. de la Motte Rouge

C.H.R.U. de Limoges, Limoges; L. Venat-Bouvet

Clinique Mutualiste de l’Estuaire, Saint-Nazaire; V. Delecroix

Clinique De L'alliance, Tours; A. Fignon

Institut Gustave Roussy, Villejuif; M. Saghatchian

Israel

Rambam Medical Center, Haifa; G. Fried

Netherlands

The Netherlands Cancer Institute, Amsterdam; S. Sonke

Onze Lieve Vrouwe Gasthuis, Amsterdam; J. Meerum

Terwogt Leids Universitair Medisch Centrum, Leiden; J. Kroep

Portugal

Centro de Lisboa, Lisboa; A. Moreira

GERMAN BREAST GROUP (GBG); O.ORTMANN, K. REIßMÜLLER, S. LOIBL

DRK Kliniken Berlin Köpenick, Berlin; A. Kleine-Tebbe

Praxis Dr Tessen, Goslar; H.W. Tessen

Martin-Luther-Universität Halle-Wittenberg, Halle an der Saale; C. Thomssen

Universitätsfrauenklinik Erlangen, Erlangen; M.W. Beckmann

Klinikum Mittelbaden/Stadtklinik Baden-Baden, Baden-Baden; A. Hahn

Dr Horst Schmidt Kliniken, Wiesbaden; F. Lorenz-Salehi

St Vincentius Kliniken, Karlsruhe; O. Tomé

Klinikum Landshut GmbH, Landshut; I. Bauerfeind

Universitäts Frauenklinik, Frankfurt/Main; C. Solbach

Caritas-Krankenhaus St Josef, Regensburg; O. Ortmann

Krankenhaus der Barmherzigen Brüder, Regensburg; H. Stauder

Cancer Trials Ireland (formerly All Ireland Cooperative Oncology Research Group; ICORG)

Beaumont Hospital, Dublin; L. Grogan

Mater Misericordiae Hospital, Dublin; J. McCaffrey

Mater Private Hospital, Dublin; J. McCaffrey

Univiversity College Hospital Galway, Galway; M. Keane

South Infirmary-Victoria University Hospital, Cork; S. O'Reilly

Adelaide, Meath & National Children's Hospital, Dublin; J. Walshe

ICR-CTSU on behalf of the National Cancer Research Institute (NCRI) Breast Clinical Studies Group, United Kingdom; R. Coleman, J. Bliss, S. Kernaghan, N. Atkins

South Tyneside District Hospital, South Shields, Tyne & Wear; G. Mazdai

Weston Park Hospital, Sheffield, South Yorkshire; R. Coleman

Mount Vernon Hospital, Northwood, Middlesex; A. Makris

Luton & Dunstable Hospital, Luton; A. Makris

Clatterbridge Center for Oncology, Wirral; S. O'Reilly

Great Western Hospital, Swindon; D. Cole

New Cross Hospital, Wolverhampton; M. Churn

Whiston Hospital, Prescot; H. Ines

Aberdeen Royal Infirmary, Aberdeen; R. Todd

Royal Marsden Hospital—Fulham, London; I.E. Smith

Royal Marsden Hospital—Sutton, Surrey; I.E. Smith

York Hospital, York; J. Joji

St James Univ Hospital, Leeds; T. Perren

Harrogate District Hospital, Harrogate; J. Joji

Stepping Hill Hospital, Stockport; A. Chittalia

Russells Hall Hospital, Dudley; P. Ramachanara

US NCI NATIONAL CLINICAL TRIALS NETWORK (NCTN)

Alliance for Clinical Trials in Oncology; E. Winer, L. Carey, A. Partridge, J. Ingle

ECOG-ACRIN Cancer Research Group; N. Davidson, V. Stearns, R. O'Regan, S. Gluck

Canadian Cancer Trials Group; K. Pritchard, T. Whelan, K. Gelmon, M. Webster

NRG Oncology; C. Geyer Jr, N. Wolmark, T Mamounas, J. White, S. Swain

SWOG; G. Hortobagyi, S. Martino, J. Gralow, A. Scott

North American Participating Centers

Canada

Doctor H. Bliss Murphy Cancer Center, St John's, Newfoundland; J. McCarthy

BCCA-Vancouver Cancer Center, Vancouver, British Columbia; H. Kennecke

CHUM- Hotel Dieu du Montreal, Montreal, Quebec; A. Robidoux

Hopital Du Sacre-Coeur de Montreal, Montreal, Quebec; J. Roy

Hôpital Charles LeMoyne, Greenfield Park, Quebec; C. Prady

Cancer Center of Southeastern Ontario at Kingston General Hospital, Kingston, Ontario; V. Kumar

Ottawa Hospital Research Institute, Ottawa, Ontario; S.F. Dent

Thunder Bay Regional Health Science Center, Thunder Bay, Ontario; D. Vergidis

Health Sciences North, Sudbury, Ontario; P.G. Lopez

Juravinski Cancer Center at Hamilton Health Sciences, Hamilton, Ontario; R. G. Tozer

Odette Cancer Center, Toronto, Ontario; K.I. Pritchard

London Regional Cancer Center, London, Ontario; K.R. Potvin

Cancercare Manitoba, Winnipeg, Manitoba; D. Grenier

Cross Cancer Institute, Edmonton, Alberta; K.S. Tonkin

Tom Baker Cancer Center, Calgary, Alberta; B.A. Walley

BCCA Cancer Center for the Southern Interior, Kelowna, British Columbia; S. Ellard

BCCA-Fraser Valley Cancer Center, Surrey, British Columbia; G. K. Pansegrau

Allan Blair Cancer Center, Regina, Saskatchewan; M. Salim

United States of America

Providence Alaska Medical Center, Anchorage, AK; J.E.

Anderson University of Alabama, Birmingham, AL; R. Diasio

University of California at Los Angeles (UCLA), Los Angeles, CA; P.A. Ganz

University of Southern California, Los Angeles, CA; C.A.

Russel Scripps Clinic - La Jolla, La Jolla, CA; J.F. Kroener

University of California San Diego Moores Cancer Center, San Diego, CA; B.A.

Parker John Muir Medical Center, Concord, CA; J.T. Ganey

Kaiser Permanente—Fremont, Fremont, CA; L. Fehrenbacher

Alta Bates Hospital, Berkeley, CA; D.H. Irwin

Kaiser Permanente Santa Teresa (San Jose), Vallejo, CA; L. Fehrenbacher

Mercy General Hospital, Carmichael, CA; M. Javeed

Kaiser Permanente-San Francisco, Vallejo, CA; L. Fehrenbacher

Santa Rosa Memorial Hospital, Santa Rosa, CA; I.C. Anderson

Stanford University Medical Center, Stanford, CA; I.L. Wapnir

Kaiser Permanente, San Diego, CA; J.A. Polikoff

Glendale Memorial Hospital and Health Center, Glendale, CA; G. Al-Jazayrly

Penrose-Saint Francis Healthcare, Colorado Springs, CO; E.R. Pajon

Front Range Cancer Specialists, Fort Collins, CO; D. Medgyesy

Longmont United Hospital, Longmont, CO; E.R. Pajon

The Shaw Regional Cancer Center, Aurora, CO; A.D. Elias

Greenwich Hospital, Greenwich, CT; B.J. Drucker

Norwalk Hospital, Norwalk, CT; R.C. Frank

Stamford Hospital, Stamford, CT; I. Tepler

Eastern Connecticut Hematology and Oncology Associates, Norwich, CT; K. Jagathambal

Northwest Connecticut Oncology - Hematology Associates, Torrington, CT; D.S. Brandt

Georgetown University Hospital, Washington, DC; C. Isaacs

Washington Hospital Center, Washington, DC; A. Aggarwal

Sibley Memorial Hospital, Washington, DC; F. Barr

Christiana Healthcare Services—Christian Hospital, Newark, DE; D.D. Biggs

Memorial Cancer Institute, Hollywood, FL

Mount Sinai Medical Center CCOP, Miami Beach, FL; M.A. Schwartz

Holy Cross Hospital, Fort Lauderdale, FL; R.C. Lilenbaum

Sarasota Memorial Hospital, Sarasota, FL Dekalb Medical Center, Atlanta, GA; T.E. Seay

Emory University, Altanta, GA; R.M. O'Regan

Memorial Health University Medical Center, Savannah, GA; H.C. Lebos

Atlanta Regional CCOP, Atlanta, GA; T.E. Seay

Augusta Oncology Associates, Inc, Augusta, GA; M.R. Keaton

St Joseph's/Candler Health System, Savannah, GA; M.A. Taylor

Mercy Medical Center - North Iowa, Mason City, IA; W.W. Bate

Medical Associates Clinic, Professional Corporation, Dubuque, IA; C. Holm

Loyola University Medical Center, Maywood, IL; K.S. Albain

Rush University Medical Center, Chicago, IL; M.A. Cobleigh

University of Chicago, Chicago, IL; H.L. Kindler

St Anthony Medical Center, Rockford, IL; R.E. Nora

Decatur Memorial Hospital, Decatur, IL; J.L. Wade

Memorial Medical Center, Springfield, IL; J.L. Wade

Ingalls Memorial Hospital, Harvey, IL; M.F. Kozloff

Carle Cancer Center CCOP, Urbana, IL; K.M. Rowland

Community Regional Cancer Care North, Indianapolis, IN; R. Walling

Indiana University Medical Center, Indianapolis, IN; K.D. Miller

Fort Wayne Medical Oncology/Hematology Incorporated, Fort Wayne, IN; S.R. Nattam

Northern Indiana Consortium, South Bend, IN; R.H. Ansari

Cancer Center of Kansas—Wichita, Wichita, KS; S.R. Dakhil

Via Christi Regional Medical Center, Wichita, KS; S.R. Dakhil

Louisiana State University, Shreveport, LA; G.M. Mills

Tufts Medical Center, Boston, MA; J.K. Erban

Massachusetts General Hospital, Boston, MA; H.J. Burstein

Dana-Farber Cancer Institute, Boston, MA; H.J. Burstein

Beth Israel Deaconess Medical Center, Boston, MA; H.J. Burstein

North Shore Cancer Center, Salem, MA; K.J. Krag

Suburban Hospital, Bethesda, MD; C.B. Hendricks

Johns Hopkins University, Baltimore, MD; A.C. Wolff

Anne Arundel Medical Center, Annapolis, MD; S.P. Watkins

Kaiser Permanente - Shady Grove Medical Center, Rockville, MD; L.C. Hwang

Eastern Maine Medical Center, Bangor, ME; H.M. Segal

Mercy Hospital, Portland, ME; R.C. Inhorn

William Beaumont Hospital, Royal Oak, MI; D. Zakalik

University of Michigan Medical Center, Ann Arbor, MI; A.F. Schott

Wayne State University, Detroit, MI; R.T. Morris

Mid-Michigan Medical Center, Midland, MI; M.R. Hurtubise

Regions Hospital, Minneapolis, MN; D.J. Schneider

United Hospital, St Paul, MN; P.J. Flynn

Duluth Clinic, Duluth, MN; R.J. Dalton

Mayo Clinic, Rochester, MN; J.N. Ingle

Saint Francis Regional Medical Center, Shakopee, MN; D.J. Schneider

Washington University School of Medicine, St Louis, MO; M.J. Naughton

Saint John's Regional Health Center, Springfield, MO; J.W. Goodwin

Missouri Baptist Medical Center, Saint Louis, MO; A.P. Lyss

Montana Cancer Consortium CCOP, Billings, MT; B.T. Marchello

University of North Carolina, Chapel Hill, NC; T.C. Shea

Mission Hospitals Inc, Asheville, NC; M.J. Messino

Forsyth Memorial Hospital, Winston-Salem, NC; J.O. Hopkins

Northeast Medical Center, Concord, NC; J.G. Wall

Hope, A Women's Cancer Center, Asheville, NC; D.J. Hertzel

Altru Hospital, Grand Forks, ND; T. Dentchev

Elliot Hospital, Manchester, NH; D. Weckstein

Dartmouth Hitchcock Medical Center, Lebanon, NH; P.A. Kaufman

New Hampshire Oncology-Hematology Associates, Concord, NH; C. Catcher

Saint Barnabas Medical Center, Livingston, NJ; R.A. Michaelson

Cooper Hospital University Medical Center, Newark, NJ; D.D. Biggs

Cancer Institute of New Jersey, New Brunswick, NJ; D.L. Toppmeyer

Cancer Institute of New Jersey At Hamilton, Trenton, NJ; D.L. Toppmeyer

University of Nevada At Reno Washoe Medical Center, Reno, NV

Saint Vincent's Hospital and Medical Center of New York, New York, NY; P. Klein

Memorial Sloan Kettering Cancer Center, New York, NY; C.A. Hudis

Weill Medical College of Cornell University, New York, NY; J. Leonard

Staten Island University Hospital, Staten Island, NY; M. Odaimi

Albert Einstein College/Medicine, Bronx, NY; C.M. Pellegrino

Montefiore Medical Center, Bronx, NY; C.M. Pellegrino

North Shore University Hospital, Manhasset, NY; D.R. Budman

Brookdale Hospital Medical Center, Brooklyn, NY; M.R. Kalavar

Roswell Park Cancer Institute, Buffalo, NY; E.G. Levine

Ohio State University Hospital, Columbus, OH; C.D. Bloomfield

Cleveland Clinic Foundation, Cleveland, OH; G.T. Budd

Case Western Reserve University, Cleveland, OH; P. Silverman

Fairview Hospital, Cleveland, OH; G.T. Budd

Aultman Hospital, Canton, OH; J.A. Schmotzer Samaritan North Health Center, Dayton, OH; H.M. Gross

Lima Memorial Hospital, Toledo, OH; P.L. Schaefer

Cleveland Clinic Wooster Specialty Center, Wooster, OH; G.T. Budd

Kaiser Permanente, Portland, OR; N.R. Tirumali

Allegheny Cancer Center Network, Pittsburgh, PA; N. Wolmark

University of Pittsburgh, Pittsburgh, PA; A.M. Brufsky

Lancaster General Hospital, Lancaster, PA; R.J. Gottlieb

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; S.M. Domchek

Fox Chase Cancer Center, Philadelphia, PA; L.J. Goldstein

Chester County Hospital, West Chester, PA; W.E. Luginbuhl

St Mary Regional Cancer Center, Langhorne, PA; R.E. Reilly

Abington Memorial Hospital, Abington, PA; W.G. Andrews

Scranton Hematology Oncology, Scranton, PA; M. Hyzinski

Rhode Island Hospital, Providence, RI; W.M. Sikov

Women's and Infants Hospital, Providence, RI; D.S. Dizon

Sioux Valley Clinic - Oncology, Sioux Falls, SD; M.A. Mazurczak

Erlanger Medical Center, Chattanooga, TN; L.L. Schlabach

Jones Clinic, Germantown, TN; B.A. Mullins

Presbyterian Hospital of Dallas, Dallas, TX; J.F. Strauss

MD Anderson Cancer Center, Houston, TX; M.C. Green

Baylor College of Medicine, Houston, TX; R.M. Elledge

Doctor's Hospital of Laredo, Laredo, TX; G.W. Unzeitig

University of Vermont, Burlington, VT; S. Burdette-Radoux

Swedish Hospital Medical Center, Seattle, WA; S.E. Rivkin

University of Washington Medical Center, Seattle, WA; S.E. Rivkin

Southwest Washington Medical Center, Vancouver, WA; K.S. Lanier

University of Wisconsin, Madison, WI; J.A. Stewart

Saint Vincent Hospital, Green Bay, WI; T.J. Saphner

Midelfort Clinic, Eau Claire, WI; G.S. Nambudiri

Green Bay Oncology Ltd at Saint Mary's Hospital, Green Bay, WI; T.J. Saphner

Marshall University Medical Center, Huntington, WV; M.R.B. Tria Tirona

DATA SHARING STATEMENT

After publication, access to deidentified individual participant data may be requested by researchers by submitting a proposal (to stat_center@ibcsg.org), which will be reviewed for scientific merit and feasibility in accordance with IBCSG guidelines for collaborative research and data sharing policy.

AUTHOR CONTRIBUTIONS

Conception and design: Prudence A. Francis, Gini F. Fleming, Silvana Martino, Harold J. Burstein, James N. Ingle, Eric P. Winer, Alan S. Coates, Richard D. Gelber, Aron Goldhirsch, Meredith M. Regan

Administrative support: István Láng, Silvana Martino, Sibylle Loibl, Barbara Ruepp

Provision of study materials or patients: Prudence A. Francis, István Láng, Eva M. Ciruelos, Hervé R. Bonnefoi, Meritxell Bellet, Miguel A. Climent, Silvana Martino, Begoña Bermejo, Harold J. Burstein, Barbara A. Walley, James N. Ingle, Robert E. Coleman, Bettina Müller, Eric P. Winer

Collection and assembly of data: Prudence A. Francis, István Láng, Eva M. Ciruelos, Hervé R. Bonnefoi, Meritxell Bellet, Antonio Bernardo, Miguel A. Climent, Silvana Martino, Begoña Bermejo, Harold J. Burstein, Nancy E. Davidson, Bettina Müller, Barbara Ruepp, Sherene Loi, Marco Colleoni, Meredith M. Regan

Data analysis and interpretation: Prudence A. Francis, Gini F. Fleming, István Láng, Eva M. Ciruelos, Miguel A. Climent, Silvana Martino, Harold J. Burstein, Nancy E. Davidson, Charles E. Geyer, Barbara A. Walley, James N. Ingle, Robert E. Coleman, Fanny Le Du, Sibylle Loibl, Sherene Loi, Meredith M. Regan

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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