SUPPLEMENTARY MATERIAL

Appendix 1 Design features common to TEXT and SOFT

As a planned suite of trials, a majority of trial design features were common to the trials, and are summarized below.

Eligibility

The trials enrolled premenopausal women with histologically-proven, resected, hormone receptor-positive (defined as ER≥10% and/or progesterone receptor (PgR)≥10% by immunohistochemistry at local institutions) early invasive breast cancer. Premenopausal status was defined by estradiol levels in the premenopausal range according to institutional parameters (the exception to biochemical confirmation was patients who had been menstruating regularly and had not used any form of hormonal contraception or any other hormonal treatments during the 6 months prior to randomization). The tumor was to be confined to the breast and axillary lymph nodes without detected metastases elsewhere, with the exception of tumor in internal mammary chain nodes by sentinel node procedure. Patients must have had proper surgery for primary breast cancer with no known clinical residual loco-regional disease, including documentation of negative margins of resection after breast-conserving surgery; radiotherapy was optional after mastectomy and was required after breast-conserving surgery. Either axillary lymph node dissection or a negative axillary sentinel node biopsy (pN0(sn) or pN1mi) was required; those patients with positive sentinel nodes must have had either an axillary dissection or radiation of axillary nodes. Radiation therapy was according to accepted guidelines and local standards. Patients with synchronous bilateral invasive disease (diagnosed histologically within 2 months) were eligible, provided the bilateral disease met all eligibility criteria.

Submission of pathology material for confirmation of hormone receptors by the IBCSG Central Pathology Office was mandatory (consent to use for future research was optional).

The exclusion criteria included: previous bilateral oophorectomy or ovarian irradiation; pregnant or lactating at the time of randomization or desiring pregnancy within 5 years; use of tamoxifen or other selective estrogen receptor modulator or hormone replacement therapy within one year prior to breast cancer diagnosis; previous or concurrent invasive malignancy cancer (other than adequately treated basal-cell or squamous-cell carcinoma of the skin, in situ non-breast carcinoma without invasion, contra- or ipsilateral in situ breast carcinoma, or selected non-breast invasive malignancies diagnosed at least 5 years prior to randomization without recurrence [stage I papillary thyroid cancer, stage Ia cervical carcinoma, stage Ia or Ib endometrioid endometrial cancer, borderline or stage I ovarian cancer]); non-malignant systemic disease that would prevent prolonged follow-up.

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Endocrine Treatment

In each trial, the oral endocrine therapy was either tamoxifen (20 mg orally daily, by prescription) or the steroidal aromatase inhibitor exemestane ([Aromasin®; Pfizer] 25 mg orally daily, by study supply) until 5 years from the date of randomization. Ovarian function suppression (OFS) was by gonadotropin-releasing hormone (GnRH) analogue triptorelin (supplied by the study either as Decapeptyl® Depot [Ipsen] or Trelstar® Depot [Debio]; 3.75 mg by intramuscular injection) every 28±3 days until 5 years from date of randomization, or bilateral surgical oophorectomy or bilateral ovarian irradiation (with biochemical confirmation of cessation of ovarian function after 2 months).

Concomitant treatments

Additional hormonal and concurrent investigational treatments were not allowed, though prior investigational agents were allowed. Bisphosphonates were not allowed except in the case that osteoporosis developed, or if the patient participated in a trial testing bisphosphonates in the adjuvant breast cancer setting. Trastuzumab was allowed when indicated.

Study procedures

Study visits were every 3 months during year one, every 6 months during the next 5 years, and yearly follow-up thereafter. Study visits required physical exam and collection of adverse events and concomitant medications, with laboratory tests and imaging as medically indicated. Targeted adverse events (Allergic Reaction/Hypersensitivity, Injection Site Reaction, Hot Flashes/Flushes, Mood Alteration-Depression, Sweating, Insomnia, Fatigue, Hypertension, Cardiac Ischemia/Infarction, Thrombosis/Embolism, Nausea, Musculoskeletal Symptoms, Osteoporosis, Fractures, Vaginal Dryness, Libido Decrease, Dyspareunia, Urinary Incontinence, central nervous system (CNS) Cerebrovascular Ischemia, CNS Hemorrhage) and other grade 3 or higher adverse events of endocrine therapies were collected using Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Participation in quality-of-life studies was required and spanned every 6 or 12 months between randomization and 6 years after randomization.

Randomization

Randomization was performed using a web-based system, either by a cooperative group randomization center or directly from the participating center, with the use of permuted blocks and was stratified according to factors specific to the trial, with institutional balancing.

Endpoints

The primary endpoint was invasive disease-free survival (DFS), defined as the time from randomization to the first suspicion of the following events: invasive recurrence at local, regional, or distant sites; a new invasive cancer in the contralateral breast; any

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secondary (non-breast) malignancy; or a death without prior cancer event. Secondary endpoints included overall survival, breast cancer-free interval, and distant recurrence-free interval1.

REFERENCES

1. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA, Sparano JA, Hunsberger S, Enos RA, Gelber RD, Zujewski JA.. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 2007;25:2127-32.

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Appendix 2 Derivation of 5-year DFS estimates for sample size considerations

A baseline 5-year DFS was estimated under the assumption that TEXT and SOFT would enroll predominantly younger premenopausal women, most receiving chemotherapy prior to enrollment (SOFT) or concurrent with GnRH analogue (TEXT), and about 60% having lymph node-positive disease. SOFT in particular aimed to focus the OFS question on the subset of women who would be most likely to benefit, i.e., women with endocrine-responsive disease plus premenopausal status either after completion of (neo)adjuvant chemotherapy or following surgery alone. These women were anticipated to be on average younger than the median age for premenopausal breast cancer and most likely under 40 years of age.

Though SOFT entered patients who did not receive chemotherapy, IBCSG did not anticipate enrolling many such patients. From IBCSG Trial VIII (enrolled 1990-1999), 15.6% of patients maintained menses following 6 cycles CMF chemotherapy, ranging from 78% of patients aged ≤35 years to 10% of patients aged 41 to 45 years 1. Patients who remain premenopausal following chemotherapy are likely to have an outcome similar to that observed for patients ≤35 years, as the majority of patients in this age group maintain menses. A review of data from IBCSG, NSABP, ECOG and SWOG indicated that women ≤35 years with ER-positive, lymph node-positive disease who were treated with chemotherapy alone had about a 40% 5-year DFS2, and assuming a 40% reduction in risk of relapse by adding tamoxifen3, estimated 5-year DFS of 58%. This estimate agrees with the 59% 5-year DFS based on 109 women in CALGB 93444

≤35 years with ER positive, lymph node-positive disease who received chemotherapy plus tamoxifen [personal communication]. Premenopausal women with ER-positive, lymph node-negative disease in IBCSG Trial V had a 70% 5-year DFS without tamoxifen5. Adding tamoxifen should improve this to 81%. Assuming that about 60% of patients enrolled in this trial would have lymph node-positive disease, 67% 5-year DFS was estimated for the tamoxifen-alone control group in SOFT (with or without prior chemotherapy).

We hypothesized a 25% additional risk reduction associated with GnRH analogue, resulting in an estimated 74.1% 5-year DFS for tamoxifen+OFS. A further 25% risk reduction for exemestane+OFS, to 79.8% 5-year DFS, was assumed.

REFERENCES

1. International Breast Cancer Study Group (IBCSG). Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 2003;95:1833-46.

2. Goldhirsch A, Gelber RD, Yothers G, Gray RJ, Green S, Bryant J, Gelber S, Castiglione-Gertsch M, Coates AS: Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monographs 2001;30:44-51.

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3. Early Breast Cancer Trialists Collaborative Group: Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67.

4. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976-83.

5. Goldhirsch A, Castiglione M, Gelber RD for the International Breast Cancer Study Group. A single perioperative adjuvant chemotherapy course for node-negative breast cancer: five-year results of Trial V. J Natl Cancer Inst Monographs 1992; 11: 89-96.

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Appendix 3 Participating Centers and Groups

Trial IBCSG 25-02 / BIG 3-02 / TEXT and IBCSG 24-02 / BIG 2-02 / SOFT

Steering Committee: P.A. Francis (Chair, SOFT Co-Chair), G.F. Fleming (SOFT Co-Chair), O. Pagani (TEXT Co-Chair), B. Walley (TEXT Co-Chair), M.M. Regan (Trial Statistician), A. Giobbie-Hurder (Trial Statistician), R. Torrisi, M. Bellet, L. Blacher, H. Bonnefoi, E. Ciruelos, A.S. Coates, M. Colleoni, N. Dif, R.D. Gelber, A. Goldhirsch, A. Hiltbrunner, R. Kammler, R. Maibach, C. Messina, K. Nixon, O. Ortmann, E.A. Perez, K.N. Price, M. Rabaglio, B. Ruepp, K. Saini, T. Scolese, H. Shaw, G. Viale, G. von Minckwitz, L. Cisar (Pfizer) , E. Chetaille (Ipsen)

IBCSG Scientific Committee: A. Goldhirsch, A.S. Coates, Marco Colleoni (Co-Chairs)

IBCSG Foundation Council: R. Stahl (President), S. Aebi, A.S. Coates, M. Colleoni, R.D. Gelber, A. Goldhirsch, M. Green, P. Karlsson, I. Kössler, I. Láng

IBCSG Coordinating Center, Bern, Switzerland: A. Hiltbrunner (Director), R. Kammler, R. Maibach, M. Rabaglio, B. Ruepp, P. Sicher, S. Roux

IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA, USA: R.D. Gelber (Director), M.M. Regan (Group Statistician), J. Aldridge, M. Bonetti, A. Giobbie-Hurder, K. Gray, H. Huang, K.N. Price, L. Zickl

IBCSG Data Management Center, Frontier Science & Technology Research Foundation, Amherst, NY, USA: L. Blacher (Director), K. Scott (Section Head), A. Cesario, A. Dickinson, M. Greco, T. Heckman-Scolese, R. Hinkle, K. Lupejkis, A. Mora de Karausch, V. Palermo, H. Shaw, J. Swick-Jemison, R. Hecker and K. Donahue

IBCSG Central Pathology Office, European Institute of Oncology, Division of Pathology, Milan, Italy: G. Viale, D. Lepanto, O. Pala

IBCSG Quality of Life Office: J. Bernhard, K. Ribi

National Cancer Institute: J. Abrams, J. Zujewki

NCI Clinical Trials Support Unit (CTSU)/Westat: M. Hering, M. Greene, A. Nelson, M. Balois Ouellette, S. Riordan

ALMAC: W. Mahon, E. Whitney, J. Bryant

CTSU Regulatory Office: R. Catalano, D. Marinucci, B. Niewood, R. Lambersky

Alliance (CALGB) Pathology Coordinating Office, Ohio State University, Columbus, OH, USA: W. Frankel, S. Jewell

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

Pfizer Study Support: B. Campanelli, J.A. Graham, B. Klingele, A. Nieto

Ipsen Study Support: E. Chetaille, J. Amauri Soares, C. Descot, S. Hemont-Dacosta

TEXT TRIALBREAST INTERNATIONAL GROUP (BIG)

International Breast Cancer Study Group (IBCSG)Australia and New Zealand Breast Cancer Trials Group (ANZBCTG)Australia

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Coffs Harbour Base Hospital, Coffs Harbour, New South WalesLiverpool Hospital, Liverpool, New South WalesMacarthur Cancer Therapy Centre, Campbelltown, New South WalesCalvary Mater Newcastle, Waratah, New South WalesRiverina Cancer Care Centre, Wagga Wagga, New South WalesTamworth Rural Referral Hospital, Tamworth, New South WalesTweed Hospital, Tweed Heads, New South WalesLismore Base Hospital, Lismore, New South Wales Royal Brisbane and Women’s Hospital, Herston, QueenslandFlinders Medical Centre, Bedford Park, South AustraliaLaunceston General Hospital, Launceston, TasmaniaRoyal Hobart Hospital, Hobart, TasmaniaAustin Health, Heidelberg, VictoriaBox Hill Hospital, Box Hill, VictoriaVictorian Breast and Oncology Care, East Melbourne, VictoriaMaroondah Hospital, Ringwood East, VictoriaPeter MacCallum Cancer Centre, East Melbourne, VictoriaSt. Vincent’s Hospital Melbourne, Fitzroy, VictoriaRoyal Perth Hospital, Perth, Western Australia

BelgiumInstitute Jules Bordet, BrusselsCentre Hospitalier Peltzer-La Tourelle, VerviersCentre Hospitalier Regional de la Citadelle, LiègeCentre Hospitalier Universitarie Sart Tilman, LiègeU.Z. Gasthuisberg, LeuvenCentre Hospitalier Rgional de Huy, Huy

EgyptNational Cancer Institute, Cairo University, CairoCairo Oncology Centre, Cairo

HungaryNational Institute of Oncology, Budapest

IndiaTata Memorial Hospital, Mumbai

ItalyDipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy Centro di Riferimento Oncologico, AvianoFondazione Salvatore Maugeri, PaviaIstituto Europeo di Oncologia, MilanoOspedale degli Infermi, RiminiOspedale di Circolo e Fondazione Macchi, VareseOspedali Riuniti di Bergamo, BergamoSandro Pitigliani Medical Oncology Unit, Hospital of Prato, PratoSpedali Civili, BresciaUnita Operativa de Medicina Oncologica, Ospedale Ramazzini, Carpi

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Azienda Sanitaria di Bolzano, BalzanoIstituto Clinico Humanitas, Rozzano

PeruInstituto de Enfermedades Neoplásicas, Lima

SloveniaInstitute of Oncology, Ljubljana

South AfricaSandton Oncology Centre, Johannesburg

SwedenSahlgrenska University Hospital, GothenburgLinkoping University Hospital, Linkoping

SwitzerlandSwiss Association for Clinical Cancer Research (SAKK)Centre Hospitalier Universitaire Vaudois, LausanneInselspital, BernOncocare Engeried, BernInstitute of Oncology of Southern Switzerland (Ospedale San Giovanni, Bellinzona; Ospedale Regionale di Lugano, (Civico & Italiano), Lugano; Ospedale Regionale Beata Vergine, Mendrisio; Ospedale Regionale La Carità, Locarno; Istituto Cantonale di Patologia, Locarno)Kantonsspital St. Gallen, St. GallenRätisches Kantonos-/Regionalspital, ChurKantonsspital Basel, BaselOnkologiezentrum Thun-Berner Oberland, ThunZürich Frauenklinik, Zürich

German Breast Group (GBG)Caritas-Krankenhaus St. Josef, RegensburgMammazentrum, Klinikum Deggendorf, DeggendorfSt. Vincentius Kliniken Karlsruhe, KarlsruheKlinikum Rosenheim, RosenheimDr. Horst Schmidt Kliniken, WiesbadenKlinikum Mittelbaden, Baden-BadenUniversitats-Frauenklinik Leubeck, Leubeck

National Cancer Research Institute (NCRI) United KingdomSouth Tyneside District Hospital, South ShieldsPeterborough District Hospital, PeterboroughSouth Manchester University Hospital, Manchester

NORTH AMERICA BREAST CANCER GROUPS

American College of Surgeons Oncology Group (ACOSOG, now part of the Alliance for Clinical Trials in Oncology)

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Cancer and Leukemia Group B (CALGB ACOSOG, now part of the Alliance for Clinical Trials in Oncology)Clinical Trials Support Unit (CTSU)Eastern Cooperative Oncology Group (ECOG, now part of ECOG/ACRIN)National Institution of Canada Clinical Trials Group (NCIC CTG)National Surgical Adjuvant Breast and Bowel Project (NSABP)North Central Cancer Treatment Group (NCCTG ACOSOG, now part of the Alliance for Clinical Trials in Oncology)Radiation Therapy Oncology Group (RTOG)Southwest Oncology Group (SWOG)

NORTH AMERICAN PARTICIPATING CENTERSCanadaCross Cancer Institute, Edmonton, AlbertaTom Baker Cancer Center, Calgary, AlbertaDr. Leon Richard Oncology Centre, Moncton, New BrunswickWindsor Regional Cancer Center, Windsor, OntarioTrillium Health Center, Mississauga, OntarioLondon Regional Cancer Center, London, OntarioHamilton Regional Cancer Center, Hamilton, OntarioTrillium Health Centre - W Toronto, Toronto, OntarioHôpital Du Sacre-Coeur de Montreal, Montreal, QuebecHôpital Charles LeMoyne, Greenfield Park, QuebecAllan Blair Cancer Center, Regina, SaskatchewanSaskatoon Cancer Center, Saskatoon, Saskatchewan

United States of AmericaUniversity of Arkansas, Little Rock, ARPresbyterian Hospital, Whittier, CAUniversity of California at San Diego, San Diego, CADesert Regional Medical Center, Palm Springs, CAUniversity of California Medical Center At Irvine, Orange, CASan Francisco General, San Francisco, CAUniversity of California at San Francisco, San Francisco, CAMercy General Hospital, Carmichael, CASaint Joseph Medical Center, Burbank, CASutter Community Hospital, Sacramento, CAUniversity of California San Diego Cancer Center, San Diego, CAUniversity of Colorado, Denver, COThe Shaw Regional Cancer Center, Aurora, COUniversity of Connecticut, Farmington, CTWalter Reed Army Medical Center, Washington, DCSibley Memorial Hospital, Washington, DCUniversity of Miami Sylvester Cancer Center, Miami, FLMayo Clinic Jacksonville, Jacksonville, FLComprehensive Cancer Care Specialist At Boca Raton, Boca Raton, FLNortheast Georgia Medical Center, Gainesville, GASiouxland Hematology - Oncology Associates, Sioux City, IASaint Luke's Mountain States Tumor Institute, Boise, IDKootenai Cancer Center, Coeur D'Alene, ID

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Evanston Northwestern Healthcare, Evanston, ILJohn H. Stroger, Jr., Hospital of Cook County, Chicago, ILResurrection Medical Center, Chicago, ILUniversity of Chicago, Chicago, ILDecatur Memorial Hospital, Decatur, ILOncology-Hematology Associates of Central Illinois, Peoria, ILCarle Cancer Center CCOP, Urbana, ILSaint Joseph's Medical Center, South Bend, INMemorial Hospital of South Bend, South Bend, INMichiana Hematology Oncology P.C., South Bend, INFort Wayne Medical Oncology/Hematology Incorporated, Fort Wayne, INNorthern Indiana Consortium, South Bend, INNorthern Indiana Cancer Research Co, South Bend, INMount Carmel Regional Cancer Center, Pittsburg, KSStormont-Vail Regional Health Center, Topeka, KSCancer Center of Kansas - Wichita, Wichita, KSVia Christi Regional Medical Center, Wichita, KSCancer Center of Kansas - Pratt, Pratt, KSCancer Center of Kansas-Medical Arts Tower, Wichita, KSAddison Gilbert, Gloucester, MATufts Medical Center, Boston, MAMassachusetts General Hospital, Boston, MADana-Farber Cancer Center, Boston, MABeth Israel Deaconess Medical Center, Boston, MAFaulkner Hospital, Boston, MANorth Shore Cancer Center, Salem, MAEmerson Hospital, Boston, MASuburban Hospital, Bethesda, MDUniversity of Maryland Cancer Center, Baltimore, MDMercy Medical Center, Baltimore, MDFrederick Memorial Hospital, Frederick, MDCentral Maine Medical Center, Lewiston, MEWilliam Beaumont Hospital, Royal Oak, MISaint Mary's Hospital, Ann Arbor, MIUnited Hospital, St. Paul, MNAbbott-Northwestern Hospital, St. Louis Park, MNMercy Hospital, Coon Rapids, MNMayo Clinic, Rochester, MNSaint John's Hospital - Healtheast, Minneapolis, MNMetro-Minnesota CCOP, Minneapolis, MNRidgeview Medical Center, Waconia, MNSaint Louis University Hospital, St Louis, MOWashington School of Medicine, St Louis, MOSaint John's Regional Health Center, Springfield, MOKansas City CCOP, Kansas City, MOBillings Clinic, Billings, MTMontana Cancer Consortium CCOP, Billings, MTMoses H. Cone Memorial, Greensboro, NCPresbyterian Hospital, Charlotte, NCMission Hospitals Inc, Asheville, NC

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Forsyth Memorial Hospital, Winston-Salem, NCMargaret R. Pardee Memorial Hospital, Hendersonville, NCHope, A Women's Cancer Center, Asheville, NCMedcenter One Health Systems, Bismarck, NDDakota Clinic, Fargo, NDUniversity of Nebraska Medical Center, Omaha, NEPortsmouth Regional Hospital, Portsmouth, NHSouth Jersey Healthcare, Vineland, NJHackensack University Medical CCOP, Hackensack, NJVirtua West Jersey Hospitals, Marlton, NJNew York University Medical Center, New York, NYAlbert Einstein College/Medicine, Bronx, NYMontefiore Medical Center, Bronx, NYRoswell Park Cancer Institute, Buffalo, NYAultman Hospital, Canton, OHGeisinger Wyoming Valley, Danville, PAGeisinger Medical Group, Danville, PANorth East Medical Oncology Associates, Hazleton, PAGreenville CCOP, Greenville, SCSioux Valley Clinic - Oncology, Sioux Falls, SDErlanger Medical Center, Chattanooga, TNDoctor's Hospital of Laredo, Laredo, TXUniversity of Vermont, Burlington, VTMountainview Medical, Berlin, VTSwedish Hospital Medical Center, Seattle, WAUniversity of Washington Medical Center, East Seattle, WAMadigan Army Medical Center, Tacoma, WAGroup Health Cooperative of Puget Sound, Seattle, WAAspirus Wausau Hospital Center, Wausau, WIOncology Alliance-Glendale, Glendale, WIColumbia Saint Mary's Hospital, Milwaukee, WIWest Virginia University, Morgantown, WV

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SOFT TRIALBREAST INTERNATIONAL GROUP (BIG)

International Breast Cancer Study Group (IBCSG)Australia and New Zealand Breast Cancer Trials Group (ANZBCTG)AustraliaCanberra Hospital, Garran, Australian Capital TerritoryBorder Medical Oncology, Wodonga, New South WalesCalvary Mater Newcastle, Waratah, New South WalesCoffs Harbour Health Campus, Coffs Harbour, New South WalesLiverpool Hospital, Liverpool, New South WalesMacarthur Cancer Therapy Centre, Campbelltown, New South WalesManning Rural Referral Hospital, Taree, New South WalesConcord Repatriation General Hospital, Concord, New South WalesTweed Hospital, Tweed Heads, New South WalesRiverina Cancer Care Centre, Wagga Wagga, New South WalesRoyal North Shore Hospital, St. Leonards, New South WalesRoyal Prince Alfred Hospital, Camperdown, New South WalesSt. George Hospital, Kogarah, New South WalesSt. Vincent's Hospital, Darlinghurst, New South WalesThe Mater Hospital, North Sydney, New South WalesNambour Hospital, Nambour, QueenslandPrincess Alexandra Hospital, Woolloongabba, QueenslandSt. Andrews Toowoomba Hospital, Toowoomba, QueenslandRoyal Brisbane and Women's Hospital, Herston, Queensland Royal Adelaide Hospital, Adelaide, South AustraliaSt. John of God Hospital, Bunbury, South AustraliaLaunceston General Hospital, Launceston, Tasmania North West Regional Hospital, Burnie, TasmaniaRoyal Hobart Hospital, Hobart, TasmaniaAustin Health, Heidelberg, VictoriaBallarat Oncology and Haematology Services, Wendouree, VictoriaAlfred Hospital, Melbourne, VictoriaBox Hill Hospital, Box Hill, VictoriaMaroondah Hospital, Ringwood East, VictoriaMonash Medical Centre, East Bentleigh, VictoriaPeter MacCallum Cancer Center, East Melbourne, Victoria St. Vincents Hospital, Fitzroy, VictoriaVictorian Breast and Oncology Care, Melbourne, VictoriaMount Hospital, Perth, Western AustraliaSir Charles Gairdner Hospital, Nedlands, Western AustraliaSt. John of God Hospital, Subiaco, Western Australia

New ZealandAuckland City Hospital, AucklandChristchurch Hospital, ChristchurchPalmerston North Hospital, Palmerston NorthWaikato Hospital, Hamilton

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BrazilHospital de Clinicas de Porto Alegre, Porto Alegre

Chile Grupo Oncológico Corporativo Chileno de Investigación (GOCCHI)Instituto Nacional del Cancer, SantiagoHospital San Juan de Dios, SantiagoHospital San Borja Arriaran, SantiagoHospital Clinico de la Universidad de Chile, SantiagoHospital dr.sotero Del Rio, SantiagoHospital Militar, SantiagoCentro De Patologia Mamaria, SantiagoHospital Dr. Juan Noe Crevani, AricaHospital Base de Valdivia, ValdiviaInstituto De Radiomedicina, Vitacura

HungaryNational Institute of Oncology, Budapest

IndiaTata Memorial Hospital, Mumbai

ItalyCentro di Riferimento Oncologico, AvianoAzienda Sanitaria di Bolzano, BalzanoOspedali Riuniti di Bergamo, BergamoOspedale degli Infermi, BiellaUnita Operativa de Medicina Oncologica, Ospedale Ramazzini, CarpiOncologia Medica Fano Italy, FanoOspedale Civile di Lecco, LeccoIstituto Europeo di Oncologia, MilanoMirandola Hospital, Mirandola, ItalyFondazione Salvatore Maugeri, PaviaSandro Pitigliani Medical Oncology Unit, Hospital of Prato, PratoOspedale degli Infermi, RiminiOspedale di Circolo e Fondazione Macchi, VareseDipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy

PeruInstituto de Enfermedades Neoplásicas, Lima

South AfricaSandton Oncology Centre, Johannesburg

SwedenSahlgrenska University Hospital, GothenburgLinkoping University Hospital, LinkopingCentral Hospital Karlstad, KarlstadKarolinska University Hospital, StockholmLund University Hospital, Lund

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Skaraborg Hospital Skovde, SkovdeSouthern Elfsborg Hospital Boras, Boras

SwitzerlandSwiss Association for Clinical Cancer Research (SAKK)Centre Hospitalier Universitaire Vaudois, LausanneInselspital, BerneKantonsspital St. Gallen, St. GallenRätisches Kantonos-/Regionalspital, ChurKantonsspital Basel, BaselOnkologiezentrum Thun-Berner Oberland, ThunOncocare Engeried, BernZürich Frauenklinik, ZürichBrust-Zentrum Zurich, ZurichDr. Mannhart, ChamKantonsspital Aarau (AG), AarauKantonsspital Baden, BadenTumor - und Brustzentrum Zetup St. Gallen, St. Gallen

Solid Tumor Intensification Group (SOLTI) SpainHospital Clinic i Provincial de Barcelona , BarcelonaHospital Universitari Vall D' Hebron, BarcelonaHospital Universitario 12 de Octubre, MadridCentro Oncologico Md Anderson, MadridHospital Son Llatzer, Palma de MallorcaClinica Univ. De Navarra, PamplonaInstituto Valenciano de Oncologia, ValenciaHospital Son Dureta (Palma de Mallorca), Palma de MallorcaHospital Santiago De Compostela, Santiago de CompostelaH.U. Arnau de Vilanova, LleidaHospital Universitario Lozano Blesa, ZaragozaHospital Universitario Virgen Macarena, SevillaHospital Clinico Universitario de Valencia, ValenciaHospital Ramon Y Cajal, MadridHospital Sant Joan de Reus, ReusHospital Reina Sofia De Cordoba, CordobaHospital Dr Negrin, Las Palmas de Gran CanariHospital Sant Pau i Santa Tecla, Tecla

CENTRAL AND EAST EUROPEAN ONCOLOGY GROUP (CEEOG)

Medical University of Gdansk, Gdansk, PolandInstitute of Oncology & Radiology of Serbia, Belgrade, Serbia

EUROPEAN ORGANISATION FOR RESEARCH AND TREATMENT OF CANCER (EORTC)

ZNA Middelheim, Antwerpen, BelgiumCliniques Universitaires St-Luc UCL, Brussels, BelgiumCentre Hospitalier Etterbeek Ixelles, Brussels, BelgiumU.Z. Leuven, Leuven, BelgiumC.H.U. Sart-Tilman, Liege, BelgiumHopital De Jolimont, Haine St. Paul, Belgium

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Clinique Sainte Elisabeth, Namur, BelgiumAlgemeen Ziekenhuis Sint-Augustinus, Wilrijk, BelgiumCentre Henri Becquerel, Rouen, FranceInstitut Claudius Regaud, Toulouse, FranceInstitut Jean Godinot, Reims, FranceCentre Leon Berard, Lyon, FranceInstitut Bergonie, Bordeaux, FranceCentre Georges Francois-Leclerc, Dijon, FranceCentre Rene Huguenin, Saint-Cloud, FranceInstitut Curie, Paris, FranceCentre Eugene Marquis, Rennes, FranceC.H.R.U. de Limoges, Limoges, FranceClinique Mutualiste de l’Estuaire, Saint-Nazaire, FranceClinique De L'alliance, Tours, FranceInstitut Gustave Roussy, Villejuif, FranceRambam Medical Center, Haifa, IsraelAssaf Harofeh Medical Center, Zerifin, IsraelThe Netherlands Cancer Institute, Amsterdam, NetherlandsOnze Lieve Vrouwe Gasthuis, Amsterdam, NetherlandsLeids Universitair Medisch Centrum, Leiden, NetherlandsCentro de Lisboa, Lisboa, PortugalMarmara University Hospital, Istanbul, Turkey

German Breast Group (GBG)

DRK Kliniken Berlin Köpenick, BerlinPraxis Dr. Tessen, GoslarMartin-Luther- Universität Halle-Wittenberg, Halle an der SaaleUniversitätsfrauenklinik Erlangen, ErlangenUniversitäts Frauenklinik Mannheim, MannheimKlinikum Mittelbaden/Stadtklinik Baden-Baden, Baden-BadenUniversitäts-Frauenklinik, Freiburg i. Br.Dr. Horst Schmidt Kliniken, WiesbadenKreisklinik Ebersberg, EbersbergSt. Vincentius Krankenhaus, KarlsruheKlinikum Landshut GmbH, LandshutUniversitäts Frauenklinik, Frankfurt/MainCaritas-Krankenhaus St. Josef, Regensburg Klinik für Frauenheilkunde und Geburtshilfe der Universität Regensburg, Regensburg

All Ireland Cooperative Clinical Research Group (ICORG)

Beaumont Hospital, DublinMater Misericordiae Hospital, DublinMater Private Hospital, DublinSouth Infirmary Victoria Hosp, CorkUniv College Hospital Galway, Galway

National Cancer Research Institute (NCRI), United Kingdom

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Southend Hospital NHS Trust, Westcliff-on-Sea, Essex, United KingdomSouth Tyneside District Hospital, South Shields, Tyne & Wear, UKWeston Park Hospital, Sheffield, South Yorkshire, EnglandMount Vernon Hospital, Northwood, Middlesex, UKLuton & Dunstable Hospital, Luton, EnglandClatterbridge Centre for Oncology, Wirral, UKIpswich Hospital, Ipswich, UKGreat Western Hospital, Swindon, UKNew Cross Hospital, Wolverhampton, UKWhiston Hospital, Prescot, UK Aberdeen Royal Infirmary, Aberdeen, UKRoyal Marsden Hospital - Fulham, London, EnglandRoyal Marsden Hospital - Sutton, Surrey, England York Hospital, YorkSt. James Univ Hospital, LeedsNorth Manchester General Hospital, ManchesterHarrogate District Hospital, HarrogateStepping Hill Hospital, StockportRussells Hall Hospital, Dudley

NORTH AMERICA BREAST CANCER GROUPS

American College of Surgeons Oncology Group (ACOSOG, now part of the Alliance for Clinical Trials in Oncology)Cancer and Leukemia Group B (CALGB, now part of the Alliance for Clinical Trials in Oncology)Clinical Trials Support Unit (CTSU)Eastern Cooperative Oncology Group (ECOG, now part of ECOG/ACRIN)National Institution of Canada Clinical Trials Group (NCIC CTG)National Surgical Adjuvant Breast and Bowel Project (NSABP)North Central Cancer Treatment Group (NCCTG, now part of the Alliance for Clinical Trials in Oncology)Radiation Therapy Oncology Group (RTOG)Southwest Oncology Group (SWOG)

NORTH AMERICAN PARTICIPATING CENTERSCanadaDoctor H. Bliss Murphy Cancer Center,St. John's, NewfoundlandBCCA-Vancouver Cancer Center, Vancouver, British ColumbiaUniversity of Montreal Hospital Group, Montreal, QuebecHopital Du Sacre-Coeur de Montreal, Montreal, QuebecHôpital Charles LeMoyne, Greenfield Park, QuebecKingston Regional Cancer Center, Kingston, OntarioOttawa Health Research Institute, Ottawa, OntarioThunder Bay Regional Health Science Centre, Thunder Bay, OntarioRegional Cancer Program of The Hopital Regional de Sudbury Region, Sudbury, OntarioHamilton Regional Cancer Center, Hamilton, OntarioOdette Cancer Centre, Toronto, OntarioLondon Regional Cancer Center, London, OntarioCancercare Manitoba, Winnipeg, ManitobaAllan Blair Cancer Center, Regina, Saskatchewan

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Cross Cancer Institute, Edmonton, AlbertaTom Baker Cancer Center, Calgary, AlbertaCancer Center - Southern Interior, Kelowna, British ColumbiaPenticton Regional Hospital, Penticton, British ColumbiaBCCA-Fraser Valley Cancer Center, Surrey, British Columbia

United States of AmericaProvidence Alaska Medical Center, Anchorage, AKUniversity of Alabama, Birmingham, ALUniversity of California at Los Angeles (UCLA), Los Angeles, CAUniversity of Southern California, Los Angeles, CAScripps Clinic - La Jolla, La Jolla, CAUniversity of California At San Diego, San Diego, CAEisenhower Medical Center, Rancho Mirage, CAKaiser Permanente South San Francisco, Vallejo, CAUniversity of California at San Francisco, San Francisco, CAJohn Muir Medical Center, Concord, CAKaiser Permanente - Fremont, Fremont, CAKaiser Permanente-Vallejo, Vallejo, CAKaiser Permanente-Walnut Creek, Vallejo, CABay Area Tumor Institution CCOP, Oakland, CAKaiser Permanente-Oakland, Vallejo, CAAlta Bates Hospital, Berkeley, CAKaiser - Santa Clara, Santa Clara, CAKaiser Permanente Santa Teresa (San Jose), Vallejo, CAMemorial Medical Center, Modesto, CAMercy General Hospital, Carmichael, CAKaiser Permanente-Sacramento, Vallejo, CAKaiser Permanente, San Francisco, San Francisco, CASanta Rosa CCOP, Sana Rosa, CAMercy Regional Cancer Center, Redding, CAKaiser Permanente, Roseville, Roseville, CAKaiser Permanente, Redwood City, Redwood City, CAStanford University Medical Center, Stanford, CAKaiser Permanente-Richmond, Richmond, CASan Joaquin CCOP, San Joaquin, CAKaiser Permanente CCOP, San Diego, CAPalo Alto Medical Foundation-Camino Division, Mountain View, CAGlendale Memorial Hospital and Health Center, Glendale, CAContra Costa Regional Medical Center, Martinez, CATom K Lee Inc, Oakland, CANorth Colorado Medical Center, Denver, COPenrose-Saint Francis Healthcare, Colorado Springs, COMemorial Hospital Colorado Springs, Colorado Springs, CONorth Suburban Medical Center, Thorton, COFront Range Cancer Specialists, Fort Collins, COLongmont United Hospital, Longmont, COSky Ridge Medical Center, Lone Tree, COThe Shaw Regional Cancer Center, Aurora, COHartford Hospital, Hartford, CT

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Greenwich Hospital, Greenwich, CTNorwalk Hospital, Norwalk, CTStamford Hospital, Stamford, CTEastern Connecticut Hematology and Oncology Associates, Norwich, CTNorthwest Connecticut Oncology - Hematology Associates, Torrington, CTWalter Reed Army Medical Center, Washington, DCGeorgetown University Hospital, Washington, DCWashington Hospital Center, Washington, DCSibley Memorial Hospital, Washington, DCChristiana Healthcare Services - Christian Hospital, Newark, DEBayhealth Medical Center, Dover, DEMemorial Cancer Institute, Hollywood, FLUniversity of Miami Sylvester Cancer Center, Miami, FLMount Sinai Medical Center CCOP, Miami Beach, FLHoly Cross Hospital, FortLauderdale, FLSarasota Memorial Hospital, Sarasota, FLDekalb Medical Center, Atlanta, GAEmory University, Altanta, GAMemorial Health University Medical Center, Savannah, GANorthside Hospital, Atlanta, GAAtlanta Regional CCOP, Atlanta, GAWellstar Kennestone Hospital, Atlanta, GAJohn B. Amos Community Cancer Center, Columbus, GAAugusta Oncology Associates, Inc., Augusta, GASt. Joseph's/Candler Health System, Savannah, GAUniversity of Hawaii, Honolula, HIMcFarland Clinic, Ames, IAMercy Medical Center - North Iowa, Mason City, IAMedical Associates Clinic, Professional Corporation, Dubuque, IAFinley Hospital, Dubuque, IAIowa Blood and Cancer Care, PLC, Cedar Rapids, IAMedical Oncology and Hematology Associates, Des Moines, IALoyola University Medical Center, Maywood, ILRush University Medical Center, Chicago, ILUniversity of Chicago, Chicago, ILWeiss Memorial Hospital, Chicago, ILSt. Anthony Medical Center, Rockford, ILDecatur Memorial Hospital, Decatur, ILMemorial Medical Center, Springfield, ILEdward Hospital, Naperville, ILIngalls Memorial Hospital, Harvey, ILCarle Cancer Center CCOP, Urbana, ILCommunity Regional Cancer Care North, Indianapolis, INIndiana University Medical Center, Indianapolis, INSaint Vincent Hospital, Indianapolis, INFort Wayne Medical Oncology/Hematology Incorporated, Fort Wayne, INNorthern Indiana Consortium, South Bend, INHorizon Oncology Center, Lafayette, INCancer Center of Kansas - Wichita, Wichita, KSVia Christi Regional Medical Center, Wichita, KS

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Louisiana State University, Shreveport, LALahey Clinic Medical Center, Burlington, MATufts Medical Center, Boston, MAMassachusetts General Hospital, Boston, MADana-Farber Cancer Center, Boston, MABeth Israel Deaconess Medical Center, Boston, MAFaulkner Hospital, Boston, MANorth Shore Cancer Center, Salem, MASuburban Hospital, Bethesda, MDJohns Hopkins University, Baltimore, MDAnne Arundel Medical Center, Annapolis, MDKaiser Permanente - Largo Medical Center, Largo, MDKaiser Permanente - Shady Grove Medical Center, Rockville, MDEastern Maine Medical Center, Brewer, MEMercy Hospital, Portland, MEWilliam Beaumont Hospital, Royal Oak, MISaint Joseph Mercy Hospital, Ann Arbor, MIUniversity of Michigan Medical Center, Ann Arbor, MIWayne State University, Detroit, MIGrand Rapids Clinical Oncology Program, Grand Rapids, MIMarquette General Hospital, Marquette, MIMid-Michigan Medical Center, Midland, MIHematology Oncology Associates of Ohio and Michigan, Lambertson, MIRegions Hospital, Minneapolis, MNUnited Hospital, St. Paul, MNDuluth Clinic, Duluth, MNMayo Clinic, Rochester, MNSaint John's Hospital - Healtheast, Minneapolis, MNVirginia Piper Cancer Institute, Minneapolis, MNMetro-Minnesota CCOP, Minneapolis, MNNorth Memorial Medical Health Center, Robbinsdale, MNSaint Francis Regional Medical Center, Shakopee, MNHutchinson Health Care, Hutchinson, MNWashington School of Medicine, St Louis, MOSaint John's Regional Health Center, Springfield, MOMissouri Baptist Medical Center, Saint Louis, MOKansas City CCOP, Kansas City, MOMontana Cancer Consortium CCOP, Billings, MTAlamance Health Services, Burlington, NCUniversity of North Carolina, Chapel Hill, NCDuke University Medical Center, Durham, NCMission Hospitals Inc, Asheville, NCWayne Memorial Hospital, Goldsboro, NCForsyth Memorial Hospital, Winston-Salem, NCFirstHealth of the Carolinas, Moore Regional Hospital, Pinehurst, NCNortheast Medical Center, Concord, NCHope, A Women's Cancer Center, Asheville, NCAltru Hospital, Grand Forks, NDMethodist Cancer Center, Omaha, NEElliot Hospital, Manchester, NH

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Frisbie Hospital, Lebanon, NHCheshire Medical Center, Dartmouth, NHDartmouth Hitchcock Medical Center, Lebanon, NHNew Hampshire Oncology Hematology, Concord, NHSaint Barnabas Medical Center, Livingston, NJCooper Hospital University Medical Center, Newark, DECancer Institute of New Jersey, New Brunswick, NJMonmouth Medical Center, Long Branch, NJCancer Institute of New Jersey At Hamilton, Trenton, NJVirtua West Jersey Hospitals, Marlton, NJHematology Oncology Associates, Albuquerque, NMUniversity of Nevada At Reno Washoe Medical Center, Reno, NVSaint Vincent's Hospital and Medical Center of New York, New York, NYMemorial Sloan Kettering Cancer Ctr, New York, NYWeill Medical College of Cornell University, New York, NYStaten Island University Hospital, Staten Island, NYAlbert Einstein College/Medicine, Bronx, NYMontefiore Medical Center, Bronx, NYNorth Shore University Hospital, Manhasset, NYLong Island Jewish Medical Center, New Hyde Park, NYBrookdale Hospital Medical Center, Brooklyn, NYRoswell Park Cancer Institute, Buffalo, NYRochester General Hospital, Rochester, NYDoctors Hospital, Columbus, OHOhio State University Hospital, Columbus, OHColumbus CCOP, Columbus, OHCleveland Clinic Foundation, Cleveland, OHCase Western Reserve University, Cleveland, OHMetroHealth Medical Center, Cleveland, OHFairview Hospital, Cleveland, OHForum Health, Youngstown, OHUniversity of Cincinnati Medical Center, Cincinnati, OHGood Samaritan Hospital - Dayton, Dayton, OHAultman Hospital, Canton, OHSamaritan North Health Center, Dayton, OHSt. Charles Hospital, Toledo, OHLima Memorial Hospital, Toledo, OHGrady Memorial Hospital, Delaware, OHCleveland Clinic Wooster Specialty Center, Wooster, OHUniversity of Oklahoma Health Science Center, Oklahoma City, OKSaint Charles Medical Center, Bend, ORKaiser Permanente, Portland, ORColumbia River Oncology Program, Portland, ORAllegheny Cancer Center Network, Pittsburgh, PAUniversity of Pittsburgh, Pittsburgh, PAMount Nittany Medical Center, Hershey, PAPenn State Milton S. Hershey Medical Center, Hershey, PAYork Hospital, York, PALancaster General Hospital, Lancaster, PAGeisinger Medical Center, Danville, PA

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Guthrie Medical Center, Sayre, PAGrand View Hospital, Sellersville, PAAbramson Cancer Center of The University of Pennsylvania, Philadelphia, PAFox Chase Cancer Center, Philadelphia, PAChester County Hospital, West Chester, PASt. Mary Regional Cancer Center, Langhorne, PAAbington Memorial Hospital, Abington, PAScranton Hematology Oncology, Scranton, PARhode Island Hospital, Providence, RIWomen's and Infants Hospital, Providence, RISpartanburg CCOP, Spartanburg, SCSpartanburg Regional Medical Center, Spartanburg, SCSioux Valley Clinic - Oncology, Sioux Falls, SDErlanger Medical Center, Chattanooga, TNMeharry Medical College, Nashville, TNThompson Cancer Survival Center, Knoxville, TNJones Clinic, Germantown, TNMedical City Dallas Hospital, Dallas, TXPresbyterian Hospital of Dallas, Dallas, TXScott and White CCOP, Temple, TXM.D. Anderson Cancer Center, Houston, TXBaylor College of Medicine, Houston, TXDoctor's Hospital of Laredo, Laredo, TXVirginia Commonwealth University, Richmond, VAUniversity of Vermont, Burlington, VTGreen Mountain Oncology Group CCOP, Bennington, VTSwedish Hospital Medical Center, Seattle, WAUniversity of Washington Medical Center, East Seattle, WASouthwest Washington Medical Center, Vancouver, WANorthwest CCOP, Tacoma, WAUniversity of Wisconsin, Madison, WISaint Vincent Hospital, Green Bay, WIAspirus Wausau Hospital Center, Wausau, WIGundersen Clinic, Limited, LaCrosse, WIMidelfort Clinic, Eau Claire, WIDean Clinic, Madison, WIAurora Baycare Medical Center, Green Bay, WIGreen Bay Oncology LTD at Saint Mary's Hospital, Green Bay, WIMarshall University Medical Center, Huntington, WVEdwards Comprehensive Cancer Center, Huntington, WV

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