ATAC Steering Committee: Judith Adams (University of Manchester, Manchester, UK), M Baum (University College London, London, UK), AR Bianco (Universita Degli Studi Di Napoli Federico II, Naples Italy); A Buzdar (The University of Texas, MD Anderson Cancer Center, Houston, USA); D Cella (Northwestern University, Evanston, IL, USA); M Coibion (Institute Bordet, Brussels, Belgium); R Coleman (Cancer Research Centre, Weston Park Hospital, Sheffield, UK); M Constenla (Hospital Montecelo, Pontevedra, Spain); J Cuzick (Cancer Research UK, London, UK); W Distler (Dresden University Clinic, Dresden, Germany); M Dowsett (The Royal Marsden Hospital, London, UK); S Duffy (St James's University Hospital, Leeds, UK); R Eastell (University of Sheffield, Sheffield, UK); LJ Fallowfield (University of Sussex, Brighton, UK); JF Forbes (University of Newcastle, Newcastle Mater Misericordiae Hospital, NSW, Australia); WD George (Beatson Oncology Centre, Western Infirmary, Glasgow, UK); J Gray (Belfast City Hospital, Belfast, UK); J-P Guastalla (Centre Léon Bérard, Lyon, France); R Hellmund, G Hoctin-Boes (AstraZeneca Pharmaceuticals, Wilmington, USA); J Houghton, N Williams (Clinical Trials Group of the Department of Surgery, UCL, London, UK); A Howell (Christie Hospital, Manchester, UK); JGM Klijn (Daniel den Hoed Kliniek and University Hospital, Rotterdam, The Netherlands); GY Locker (Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, IL, USA); J Mackey (Cross Cancer Institute, Edmonton, Alberta, Canada); RE Mansel (University of Wales College of Medicine, Cardiff, UK); JM Nabholtz (Hartman Oncology Institute, Levallois-Perret, France); T Nagykalnai (Uzsoki U Hospital, Budapest, Hungary); A Nicolucci (GIVIO Co-ordinating Centre, Consortium of Mario Negri Sud, Center of Pharmacological and Biomedical Research, Chieta, Italy); U Nylen (Radiumhemmet, Karolinska Sjukhuset, Stockholm, Sweden); R Sainsbury (University College London [UCL], London, UK); F Sapunar, VJ Suarez-Mendez (AstraZeneca Pharmaceuticals, Macclesfield, UK); JS Tobias (The Meyerstein Institute of Clinical Oncology, Middlesex Hospital, London, UK); International Project Team (A Doe, F Sapunar, VJ Suarez-Mendez: AstraZeneca Pharmaceuticals, Macclesfield, UK; E Foster: ISD Cancer Clinical Trials Team, Edinburgh, UK; J Houghton, N Williams: Clinical Trials Group of the Department of Surgery, UCL, London, UK; A Nicolucci: Mario Negri Institute, Chieta, Italy; S Pollard: Clinical Trials Research Unit, Leeds, UK); Data Monitoring Committee (M Buyse: International Institute for Drug Development [ID squared], Brussels, Belgium; J Cuzick [Independent statistician]: Cancer Research UK, London, UK; R Margolese: McGill University, The Sir Mortimer B Davis Jewish General Hospital, Montreal, Québec, Canada; JJ Body: Institute J Bordet, Brussels, Belgium); Collaborative/operational Groups (JF Forbes [Group Co-ordinator], JK Wakeham [Study Coordinator]: Australian New Zealand Breast Cancer Trials Group Operations Office; S de Placido [Study Co-ordinator], C Carlomagno [Study Co-ordinator]: Universita Degli Studi Di Napoli Federico II, Italy; A Nicolucci [Group Co-ordinator], M Belfiglio [Study Co-ordinator], M Valentini [Study Co-ordinator]: GIVIO Group, Consortium of Mario Negri Sud, Italy; E Foster: ISD Cancer Clinical Trials Team, Edinburgh, UK [Liz.Foster@isd.csa.scot.nhs.uk]; C Lacey [Trial monitor]: North West Breast Group, Burnley, Lancashire, UK; S Pollard [Head of Pharmaceutical Collaboration]: Clinical Trials Research Unit, University of Leeds, Leeds, UK; J Houghton [Senior Lecturer in Clinical Trials and CTG contact], N Williams [Trial Co-ordinator]: Clinical Trials Group of the Department of Surgery, UCL, London, UK, firstname.lastname@example.org); and Principal and Main Co-Investigators in the ATAC Trial (Argentina – F Coppola, C Bas: Hospital Aleman, Capital Federal, Buenos Aires; J Itala, G Cortese: Hospital de Clinicas, Buenos Aires University, Capital Federal, Buenos Aires; A Nuñez de Pierro, D Allemand: Hospital General de Agudos-Juan Fernandez, Capital Federal, Buenos Aires; H Guixa, R Testa: Hospital Italiano, Capital Federal, Buenos Aires; J Lebron: University of Buenos Aires, Capital Federal, Buenos Aires; Australia – G Gill, J Kollias: Royal Adelaide Hospital, Adelaide, SA; J Chirgwin, M Leyden: Box Hill Hospital, Box Hill, VIC; J Beith, A Sullivan: Royal Prince Albert Hospital, Camperdown, NSW; S Della-Fiorentina, A Goldrick: Liverpool Hospital, Liverpool, NSW; J Chirgwin: Maroondah Hospital, Maroondah, VIC; G Richardson, S Hart: Monash Medical Centre, Melbourne, VIC; G Toner, P Francis: Peter MacCallum Cancer Institute, East Melbourne, VIC; R Snyder, I Burns: St Vincents Hospital, Melbourne, VIC; M Friedlander, D Goldstein: Prince of Wales Hospital, Randwick, NSW; JF Forbes, D Jackson: University of Newcastle, Newcastle Mater Misericordiae Hospital, Waratah, NSW; Belgium – A Makar, D Van den Weyngaert: AZ Middelheim, Antwerp; D Gangji, T Velu: Hôpital Erasme, Brussels; M Coibion, J-M Nogaret: Institute Bordet, Brussels; P Neven, Laurent: St Jan Ziekenhuis, Brussels; J De Mol, F Van Aelst: Heilig Hart Ziekenhuis, Roeselare; Canada – SR Sehdev, MD: Queen Lynch Medical Centre, Brampton, Ontario; R Simard: Complexe Hospitalier de la Sagami, Chicoutimi, Quebec; J Mackey, MD: Cross Cancer Institute, Edmonton, Alberta; J Dufresne, MD: CHUS Hospital Fleurimont, Fleurimont, Québec; WS Lofters: Kingston Regional Cancer Center, Kingston, Ontario; DR Holland: Lethbridge Cancer Centre, Lethbridge, Alberta; HL Solow: Markham Stouffville Health Centre, Markham, Ontario; JA Gapski: Trillium Health Centre, Mississauga, Ontario; SH Rubin: South East Health Care Oncology Department, Moncton Hospital, Moncton, New Brunswick; A Robidoux: CHUM Campus Hotel – Dieu, Montreal, Quebec; B L'Esperance, MD: Sacred Heart Hospital of Montreal, Québec; LC Panasci: McGill Department of Oncology, Montreal, Quebec; LA Zibdawi, MD: Southlake Regional Health Centre, Newmarket, Ontario; J Chang: Lakeridge Health, Oshawa, Ontario; S Arif, MD: Penticton Regional Hospital, Penticton, British Columbia; RF Wierzbicki: Peterborough Regional Health Center Oncology Clinic, Peterborough, Ontario; BP Findlay: Hotel Dieu Hospital Oncology Department, Quebec City, Quebec; J Robert, CHAUQ – Hospital of St-Sacrement, Québec City, Québec; S Lebel: Hospital Laval, Quebec City, Quebec; M Jancewicz: Allan Blair Cancer Center, Regina, Saskatchewan; MJ Burnell: Atlantic Health Sciences Corp, St. John, New Brunswick; A Sami: Saskatoon Cancer Centre, Saskatoon, Saskatchewan; PLD Walde: Algoma Regional Cancer Program, Sault Ste Marie, Ontario; PK Ganguly: H Bliss Murphy Cancer Centre, St Johns, Newfoundland; CJ Germond, MD: Northeastern Ontario Regional Cancer Center, Sudbury, Ontario; Y Rahim: Toronto East General Hospital, Toronto, Ontario; JJ Wilson: Humber River Regional Hospital, Weston, Ontario; AL Cooke: Manitoba Cancer Treatment and Research Foundation, Winnipeg, Manitoba; Czech Republic – K Petrakova, R Demlova: Masarykuv onkologicky ustav, Brno; P Vodvarka, T Kysela: FNsP Ostrava, Ostrava Poruba; B Konopasek, P Mares: Vseobecna fakultni nemocnice, Praha; France – J-E Mention: Centre de Gyneco-Obst, CHU, Amiens; D Serin, Y Goubely-Brewer: Clinique Ste Catherine, Avignon; J-P Labat, J-P Malhaire: CHU Brest, Brest; G Devulder, S Mirdat-Dako: Centre Hospitalier Laënnec, Creil; JM Nabholtz: Hartman Oncology Institute, Levallois-Perret, France; D Houze De L'Aunoit, J-Y Charvolin: Hospital St. Philibert, Lomme; J-P Guastalla, J Guastalla: Centre Léon Bérard, Lyon; R Coquard, B Velay: Clinc St Jean, Lyon; C Lejeune, D Hadjadj-Aoul: Hospital of la Conception, Marseille; M Untereiner: Hôpital-Clinique Claude Bernard, Metz; PI Laffargue: Hospital Arnaud de Villeneuve, Montpellier; M Rios: Centre Alexis Vautrin, Nancy; J-M Vannetzel, R Mahjoubi: Centre Chirurgical Henri Hartmann, Neuilly sur Seine; R Samak: Cabinet Medical, Nice; F Morvan, F Rousseau: Centre Hospitalier, Pontoise; C Veyret, JP Julien: Centre Henri Becquerel, Rouen; P Quetin: Centre Paul Strauss, Strasbourg; J-P Brettes, C Mathelin: Civil Hospital, Strasbourg; Germany – W Distler, U Canzler: Dresden University Clinic; MW Beckmann, PA Fasching: Universität Erlangen-Nuernberg, Erlangen; C Oberhoff, K Naberger: Essen University Clinic, Essen; A Schneider: Friedrich-Schiller Universität Jena, Jena; W Eiermann: Frauenklinik vom Roten Kreuz, Munich; Hungary – C Polgar: National Oncology Institute, Budapest; K Moskovits, Z Nagy: St Imre Hospital, Budapest; T Nagykalnai, L Landherr: Uzsoki st. Hospital, Budapest; T Pinter, G Herodek: Petz Aladar Hospital, Gyor; B Piko, I Szegedi: Pandy Kalman County Hospital, Gyula; J Szanto, L Marazi: BAZ County Hospital, Miskolc; Z Kahan: SZTE Oncotherapy Clinic, Szeged; Ireland – E McDermott, N O'Higgins: St Vincent's Hospital, Dublin; T Gorey: The Mater Hospital, Dublin, Ireland; F Given, S Tormey: University College Galway, Galway; Italy – M Bonsignori, S Rossini: Hospital Torrette, Ancona; F Di Vito, M Cucchi: Regional Hospital, Aosta; F Testore, L Giaretto: Dr Ospedale Civile, Asti; F Recchia, S De Filippis: Ospedale Civile, Avezzano; LR Vito: first Oncologia Mater Dei-Bari, Bari; M De Lena, F Schittulli: Istituto Scientifico Oncologico, Bari; A Martoni, E Piana: Ospedale S Orsola-M Malpighi, Bologna; G Marini, P Marpicati: Spedali Civili, Brescia; M Pintus, A Tedde: Ospedale Oncologico A Businco, Cagliari; M Botta, A Muzio: Ospedale S Spirito, Casale Monferrato; L Basilico, M Taraborrelli: Ospedale SS Annunziata, Chieti; S Bravi, F Biagioni: Ospedale Civile, Città di Castello; M Giordano, G Luchena: Ospedale S. Anna, Como; G Scognamiglio, A Beretta: Ospedale Valduce, Como; P Marchetti, ME D'Addario: Università degli Studi, Coppito [L'Aquila]; M Obialero, F Peradotto: Ospedale Civile, Cuorgné; M Indelli, G Lelli: Arcispedale S. Anna, Ferrara; A Nuzzo, L Laudadio: Ospedale Floraspe Renzetti, Lanciano; M D'Aprile, M Natali: Ospedale S Maria Goretti, Latina; G Cruciani, E Montanari: Ospedale Umberto I, Lugo; E Aitini, G Cavazzini: Ospedale C Poma, Mantova; V Adamo, G Altavilla: University Polyclinic “G Martino”, Messina; G Gardani, A Ardizzoia: Ospedale S. Gerardo, Monza; AR Bianco: Universita Degli Studi Di Napoli Federico II, Naples; A De Matteis, G Landi: Istituto Nazionale Studi e Cura Tumori “G Pascale”, Naples; G D'Aiuto, P Oliviero: Istituto Nazionale Tumori “G Pascale”, Naples; R Lauria, M De Laurentis: Universita Federico II, Naples; A Fornasiero, S Monfardini: Ospedale Civile, Padova; A Agostara, L Mesi: M Ascoli Oncology Hospital, Palermo; A Riccardi, P Pugliese: S Matteo Polyclinic, Pavia; GM Corradini, G Pavia: Ospedale Civile, Rho; F Cognetti, P Papaldo: Regina Elena Institute, Rome; G Gasparini, MA Castellana: Ospedale S Filippo Neri, Rome; M Mattarei, S Robbiati: Ospedale Civile S Maria delle Grazie, Rovereto; A Farris, G Sanna: Istituto Clinical Medica, Sassari; M Viglietta: SS Annunziata Hospital, Savigliano; G Fornari, A Turletti: Ospedale Evangelico Valdese, Turin; G Nastasi, G Rodà: Ospedale Civile S. Isidoro, Trescore Balneario; M Tordiglione, M Molteni: AO Ospedale di Circolo e Fondazione Macchi, Varese; New Zealand – I Campbell; R Gannaway: Waikato Hospital Breast Care Centre, Hamilton; Poland – J Tujakowski, M Osmanska: Regional Oncology Centre, Bydoszcz; P Koralewski, M Urbanska: Ludwick Rydygier Memorial Hospital, Krakow; B Karczmarek-Borowska, B Kukielka-Budny: Regional Oncology Centre, Lublin; M Teresiak, P Laski: Regional Oncology Centre, Pozan; M Krzakowski, E Pucula: Maria Sklodowska-Curie Memorial Oncology Centre, Warszawa; Portugal – D Jardim da Pena, R Nabiço: Hospital de S Marcos, Braga, Portugal; M Barros: Centro Hospitalar das Caldas da Rainha, Caldas de Rainha; M Chumbo: Hospital Condes de Castro Guimaraes, Cascais; O Campos, H Gervasio: IPO – Hospital de Dia, Coimbra; I Botto: Maternidade Bissaya Barreto, Coimbra, Portugal; O de Carlos: Hospitais da Universidade de Coimbra, Coimbra, Portugal; O Candeias, B da Costa: Hospital de Sta. Maria, Lisboa; RA Alves Dias dos reis: Hospital de S. Joao, Porto, Portugal; A Alcazar: Hospital Reynaldo dos Santos, Vila Franca de Xira, Portugal; Slovak Republic – S Spanik, I Vochyanova: Onkologicky ustav sv. Alzbety, Bratislava; M Wagnerova, I Andrasina: FNsP L Pasteura, Kosice; South Africa – A Maxwell: Berea; L Goedhals, L Smith: Nationale Hospital, Bloemfontein; I Werner, E Murray: Groote Schuur Hospital, Cape Town; J Apffelstaedt, I Loubser: Tyerberg Hospital, Cape Town, South Africa; D Hacking, Durban Oncology Centre, Westridge, Durban; G Landers: Parklands Hospital, Durban; D Vorobiof: Sandton Oncology Centre, Sandton, Johannesburg; Spain – L Giner: Hospital San Juan de Alicante, Alicante; M Margeli, Barnadas: Hospital Germans Trias i Pujol, Barcelona; C Alonso Muñoz: Hospital Santa Cruz y San Pablo, Barcelona; J Baselga, S Calvo: Hospital Vall D'Hebron, Barcelona; M Beltrán: Hospital Josep Trueta, Gerona; S Menjón: Virgen de las Nieves, Granada; L Calvo: Hospital Juan Canalejo, La Coruña; JR Mel: Hospital Xeral de Logo, Lugo; P España, R Cubedo: Hospital Clinica Puerta de Hierro, Madrid; Pérez Manga: Hospital Gregorio Marañón, Madrid; M Repolles Escarda: Hospital Ramón y Cajal, Madrid; P Aramburo, JE Alés: Hospital Ruber Internacionale, Madrid; JJ Valerdi: Hospital de Navarra, Pamplona; M Constenla, RGa Arroyo: Hospital Mentecelo, Pontevedra; JM Lopez-Vega: Hospital Marques de Vadecilla, Santander; MaD Menéndez: Hospital Provincial Conxo de Santiago, Santiago de Compostela; JA Moreno Nogueira: Hospital Virgen del Rocio, Sevilla; J Montalar: Hospital La Fe, Valencia; V Guillem, A Llombart: Instituto Valenciano de Oncologia, Valencia; G Huidobro Vence, J Casal: Hospital Meixoeiro, Vigo; Sweden – S-Å Olsson, L Ryden: Sjukhuset, Ängelholm; S Rotstein, D Pettersson-Sköld: Danderyds sjukhus, Stockholm; B Börjesson, B Bengt: Länssjukhuset, Halmstad; P-E Jönsson, M Malmberg: Helsingborg Hospital, Helsingborg; L Lovén, I Grybäck: Centralsjukhuset, Kristianstad; C Ingvar, P Lindblom: University Hospital, Lund; S B Holmberg: SU/Mölndal Hospital, Mölndal, Sweden; U Nylén, E Lidbrink: Karolinska sjukhuset, Stockholm; T Fornander, G Winblad: Södersjukhuset, Stockholm; R Fernstad, L Löfgren: St Görans Sjukhus, Stockholm; T Ambré, M Nilsson: Centrallasarettet, Växjö; the Netherlands – L Siegenbeek van Heukelom: Medisch Centrum Alkmaar, Alkmaar; AH Baan, D van Geldere: Ziekenhuis Amstelveen, Amstelveen; F Valster: St Lievensberg Ziekenhuis, Bergen Op Zoom; E Maartense: Reinier de Graaf Gasthuis, Delft; P van der Velden: St het Van Weel-Bethesda Ziekenhuis, Dirksland; G van der Linden: Albert Schweitzer Ziekenhuis, Dordrecht; D Halkema: Albert Schweitzer Ziekenhuis, Dordrecht; C Dijkhuis: Oosterschelde Ziekenhuis, Goes; M van Hennik: Beatrix Ziekenhuis, Gorinchem; P Willemse: Academisch Ziekenhuis Groningen, Groningen; H de Graff: Medisch Centrum Leeuwarden, Leeuwarden; A de Boer: Ljsselland Ziekenhuis, Ljssel; E Bruggink, L Strobbe: Nijmeegs Interconfessioneel, Ziekenhuis Canisius Wilhelmina, Nijmegen; D de Gooyer: Ziekenhuis Franciscus, Roosendaal; van der Gaast: Academisch Ziekenhuis Rotterdam/Dijlzigt, Rotterdam; J Klijn, C Seynaeve: Academisch Ziekenhuis Rotterdam, loc. Daniel den Hoed, Rotterdam; P Wismans: Haven Ziekenhuis, Rotterdam; M Baggen: Ikazia Ziekenhuis Rotterdam, Rotterdam; M Leijs: St Clara Ziekenhuis, Rotterdam; J Braun: Schieland Ziekenhuis Schiedam, Schiedam; F Erdkamp: Maasland Ziekenhuis, Sittard; F Kauw: Albert Schweitzer Ziekenhuis, Sliedrecht; A van Reisen: Ziekenhuis Zeeuws Vlaanderen, loc. de Honte, Terneuzen, The Netherlands; C van der Heul: St Elisabeth Ziekenhuis, Tilburg; J Ruit: Vlietland Ziekenhuis, Vlaardingen; L Kerhofs: Ziekenhuis Walcheren, Vlissingen; R Hellingman: Zweedse Rode Kruis Ziekenhuis, Zierikzee; E Trommel: Albert Schweitzer Ziekenhuis, Zwijndrecht; J Coenen: Isala Klinieken, loc. Sophia, Zwolle; Turkey – E Baltali: Hacettepe University, Oncology Hospital, Ankara; A Aydiner: Istanbul University Oncology Institiute Faculty, Istanbul; UK – A Hutcheon, T Sarkar: Aberdeen Royal Infirmary, Aberdeen; T Bates, N Griffiths: South Kent Hospitals NHS Trust, William Harvey Hospital, Ashford; M Carr: Cheviot & Wansbeck NHS Trust, Wansbeck General Hospital, Ashington; C Alcock: Stoke Mandeville Hospital NHS Trust, Aylesbury; B Lavery, E Sugden: Horton Hospital Radcliffe Hospitals NHS Trust, Banbury; N Stuart, Derek Crawford: Gwynedd Hospital NHS Trust, Bangor; AJ Wilkinson: Belfast City Hospital NHS Trust, Belfast; A Aukland, D Spooner: Sandwell Healthcare NHS Trust, Sandwell District General Hospital, Birmingham; H Bishop, R Salem: The Royal Bolton Hospital, Bolton; T Hickish, A Skene: Royal Bournemouth & Christchurch NHS Trust, Royal Bournemouth Hospital, Bournemouth; C Bradley, Dennis Parker: Bradford Royal Infirmary, Bradford; S Cawthorn, M Shere: Frenchay Healthcare NHS Trust, Frenchay Hospital, Bristol; S Goodman, E Whipp: United Bristol Healthcare NHS Trust, Bristol Royal Infirmary, Bristol; A Moody: West Suffolk Hospital NHS Trust, Bury St Edmunds; C Wilson, E Cox: Addenbrookes's NHS Trust Hospital, Cambridge; R Mansel, H Sweetland: University Hospital of Wales NHS Trust, Cardiff; P Sauven, S Chandrasekharan: Mid Essex Hospital Services NHS Trust, Chelmsford and Essex Centre, Chelmsford; A Neal: St Peters Hospital NHS Trust, Chertsey; P Murray, F MacNeill: Essex Rivers Healthcare NHS Trust, Essex County Hospital, Colchester; J Fox: Castle Hill Hospital, Cottingham; A Ball: Crawley Horsham NHS Trust, Crawley Hospital, Crawley; G Rawsthorne: Mid-Cheshire Hospitals NHS Trust, Leighton Hospital, Crewe; R Burns, R Blunt: Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley; J Dewar, A Thompson: Ninewells Hospital & Medical School, Dundee; W Taylor, A Cook: North Durham NHS Trust, Hospital, Durham; I Kunkler: Western General Hospital, Edinburgh; D Cameron, R Leonard: Western General Hospital, Edinburgh; W Cunliffe, D Browell: Gateshead Hospitals NHS Trust, Queen Elizabeth Hospital, Gateshead; WD George, AN Harnett, CT Twelves: Western Infirmary, Glasgow; DC Smith: Victoria Infirmary, Glasgow; M Kissin: The Royal Surrey County and St Lukes NHS Trust, Royal Surrey County Hospital, Guildford; V Modgill, P Surtees: Halifax Royal Infirmary, Halifax; R Knox, Harrogate District Hospital, Harrogate; J Joffe: Huddersfield Royal Infirmary, Huddersfield; B Lavery, A Harris: Oxford Radcliffe Hospital NHS Trust, John Radcliffe Hospital, Headington, Oxford; S Raymond: St Albans & Hemel Hempstead NHS Trust; B Lavery, N Rowell: South Bucks NHS Trust, Wycombe General Hospital, High Wycombe; J LeVay, T Archer: Ipswich Hospitals NHS Trust, Ipswich; A Nejim, I Hutchinson: Airedale General Hospital, Keighley; M Lansdown, T Perren: St James's University Hospital, Leeds; K Horgan, D Dodwell: Leeds General Infirmary, Leeds; C Holcombe: Royal Liverpool University Hospital NHS Trust, Royal Liverpool Hospital, Liverpool; J Rainey: St Johns Hospital, Howden, Livingston; G Howard: Western General Hospital, Edinburgh; S Holt, Y Sharaiha: Llanelli & Dinefwr NHS Trust, Price Phillip Hospital, Llanelli; J Tobias, M Gaze: UCL Hospitals NHS Trust, The Middlesex Hospital, London; J Mansi, N Sacks: St Georges NHS Trust Hospital, Tooting, London; C Coulter, S Stewart: St Mary's NHS Trust Hospital, London; A Jones, T Davidson: Royal Free Hampstead NHS Trust, The Royal Free Hospital, London; A Jones, A Wilson: Whittington Hospital NHS Trust, London; I Smith, G Gui: The Royal Marsden Hospital NHS Trust, The Royal Marsden Hospital, London; D Matheson: Macclesfield District General Hospital, Macclesfield; A Howell, A Wardley: Christie Hospital, Manchester; L Barr, N Bundred: Withington Hospital, Manchester; Miss P Durning, A Clason: James Cook University Hospital, Middlesborough; R Souter: Milton Keynes General Hospital, Milton Keynes; C Griffith, A Griffiths: Newcastle Hospitals NHS Trust, Royal Victoria Infirmary, Newcastle-upon-Tyne; C Gaffney: Glan Hafren NHS Trust, Royal Gwent Hospital, Newport; M Stokes, Daisy Hill Hospital, Newry; J Dawson, S Powis: Northampton General Hospital NHS Trust, Northampton; I Goulbourne: North Tyneside Health Care NHS Trust, North Tyneside General Hospital, North Shields; A Makris, E Maher: Mount Vernon & Watford Hospitals NHS Trust, Mount Vernon Hospital, Northwood; JR Robertson: Nottingham City Hospital NHS Trust, Nottingham; R Nangalia: George Eliot Hospital NHS Trust, Nuneaton; I McIntosh: Royal Oldham Hospital, Oldham; D Pinto, Sperrin Lakelands: Health & Social Care Trust, Tyrone County Hospital, Omagh; B Lavery, A Jones: Oxford Radcliffe Hospital NHS Trust, The Churchill Hospital, Oxford; R Watkins: Plymouth Hospital NHS Trust, Derriford Hospital, Plymouth; C Tyrrell: Plymouth Hospital NHS Trust, Derriford Hospital, Plymouth; C Yiangou, P Perry: Portsmouth Hospital NHS Trust, Portsmouth; I McIntosh: Birch Hill Hospital, Rochdale; M Quigley: Havering Hospitals NHS Trust, Oldchurch Hospital, Romford; Z Saad, E Hoare: Salford Royal Hospitals NHS Trust, Hope Hospital, Salford; R Coleman, S Kohlhardt: Weston Park Hospital, Sheffield; B Harrison: Northern General Hospital, Sheffield; R Agrawal: Royal Shrewsbury NHS Trust, Shrewsbury; M Galea: Ealing Hospital NHS Trust, Ealing Hospital, Southall; G Fraser: Stirling Royal Infirmary, Stirling; P England: Stepping Hill Hospital, Stockport; C Hennessy, A Peel: North Tees General Hospital, Stockton-on-Tees; AKR Al Debbagh: Trafford General Hospital, Trafford; A Paterson, K Stepp: Royal Cornwall Hospitals NHS Trust, Treliske Hospital, Truro; S Kumar: Pinderfield Hospital, Wakefield; R Grieve, T Waterworth: Walsgrave Hospitals NHS Trust, Walsgrave; G Copeland: Warrington Hospital NHS Trust, Warrington; D Jones: South Warwickshire General Hospitals NHS Trust, Warwick; A Robinson, C Trask: Southend Healthcare NHS Trust Hospital, Westcliffe-on-Sea; P Barrett-Lee: Velindre NHS Trust Hospital, Whitchurch; V Hall: Royal Hampshire County Hospital, Winchester & Eastleigh Healthcare NHS Trust, Winchester; D Berstock, R Errington: Wirral Hospital NHS Trust, Wirral; D Fairlamb: Royal Wolverhampton Hospitals NHS Trust, New Cross Hospital, Wolverhampton; A Salman, A Johri: Worthing Southlands Hospital NHS Trust, Worthing Hospital, Worthing; S Goodman, G Sparrow: East Somerset NHS Trust, Yeovil District Hospital, Yeovil; S Nicholson: York District Hospital, York; USA – SJ Yee, MD: Arcadia, CA; J Feigert, MD: Arlington Fairfax Hemat-Oncology, Arlington, VA; RO Kerr, MD: Southwest Regional Cancer Center, Austin, TX; K Tkaczuk, MD: University of Maryland Cancer Center, Baltimore, MD; M Thant, MD: Maryland Hematology/Oncology Associates, Baltimore, MD; CE Hartz, MD: Eastern Maine Medical Center, Cancer Care of Maine, Bangor, ME; GP Miletello, MD: Baton Rouge General Regional Cancer Center, Baton Rouge, LA; W Popovic, MD: Illinois Oncology Ltd, Belleville, IL; DB Myers, MD: Billings Interhospital Oncology Project, Billings, MT; Thomas, MD: Mid Dakota Clinic, Bismarck, ND; P Radice: Lynn Regional Cancer Center – West, Boca Raton, FL; MS Rubin, MD: Florida Cancer Specialists, Bonita Springs, FL; E Levine, MD: Roswell Park Cancer Institute, Buffalo, NY; CF White, MD: Lahey Clinic, Department of Medical Oncology, Burlington, MA; K Weeman, MD: Aultman Hospital, Clinical Research Cancer Center, Canton, OH; L Schlabach, MD: University Oncology Associates, Chattanooga, TN; M Vohra, MD: Creticos Cancer Center, Chicago, IL; P Silverman, MD: University Hospitals of Cleveland, Ireland Cancer Center, Cleveland, OH; DL Headley DO: Cancer Center of Colorado Springs, CO Springs, CO; MF Gonzalez, MD: Liberty Hematology/Oncology, Columbia, SC; LR Laufman, MD: Community Clinical Oncology Program, Columbus, OH; JL Blum, MD, PhD: Texas Oncology, Dallas, TX; H Shaw, MD: Duke University Medical Center, Durham, NC; H Puc, MD, Hematology & Oncology Associates of CNY, East Syracuse, NY; JM Rothman, MD: The Regional Cancer Center, Erie, PA; GY Locker, MD: Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, IL; N Robert, MD: Fairfax Northern Virginia Hematology–Oncology, Fairfax, VA; GR Justice, MD: Pacific Coast Hematol/Oncol Med Group Inc, Fountain Valley, CA; K Yost, MD: Grand Rapids Clinical Oncology Program, Grand Rapids, MI; AU Buzdar, MD: University of Texas, MD Anderson Cancer Center, Houston, TX; JK Hon, MD, Comprehensive Cancer Care Institute, Huntsville, AL; M Trimble: Hematology/Oncology Associates, Jackson, MI; S Sanal: Florida Oncology Associates, Hematology & Oncology Association, Jacksonville, FL; AM Grossman, MD: Knoxville Cancer Center, Knoxville, TN; HP DeGreen, MD: Lancaster Cancer Center Ltd, Lancaster, PA; NV Dimitrov, MD: Great Lakes Cancer Institute, Breslin Cancer Center, Lansing, MI; HJ Allen, MD: Comprehensive Cancer Center of Nevada, Las Vegas, NV; JD Conroy Jr, DO, FACP, FACOI: Central PA Hematology & Med Oncol Assoc, Lemoyne, PA; K Pendergrass, MD: Kansas City Oncology and Hematology Group, Lenexa, KS; JJ Sternberg, MD: Arkansas Oncology Associates, Little Rock, AR; G Sarna, MD: Cedars Sinai Comprehensive Cancer Center, Los Angeles, CA; L Bhupalam, MD: James Graham Brown Cancer Center, University of Louisville, Louisville, KY; W Bate, MD: Mercy Medical Center – North Iowa, Mercy Cancer Center, Mason City, IA; PV Pickens, MD: Abington Hematology–Oncology Assoc, Meadowbrook, PA; M Schwartz, MD: Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; JP Singson, MD: St. Francis Cancer Care Center, Milwaukee, WI; JG Schneider, MD: Winthrop University Hospital, Oncology/Hematology Division, Mineola, NY; D Schneider, MD: Virginia Piper Cancer Institute, Minneapolis, MN; MW Meshad, MD: Oncology Center-Med Group, Mobile, AL; A Greco, MD: Sarah Cannon Cancer Center, Nashville, TN; MJ Guarino, MD: Cancer Research Office, Newark, DE; KK Boatman, MD: INTEGRIS Oncology Services, OK, OK; PT Silberstein, MD: Creighton University Hematology/Oncology, Omaha, NE; AS Kelley, MD, Ventura County Hematology–Oncology Specialists, Oxnard, CA; E Camacho, MD: Comprehensive Cancer Centers at the Desert Regional Med Ctr., Palm Springs, CA;R Hirsch, MD: South Florida Hematology/Oncology, Pembroke Pines, FL; MS Roberts, MD: Hematology Associates Ltd, Phoenix, AZ; JI Spector, MD: Berkshire Hematology Oncology, PC, Pittsfield, MA; N Tirumali, MD: Central Interstate Medical Office, Portland, OR; MA Deutsch, MD: Raleigh Hematology Oncology Assoc, Raleigh, NC; P Bushunow, MD: Rochester General Hospital, Rochester, NY; T Woodlock, MD: St. Mary's Hospital/Unity Health System, Rochester, NY; DM Sahasrabudhe, MD: University of Rochester Cancer Center, Rochester, NY; WR Edwards, MD: ACT Medical Group, Rockford, IL; I Jaiyesimi, DO: Cancer Clinical Trials Office, Royal Oak, MI; F Kass, MD: Cancer Center of Santa Barbara, Santa Barbara, CA; W Keiser, MD: Redwood Regional Medical Group, Santa Rosa, CA; G Burton, MD: Louisiana State University Medical Center, Shreveport, LA; JC Michalak, MD: Siouxland Hematology/Oncology Associates, Sioux City, IA; MS McHale, MD: North Central Hematology/Oncology, Sioux Falls, SD; JR Goodman, MD: Providence Hospital, Southfield, MI; PD Byeff, MD: Hematology/Oncology, Southington, CT; K Hoelzer, MD: Regional Cancer Center, Springfield, IL; EP Lester, MD: Oncology Care Associates, St Joseph, MI; M Woodson, MD: Hematology Oncology Consultants, St Louis, MO; AP Lyss, MD: Missouri Baptist Cancer Center, St Louis, MO; F Senecal, MD, Hematology Oncology Northwest, Tacoma, WA; J Horton, MB ChB: Moffitt Cancer Center & Research Institute, Tampa, FL; J Posada, MD: Scott & White Clinic, Temple, TX; IS Lowenthal, MD: Northwestern Connecticut Oncology & Hematology Associates, Torrington, CT; AN Dave, MD: Cancer Treatment Centers of America at Southwestern Regional Medical Center, Tulsa, OK; G Grana, MD: Cooper Cancer Institute, Voorhees, NJ; E Gelmann, MD: Georgetown University Medical Center, Vincent T. Lombardi Cancer Research Center, Washington, DC; M Vukelich, MD: West Bend, WI; K Seetharaman, MD: Worcester Medical Center, Worcester, MA)
The 33-month median follow-up of the ATAC (anastrozole and tamoxifen, alone or in combination) trial showed a potential interaction between anastrozole and previous chemotherapy; however, this was much smaller at 47 months' median follow-up. When the effects of different chemotherapy regimens were evaluated at that time, the apparent interaction was limited to patients who had received cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).
In this retrospective analysis of 68-month data, we investigated the impact of prior chemotherapy, including different chemotherapy regimens, on time to recurrence. The chemotherapy regimens were 1) CMF only; 2) anthracycline-containing regimens (anthracycline or anthracycline and CMF); and 3) other chemotherapy regimens, including taxane-containing combinations.
No evidence was found for an interaction between prior chemotherapy and anastrozole (hazard ratio [HR] 0.89 vs. 0.74 for those with or without prior chemotherapy, respectively; P = .21 for interaction). For those with prior chemotherapy, the HR of anastrozole when compared with that of tamoxifen shifted from 0.98 (95% confidence intervals [CI], 0.76–1.28) at 47 months' median follow-up to 0.89 (95% CI, 0.71–1.12) at 68 months' median follow-up and was closer to the overall treatment effect (HR, 0.79; 95% CI, 0.70–0.90). No differences according to type of chemotherapy were seen, and a benefit for anastrozole was also now apparent for patients receiving prior CMF (HR, 0.89; 95% CI, 0.63–1.24).
Endocrine therapy and chemotherapy are the 2 major forms of adjuvant treatment for women with breast cancer. Until recently, 5 years of tamoxifen therapy has been the established standard of care for the adjuvant treatment of postmenopausal women with hormone-receptor–positive early breast cancer. However, aromatase inhibitors are being increasingly recommended in this setting.1 Adjuvant chemotherapy now plays a significant role in reducing the risk of recurrence and death, both in pre- and postmenopausal women with early stage breast cancer.2
The decision to recommend adjuvant endocrine therapy is primarily based on the presence of hormone receptors, whereas chemotherapy can be used in patients regardless of nodal or hormone-receptor status. However, each individual patient has to consider the additional side effects associated with cytotoxic chemotherapy regimens. The most commonly used adjuvant chemotherapy regimens for pre- and postmenopausal women with either node-positive or node-negative disease are cyclophosphamide, methotrexate, and 5-fluoruracil (CMF), and anthracycline-based regimens, which include doxorubicin and cyclophosphamide (AC); 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC); 5-fluorouracil, epirubicin, and cyclophosphamide (FEC); anthracycline and paclitaxel; and doxorubicin, followed by CMF. Anthracycline-based regimens such as those containing doxorubicin or epirubicin result in a statistically significant improvement in survival when compared with nonanthracycline-based regimens.2 The taxanes docetaxel and paclitaxel have proven efficacy in metastatic breast cancer3 and are effective in further reducing the risk of recurrence in the adjuvant setting. Adjuvant chemotherapy and endocrine treatment can also be used sequentially for hormone receptor–positive patients.
Third-generation aromatase inhibitors such as anastrozole (Arimidex) strongly challenge tamoxifen as the standard endocrine therapy for postmenopausal women with hormone receptor–positive breast cancer. At 68 months' median follow-up, the Completed Treatment Analysis of the ATAC (anastrozole and tamoxifen, alone or in combination) trial reinforces previous analyses4, 5 and demonstrates that anastrozole provides additional efficacy and tolerability benefits over and above those offered by tamoxifen.6 Notably, in terms of disease-free survival and time to recurrence, the absolute benefit of anastrozole over tamoxifen increased over time, with absolute differences increasing out to 6 years, beyond completion of the 5-year treatment period.
At a median follow-up of 33 months, an exploratory subgroup analysis revealed a potential difference in treatment outcome between patients who had received prior chemotherapy and those who had not.4 This difference was not apparent at 47 months' median follow-up.5 When the effects of different chemotherapy regimens were retrospectively evaluated, an apparent interaction was limited to patients who had received CMF.
We present results of a retrospective, exploratory analysis of data from the ATAC trial, investigating the impact of prior chemotherapy, including different chemotherapy regimens, on time to recurrence, at a median follow-up of 68 months.
MATERIALS AND METHODS
The ATAC trial is a large, multinational, randomized, double-blind, long-term study evaluating the efficacy and tolerability of anastrozole and tamoxifen, both alone and in combination, for the adjuvant treatment of postmenopausal women with histologically proven, operable, invasive breast cancer who had previously completed primary therapy and chemotherapy (where administered) (Fig. 1). Full details of the trial design, methodology, primary objectives, and endpoints are provided in the report on the initial efficacy analysis performed at a median follow-up of 33 months.4 Since combination therapy demonstrated no efficacy or tolerability benefit when compared with tamoxifen, this treatment arm was discontinued following this analysis.5
Exploratory Analysis of the Impact of Chemotherapy Regimens on Time to Recurrence
In this retrospective exploratory analysis, data forthe 2 monotherapy arms from the Completed Treatment Analysis at a median follow-up of 68 months were used to assess the effect of adjuvant chemotherapy regimens prior to starting endocrine therapy on the relative efficacy of anastrozole and tamoxifen in terms of time to recurrence. The chemotherapy regimens were divided into 3 subgroups: 1) CMF only; 2) anthracycline-containing regimens (anthracycline or anthracycline and CMF); and 3) other chemotherapy regimens, including taxane-containing combinations. The impact of chemotherapy regimens on time to recurrence was determined by retrospective analysis and expressed as a hazard ratio (HR), with associated 95% confidence interval (CI), obtained from a log rank test. To adjust for the potential impact of chemotherapy type on the overall trial results, a Cox proportional hazards model with terms for treatment and chemotherapy type (none, CMF only, anthracycline-containing, or other) was also considered.
Of a total of 9366 postmenopausal women in the study, 6241 were randomized to either anastrozole or tamoxifen monotherapy. Baseline characteristics and primary treatment received were well balanced between these treatment arms (Table 1). A total of 1345 (21.6%) of these patients had received prior chemotherapy, which consisted of CMF therapy, anthracycline-containing regimens, and/or other chemotherapy regimens, including taxane-containing combinations (Fig. 2). The 3 subgroups were well balanced with respect to age and hormone-receptor status (Table 2).
Table 1. Baseline Characteristics of Patients and Primary Treatment According to Allocated Hormone Therapy
Anastrozole (n = 3125)
Tamoxifen (n = 3116)
HRT indicates hormone replacement therapy; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil.
Time to Recurrence in Chemotherapy Regimen Subgroups
At 68 months' median follow-up, the previously reported potential treatment interaction between patients who had received prior chemotherapy and those who had not was no longer apparent (HR, 0.89 vs. 0.74 for those with or without prior chemotherapy, respectively; P = 0.21 for interaction) (Fig. 3). Although the upper CI crosses 1.00 in the subgroup of patients receiving prior adjuvant chemotherapy, this may not be interpreted as lack of treatment effect7 and the benefits of anastrozole in these patients did not differ significantly from those in the overall population, as demonstrated by an interaction test.
Consistent with the 47-month exploratory analysis, a longer time to recurrence was maintained for anastrozole than for tamoxifen in the anthracycline-containing (HR, 0.92; 95% CI, 0.60–1.40) and taxane-containing (HR, 0.85; 95% CI, 0.52–1.38) subgroups. This is now evident for the CMF subgroup (HR, 0.89; 95% CI, 0.63–1.24) (Table 3) (Fig. 4). Adjusting for chemotherapy type had almost no effect on the time to recurrence analysis in the intent-to-treat population (unadjusted HR, 0.79; 95% CI, 0.70–0.90 vs. adjusted HR, 0.79; 95% CI, 0.69–0.90) (Table 3) (Fig. 4).
Table 3. Effect of Prior Chemotherapy Regimen on Hazard Ratios for Time to Recurrence (Intent-to-Treat Population)
Trends similar to those reported in the overall population were observed in the hormone-receptor–positive patient population: CMF (n = 470; HR, 0.95; 95% CI, 0.63–1.44), anthracycline-containing (n = 401; HR, 1.10; 95% CI, 0.67–1.80), and other, including taxane-containing (n = 208; HR, 0.81; 95% CI, 0.46–1.40).
In the initial efficacy analysis of the ATAC trial, at a median follow-up of 33 months, a potential treatment interaction with chemotherapy was reported.4 However, at a median follow-up of 47 months, this potential interaction was much weaker, with the HR now indicating a marginal benefit in the anastrozole arm (HR, 0.98; 95% CI, 0.76–1.28).5 Findings from the Completed Treatment Analysis show that the benefit in the prior chemotherapy group (HR, 0.89; 95% CI, 0.71–1.12) is now similar to that observed in the overall population (HR, 0.79; 95% CI, 0.70–0.90). In addition, the possible interaction with CMF treatment is no longer apparent. Although the CI still crosses the no-effect point (1.00) in the subgroup of patients receiving prior adjuvant chemotherapy, this is likely to be a result of the comparatively few events in this subgroup, which makes the confidence limits wide.8
Subgroup analysis is fraught with statistical difficulties and has led to a substantial amount of misinterpretation of clinical data.7, 8 Early analysis of subgroups, when there is likely to be fewer events, is inappropriate. An effect may be attributed to a subgroup when there is no overall effect and no evidence for heterogeneity. Furthermore, a lack of effect may be claimed in a subgroup when the overall effect is significant. Unless a difference in subgroups has already been established in previous studies (such as a lack of response to hormone treatment in estrogen-receptor (ER)–negative women), subgroup analysis should concentrate on differences from the average overall treatment effect via tests of heterogeneity or interaction.9 In a retrospective analysis of data from the ATAC trial, node positivity (in particular 4 or more nodes), tumor size ≥2 cm, poorly differentiated tumors, ER-negative receptor status, and use of mastectomy predicted for receiving adjuvant chemotherapy. Notably, nationality was found to be a statistically significant independent predictor for the use of adjuvant chemotherapy.10
Anthracycline-containing combination regimens are considered standard adjuvant chemotherapy for breast cancer after a metaanalysis by the Early Breast Cancer Trialists' Collaborative Group showed that anthracycline-containing regimens are superior in efficacy to CMF.2 Taxane-containing regimens also show promise as adjuvant treatment of early breast cancer. Completion of ongoing large clinical trials and mature data are required to define their future role.11 Taxane–anthracycline combinations are also under investigation.
Overall, data for the ATAC trial at 68 months' median follow-up demonstrate that anastrozole maintains superiority over tamoxifen for the treatment of postmenopausal women with early breast cancer. At 68 months' median follow-up, the benefits of anastrozole are observed regardless of whether or not the patient has received prior chemotherapy and of the chemotherapy regimen used.
First and foremost, we thank all the patients for their participation in the trial. We also thank the trial investigators, nurses, data managers, pharmacists, and other support staff at the local sites; the monitors and data management staff of AstraZeneca and the various collaborative groups; the members of the International Steering Committee, the Independent Data Monitoring Committee, and the International Project Team. We also thank Mark Walker, PhD, from Complete Medical Communications, for providing medical writing support.