Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.
Regan MM,
Neven P,
Giobbie-Hurder A,
Goldhirsch A,
Ejlertsen B,
Mauriac L,
Forbes JF,
Smith I,
Láng I,
Wardley A,
Rabaglio M,
Price KN,
Gelber RD,
Coates AS,
Thürlimann B;
BIG 1-98 Collaborative Group;
International Breast Cancer Study Group (IBCSG).
Thürlimann B, Aebi S, Blacher L, Bonnefoi H, Coates AS, Cufer T, Ejlertsen B, Forbes JF, Gelber RD, Giobbie-Hurder A, Goldhirsch A, Hiltbrunner A, Holmberg SB, Maibach R, Martoni A, Mauriac L, MacGrogan G, Mouridsen HT, Paridaens R, Phuong D, Price KN, Rabaglio M, Rasmussen BB, Regan MM, Santoro A, Smith IE, Wardley A, Viale G, Chaudri-Ross HA, Segal S, Aebi S, Coates AS, Colleoni M, Collins JP, Cortés Funes H, Gelber RD, Goldhirsch A, Green M, Hiltbrunner A, Holmberg SB, Karlsson P, Kössler I, Láng I, Lindtner J, Paganetti F, de Stoppani M, Rudenstam CM, Senn HJ, Stahel R, Thürlimann B, Veronesi A, Castiglione M, Hiltbrunner A, Rabaglio M, Egli G, Hawle H, Cliffe B, Ribeli-Hofmann S, Munarini F, Kammler R, Studer R, Ruepp B, Maibach R, Munarini N, Gelber RD, Regan MM, Price KN, Giobbie-Hurder A, Keshaviah A, Litman H, Cole BF, Sun Z, Gray PK, Huang H, Somos LJ, Timmers B, Nickerson L, Blacher L, Heckman Scolese T, Belisle M, Caporale M, Celano J, Dalfonso L, Dooley L, Fischer S, Galloway K, Gould J, Hinkle R, Holody M, Jones G, Krall R, Lippert S, Meshulam J, Mundy L, Pavlov-Shapiro A, Scott K, Scott M, Shepard S, Swick J, Uhteg L, Weinbaum D, Westby C, Zielinski T, Gusterson BA, Mallon E, Viale G, Dell'Orto P, Mastropasqua M, Del Curto B, Waldie E, van Hoomissen I, De Smet M, Trostmann U, Schmidt W, Bolton A, Hackl W, Snyder RD, Chirgwin J, Forbes JF, Coates AS, Boyle F, Lindsay D, Preece D, Cowell J, Talbot D, Whipp A, Abell F, Basser R, Bell R, Brady B, Blakey D, Briggs P, Burns I, Campbell P, Chao M, Chirgwin J, Chua B, Clarke K, Collins J, De Boer R, Din JC, Doig R, Dowling A, Drummond R, Efe N, Fan ST, Francis M, Francis P, Ganju V, Gibbs P, Goss G, Green M, Gregory P, Griffiths J, Haines I, Henderson M, Holmes R, James P, Kiffler J, Lehman M, Leyden M, Lim L, Lindeman G, Lynch R, Mann B, McKendrick J, McLachlan S, McLennan R, Mitchell G, Mitra S, Murphy C, Parker I, Phillips K, Porter I, Richardson G, Scarlet J, Sewak S, Shapiro J, Snyder R, Stanley R, Steer C, Stoney D, Strickland A, Toner G, Underhill C, White K, White M, Wirth A, Wong S, Holman Clinic WP, Byram D, Byard I, Della-Fiorentina S, Goldrick A, Hovey E, Moylan E, Segelov E, Chan A, Buck M, Hastrich D, Ingram D, Van Hazel G, Willsher P, Wilcken N, Crombie C, Forbes JF, Abell F, Ackland S, Bonaventura A, Cox S, Denham J, Gourlay R, Jackson D, Sillar R, Stewart J, Lewis C, Brigham B, Goldstein D, Friedlander M, Walpole E, Thompson D, Gill PG, Bochner M, Coventry J, Kollias J, Malycha P, Olver I, Colosimo M, Cheuk R, Kenny L, McCarthy N, Wyld D, Young R, Harrup R, Kimber R, Lowenthal R, Trotter J, Bayliss E, Chan A, Ransom D, Byrne M, Buck M, Dewar J, Nowak A, Powell A, Van Hazel G, Abdi EA, Brodribb R, Volobueva Z, Harnett P, Ahern V, Gurney H, Wilcken N, Harvey VJ, Evans B, Jones W, McCrystal M, Porter D, Thompson P, Vaughan M, Gibbs D, Atkinson C, Burcombe R, Fitzharris B, Hickey B, Jeffery M, Robinson B, McLaren B, Costello S, North J, Perez D, Campbell ID, Gilbert L, Gannaway R, Jameson M, Kennedy I, Long J, Round G, Spellman L, Whittle D, Woolerton D, Menke C, Biazús J, Cericatto R, Cavalheiro J, Xavier N, Bittelbrunn A, Rabin E, Gutiérrez J, Arriagada R, Bronfman L, Zuñiga M, Gutiérrez J, Acevedo JC, Torres S, León A, Salazar E, Soto Diaz L, Duval R, Oddeshede N, Venti MC, Peña K, Puente L, Maidana V, Baeza R, Arriagada R, Olfos P, Solé J, Vinés E, Mariani C, Láng I, Hitre E, Szabó E, Horváth Z, Ganofszky E, Juhos E, Veronesi A, Crivellari D, Magri MD, Buonadonna A, Coran F, Borsatti E, Candiani E, Massarut S, Roncadin M, Arcicasa M, Carbone A, Perin T, Gloghini A, Tondini C, Labianca R, Poletti P, Bettini A, Clerico M, Vincenti M, Malossi A, Seles E, Perfetti E, Sartorello B, Simoncini E, Marini G, Marpicati P, Farfaglia R, Bianchi AM, Grigolato P, Lucini L, Frata P, Huscher A, Micheletti E, Fogazzi C, Medicina UO, Artioli F, Cagossi K, Scaltriti L, Bandieri E, Botticelli L, Giovanardi G, Ravaioli A, Pasquini E, Rudnas B, Foghin L, Manzoni A, Visini M, Zavallone L, Ucci G, Colleoni M, Viale G, Veronesi P, Peruzzotti G, Corsetto L, Ghisini R, Renne G, Luini A, Orlando L, Torrisi R, Rocca A, De Pas T, Munzone E, Galimberti V, Zurrida S, Intra M, Nolé F, Orecchia R, Martinelli G, de Braud F, Goldhirsch A, Ravaioli A, Gianni L, Gome H, Cufer T, Pajk B, Cervek J, Werner ID, Murray E, Govender D, Dalvie S, Erasmus T, Robertson B, Read B, Nel E, Toop J, Nedeva N, Panieri E, Vorobiof D, Chasen M, McMichael G, Mohammed C, Holmberg SB, Holmberg SB, Mattsson J, Sellström H, Lindberg B, Goldhirsch A, Herrmann R, Thürlimann B, Schönenberger A, Mingrone W, Honegger Ch, Bärtschi E, Neter M, Rederer M, Schär G, Rochlitz C, Herrmann R, Oertli D, Wight E, Moch H, Bernier J, Bronz L, Cavalli F, Gallerani E, Richetti A, Franzetti A, Conti-Beltraminelli M, Ghielmini M, Gyr T, Mauri S, Saletti PC, Goldhirsch A, Pagani O, Graffeo R, Locatelli M, Longhi S, Rey PC, Ruggeri M, Zucca E, Wyss D, Mazzucchelli L, Pedrinis E, Rusca T, Aebi S, Fey MF, Castiglione M, Rabaglio M, Aebi S, Fey MF, Zuber M, Beck G, Aebi S, Fey MF, Schönenberger R, Lüthi JM, Rauch D, Bonnefoi H, Egli F, Steiner R, Fehr P, Perey L, de Grandi P, Jeanneret W, Leyvraz S, Delaloye JF, Thürlimann B, Köberle D, Weisser F, Mattemann S, Müller A, Cerny T, Späti B, Höfliger M, Fürstenberger G, Bolliger B, Öhlschlegel C, Lorenz U, Bamert M, Kehl-Blank J, Vogel E, Thürlimann B, Hess D, Senn I, Köberle D, Ehrsam A, Nauer C, Öhlschlegel C, Kehl-Blank J, Vogel E, Widmer L, Häfner M, Pestalozzi BC, Fehr M, Caduff R, Varga Z, Trüb R, Fink D, Bättig BA, Buser K, Bürki N, Dieterle A, Hasler L, Mannhart-Harms M, Rageth C, Richner J, Spataro V, Umbricht M, Ellis P, Harris S, Akbar N, McVicars H, Lees C, Raman R, Crane G, Ejlertsen B, Mouridsen HT, Mouridsen HT, Jakobsen E, Cold S, Kamby C, Ewertz M, Vestlev PM, Andersen J, Grundtvig P, Sandberg E, Philip P, Madsen EL, Moeller KA, Haahr V, Johansson J, Mauriac L, Debled M, Bonnefoi H, Campo P, Larregain-Fournier D, Remy S, Auvray H, De Gislain C, Delille F, Porteret MC, Servent V, Chapoutier M, Tubiana-Mathieu N, Lavau-Denes S, Bosc P, Guastalla JP, Bachelot T, Arbault C, Netter-Pinon G, Perrin V, Monnier A, Hammoud Y, Romieu G, Culine L, Pinosa V, Cany L, Maguire C, Daban A, Le Saux M, Grandon C, Kerbrat P, Catheline C, Veyret C, Jugieau E, Talon V, Le Mevel A, Maury S, Gladieff L, Lignon N, Dodwell D, Dodwell D, Joffe J, Drew P, Yorkshire W, Nejim A, Dodwell D, Horgan K, Lansdown M, Perren T, Coleman RE, Campos D, Cóppola F, Martinez J, Freue M, Wainstein C, Zori Comba A, Cazap E, Roffo AH, Mickiewicz E, Mendez A, Balbiani L, Osuna A, Palazzo E, de Romedis M, Cagnolati S, Delfino CA, Caccia G, de Angelis RL, Fein L, Sala R, Nassurdi C, Berra AC, Viroglio R, Blajman C, Requejo H, Silberman L, Birrell S, Eaton M, Hoffman C, Humeniuk V, Craft P, Stuart-Harris R, Yip D, Bell R, Abell F, Francis M, Kiffer J, Lynch R, McLennan R, White K, Green M, Basser R, Collins J, De Boer R, Din JC, Efe N, Fan ST, Lindeman G, Wong S, Green M, Basser R, Collins J, De Boer R, Din JC, Efe N, Fan ST, Lindeman G, Wong S, Stewart J, Abell F, Ackland S, Bonaventura A, Trotter J, Bayliss E, Chan A, Ransom D, Redfern A, de Souza P, Links M, Dalley D, Grygiel J, Ward R, Underhill C, Clarke K, Steer C, Walpole E, Thompson D, Nogaret JM, Christiaens MR, Neven P, Paridaens R, Smeets A, Vergote I, Weltens C, Wildiers H, Focan C, Marcelis L, Etterbeek CH, Kains JP, Canon JL, André Vèsale CH, Brohèe D, Gowing J, Yelle L, Dubé P, Vogel C, León Prieto M, Petrakova K, Palacova M, Demlova R, Siffnerova H, Fischer J, Bustova I, Kankova H, Pintova M, Vitek P, Abrahamova J, Kordikova D, Petruzelka L, Sedlackova E, Honova H, Heinrich B, Wischnik A, Oberhoff C, Schindler AE, Münstedt K, Meyer D, Grosse R, Kölbl H, Schmidt W, Mink D, Jänicke F, Lück HJ, Dornoff W, Hoffmann G, Hackmann J, Bader W, Kahan Z, Pajkos G, Kristo K, Dank M, Nagykalnai T, Landherr L, Kner E, Kispál M, Dani Á, Martoni A, Zamagni C, Giaquinta S, Piana E, Mattioli R, Imperatori L, Santoro A, Carnaghi C, Rimassa L, Gasparini G, Sciarretta G, Morabito A, Barni S, Cazzaniga M, Cabiddu M, Puglisi F, Cellerino R, Antognoli S, Freddari F, Mantovani G, Massa E, Astara G, Segati R, Rosso R, Del Mastro L, Venturini M, Bighin C, Bajetta E, Zilembo N, Paleari D, Procopio G, Salvagni S, Perrone MA, Franciosi V, Salvatore S, Catalano G, Luzi Fedeli S, Pinotti G, Giardina G, Vallini I, Massidda B, Ionta MT, Deidda MC, Nalli G, Sita G, Carreca I, Cucciarré S, Burgio D, Lombardo M, Pandoli G, Di Stefano P, Boni C, Bisagni G, Banzi MC, Linarello P, Colosini G, Spasiano A, Caldonazzo A, Pacquola MG, Sleeboom HP, Rutten HJ, Luiten EJ, Roerdink HT, Roumen RH, McLaren B, Costello S, North J, Perez D, Pfieffer M, Kennedy I, Campbell ID, Gilbert L, Gannaway R, Jameson M, Long J, Round G, Spellman L, Whittle D, Woolerton D, Jassem J, Welnicka-Jaskiewicz M, Senkus-Konefka E, Matuszewska K, Koralewski P, Pernal J, Pienkowski T, Brewczynska E, Bauer-Kosinska B, Sienkiewicz-Kozlowska R, Jagiello-Gruszfeld A, Sudol K, Tujakowski J, Zurawski B, Pawlega J, Jablonska E, Zygulska A, Górnasiowa M, Filypczyk-Cisarz E, Pajak K, Damasceno M, Albano JQ, da Costa B, Costa L, Henriques A, Amaral H, Marques F, Komov DV, Polikarpova SB, Makhson AN, Zabaznyi NV, Vozny EK, Dobrovolskaya NY, Bolshakova S, Yurgina OV, Emmanuel NM, Korman DB, Maslova IA, Petrov NN, Semiglazov V, Ivanov V, Manikhas G, Dolmatov G, Apffelstaedt J, Eedes D, Slabber C, Coccia MA, Maart K, Alés Martinez JE, Aramburo P, Sánchez R, Rifa J, Martin J, Pérez-Carrión R, González Larriba JL, Cubillo A, Jiménez MM, Casado A, Fra J, Vieitez JM, Esteban E, Lacave AJ, Wight E, Bartens S, Decio R, Güth U, Breitenstein U, Icli F, Dincol D, Baltali E, Ozisik Y, Topuz E, Basaran M, Aydiner A, Ozdedeli E, Harmancioglu O, Yilmaz AU, Smith IE, Thompson AM, Wardley A, Hickish T, Neave F, Sabini G.
Source
International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. mregan@jimmy.harvard.edu
Abstract
BACKGROUND:
Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up.
METHODS:
BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205.
FINDINGS:
8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI.
INTERPRETATION:
For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability.
FUNDING:
Novartis, United States National Cancer Institute, International Breast Cancer Study Group.
Copyright © 2011 Elsevier Ltd. All rights reserved.
- PMID:
- 22018631
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3235950
- [Available on 2012/9/1]
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