Lancet. 2011 Aug 27;378(9793):771-84. Epub 2011 Jul 28.

Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R.

Collaborators (693)

Albain K, Anderson S, Arriagada R, Barlow W, Bergh J, Bliss J, Buyse M, Cameron D, Carrasco E, Clarke M, Correa C, Coates A, Collins R, Costantino J, Cutter D, Cuzick J, Darby S, Davidson N, Davies C, Davies K, Delmestri A, Di Leo A, Dowsett M, Elphinstone P, Evans V, Ewertz M, Gelber R, Gettins L, Geyer C, Goldhirsch A, Godwin J, Gray R, Gregory C, Hayes D, Hill C, Ingle J, Jakesz R, James S, Kaufmann M, Kerr A, MacKinnon E, McGale P, McHugh T, Norton L, Ohashi Y, Paik S, Pan HC, Perez E, Peto R, Piccart M, Pierce L, Pruneri G, Pritchard K, Raina V, Ravdin P, Robertson J, Rutgers E, Shao YF, Swain S, Taylor C, Valagussa P, Viale G, Whelan T, Winer E, Wang Y, Wood W, Abe O, Abe R, Enomoto K, Kikuchi K, Koyama H, Masuda H, Nomura Y, Ohashi Y, Sakai K, Sugimachi K, Toi M, Tominaga T, Uchino J, Yoshida M, Haybittle JL, Leonard CF, Calais G, Geraud P, Collett V, Davies C, Delmestri A, Sayer J, Harvey VJ, Holdaway IM, Kay RG, Mason BH, Forbes JF, Wilcken N, Bartsch R, Dubsky P, Fesl C, Fohler H, Gnant M, Greil R, Jakesz R, Lang A, Luschin-Ebengreuth G, Marth C, Mlineritsch B, Samonigg H, Singer CF, Steger GG, Stöger H, Canney P, Yosef HM, Focan C, Peek U, Oates GD, Powell J, Durand M, Mauriac L, Di Leo A, Dolci S, Larsimont D, Nogaret JM, Philippson C, Piccart MJ, Masood MB, Parker D, Price JJ, Lindsay MA, Mackey J, Martin M, Hupperets PS, Bates T, Blamey RW, Chetty U, Ellis IO, Mallon E, Morgan DA, Patnick J, Pinder S, Olivotto I, Ragaz J, Berry D, Broadwater G, Cirrincione C, Muss H, Norton L, Weiss RB, Abu-Zahra HT, Portnoj SM, Bowden S, Brookes C, Dunn J, Fernando I, Lee M, Poole C, Rea D, Spooner D, Barrett-Lee PJ, Mansel RE, Monypenny IJ, Gordon NH, Davis HL, Cuzick J, Lehingue Y, Romestaing P, Dubois JB, Delozier T, Griffon B, Mace Lesec'h J, Rambert P, Mustacchi G, Petruzelka L, Pribylova O, Owen JR, Harbeck N, Jänicke F, Meisner C, Schmitt M, Thomssen C, Meier P, Shan Y, Shao YF, Wang X, Zhao DB, Chen ZM, Pan HC, Howell A, Swindell R, Burrett JA, Clarke M, Collins R, Correa C, Cutter D, Darby S, Davies C, Davies K, Delmestri A, Elphinstone P, Evans V, Gettins L, Godwin J, Gray R, Gregory C, Hermans D, Hicks C, James S, Kerr A, MacKinnon E, Lay M, McGale P, McHugh T, Peto R, Sayer J, Taylor C, Wang Y, Albano J, de Oliveira CF, Gervásio H, Gordilho J, Johansen H, Mouridsen HT, Gelman RS, Harris JR, Hayes D, Henderson C, Shapiro CL, Winer E, Christiansen P, Ejlertsen B, Ewertz M, Jensen MB, Møller S, Mouridsen HT, Carstensen B, Palshof T, Trampisch HJ, Dalesio O, de Vries EG, Rodenhuis S, van Tinteren H, Comis RL, Davidson NE, Gray R, Robert N, Sledge G, Solin LJ, Sparano JA, Tormey DC, Wood W, Cameron D, Chetty U, Dixon JM, Forrest P, Jack W, Kunkler I, Rossbach J, Klijn JG, Treurniet-Donker AD, van Putten WL, Rotmensz N, Veronesi U, Viale G, Bartelink H, Bijker N, Bogaerts J, Cardoso F, Cufer T, Julien JP, Rutgers E, van de Velde CJ, Cunningham MP, Huovinen R, Joensuu H, Costa A, Tinterri C, Bonadonna G, Gianni L, Valagussa P, Goldstein LJ, Bonneterre J, Fargeot P, Fumoleau P, Kerbrat P, Luporsi E, Namer M, Eiermann W, Hilfrich J, Jonat W, Kaufmann M, Kreienberg R, Schumacher M, Bastert G, Rauschecker H, Sauer R, Sauerbrei W, Schauer A, Schumacher M, Blohmer JU, Costa SD, Eidtmann H, Gerber B, Jackisch C, Loibl S, von Minckwitz G, de Schryver A, Vakaet L, Belfiglio M, Nicolucci A, Pellegrini F, Pirozzoli MC, Sacco M, Valentini M, McArdle CS, Smith DC, Stallard S, Dent DM, Gudgeon CA, Hacking A, Murray E, Panieri E, Werner ID, Carrasco E, Martin M, Segui MA, Galligioni E, Lopez M, Erazo A, Medina JY, Horiguchi J, Takei H, Fentiman IS, Hayward JL, Rubens RD, Skilton D, Scheurlen H, Kaufmann M, Sohn HC, Untch M, Dafni U, Markopoulos C, Dafni U, Fountzilas G, Mavroudis D, Klefstrom P, Blomqvist C, Saarto T, Gallen M, Margreiter R, de Lafontan B, Mihura J, Roché H, Asselain B, Salmon RJ, Vilcoq JR, Arriagada R, Bourgier C, Hill C, Koscielny S, Laplanche A, Lê MG, Spielmann M, A'Hern R, Bliss J, Ellis P, Kilburn L, Yarnold JR, Benraadt J, Kooi M, van de Velde AO, van Dongen JA, Vermorken JB, Castiglione M, Coates A, Colleoni M, Collins J, Forbes J, Gelber RD, Goldhirsch A, Lindtner J, Price KN, Regan MM, Rudenstam CM, Senn HJ, Thuerlimann B, Bliss JM, Chilvers CE, Coombes RC, Hall E, Marty M, Buyse M, Possinger K, Schmid P, Untch M, Wallwiener D, Foster L, George WD, Stewart HJ, Stroner P, Borovik R, Hayat H, Inbar MJ, Robinson E, Bruzzi P, Del Mastro L, Pronzato P, Sertoli MR, Venturini M, Camerini T, De Palo G, Di Mauro MG, Formelli F, Valagussa P, Amadori D, Martoni A, Pannuti F, Camisa R, Cocconi G, Colozza A, Passalacqua R, Aogi K, Takashima S, Abe O, Ikeda T, Inokuchi K, Kikuchi K, Sawa K, Sonoo H, Korzeniowski S, Skolyszewski J, Ogawa M, Yamashita J, Bastiaannet E, van de Velde CJ, van de Water W, van Nes JG, Christiaens R, Neven P, Paridaens R, Van den Bogaert W, Braun S, Janni W, Martin P, Romain S, Janauer M, Seifert M, Sevelda P, Zielinski CC, Hakes T, Hudis CA, Norton L, Wittes R, Giokas G, Kondylis D, Lissaios B, de la Huerta R, Sainz MG, Altemus R, Camphausen K, Cowan K, Danforth D, Lichter A, Lippman M, O'Shaughnessy J, Pierce LJ, Steinberg S, Venzon D, Zujewski JA, D'Amico C, Lioce M, Paradiso A, Chapman JA, Gelmon K, Goss PE, Levine MN, Meyer R, Parulekar W, Pater JL, Pritchard KI, Shepherd LE, Tu D, Whelan T, Nomura Y, Ohno S, Anderson S, Bass G, Brown A, Bryant J, Costantino J, Dignam J, Fisher B, Geyer C, Mamounas EP, Paik S, Redmond C, Swain S, Wickerham L, Wolmark N, Baum M, Jackson IM, Palmer MK, Perez E, Ingle JN, Suman VJ, Bengtsson NO, Emdin S, Jonsson H, Del Mastro L, Venturini M, Lythgoe JP, Swindell R, Kissin M, Erikstein B, Hannisdal E, Jacobsen AB, Varhaug JE, Erikstein B, Gundersen S, Hauer-Jensen M, Høst H, Jacobsen AB, Nissen-Meyer R, Blamey RW, Mitchell AK, Morgan DA, Robertson JF, Ueo H, Di Palma M, Mathé G, Misset JL, Levine M, Pritchard KI, Whelan T, Morimoto K, Sawa K, Takatsuka Y, Crossley E, Harris A, Talbot D, Taylor M, Martin AL, Roché H, Cocconi G, di Blasio B, Ivanov V, Paltuev R, Semiglazov V, Brockschmidt J, Cooper MR, Falkson CI, A'Hern R, Ashley S, Dowsett M, Makris A, Powles TJ, Smith IE, Yarnold JR, Gazet JC, Browne L, Graham P, Corcoran N, Deshpande N, di Martino L, Douglas P, Hacking A, Høst H, Lindtner A, Notter G, Bryant AJ, Ewing GH, Firth LA, Krushen-Kosloski JL, Nissen-Meyer R, Anderson H, Killander F, Malmström P, Rydén L, Arnesson LG, Carstensen J, Dufmats M, Fohlin H, Nordenskjöld B, Söderberg M, Carpenter JT, Murray N, Royle GT, Simmonds PD, Albain K, Barlow W, Crowley J, Hayes D, Gralow J, Green S, Hortobagyi G, Livingston R, Martino S, Osborne CK, Ravdin PM, Adolfsson J, Bergh J, Bondesson T, Celebioglu F, Dahlberg K, Fornander T, Fredriksson I, Frisell J, Göransson E, Iiristo M, Johansson U, Lenner E, Löfgren L, Nikolaidis P, Perbeck L, Rotstein S, Sandelin K, Skoog L, Svane G, af Trampe E, Wadström C, Castiglione M, Goldhirsch A, Maibach R, Senn HJ, Thürlimann B, Hakama M, Holli K, Isola J, Rouhento K, Saaristo R, Brenner H, Hercbergs A, Martin AL, Roché H, Yoshimoto M, Paterson AH, Pritchard KI, Fyles A, Meakin JW, Panzarella T, Pritchard KI, Bahi J, Reid M, Spittle M, Bishop H, Bundred NJ, Cuzick J, Ellis IO, Fentiman IS, Forbes JF, Forsyth S, George WD, Pinder SE, Sestak I, Deutsch GP, Gray R, Kwong DL, Pai VR, Peto R, Senanayake F, Boccardo F, Rubagotti A, Baum M, Forsyth S, Hackshaw A, Houghton J, Ledermann J, Monson K, Tobias JS, Carlomagno C, De Laurentiis M, De Placido S, Williams L, Hayes D, Pierce LJ, Broglio K, Buzdar AU, Love RR, Ahlgren J, Garmo H, Holmberg L, Liljegren G, Lindman H, Wärnberg F, Asmar L, Jones SE, Gluz O, Harbeck N, Liedtke C, Nitz U, Litton A, Wallgren A, Karlsson P, Linderholm BK, Chlebowski RT, Caffier H.

Abstract

BACKGROUND:

As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen.

METHODS:

We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment.

FINDINGS:

In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0-4, 0·66 [0·05] during years 5-9, and 0·68 [0·08] during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality.

INTERPRETATION:

5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen.

FUNDING:

Cancer Research UK, British Heart Foundation, and Medical Research Council.

Comment in

With maturity comes confidence: EBCTCG tamoxifen update. [Lancet. 2011]
With maturity comes confidence: EBCTCG tamoxifen update.Chia SK, Wolff AC. Lancet. 2011 Aug 27; 378(9793):747-9. Epub 2011 Jul 28.
ACP Journal Club. Meta-analysis: adjuvant tamoxifen reduces recurrence and death at 15 years in ER-positive early breast cancer. [Ann Intern Med. 2012]
ACP Journal Club. Meta-analysis: adjuvant tamoxifen reduces recurrence and death at 15 years in ER-positive early breast cancer.Kiely B, Stockler M. Ann Intern Med. 2012 Mar 20; 156(6):JC3-4.