Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.
Viale G,
Giobbie-Hurder A,
Regan MM,
Coates AS,
Mastropasqua MG,
Dell'Orto P,
Maiorano E,
MacGrogan G,
Braye SG,
Ohlschlegel C,
Neven P,
Orosz Z,
Olszewski WP,
Knox F,
Thürlimann B,
Price KN,
Castiglione-Gertsch M,
Gelber RD,
Gusterson BA,
Goldhirsch A;
Breast International Group Trial 1-98.
Thürlimann B, Aebi S, Blacher L, Castiglione-Gertsch M, Coates AS, Cufer T, Forbes JF, Gelber RD, Giobbie-Hurder A, Goldhirsch A, Hiltbrunner A, Holmberg SB, Maibach R, Martoni A, Mauriac L, McGrogan G, Mouridsen HT, Paridaens R, Price KN, Rabaglio M, Rasmussen BB, Regan MM, Santoro A, Smith IE, Wardley A, Vantongelen K, Viale G, Chaudri-Ross HA, Emanuel D, Evans DB, Sguotti C, Trostmann U, Goldhirsch A, Coates AS, Blacher L, Castiglione-Gertsch M, Forbes JF, Gelber RD, Gusterson BA, Hiltbrunner A, Hürny C, Murray E, Price KN, Rabaglio M, Studer R, Viale G, Wallgren A, Stahel R, Castiglione-Gertsch M, Coates AS, Collins JP, Gelber RD, Goldhirsch A, Green M, Hiltbrunner A, Holmberg SB, Hossfeld DK, Karlsson P, Láng I, de Stoppani M, Rudenstam CM, Thürlimann B, Veronesi A, Hiltbrunner A, Rabaglio M, Egli G, Cliffe B, Ribeli-Hofmann S, Kammler R, Studer R, Ruepp B, Maibach R, Munarini N, Castiglione-Gertsch M, Hiltbrunner A, Rabaglio M, Egli G, Cliffe B, Ribeli-Hofmann S, Munarini F, Kammler R, Studer R, Ruepp B, Maibach R, Munarini N, Gelber RD, Price KN, Giobbie-Hurder A, Regan M, Sun Z, Keshaviah A, Litman H, Huang H, Somos LJ, Timmers B, Nickerson L, Blacher L, Scolese TH, 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, Hayes DF, Garber JE, Lagakos SW, Lindgren I, Waldie E, van Hoomissen I, De Smet M, Schmidt W, Bolton A, Hackl W, Chirgwin JH, Forbes JF, Boyle FM, Lindsay D, Preece D, Oleksyn K, 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, 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, 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P, Farfaglia R, Bianchi AM, Grigolato P, Lucini L, Frata P, Huscher A, Micheletti E, Fogazzi C, Artioli F, Cagossi K, Scaltriti L, Bandieri E, Botticelli L, Giovanardi G, Ravaioli A, Pasquini E, Rudnas B, Foghin L, 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, 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, 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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-Ixelles CH, Kains JP, Canon JL, Brohèe D, Gowing J, Yelle Y, 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, 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Thompson AM, Wardley A, Hickish T, Neave F, Sabini G.
Source
Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy. giuseppe.viale@ieo.it
Abstract
PURPOSE:
To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer.
PATIENTS AND METHODS:
Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%.
RESULTS:
Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09).
CONCLUSION:
Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.
- PMID:
- 18981464
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC2651094
Free PMC ArticleFig 2.
Kaplan-Meier estimates of disease-free survival according to (A) level of Ki-67 labeling index (high > 11% v low ≤ 11%) and (B) treatment assignment.
J Clin Oncol. J Clin Oncol;26(34):5569-5575.
Fig 4.
Subpopulation Treatment Effect Pattern Plot analysis of the treatment effect of letrozole versus tamoxifen as measured by 4-year disease-free survival according to overlapping subpopulations defined by percentages of Ki-67 labeling index (LI). The x-axis indicates the median percentage of Ki-67 LI for patients in each of the overlapping subpopulations.
J Clin Oncol. J Clin Oncol;26(34):5569-5575.
Fig 1.
Patients from the Breast International Group 1-98 trial included and excluded in this study according to treatment group and availability of tumor material. L, letrozole; T, tamoxifen; ER, estrogen receptor.
J Clin Oncol. J Clin Oncol;26(34):5569-5575.
Fig 3.
Kaplan-Meier estimates of disease-free survival according to level of Ki-67 labeling index (LI) (high > 11% v low ≤ 11%) and treatment assignment, separately for patients (A) with lymph node–negative disease and (B) node-positive disease, and with tumors that are (C) estrogen receptor expressing (1% to 79%) and (D) strongly estrogen receptor expressing (≥ 80%).
J Clin Oncol. J Clin Oncol;26(34):5569-5575.
Fig 5.
Proportional hazards model results of disease-free survival in subgroups. The size of each box is inversely proportional to the SE of the hazard ratio (HR). The solid vertical line is placed at HR = 0.63, which is the HR estimate for the overall analysis of letrozole compared with tamoxifen in this analytic cohort. HER-2, human epidermal growth factor receptor 2; LI, labeling index; ER, estrogen receptor.
J Clin Oncol. J Clin Oncol;26(34):5569-5575.
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