Journal of the National Cancer Institute Advance Access originally published online on January 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(3):207-212; doi:10.1093/jnci/djm289
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© The Author 2008. Published by Oxford University Press.
Predictive Value of Tumor Ki-67 Expression in Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer
On the behalf of the International Breast Cancer Study Group
Affiliations of the authors: Divisions of Pathology and Laboratory Medicine (GV, MGM, FM) and Medical Oncology (MC, AG), European Institute of Oncology, University of Milan, Milan, Italy; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute, Frontier Science and Technology Research Foundation, Harvard School of Public Health, Boston, MA (MMR, KNP, RDG); Department of Pathological Anatomy, University of Bari, Bari, Italy (EM); The Institute of Oncology, Ljubljana, Slovenia (RG); Division of Pathology, Centro di Riferimento Oncologico, Aviano, Italy (TP); Melbourne Pathology, Collingwood, Victoria, Australia (RWB); Department of Pathology, Göteborg/Sahlgrenska University Hospital, Göteborg, Sweden (AK); Division of Anatomical Pathology, Department of Clinical Laboratory Sciences, University of Cape Town, National Health Laboratory Services and Groote Schuur Hospital, Cape Town, South Africa (KP); Kantonspital, St Gallen, Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland (CO); Division of Cancer Sciences and Molecular Pathology, Western Infirmary, University of Glasgow, UK (BAG); IBCSG Coordinating Center, Bern, Switzerland (MCG); Oncology Institute of Southern Switzerland, Bellinzona, Switzerland (AG); IBCSG, Bern, Switzerland (ASC); University of Sydney, Australia (ASC)
Correspondence to: Giuseppe Viale, MD, FRCPath, Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Via Ripamoniti 435, Milan, Italy (e-mail: giuseppe.viale{at}ieo.it).
Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studies.
| CONTEXT AND CAVEATS Prior knowledge Some studies have suggested that having a high percentage of breast tumor cells that label with an antibody against the proliferation antigen Ki-67 predicts a better response to primary (ie, neoadjuvant) chemotherapy. Study design A retrospective assessment of the predictive value of a high Ki-67 labeling index for response to therapy among women enrolled in two randomized trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. Contribution A high Ki-67 labeling index did not predict which women would benefit from further treatment with chemotherapy added to endocrine therapy. Limitations Only women with node-negative breast cancer were included in this study. Implications Other biomarkers are needed to define which women with endocrine-responsive node-negative early breast cancer could benefit from the addition of adjuvant chemotherapy to endocrine therapy.
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Reprint requests to: International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, CH-3008 Bern, Switzerland (e-mail: giuseppe.viale{at}ieo.it).
We thank the many pathologists who submitted tumor blocks and slides, Rosita Kammler and the pathology team in Bern, and Stefania Andrighetto and data management team at the pathology office in Milan. We thank the patients, physicians, nurses, and data managers who participate in the IBCSG trials.
A. Goldhirsch received honoraria from Novartis, Pfizer, and AstraZeneca.
The authors and the IBCSG were responsible for the trial design and conduct; collection, analysis, and interpretation of data; writing of the manuscript; and the decision to submit the manuscript for publication.
International Breast Cancer Study Group
Scientific Committee: A. Goldhirsch, A. S. Coates (Co-chairs).
Foundation Council: B. Thürlimann (President), M. Castiglione-Gertsch, A. S. Coates, J. P. Collins, H. Cortés Funes, M. de Stoppani, R. D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S. B. Holmberg, D. K. Hossfeld, I. Láng, J. Lindtner, C.-M. Rudenstam, R. Stahel, H.-J. Senn, A. Veronesi.
Coordinating Center, Bern, Switzerland: M. Castiglione-Gertsch (CEO and Study Chair), A. Hiltbrunner (Director); G. Egli, M. Rabaglio, R. Maibach, R. Studer, B. Ruepp, E. Marbot; Pathology Office: R. Kammler (Head Pathology Coordinating Office), H.-R. Pauli, A. Aeschbacher, S. Oelhafen.
Statistical Center, Harvard School of Public Health and Dana-Farber Cancer Institute, Boston, MA: R. D. Gelber (Group Statistician), K. Price (Director of Scientific Administration), M. Regan, D. Zahrieh, S. Gelber, A. Keshaviah, Z. Sun, B. Cole, L. Nickerson.
Data Management Center, Frontier Science and Technology Research Foundation, Amherst, NY: L. Blacher (Director), R. Hinkle (Trial Data Manager), S. Lippert, J. Celano.
Pathology Office, European Institute of Oncology, Milan, Italy: G. Viale, E. Maiorano, M. Mastropasqua, S. Andrighetto, G. Peruzzotti, R. Ghisini, E. Scarano, P. Dell’Orto, B. Del Curto.
Pathology Office, University of Glasgow, Scotland, UK: B. Gusterson, E. Mallon.
The Ontario Cancer Treatment and Research Foundation, Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada: K. Pritchard, D. Sutherland, C. Sawka, G. Taylor, R. Choo, C. Catzavelos, K. Roche, H. Wedad.
National Institute of Oncology, Budapest, Hungary: I. Láng, E. Hitre, E. Juhos, I. Szamel, J. Toth, Z. Orosz, I. Peter.
Centro di Riferimento Oncologico, Aviano, Italy: D. Crivellari, S. Monfardini, E. Galligioni, M. D. Magri, A. Veronesi, A. Buonadonna. S. Massarut, C. Rossi, E. Candiani, A. Carbone, T. Perin, R. Volpe, M. Roncadin, M. Arcicasa, F. Coran, S. Morassut.
Spedali Civili & Fondazione Beretta, Brescia, Italy: E. Simoncini, G. Marini, P. Marpicati, M. Braga, P. Grigolato, L. Lucini.
General Hospital, Gorizia, Italy: S. Foladore, L. Foghin, G. Pamich, C. Bianchi, B. Marino, A. Murgia, V. Milan.
European Institute of Oncology, Milano, Italy: A. Goldhirsch, M. Colleoni, G. Martinelli, L. Orlando, F. Nolé, A. Luini, R. Orecchia, G. Viale, G. Renne, G. Mazzarol, F. Peccatori, F. de Braud, A. Costa, S. Zurrida, P. Veronesi, V. Sacchini, V. Galimberti, M. Intra, S. Cinieri, G. Peruzzotti, U. Veronesi.
Ospedale Infermi, Rimini, Italy: A. Ravaioli, D. Tassinari, G. Oliverio, F. Barbanti, P. Rinaldi, L. Gianni, G. Drudi.
Ospedale S. Eugenio, Roma, Italy: M. Antimi, M. Minelli, V. Bellini, R. Porzio, E. Pernazza, G. Santeusanio, L. G. Spagnoli.
Ospedale S. Bortolo, Vicenza, Italy: M. Magazu, V. Fosser, P. Morandi, G. Scalco, M. Balli, E. S. G. d’Amore, S. Meli, G. Torsello.
The Institute of Oncology, Ljubljana, Slovenia: J. Lindtner, D. Erzen, E. Majdic, B. Stabuc, A. Plesnicar, R. Golouh, J. Lamovec, J. Jancar, I. Vrhovec, M. Kramberger.
Groote Schuur Hospital and University of Cape Town, Cape Town, Republic of South Africa: D. M. Dent, A. Gudgeon, E. Murray, G. Langman, I. D. Werner, P. Steynor, J. Toop, E. McEvoy.
Sandton Oncology Center, Johannesburg, Republic of South Africa: D. Vorobiof, M. Chasen, G. Fotheringham, G. de Muelenaere, B. Skudowitz, C. Mohammed, A. Rosengarten, C. Thatcher.
Madrid Breast Cancer Group, Madrid, Spain: H. Cortés-Funes, C. Mendiola, J. Hornedo, R. Colomer, F. Cruz Vigo, P. Miranda, A. Sierra, F. Martinez-Tello, A. Garzon, S. Alonso, A. Ferrero.
West Swedish Breast Cancer Study Group, Göteborg, Sweden: C. M. Rudenstam, M. Suurküla, Ö. Sjukhuset, G. Havel, S. Persson, J. H. Svensson, G. Östberg, S. B. Holmberg, A. Wallgren, S. Ottosson-Lönn, R. Hultborn, G. Colldahl-Jäderström, E. Cahlin, J. Mattsson, L. Ivarsson, O. Ruusvik, L. G. Niklasson, S. Dahlin, G. Karlsson, B. Lindberg, A. Sundbäck, S. Bergegårdh, H. Salander, C. Andersson, M. Heideman, Y. Hessman, O. Nelzén, G. Claes, T. Ramhult, A. Kovacs, P. Liedberg.
Swiss Group for Clinical Cancer Research (SAKK) member institutions—Inselspital, Bern, Switzerland: M. F. Fey, M. Castiglione-Gertsch, E. Dreher, H. Schneider, S. Aebi, J. Ludin, G. Beck, A. Haenel, J. M. Lüthi, L. Mazzucchelli, J. P. Musy, H. J. Altermatt, M. Nandedkar, K. Buser.
Kantonsspital, St Gallen, Switzerland: H. J. Senn, B. Thürlimann, C. Oehlschlegel, G. Ries, M. Töpfer, U. Lorenz, O. Schiltknecht, B. Späti, A. Ehrsam, M. Bamert, W. F. Jungi.
Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland: F. Cavalli, O. Pagani, H. Neuenschwander, L. Bronz, C. Sessa, M. Ghielmini, T. Rusca, P. Rey, J. Bernier, E. Pedrinis, T. Gyr, L. Leidi, G. Pastorelli, G. Caccia, A. Goldhirsch.
Kantonsspital, Basel, Switzerland: R. Herrmann, C. F. Rochlitz, J. F. Harder, S. Bartens, U. Eppenberger, J. Torhorst, H. Moch.
Hôpital des Cadolles, Neuchâtel, Switzerland: D. Piguet, P. Siegenthaler, V. Barrelet, R. P. Baumann, B. Christen.
University Hospital, Zürich, Switzerland: B. Pestalozzi, C. Sauter, D. Fink, M. Fehr, U. Haller, U. Metzger, P. Huguenin, R. Caduff.
Centre Hospitalier Universitaire Vandois, Lausanne, Switzerland: L. Perey, S. Leyvraz, P. Anani, F. Gomez, D. Wellman, G. Chapuis, P. De Grandi, P. Reymond, M. Gillet, J. F. Delaloye, C. Genton, M. Fiche.
Hôpital Cantonal, Geneva, Switzerland: P. Alberto, H. Bonnefoi, P. Schäfer, F. Krauer, M. Forni, M. Aapro, R. Egeli, R. Megevand, E. Jacot-des-Combes, A. Schindler, B. Borisch, S. Diebold, M. Genta, M. Pelte.
Kantonsspital Graubünden, Chur, Switzerland: F. Egli, P. Forrer, A. Willi, R. Steiner. J. Allemann, T. Rüedi, A. Leutenegger, U. Dalla Torre, H. Frick.
Australian New Zealand Breast Cancer Trials Group member institutions—Operations Office, University of Newcastle: J. F. Forbes, D. Lindsay.
The Cancer Council Victoria (previously Anti-Cancer Council of Victoria), Clinical Trials Office, Melbourne: J. Collins, R. Snyder, B. Brown, E. Abdi, H. Armstrong, A. Barling, R. Basser, P. Bhathal, W. I. Burns, M. Chipman, J. Chirgwin, I. Davis, R. Drummond, D. Finkelde, P. Francis, D. Gee, G. Goss, M. Green, P. Gregory, J. Griffiths, S. Hart, D. Hastrich, M. Henderson, R. Holmes, P. Jeal, D. Joseph, P. Kitchen, P. Kostos, G. Lindeman, B. Mann, R. McLennan, L. Mileshkin, P. Mitchell, C. Murphy, S. Neil, I. Olver, M. Pitcher, A. Read, D. Reading, R. Reed, G. Richardson, A. Rodger, I. Russell, M. Schwarz, S. Slade, R. Stanley, M. Steele, J. Stewart, C. Underhill, J. Zalcberg, A. Zimet, C. Dow, R. Valentine.
Flinders Medical Centre, Bedford Park, South Australia: T. Malden.
Mount Hospital, Perth, Western Australia: G. Van Hazel.
Newcastle Mater Misericordiae Hospital Waratah, Newcastle, Australia: J. F. Forbes, S. Braye, J. Stewart, D. Jackson, R. Gourlay, J. Bishop, S. Cox, S. Ackland, A. Bonaventura, C. Hamilton, J. Denham, P. O’Brien, M. Back, S. Brae, R. Muragasu.
Prince of Wales, Randwick, New South Wales, Australia: M. Friedlander, B. Brigham, C. Lewis.
Royal Adelaide Hospital, Adelaide, Australia: I. N. Olver, D. Keefe, M. Brown, P. G. Gill, A. Taylor, E. Yeoh, E. Abdi, J. Cleary, F. Parnis.
Sir Charles Gairdner Hospital, Nedlands, Western Australia: M. Byrne, G. Van Hazel, J. Dewar, M. Buck, G. Sterrett, D. Ingram, D. Hastrich, D. Joseph, F. Cameron, K. B. Shilkin, P. Michell, J. Sharpio, G. Harloe, J. Lewis, B. Snowball, P. Garcia Webb, J. Harvey, W. D. De Boer, P. Robbins, N. Buxton, M. N. I. Walters.
University of Sydney, Dubbo Base Hospital and Royal Prince Alfred Hospital, Sydney, Australia: J. Beith, M. H. N. Tattersall, A. S. Coates, F. Niesche, R. West, S. Renwick, J. Donovan, P. Duval, R. J. Simes, A. Ng, D. Glenn, R. A. North, R. G. O’Connor, M. Rice, G. Stevens, J. Grassby, S. Pendlebury, C. McLeod, M. Boyer, A. Sullivan, J. Hobbs, D. Lind, J. Grace, P. McKenzie.
W. P. Holman Clinic, Launceston: D. Boadle, T. Brain, I. Byard, D. Byram.
Auckland Breast Cancer Study Group, Auckland, New Zealand: V. J. Harvey, R. G. Kay, P. Thompson, D. Porter, C. S. Benjamin, A. Bierre, M. Miller, B. Hochstein, A. Lethaby, J. Webber, J. P. Allen, M. Allon, J. F. Arthur, M. Gurley, P. Symmans, M. Christie, A. R. King.
Waikato Hospital, Hamilton, New Zealand: I. Kennedy, G. Round, J. Long.
Manuscript received July 5, 2007; revised November 21, 2007; accepted November 27, 2007.
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