Originally published as JCO Early Release 10.1200/JCO.2007.11.9453 on August 6 2007

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Prognostic and Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors in a Randomized Trial Comparing Letrozole and Tamoxifen Adjuvant Therapy for Postmenopausal Early Breast Cancer: BIG 1-98

Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Patrizia Dell'Orto, Birgitte Bruun Rasmussen, Johnny Raffoul, Patrick Neven, Zsolt Orosz, Stephen Braye, Christian Öhlschlegel, Beat Thürlimann, Richard D. Gelber, Monica Castiglione-Gertsch, Karen N. Price, Aron Goldhirsch, Barry A. Gusterson, Alan S. Coates

From the Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy; International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA; Department of Pathological Anatomy, University of Bari, Bari, Italy; Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy; Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy; Department of Pathology, Nordsjaellands Hospital, Hilleroed, Denmark; Service d'Anatomie et de Cytologie Pathologiques, Centre Hospitalier-site-Belfort-Montbéliard, Montbéliard, France; Department of Gyn Oncol and Multidisciplinary Breast Centre, UZ-KULeuven, Leuven, Belgium; Department of Pathology, National Institute of Oncology, Budapest, Hungary; Australian New Zealand Breast Cancer Trials Group, University of Newcastle and Anatomical Pathology, Hunter Area Pathology Service, John Hunter Hospital, New Lambton Heights, NSW, Australia; Kantonsspital, St Gallen, Swiss Group for Clinical Cancer Research, Bern, Switzerland; Senology Center of Eastern Switzerland, Kantonsspital, St Gallen, Switzerland, Swiss Group for Clinical Cancer Research; IBCSG Statistical Center, Dana-Farber Cancer Institute, Frontier Science and Technology Research Foundation, Harvard School of Public Health, Boston, MA; IBCSG Coordinating Center, Bern, Switzerland; IBCSG Statistical Center and Frontier Science and Technology Research Foundation, Boston, MA; European Institute of Oncology, Milan, Italy; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Division of Cancer Sciences and Molecular Pathology, Western Infirmary, University of Glasgow, UK; International Breast Cancer Study Group, Bern, Switzerland and University of Sydney, Australia

Address reprint requests to Giuseppe Viale, MD, FRCPath, Divisione di Anatomia Patologica e Medicina di Laboratorio, Istituto Europeo di Oncologia, Via Ripamonti, 435, 20141 Milano, Italy; e-mail: giuseppe.viale{at}ieo.it

Purpose To evaluate locally versus centrally assessed estrogen (ER) and progesterone (PgR) receptor status and the impact of PgR on letrozole adjuvant therapy compared with tamoxifen in postmenopausal women with early breast cancer.

Patients and Methods Breast International Group (BIG) 1-98 randomly assigned 8,010 patients to four arms comparing letrozole and tamoxifen with sequences of each agent. The Central Pathology Office received material for 6,549 patients (82%), of which 79% were assessable (6,291 patients). Prognostic and predictive value of both local and central hormone receptor expression on disease-free survival (DFS) were evaluated among 3,650 assessable patients assigned to the monotherapy arms. Prognostic value and the treatment effect were estimated for centrally assessed ER and PgR expression levels using the Subpopulation Treatment Effect Pattern Plot.

Results Central review confirmed 97% of tumors as hormone receptor–positive (ER and/or PgR 10%). Of 105 tumors locally ER-negative, 73 were found to have more than 10% positive cells, and eight had 1% to 9%. Of 6,100 tumors locally ER positive, 66 were found to have no staining, and 54 had only 1% to 9%. Discordance was more marked for PgR than ER. Patients with tumors reclassified centrally as ER-negative, or as hormone receptor–negative, had poor DFS. Centrally assessed ER and PgR showed prognostic value. Among patients with centrally assessed ER-expressing tumors, letrozole showed better DFS than tamoxifen, irrespective of PgR expression level.

Conclusion Central review changed the assessment of receptor status in a substantial proportion of patients, and should be performed whenever possible in similar trials. PgR expression did not affect the relative efficacy of letrozole over tamoxifen.

published online ahead of print at www.jco.org on August 6, 2007.

Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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