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Chemoendocrine Compared With Endocrine Adjuvant Therapies for Node-Negative Breast Cancer: Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors—International Breast Cancer Study Group

Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Rastko Golouh, Tiziana Perin, Robert W. Brown, Anikó Kovács, Komala Pillay, Christian Öhlschlegel, Stephen Braye, Piergiovanni Grigolato, Tiziana Rusca, 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; Department of Pathological Anatomy, University of Bari, Bari; Division of Pathology, Centro di Riferimento Oncologico, Aviano; Anatomia Patologica, Spedali Civili di Brescia, Universita Degli Studi di Brescia, Brescia, Italy; International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA; Institute of Oncology, Ljubljana, Slovenia; Melbourne Pathology, Collingwood, Victoria; Australian New Zealand Breast Cancer Trials Group, University of Newcastle and Anatomical Pathology, Hunter Area Pathology Service, John Hunter Hospital, New Lambton Heights, New South Wales; University of Sydney, Sydney, Australia; Department of Pathology, Göteborg/Sahlgrenska University Hospital, Göteborg, Sweden; Department of Clinical Laboratory Sciences, Division of Anatomical Pathology, University of Cape Town, National Health Laboratory Services and Groote Schuur Hospital, Cape Town, South Africa; Kantonspital, St Gallen, Swiss Group for Clinical Cancer Research and International Breast Cancer Study Group Coordinating Center, Bern; Istituto Cantonale di Patologia, Locarno; Swiss Group for Clinical Cancer Research; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, United Kingdom

Corresponding author: 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 centrally assess estrogen receptor (ER) and progesterone receptor (PgR) levels by immunohistochemistry and investigate their predictive value for benefit of chemo-endocrine compared with endocrine adjuvant therapy alone in two randomized clinical trials for node-negative breast cancer.

Patients and Methods International Breast Cancer Study Group Trial VIII compared cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for 6 cycles followed by endocrine therapy with goserelin with either modality alone in pre- and perimenopausal patients. Trial IX compared three cycles of CMF followed by tamoxifen for 5 years versus tamoxifen alone in postmenopausal patients. Central Pathology Office reviewed 883 (83%) of 1,063 patients on Trial VIII and 1,365 (82%) of 1,669 on Trial IX and determined ER and PgR by immunohistochemistry. Disease-free survival (DFS) was compared across the spectrum of expression of each receptor using the Subpopulation Treatment Effect Pattern Plot methodology.

Results Both receptors displayed a bimodal distribution, with substantial proportions showing no staining (receptor absent) and most of the remainder showing a high percentage of stained cells. Chemo-endocrine therapy yielded DFS superior to endocrine therapy alone for patients with receptor-absent tumors, and in some cases also for those with low levels of receptor expression. Among patients with ER-expressing tumors, additional prediction of benefit was suggested in absent or low PgR in Trial VIII but not in Trial IX.

Conclusion Low levels of ER and PgR are predictive of the benefit of adding chemotherapy to endocrine therapy. Low PgR may add further prediction among pre- and perimenopausal but not postmenopausal patients whose tumors express ER.

Supported by the International Breast Cancer Study Group, which is supported by Swiss Group for Clinical Cancer Research, Frontier Science and Technology Research Foundation, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (National Health Medical Research Council Grants No. 920876, 950328, 980379, and 100925), National Cancer Institute (Grant No. CA-75362), Swedish Cancer Society, Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK), Cancer Association of South Africa (for South African participation), and Oncosuisse/Cancer Research Switzerland (for collection of tumor blocks within Switzerland).

Presented in part at the San Antonio Breast Cancer Symposium, December 6, 2003, San Antonio, TX.

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

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