This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Viale, G. Articles by Coates, A. S. Search for Related Content PubMed PubMed Citation Articles by Viale, G. Articles by Coates, A. S. Related Articles Related Editorial Social Bookmarking                            What's this?

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
Estrogen receptor (ER) and progesterone receptor (PgR) content in the primary tumor of patients with early-stage invasive breast cancer are powerful predictors of response to adjuvant endocrine therapies¹ and chemo-sensitivity of the primary tumor.^2,3 It is recommended that endocrine receptors be measured on all primary breast cancer specimens,⁴ and endocrine responsiveness is now the first consideration for selection of adjuvant systemic therapy.⁵ It is also recognized that there are tumors of uncertain endocrine responsiveness, in which receptor expression is either quantitatively low or qualitatively insufficient to indicate a substantial chance for response to endocrine therapies alone, which may suggest the need for chemotherapy.⁵ Whether a boundary exists between endocrine responsive and uncertain responsiveness—which may differ in different clinical settings—or whether detectable receptor expression should be considered on the continuum is unresolved.

International Breast Cancer Study Group (IBCSG) Trials VIII and IX^6,7 are randomized clinical trials that compared adjuvant endocrine therapy alone with sequential chemotherapy followed by endocrine therapy for lymph node-negative invasive breast cancer among pre- and perimenopausal (Trial VIII) and postmenopausal women (Trial IX). Previous reports of the outcome of these trials included the histopathologic characteristics and ER status of the tumors, as assessed by each participating institution. Receptor levels were determined by dextran charcoal radio-immuno assay or immunohistochemistry using institutional definitions of positivity.

Both trials showed that women with ER-negative, lymph node–negative breast cancer derived benefit from adjuvant chemotherapy.^6,7 In postmenopausal women with ER-positive tumors, no benefit of chemotherapy was observed,⁷ whereas chemotherapy followed by ovarian function suppression in premenopausal patients with ER-positive, lymph node–negative breast cancer showed no overall benefit, although there was a trend to benefit among young patients.⁶

The present study is based on re-evaluation of histopathologic features and immunohistochemical determination of receptor levels by central assessment of available tumor blocks and/or slides of patients registered on Trials VIII and IX. Its aims were to describe the distributions of immunohistochemically determined ER and PgR in clinical trial cohorts of pre- and postmenopausal patients with lymph node–negative disease and to investigate their predictive value by exploring chemo-endocrine responsiveness across the continuum of quantitative expression levels.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
The designs of IBCSG Trials VIII⁶ and IX⁷ have been previously described. Briefly, Trial VIII enrolled pre/perimenopausal women with lymph node–negative breast cancer. The trial evaluated whether sequential treatment with six 28-day courses of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy followed by 18 monthly subcutaneous implants of goserelin significantly improved disease-free survival (DFS) as compared with either six 28-day courses of classical CMF alone or 24 monthly implants of goserelin alone. From 1990 through 1999, a total of 1,063 assessable patients were randomly assigned. Trial IX enrolled postmenopausal women with lymph node–negative breast cancer and evaluated whether sequential treatment with three 28-day courses of classical CMF chemotherapy followed by tamoxifen for 57 months significantly improved DFS as compared with tamoxifen alone for 5 years. From 1988 through 1999, a total of 1,669 eligible and assessable patients were randomly assigned. Institutional review boards reviewed and approved the protocols, and informed consent was required according to the criteria established within the individual countries.

In both trials, patients with ER-positive, ER-negative, and ER-unknown tumors (ER unknown status allowed only if ER determination was not possible because of the lack of tumor material) were eligible until 1998. At that time, protocol amendments restricted entry to patients with ER-positive tumors on the basis of evidence from other trials that tamoxifen was not effective and that ovarian ablation might not be effective for patients with ER-negative tumors.^8,9

Pathology Methods
Retrospective tissue collection was carried out in accordance with institutional guidelines and national laws. More than 80% of patients randomly assigned in Trials VIII and IX had archival tumor material available for immunohistochemical hormone receptor evaluation. In the IBCSG Central Pathology Laboratory, expression of ER and PgR in the primary tumors was determined by immunohistochemistry (IHC) as previously described without knowledge of treatment assignment or outcome.^10,11 Whole tumor sections were incubated with the specific primary mouse monoclonal antibodies to ER (clone 1D5, 1:100 dilution) or PgR (clone 1A6, 1:800 dilution; Dako, Glostrup, Denmark) for 30 minutes at room temperature and subsequently treated with a high-sensitivity detection kit (EnVision Plus-HRP, Dako) according to the manufacturer's instructions, using an automatic immunostainer (Autostainer; Dako). At least 10 high-power fields (x400) comprising a minimum of 2,000 invasive tumor cells were evaluated, and the number of cells showing nuclear immunostaining (irrespective of the staining intensity) was counted over the total number of neoplastic cell and was recorded as an overall percentage. The statistical analysis focuses on this percentage¹² and does not take into account the intensity of staining, which may be affected by heterogeneity of fixation modalities across institutions.¹³ ER or PgR expression levels were not assessable among 2% and 3% of cases, respectively, for whom no additional material was available to restain after detachment of tissue sections from slides during the staining procedure or other technical problems occurred.

Statistical Methods
The nonparametric Subpopulation Treatment Effect Pattern Plot (STEPP) methodology^14,15 was used to investigate trends in treatment effect differences across the continuum of hormone receptor expression. The STEPP method was developed to help identify features that predict responsiveness to the treatments under study in a randomized clinical trial without resorting to the selection of a single cut point in the distribution of a continuous feature such as ER expression. STEPP involves defining several overlapping subpopulations of patients on the basis of the covariate of interest and studying the resulting pattern of the treatment effects estimated within each subpopulation. The subpopulations contain a fixed number of patients; the patients are ordered according to the value of the covariate of interest, and each subpopulation is formed starting with the fixed number of patients with the lowest covariate values then dropping approximately 10 to 20 patients with the lowest covariate values and adding approximately 10 to 20 patients with the next higher covariate values. The plot's x-axis indicates the median covariate value for patients in each subpopulation; the y-axis indicates the treatment effects, measured as the t-year disease-free survival (DFS) percentage estimated using the Kaplan-Meier method¹⁶ on data of patients in each subpopulation. A resampling-based test for treatment-by-covariate interaction across subpopulations was calculated.

In this report, ER and PgR expression of the primary tumor were the covariates of interest, and the treatment effects estimated within each ER or PgR subpopulation were measured in terms of 5-year DFS percentages. For the analyses of Trial VIII, each subpopulation contained approximately 90 patients, with subsequent subpopulations formed by dropping and adding 15 patients. For Trial IX, the analysis of ER used subpopulations of approximately 80 patients, with subsequent subpopulations changing by 10 patients, and the analysis of PgR used subpopulations of approximately 160 patients, with subsequent subpopulations changing by 20 patients.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
Material was available and assessable for ER and/or PgR expression by IHC from 883 (83%) of 1,063 premenopausal patients with lymph node–negative disease randomly assigned on Trial VIII and from 1,365 (82%) of 1,669 postmenopausal patients with lymph node–negative disease randomly assigned on Trial IX. The clinical and tumor characteristics of patients included in this analysis were comparable with the overall trial cohorts (data not shown). In the Trial VIII analysis cohort, the median age was 45 years (interquartile range [IQR], 41 to 48 years), 43% of patients had undergone total mastectomy, 38% of patients had tumors greater than 2.0 cm, and 39% of patients had grade 3 tumors. In the Trial IX analysis cohort, 57% of patients were 60 years of age or older, 50% of patients had undergone total mastectomy, 39% of patients had tumors greater than 2.0 cm, and 36% of patients had grade 3 tumors. Median duration of follow-up was 8.2 and 9.4 years in Trials VIII and IX analysis cohorts, respectively.

Distributions of ER and PgR
The distributions of ER and PgR in the two trial populations are displayed in Figure 1. Among the premenopausal patients in Trial VIII, the median ER and PgR values were 74% (IQR, 15% to 90%) and 60% (IQR, 0% to 90%) of cells, respectively. The Spearman correlation between ER and PgR was 0.70. Among the postmenopausal patients in Trial IX, the median values of ER and PgR were 85% (IQR, 35% to 95%) and 17% (IQR, 0% to 75%) of cells, respectively. The correlation between ER and PgR was 0.56.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Distribution of estrogen receptor (ER) and progesterone receptor (PgR), as percent immunoreactive cells, for premenopausal (Trial VIII; A, C) and postmenopausal (Trial IX; B, D) patients with lymph node–negative disease. Histogram bars are in 5-unit bins, beginning with 0% of cells, 1% to 5%, 6% to 10%, and so on. Horizontal lines indicate the median and range of each subpopulation for the corresponding Subpopulation Treatment Effect Pattern Plot analyses.

By contrast, PgR expression was less distinctly bimodal. Overall, 30% of tumors expressed 0% PgR (PgR-absent tumors), and there was more spread of PgR values across the 1% to 100% range. There was also greater difference observed between trial populations, with more than half of postmenopausal patients' tumors expressing less than 20% PgR (including 35% of tumors which were PgR-absent) and more than half of premenopausal patients' tumors expressing 60% PgR.

In both trial populations, approximately 80% of patients' tumors expressed at least one receptor (ie, 1% expression of ER and/or PgR). Among pre- and perimenopausal women in Trial VIII, 70% of tumors expressed both ER and PgR, 6% expressed ER but not PgR and 1.5% expressed ER while PgR was unknown. Fewer than 3% expressed PgR with ER absent (1.5%) or unknown (1.4%). Correspondingly, in postmenopausal women in Trial IX, 61% of tumors expressed both ER and PgR, 15% expressed ER but not PgR, and in 3% ER was expressed but PgR was unknown. Fewer than 2% expressed PgR with ER absent (0.4%) or unknown (1.3%).

Disease Responsiveness
STEPP analyses were used to evaluate patients' 5-year DFS according to treatment regimen and quantitative values of ER and PgR. The analyses suggest heterogeneity of the treatment effect comparing CMF-endocrine versus endocrine therapy alone across ER expression levels in both trials (Trial VIII, P = .12 for interaction; Trial IX, P = .01 for interaction). Among premenopausal women in Trial VIII (Fig 2A), the benefit of sequential CMF followed by goserelin compared with goserelin alone was evident for several ranges of ER expression. For patients with ER-absent (0%) tumors, an absolute difference in 5-year DFS of 13% (95% CI, –2% to 28%) was observed. Somewhat surprisingly for the ER-absent cohort, the 5-year DFS for patients treated with CMF alone was lower than that for patients receiving sequential CMF followed by goserelin. For premenopausal women with ER-present disease, variability in the pattern of treatment effect differences between CMF-goserelin and goserelin alone was suggested. For example, although there was no separation between the CMF-goserelin and goserelin alone STEPP curves for the first ER-present subpopulation cohort (median ER immunoreactivity of 26%), separation between the curves was observed for the five subpopulations with medians of 50% ER to 78% ER. The estimated differences in 5-year DFS for these five intermediate ER value subpopulations had wide CIs and ranged between 8% (95% CI, –9% to 24%) and 23% (95% CI, 5% to 41%).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Subpopulation Treatment Effect Pattern Plot analyses evaluating premenopausal patients' responsiveness, in terms of 5-year disease-free survival (DFS), to cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy followed by goserelin or either treatment alone for lymph node–negative disease (Trial VIII) according to quantitative values of estrogen receptor (ER) % (A; P = .12 for interaction) and progesterone receptor (PgR) % (B; P = .27 for interaction).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Subpopulation Treatment Effect Pattern Plot analyses to evaluate postmenopausal patients' responsiveness, in terms of 5-year disease-free survival (DFS), to sequential cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy followed by tamoxifen compared with tamoxifen alone for lymph node–negative disease (Trial IX) according to quantitative values of estrogen receptor (ER) % (A; P = .01 for interaction) and progesterone receptor (PgR) % (B; P = .32 for interaction).

Analyses were also undertaken to investigate whether PgR expression provided additional information among patients whose tumors expressed ER ( 1% immunoreactivity; Fig 4). For premenopausal women in Trial VIII (Fig 4A), the benefit of CMF before goserelin versus goserelin alone was large among the subpopulation with PgR-absent tumors (20% absolute difference in 5-year DFS; 95% CI, –3% to 43%), marginal in those with low expression of PgR (approximately 6% absolute difference; 95% CI, –15% to 29%), and not evident in subpopulations with higher PgR expression. The heterogeneity of treatment effects according to PgR expression levels was not statistically significant (P = .71 for interaction). The tumors that were PgR-absent and ER-present had a median of 60% ER expression, as compared with 80% ER expression in tumors that expressed both PgR and ER.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Among the subset of patients whose tumors expressed estrogen receptor (ER; 1% ER), Subpopulation Treatment Effect Pattern Plot analyses to evaluate patients' responsiveness, in terms of 5-year disease-free survival (DFS), to the different treatments for lymph node–negative disease according to quantitative values of progesterone receptor (PgR) % for premenopausal (A; P = .71 for interaction) and postmenopausal patients (B; P = .72 for interaction). CMF, cyclophosphamide, methotrexate, and fluorouracil.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
Our study is based on clinical trial patients, with closely similar and documented patient and tumor characteristics and standardized treatments and follow-up. The bimodal distribution of ER expression is consistent with that of recent reports.^13,17 We observed minor differences in the pattern of ER levels between premenopausal and postmenopausal patients, with a more sharply bimodal pattern in the latter. PgR levels were lower among postmenopausal women than among pre- and perimenopausal women despite higher levels of ER, so that tumors expressing ER but not PgR were more common among postmenopausal patients (15%) than pre- and perimenopausal patients (5%). It may be that the PgR levels in postmenopausal women reflect the lower levels of circulating estrogen in these older women, with a lower activation of ER and hence a lower transcription of the PgR genes.¹⁸ Unlike Nadji et al,¹³ we did observe some patients whose tumors expressed PgR but not ER, albeit at a low frequency. These may be false-negative immunohistochemical results in the assessment of ER, which could result from variations in fixation schedules in different pathology laboratories.

The STEPP methodology is useful for investigating patterns of treatment responsiveness across a continuum of values of covariates such as degree of receptor expression. It demonstrated decreasing benefit of chemotherapy with increasing ER expression, indicating the inadequacy of endocrine therapy alone for patients with absent ER. In postmenopausal patients, chemotherapy benefit seemed to extend also to those with low levels of ER expression, whereas this was not assessable in pre- and perimenopausal patients. Statistical reliability was limited for the premenopausal cohort as a result of the relatively smaller sample size and inclusion of three treatment groups in Trial VIII. Overall, the pattern seen with PgR was similar to that observed for ER, though when PgR is examined only in patients whose tumors expressed ER, a pattern was suggestive only in pre- and perimenopausal patients, with chemotherapy particularly adding benefit in those with low or absent PgR expression. Given the long natural history of breast cancer, especially with endocrine-responsive disease, it is possible that patterns of responsiveness may differ over even longer periods of follow-up.

We have previously reported on the concordance of hormone receptor results as determined centrally using IHC and locally using extraction assays and on their value for predicting response to endocrine therapy.¹¹ Concordance ranged from 74% for PgR among postmenopausal women to 88% for ER among postmenopausal women, with concordance near 80% observed for ER and PgR among premenopausal women. PgR as determined by IHC could predict response to endocrine therapy better than that determined by extraction assays, in particular among premenopausal women.

We have previously compared three with six cycles of CMF and found that three initial cycles were as effective as six cycles for older patients (older than 40 years) with ER-positive tumors.¹⁹ Three cycles was clearly effective in patients with ER-absent tumors, and on the basis of this, we believe that the three cycles of CMF used in Trial IX provided a valid test of the value of adding chemotherapy in these patients. Although our study found no evidence of benefit from the addition of chemotherapy before tamoxifen in postmenopausal patients with tumors expressing higher levels of ER, the Early Breast Cancer Trialists' Collaborative Group Overview suggested benefit of addition of chemotherapy, even in patients whose tumors were ER-positive.²⁰ Perhaps the most closely similar trial to IBCSG Trial IX is the National Surgical Adjuvant Breast and Bowel Project trial B-20, which examined the addition of chemotherapy with CMF (or methotrexate and fluorouracil) with tamoxifen in women with ER-positive tumors. The benefit seen from addition of chemotherapy was markedly less among patients 60 years of age or older (hazard ratio [HR] = 0.80), whereas patients aged 49 years and 50 to 59 years showed more substantial benefit (HR = 0.46 and 0.44, respectively). Many patients aged 49 years and some of those aged 50 to 59 years would have been premenopausal and may have derived some of the benefit through ovarian function suppression. In National Surgical Adjuvant Breast and Bowel Project Trial B-20, menopausal status was recorded by patient self-report, without predefined criteria.^21,22 Further studies involving careful measurement of ER, definition of menopausal status, and inclusion of a variety of newer chemotherapy regimens will be required to answer the clinically important question of whether a group of patients can be defined who derive no additional benefit from the addition of chemotherapy to endocrine therapy.

The 2005 St Gallen consensus recognized that there are tumors of uncertain endocrine responsiveness in which there is some receptor expression, either quantitatively low or qualitatively insufficient to indicate a substantial chance for response to endocrine therapies alone, which may suggest the need for chemotherapy.⁵ Our evaluation of clinical trial patients with lymph node–negative disease supports this emphasis on the quantitative levels of hormone receptor expression rather than use of an absolute cutoff point. Further, it highlights that there are differences between pre/perimenopausal patients and postmenopausal patients in what might be considered uncertain endocrine responsiveness.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
Conception and design: Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Richard D. Gelber, Monica Castiglione-Gertsch, Karen N. Price, Aron Goldhirsch, Alan S. Coates

Administrative support: Monica Castiglione-Gertsch, Karen N. Price

Provision of study materials or patients: Giuseppe Viale, Rastko Golouh, Tiziana Perin, Robert W. Brown, Anikó Kovács, Komala Pillay, Christian Öhlschlegel, Stephen Braye, Piergiovanni Grigolato, Tiziana Rusca, Aron Goldhirsch

Collection and assembly of data: Giuseppe Viale, Meredith M. Regan, Eugenio Maiorano, Mauro G. Mastropasqua, Monica Castiglione-Gertsch, Barry A. Gusterson

Data analysis and interpretation: Giuseppe Viale, Meredith M. Regan, Richard D. Gelber, Karen N. Price, Alan S. Coates

Manuscript writing: Giuseppe Viale, Meredith M. Regan, Barry A. Gusterson, Alan S. Coates

Final approval of manuscript: 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

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
International Breast Cancer Study Group participants and authors are as follows:
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, 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 (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, USA. 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 & Technology Research Foundation, Amherst, NY, USA. 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, Rep. 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, Rep. 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, Ch. 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 (ANZ BCTG) 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

Calgary Mater Newcastle, 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, NSW, 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, Tasmania, Australia. 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

	ACKNOWLEDGMENTS

 
We thank the many pathologists who submitted tumor blocks and slides, Rosita Kammler and the pathology team in Bern for coordination of the pathology material transmission, and Stefania Andrighetto for data management at the pathology office in Milan. We also thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials.

	NOTES

 
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.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... Author Contributions Appendix REFERENCES

 
1. Bardou VJ, Arpino G, Elledge RM, et al: Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 21:1973-1979, 2003[Abstract/Free Full Text]

2. Lippman ME, Allegra JC, Thompson EB, et al: The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. N Engl J Med 298:1223-1228, 1978[Abstract]

3. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-Receptor Status and Outcomes of Modern Chemotherapy for Patients With Node-Positive Breast Cancer. JAMA 295:1658-1667, 2006[Abstract/Free Full Text]

4. Anonymous: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer: Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14:2843-2877, 1996[Abstract/Free Full Text]

5. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569-1583, 2005[Abstract/Free Full Text]

6. International Breast Cancer Study Group: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 95:1833-1846, 2003[Abstract/Free Full Text]

7. International Breast Cancer Study Group: Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 94:1054-1065, 2002[Abstract/Free Full Text]

8. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998[CrossRef][Medline]

9. Early Breast Cancer Trialists' Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189-1196, 1996[CrossRef][Medline]

10. Manzotti M, Dell'Orto P, Maisonneuve P, et al: Down-regulation of beta(1C) integrin in breast carcinomas correlates with high proliferative fraction, high histological grade, and larger size. Am J Pathol 156:169-174, 2000[Abstract/Free Full Text]

11. Regan MM, Viale G, Mastropasqua MG, et al: Re-evaluating adjuvant breast cancer trials according to hormone receptors determined by immunohistochemistry versus extraction assays. J Natl Cancer Inst 98:1571-1581, 2006[Abstract/Free Full Text]

12. Diaz LK, Sneige N: Estrogen receptor analysis for breast cancer: Current issues and keys to increasing testing accuracy. Adv Anat Pathol 12:10-19, 2005[CrossRef][Medline]

13. Nadji M, Gomez-Fernandez C, Ganjei-Azar P, et al: Immunohistochemistry of estrogen and progesterone receptors reconsidered: Experience with 5,993 breast cancers. Am J Clin Pathol 123:21-27, 2005[CrossRef][Medline]

14. Bonetti M, Gelber RD: A graphical method to assess treatment-covariate interactions using the Cox model on subsets of the data. Stat Med 19:2595-2609, 2000[CrossRef][Medline]

15. Bonetti M, Gelber RD: Patterns of treatment effects in subsets of patients in clinical trials. Biostatistics 5:465-481, 2004[Abstract]

16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef]

17. Collins LC, Botero ML, Schnitt SJ: Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: An analysis of 825 cases. Am J Clin Pathol 123:16-20, 2005[CrossRef][Medline]

18. Horwitz KB, McGuire WL: Estrogen control of progesterone receptor in human breast cancer: Correlation with nuclear processing of estrogen receptor. J Biol Chem 253:2223-2228, 1978[Free Full Text]

19. Colleoni M, Litman HJ, Castiglione-Gertsch M, et al: Duration of adjuvant chemotherapy for breast cancer: A joint analysis of two randomized trials investigating 3 versus 6 courses of CMF (cyclophosphamide, methotrexate and 5-fluorouracil). Br J Cancer 86:1705-1714, 2002[CrossRef][Medline]

20. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline]

21. Fisher B, Jeong JH, Bryant J, et al: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: Long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364:858-868, 2004[CrossRef][Medline]

22. Fisher B, Jeong JH, Anderson S, et al: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: Updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96:1823-1831, 2004[Abstract/Free Full Text]

Submitted January 2, 2007; accepted October 3, 2007.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Interactions Between Treatment and Continuous Covariates: A Step Toward Individualizing Therapy
  Patrick Royston and Willi Sauerbrei
  JCO 2008 26: 1397-1399 [Full Text]

This article has been cited by other articles:

				C.-H. Lin, J.-Y. Liau, Y.-S. Lu, C.-S. Huang, W.-C. Lee, K.-T. Kuo, Y.-C. Shen, S.-H. Kuo, C. Lan, J. M. Liu, et al. Molecular Subtypes of Breast Cancer Emerging in Young Women in Taiwan: Evidence for More Than Just Westernization as a Reason for the Disease in Asia Cancer Epidemiol. Biomarkers Prev., June 1, 2009; 18(6): 1807 - 1814. [Abstract] [Full Text] [PDF]

				A. A. Iverson, C. Gillett, P. Cane, C. D. Santini, T. M. Vess, L. Kam-Morgan, A. Wang, M. Eisenberg, C. M. Rowland, J. J. Hessling, et al. A Single-Tube Quantitative Assay for mRNA Levels of Hormonal and Growth Factor Receptors in Breast Cancer Specimens J. Mol. Diagn., March 1, 2009; 11(2): 117 - 130. [Abstract] [Full Text] [PDF]

				M. Bonetti, B. F. Cole, and R. D. Gelber Another STEPP in the Right Direction J. Clin. Oncol., August 1, 2008; 26(22): 3813 - 3814. [Full Text] [PDF]

				P. Royston and W. Sauerbrei Interactions Between Treatment and Continuous Covariates: A Step Toward Individualizing Therapy J. Clin. Oncol., March 20, 2008; 26(9): 1397 - 1399. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Viale, G. Articles by Coates, A. S. Search for Related Content PubMed PubMed Citation Articles by Viale, G. Articles by Coates, A. S. Related Articles Related Editorial Social Bookmarking                            What's this?