Originally published as JCO Early Release 10.1200/JCO.2005.03.0783 on February 27 2006

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 Search for Related Content PubMed PubMed Citation Related Articles Related Editorial Social Bookmarking                            What's this?

Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph Node-Positive Breast Cancer: International Breast Cancer Study Group Trial 13-93

International Breast Cancer Study Group

From the International Breast Cancer Study Group. The members and affiliations of the writing committee, as well as the participants and authors of Trial 13-93, are listed in the Appendix

Address reprint requests to Marco Colleoni, MD, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy; e-mail: marco.colleoni{at}ieo.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: The value of adjuvant tamoxifen after chemotherapy for premenopausal women with breast cancer has not been adequately assessed.

PATIENTS AND METHODS: Between 1993 and 1999, International Breast Cancer Study Group Trial 13-93 enrolled 1,246 assessable premenopausal women with axillary node-positive, operable breast cancer. All patients received chemotherapy (cyclophosphamide plus either doxorubicin or epirubicin for four courses followed by immediate or delayed classical cyclophosphamide, methotrexate, and fluorouracil for three courses), which was followed by either tamoxifen (20 mg daily) for 5 years or no further treatment. The primary end point was disease-free survival (DFS). Tumors were classified as estrogen receptor (ER) -positive (n = 735, 59%) if immunohistochemical (IHC) or ligand-binding assays (LBA) were clearly positive. The ER-negative group included all other tumors (n = 511, 41%). A subset of the ER-negative group was defined as ER absent (n = 108, 9%) if IHC staining was none or if the LBA result was 0 fmol/mg cytosol protein. The median follow-up time was 7 years.

RESULTS: Tamoxifen improved DFS in the ER-positive cohort (hazard ratio [HR] for tamoxifen v no tamoxifen = 0.59; 95% CI, 0.46 to 0.75; P < .0001) but not in the ER-negative cohort (HR = 1.02; 95% CI, 0.77 to 1.35; P = .89). Tamoxifen had a detrimental effect on patients with ER-absent tumors compared with no tamoxifen in an unplanned exploratory analysis (HR = 2.10; 95% CI, 1.03 to 4.29; P = .04). Patients with ER-positive tumors who achieved chemotherapy-induced amenorrhea had a significantly improved outcome (HR for amenorrhea v no amenorrhea = 0.61; 95% CI, 0.44 to 0.86; P = .004), whether or not they received tamoxifen.

CONCLUSION: Tamoxifen after adjuvant chemotherapy significantly improved treatment outcome in premenopausal patients with endocrine-responsive disease, but its use as adjuvant therapy for patients with ER-negative tumors is not recommended.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Chemotherapy and tamoxifen are individually effective adjuvant treatments and are an established component of the adjuvant treatment programs for the majority of patients with estrogen receptor (ER) -positive breast cancer.^1-3 The 2005 update of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis of tamoxifen trials has provided consolidated data on hormonal treatments for many categories of patients with early-stage breast cancer; the results showed that the efficacy of adjuvant tamoxifen increased with longer duration of therapy,⁴ irrespective of age, menopausal status, and administration of chemotherapy. However, nearly all of the evidence on sequential chemoendocrine therapy involved older women, and limited data are available specifically for premenopausal women randomly assigned to chemotherapy or chemotherapy plus tamoxifen for 5 years.

The value of chemoendocrine therapy for premenopausal patients has been defined only recently. In fact, only 205 women less than 50 years of age were included in the 1998 EBCTCG overview, of whom only 177 were reported to have had ER-positive disease, leading to a statistically uncertain advantage in disease-free survival (DFS) and overall survival (OS) with the addition of tamoxifen.² Previous overview data invited even fewer conjectures about the addition of tamoxifen to chemotherapy for premenopausal women with endocrine-responsive tumors and little insight into whether the use of this drug might be extended to patients with endocrine-nonresponsive disease.^5-8

Within this historical context, in 1993, the International Breast Cancer Study Group (IBCSG) initiated Trial 13-93 for premenopausal patients with lymph node-positive breast cancer to examine the role of adjuvant treatment using chemotherapy or the sequential combination of chemotherapy and tamoxifen. The sequential administration was chosen to avoid the possible interaction of chemotherapy and tamoxifen when administered concurrently.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Study Design
Trial 13-93 is a randomized, 2 x 2 factorial design, phase III clinical trial comparing 5 years of tamoxifen therapy with no endocrine treatment and comparing a 16-week gap between chemotherapy regimens with no treatment gap. From May 1993 to August 1999, 1,294 premenopausal patients with node-positive breast cancer, who were not suitable for endocrine therapy alone, were randomly assigned to receive either tamoxifen (20 mg daily) for up to 5 years or no hormonal therapy after administration of chemotherapy. Chemotherapy consisted of four 21-day courses of either doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² intravenously on day 1 or epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² intravenously on day 1, followed by immediate or delayed (16-week gap) three 28-day courses of classical cyclophosphamide 100 mg/m² orally on days 1 through 14, methotrexate 40 mg/m² intravenously on days 1 and 8, and fluorouracil 600 mg/m² intravenously on days 1 and 8. Systemic adjuvant therapy was to begin within 6 weeks of primary surgery. Informed consent was required according to the criteria established within individual countries. The protocol was reviewed and approved by local institutional review boards.

Random assignment was conducted centrally (at coordinating centers in Bern, Switzerland or Sydney, Australia) after stratification according to ER status (positive v negative), institution, and primary therapy (mastectomy v breast conservation with radiotherapy planned v breast conservation without radiotherapy). The permuted blocks randomization schedule was produced using pseudorandom numbers generated by a congruence method.

Premenopausal status was defined as having one of the following sets of characteristics: (1) normal menstrual period within 6 calendar months before random assignment, with no hormone replacement therapy (HRT) and no previous hysterectomy; (2) previous hysterectomy, not receiving HRT, and younger than 40 years of age or 40 years of age or older with premenopausal luteinizing hormone, follicle-stimulating hormone, and estradiol levels; or (3) receiving HRT, 49 years old or younger, and a menstrual period within 6 calendar months before starting HRT.

All patients had a histologically proven unilateral breast cancer of stage pT1, pT2, or pT3, pN1, M0 (Union Internationale Contre le Cancer 1987⁹), with either ER-positive or ER-negative primary tumors. Steroid hormone receptor content in the primary tumors was determined by standard methods.^10,11 Participating centers were encouraged to perform quantitative biochemical ligand-binding assays (LBA). However, during the course of the trial, immunohistochemical (IHC) methodology was developed, and participating centers were allowed to report IHC results. Tumors were classified as ER-positive if IHC or LBA were clearly positive. The ER-negative group included all other tumors, and a subset of the ER-negative group was identified as ER-absent if quantitative IHC staining was none or if the LBA result was 0 fmol/mg cytosol protein. Progesterone status was determined in the same manner. ER status was evaluated with quantitative IHC in 354 patients (28%), with qualitative IHC (positive or negative) in 347 patients (28%), and with LBA in 545 patients (44%).

Tumor grade determination was based on the local Bloom-Richardson (BR) scoring, if available (n = 806, 65%). If the BR scoring was not available from the participating center, then grade was based the local 3-point differentiation scale (n = 373, 30%). If neither the local BR nor the local differentiation scale was available, then grade was based on the central review BR scoring (n = 33, 3%). Tumor grade was unavailable for 34 patients (3%).

Surgery to remove the primary tumor was either a total mastectomy with axillary clearance or a conservative procedure (quadrantectomy or lumpectomy) with axillary lymph node dissection. Radiotherapy was recommended after breast conservation and was postponed until the end of chemotherapy.¹² Staging before random assignment included chest x-ray, contralateral mammogram, bone scintigram (if clinically indicated), and hematologic, liver, and renal function tests. Clinical, hematologic, and biochemical assessments were required every 3 months for the first year, every 6 months for the second year, and yearly thereafter. Modified WHO toxicity grading criteria were used.¹³ Mammography was performed yearly. The data management and medical staff reviewed all study records (initial data, treatment, toxicity, and recurrence) and conducted regular site visit audits. In particular, the study chair reviewed the records for all grade 3 or worse toxicities and clarified attribution. Menses data were collected every 3 months during the patient's first 2 years on study, every 6 months for the next 3 years, and yearly thereafter.

End Points and Statistical Considerations
DFS was defined as the length of time from the date of random assignment to any relapse (including ipsilateral or contralateral breast recurrence), the appearance of a second primary malignancy, or death, whichever occurred first. OS was defined as the length of time from the date of random assignment to death from any cause. DFS and OS percentages, SEs, and hazard ratios (HRs) and 95% CIs for the treatment comparisons were obtained using the Kaplan-Meier method,¹⁴ Greenwood's formula,¹⁵ and the log-rank test,¹⁶ respectively. Cox proportional hazards regression models¹⁷ were used to control for prognostic features and to test for interactions between potential prognostic factors and treatment effects. All probability values were obtained from two-sided tests. P values used for the comparison of tamoxifen versus no tamoxifen were stratified by gap versus no gap. A landmark analysis¹⁸ was used to assess the prognostic significance of chemotherapy-induced amenorrhea (CA). Results are reported at a median follow-up time of 7 years.

Cox proportional hazards models were used to test for an interaction between the gap and the tamoxifen comparisons, both overall and according to ER status. No significant interactions were observed (all P > .10). Therefore, it is appropriate to report outcomes by the tamoxifen groups using stratified analyses based on the 2 x 2 factorial design. These intent-to-treat (ITT) analyses evaluate the randomized comparison of tamoxifen versus no tamoxifen after completion of adjuvant chemotherapy.

The random assignment was performed within 6 weeks of surgery before the start of any chemotherapy. Patients were stratified according to ER status, and the intention to perform separate analyses according to ER status was specified in the original protocol. The trial was opened in 1993 and amended to increase the sample size from 900 to 1,225 in 1997 when it was observed that the patients entered had more favorable prognoses than were expected when the study was designed. The Data Safety Monitoring Committee (DSMC) reviewed accrual and safety data twice a year. Two predetermined interim efficacy analyses were performed (in January 1999 and November 2000), and the DSMC recommended to continue the study on both occasions. Four hundred thirty-four events were required; 470 were observed at the time of this analysis.

On the basis of the recommendation of the IBCSG DSMC and results emerging from other studies, in August 2000 (1 year after the random assignment of the last patient), the Scientific Committee recommended that patients with ER-positive tumors who were randomly assigned to not receive tamoxifen be offered this treatment. Three hundred thirty-two patients were identified as possible candidates to receive late tamoxifen, and 60 began tamoxifen. Reasons for not starting late tamoxifen included patient refusal, clinician decision, and tamoxifen begun earlier on relapse. In addition, in August 2002, letters were sent to the investigators for the 64 patients with ER-negative tumors who were randomly assigned to the tamoxifen arms and still receiving tamoxifen. Investigators were asked to consider the endocrine responsiveness and to discontinue the tamoxifen in patients with endocrine-nonresponsive disease. Six of these patients stopped their tamoxifen treatment.

Patient Eligibility and Characteristics
A total of 1,294 patients were enrolled onto the study, but 47 patients were excluded as a result of the noncompliance of a single institution, and one additional patient was excluded because documentation of informed consent was unavailable (Fig 1). None of the excluded patients are included in the ITT analyses. Seventeen patients did not match eligibility criteria but are included in the ITT analyses; six patients were postmenopausal, two had inadequate surgery, one had bilateral breast cancer, four had an incorrect disease stage, one was medically unsuitable, two were pregnant at diagnosis, and one was lactating.

View larger version (26K): [in this window] [in a new window]   Fig 1. Consort flow chart of International Breast Cancer Study Group Trial 13-93.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

View larger version (20K): [in this window] [in a new window]   Fig 2. Outcomes comparing tamoxifen versus no tamoxifen according to estrogen receptor (ER) status. (A) Disease-free survival and (B) overall survival for the 511 patients in the ER-negative cohort, and (C) disease-free survival and (D) overall survival for the 735 patients in the ER-positive cohort. Log-rank P values are stratified by gap versus no gap.

View larger version (11K): [in this window] [in a new window]   Fig 3. (A) Disease-free and (B) overall survival comparing tamoxifen versus no tamoxifen within the subgroup of 108 patients whose tumors did not express estrogen receptor (estrogen receptor absent). Log-rank P values are stratified by gap versus no gap.

Incidence of Amenorrhea
Table 5 lists the proportions of women who had amenorrhea after chemotherapy (CA) according to age at study entry and treatment assignment. A patient was considered to have CA if there was at least one report of no menses during the first 15 months after randomization (the first five follow-up reports). The incidence of CA was significantly higher for patients aged 35 years or older at the time of study entry compared with patients younger than 35 years old (91% v 42%, respectively; P < .0001). Ninety-six percent of patients 40 years of age or older had CA by the end of chemotherapy. The median age of the 918 women who achieved CA was 45 years, and 104 women (11%) had some recovery, with at least one report of menses during months 18 and 36.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Trial 13-93 was the first trial to address the question of whether it is beneficial to use sequential adjuvant endocrine therapy for premenopausal patients whose physicians have prescribed adjuvant chemotherapy. When the trial was designed, EBCTCG overview analyses indicated that tamoxifen was not likely to be efficacious for women younger than 50 years of age.⁷ Endocrine treatment effects were considered of secondary importance for younger women presenting with a node-positive breast cancer. However, based on information from the EBCTCG overview indicating a large benefit from chemotherapy for premenopausal women, all women who participated in this trial were offered a full program of adjuvant cytotoxics.

Several past studies reported the value of adjuvant chemoendocrine treatment in the management of premenopausal patients with node-positive early breast cancer.^8,19-21 Results of the National Surgical Adjuvant Breast and Bowel Project Trial B-09 showed that adding tamoxifen for a duration of 2 years, concurrently and after chemotherapy, improved treatment outcome for premenopausal women with ER- and/or progesterone receptor-positive disease.⁸ Three other small studies failed to demonstrate an advantage of adding tamoxifen concurrently with a chemotherapy regimen like cyclophosphamide, methotrexate, and fluorouracil (tamoxifen administered for a maximum duration of 2 years) compared with chemotherapy alone.^19-21 Chemotherapy alone is associated with poor treatment outcome for young women with ER-positive disease.²² The North American Breast Cancer Intergroup recently reported that adding 5 years of tamoxifen after chemotherapy with or without luteinizing hormone-releasing hormone agonist significantly improved DFS for these patients.²³ Despite the conflicting results available from individual trials, adjuvant tamoxifen is currently considered standard care for premenopausal women with endocrine-responsive disease.^4,24

The results of IBCSG Trial 13-93 are important for clarifying the role of adjuvant tamoxifen in premenopausal patients and provide some indirect information on the importance of ovarian function suppression resulting from chemotherapy and its impact on the efficacy of tamoxifen. The data suggest that there is a different pattern of outcome according to the degree of potential endocrine responsiveness (defined as steroid hormone receptor positive, negative, or absent). The benefit from tamoxifen was evident among the cohort of patients with ER-positive tumors, whereas no benefit was observed in patients with ER-negative tumors. Several other laboratory and clinical studies have provided evidence of different interactions of tamoxifen with cellular growth according to ER status. A significant decrease of Ki-67 after a short-term tamoxifen treatment was seen in patients with ER-positive disease, whereas no effect was observed in patients with ER-negative breast cancer.²⁵ In patients with ER-negative disease, the dominant influence of growth factors, such as epidermal growth factor, heregulins, and insulin-like growth factors, on tumor cell growth might be mediated through specific receptor tyrosine kinases at the cell surface,²⁶ and cross talk between tamoxifen and growth factor receptor pathways might be responsible for tumor progression.²⁷ In particular, tamoxifen may stimulate estrogen-induced expression of genes encoding growth factors and their receptors, and other signaling molecules may provide cell proliferation and survival stimuli.^28,29 Clinical data emerging in the late 1980s and early 1990s have convincingly indicated a significant inverse relationship between the expression of the epidermal growth factor receptor and, to a lesser extent, c-erbB-2 protein²⁹ and the degree of endocrine sensitivity in breast cancer.

In the trials described in the previous paragraphs, analyses were performed based on a so-called receptor-negative grouping, which included receptor-absent status within the ER-negative group. Some clinical studies³⁰ and gene expression profiling^31,32 have provided information suggesting that receptor-absent breast cancer is a distinct entity from breast cancer with low levels of receptor expression. In the present trial, within the ER-negative cohort, we observed that the use of adjuvant tamoxifen was detrimental in patients with no expression of ERs (ER-absent tumors), despite the fact that tamoxifen and chemotherapy were not administered concurrently. Although the exact threshold of steroid hormone receptors needed to distinguish endocrine-responsive from endocrine-nonresponsive tumors is unknown, it is evident that the absence of staining for hormone receptors confers definite endocrine nonresponsiveness with a different clinical behavior, as indicated by the results of our trial. This crucial distinction implies the absolute necessity for reporting quantitative results from IHC staining with appropriate quality control. Finally, caution is required when using endocrine therapies for women with endocrine-nonresponsive tumors at high risk of relapse. A recently published survey on clinical practice in Italy indicated that adjuvant endocrine therapy was administered to 12% of patients classified as having hormone receptor-negative disease.³³

Ovarian function suppression is effective adjuvant therapy in the absence of chemotherapy for patients with early breast cancer.⁴ The effects of CA have been studied but remain controversial.^34-37 In retrospective analyses, the effect of amenorrhea on outcome is confounded with chemotherapy dose-intensity and duration. More recently, induction of amenorrhea was found to be more important as an indicator of improved outcome for less dose-intense and shorter duration regimens³⁸ as well as for some more intensive, anthracycline-containing regimens.³⁹

The incidence of amenorrhea was meticulously studied in Trial 13-93, and we found that achievement of amenorrhea was significantly correlated with improved DFS for patients with endocrine-responsive disease, thus supporting a role for ovarian suppression in the adjuvant treatment of premenopausal patients with endocrine-responsive disease. No interaction was observed between the use of tamoxifen and CA, suggesting that iatrogenic amenorrhea should not be considered a replacement for or an argument against tamoxifen. The question of whether additional benefit can be obtained from ovarian suppression in premenopausal patients receiving tamoxifen is now being directly addressed by the global Suppression of Ovarian Function Trial coordinated by the IBCSG on behalf of the Breast International Group and the North American Breast Cancer Intergroup. The Suppression of Ovarian Function Trial compares tamoxifen alone versus ovarian function suppression plus tamoxifen versus ovarian function suppression plus exemestane for patients with steroid hormone receptor-positive tumors who remain premenopausal after adjuvant chemotherapy or for whom tamoxifen alone is considered a reasonable treatment option.^40,41

The results of Trial 13-93 indicate that the effect of tamoxifen administered sequentially with chemotherapy is largely dependent on the endocrine responsiveness of the tumor. The positive effect for premenopausal patients with ER-positive, node-positive disease definitively promotes a role for tamoxifen for these patients.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Writing Committee: Marco Colleoni, Shari Gelber, Aron Goldhirsch, Stefan Aebi, Monica Castiglione-Gertsch, Karen N. Price, Alan S. Coates, Richard D. Gelber; Scientific Committee: A. Goldhirsch, A.S. Coates (Co-Chairs);Foundation Council: B. Thürlimann (President), M. Castiglione, 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, F. Paganetti, C.-M. Rudenstam, R. Stahel, H.-J. Senn, A. Veronesi; Coordinating Center (Bern, Switzerland): M. Castiglione-Gertsch (CEO), A. Hiltbrunner (Director), G. Egli, M. Rabaglio, R. Maibach; Statistical Center (Harvard School of Public Health and Dana-Farber Cancer Institute, Boston, MA, USA): R. Gelber (Group Statistician), K. Price (Director of Scientific Administration), S. Gelber (Trial Statistician), B. Cole, A. Keshaviah, M. Regan, D. Zahrieh; Quality of Life Office (Bern, Switzerland): J. Bernhard, Ch. Hürny; Pathology Office: B. Gusterson, G. Viale, V. Spataro; Data Management Center (Frontier Science & Tech. Res. Found., Amherst, NY, USA): L. Blacher (Director), J. Celano, M. Isley, R. Hinkle, S. Lippert, K. Scott; Ce ntro di Riferimento Oncologico Aviano, Italy: A. Veronesi, D. Crivellari, S. Monfardini, E. Galligioni, M. D. Magri, A. Buonadonna, S. Massarut, C. Rossi, E. Candiani, A. Carbone, 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; Istituto Europeo di Oncologia, Milano, Italy: A. Goldhirsch, M. Colleoni, G. Martinelli, G. Viale, L. Orlando, F. Nolè, R. Torrisi, T. De Pas, F. de Braud, S. Cinieri, F. Peccatori, A. Luini, R. Orecchia, G. Renne, F. de Braud, A. Costa, S. Zurrida, P. Veronesi, V. Sacchini, V. Galimberti, M. Intra, U. Veronesi; Quality of Life Office (Bern, Switzerland) J. Bernhard, Ch. Hürny; Pathology Office: B. Gusterson, G. Viale, V. Spataro; Data Management Center (Frontier Science & Tech. Res. Found., Amherst, NY, USA): L. Blacher (Director), J. Celano, M. Isley, R. Hinkle, S. Lippert, K. Scott; Centro di Riferimento Oncologico Aviano, Italy: A. Veronesi, D. Crivellari, S. Monfardini, E. Galligioni, M. D. Magri, A. Buonadonna, S. Massarut, C. Rossi, E. Candiani, A. Carbone, 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; Istituto Europeo di Oncologia Milano, Italy: A. Goldhirsch, M. Colleoni, G. Martinelli, G. Viale, L. Orlando, F. Nolè, R. Torrisi, T. De Pas, F. de Braud, S. Cinieri, F. Peccatori, A. Luini, R. Orecchia, G. Renne, F. de Braud, A. Costa, S. Zurrida, P. Veronesi, V. Sacchini, V. Galimberti, M. Intra, U. Veronesi; Ospedale Infermi Rimini, Italy: A. Ravaioli, D. Tassinari, G. Oliverio, F. Barbanti, P. Rinaldi, E. Pini, G. Drudi; Ospedale S. Eugenio Roma, Italy: M. Antimi, M. Minelli, V. Bellini, R. Porzio, E. Pernazza,G. Santeusanio, L.G. Spagnoli; General Hospital, Gorizia, Italy: S. Foladore, L. Foghin, G. Pamich, C. Bianchi, B. Marino, A. Murgia, V. Milan; West Swedish Breast Cancer Study Group, Göteborg, Sweden: C.M. Rudenstam, A. Wallgren, S. Ottosson-Lönn, R. Hultborn, G. Colldahl-Jädeström, E. Cahlin, J. Mattsson, S. B. Holmberg, O. Ruusvik, L.G. Niklasson, S. Dahlin, G. Karlsson, B. Lindberg, A. Sundbäck, S. BergegÂrdh, O. Groot, L.O. Dahlbäck, H. Salander, C. Andersson, M. Heideman, A. Nissborg, A. Wallin, G. Claes, T. Ramhult, J.H. Svensson, P. Liedberg, A. Nilsson, G. Havel, G. Oestberg, S. Persson, M. Suurküla, J. Matusik; The Institute of Oncology, Ljubljana, Slovenia: J. Lindtner, D. Erzen, T. Cufer, J. Cervek, O. Cerar, B. Zakotnik, E. Majdic, R. Golouh, J. Lamovec, J. Jancar, I. Vrhovec, M. Kramberger; Groote Schuur Hospital, Cape Town, Rep. of South Africa: E. Murray, I.D. Werner, D.M. Dent, A. Gudgeon, E. Panieri, E. McEvoy, J. Toop, R. Bowen; Sandton Oncology Center, Johannesburg, South Africa: D. Vorobiof, M. Chasen, G. Fotheringham, G. de Muelenaere, B. Skudowitz, C. Mohammed, A. Rosengarten; Madrid Breast Cancer Group, Madrid, Spain: H. Cortès-Funes, C. Mendiola, C. Gravalos, R. Colomer, M. Mendez, F. Cruz Vigo, P. Miranda, A. Sierra, F. Martinez-Tello, A. Garzon, S. Alonso, A. Ferrero, C. Vargas; SAKK (Swiss Group for Clinical Cancer Research):Inselspital, Bern: M.F. Fey, M. Castiglione-Gertsch, E. Dreher, H. Schneider, S. Aebi, K. Buser, J. Ludin, G. Beck, A. Haenel, J.M. Lüthi, H.J. Altermatt, M. Nandedkar; Kantonsspital, St. Gallen: H.J. Senn, B. Thürlimann, Ch. Oehlschlegel, G. Ries, M. Töpfer, U. Lorenz, A. Ehrsam, B. Späti, E. Vogel; Ospedale San Giovanni, Bellinzona: 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, A. Goldhirsch; Kantonsspital, Basel: R. Herrmann, C.F. Rochlitz, J.F. Harder, O. Köchli, U. Eppenberger, J. Torhorst; Hôpital des Cadolles, Neuchâtel: D. Piguet, P. Siegenthaler, V. Barrelet, R.P. Baumann; Kantonsspital, Zürich: B. Pestalozzi, C. Sauter, V. Engeler, U. Haller, U. Metzger, P. Huguenin, R. Caduff; Centre Hôpitalier Universitaire, Lausanne: L. Perey, S. Leyvraz, P. Anani, C. Genton, F. Gomez, P. De Grandi, P. Reymond, R. Mirimanoff, M. Gillet, J.F. Delaloye; Hôpital Cantonal, Geneva: 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; Kantonsspital Graubünden, Chur: F. Egli, P. Forrer (deceased), A. Willi, R. Steiner. J. Allemann, T. Rüedi, A. Leutenegger, U. Dalla Torre; Kantonsspital Aarau: A. Schönenberger, M. Wernli, M. Bargetzi, W. Mingrone, P. Schmid, E. Bärtschi, K. Beretta; Australian New Zealand Breast Cancer Trials Group (ANZ BCTG): J.F. Forbes, D. Lindsay, A. Wilson, D. Preece; Statistical Center, NHMRC CTC, University of Sydney: R. J. Simes, H. Dhillon; The Cancer Council Victoria, Melbourne, VIC: J. Collins, R. Snyder, E. Abdi, R. Abraham, R. Basser, P. Briggs, W.I. Burns, M. Chipman, J. Chirgwin, V. Ganju, G. Goss, M. Green, I. Haines, S. Hart, R. Holmes, G. Lindeman, J. McKendrick, S. McLachlan, R. McLennan, P. Mitchell, G. Richardson, C. Underhill; Flinders Medical Centre,Bedford Park, SA: T. Malden; Newcastle Mater Misericordiae Hospital, Waratah, NSW: J.F. Forbes, J. Stewart, S. Ackland, A. Bonaventura, D. Jackson; Mount Hospital, Perth, WA: G. van Hazel; Prince of Wales Hospital, Randwick, NSW: M. Friedlander, B. Brigham, C. Lewis; Royal Perth Hospital, Perth, WA: E. Bayliss, A. Chan, D. Ransom, J. Trotter; Sir Charles Gairdner Hospital, Nedlands, WA: M. Byrne, G. van Hazel, A. Davidson, J. Dewar, M. Buck;. Royal Prince Alfred Hospital and Dubbo Base Hospital, Sydney, NSW: J. Beith, M. Boyer, A.S. Coates, R. J. Simes, A. Sullivan, M.H.N. Tattersall; St George Hospital. Kogarah, NSW: P. de Souza; Auckland Hospital, Auckland, New Zealand: V.J. Harvey, P. Thompson, D. Porter

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Marco Colleoni, Aron Goldhirsch, Monica Castiglione-Gertsch, Karen N. Price, Alan S. Coates, Richard D. Gelber Administrative support: Monica Castiglione-Gertsch, Karen N. Price Provision of study materials or patients: Marco Colleoni, Stefan Aebi, Alan S. Coates Collection and assembly of data: Marco Colleoni, Shari Gelber, Monica Castiglione-Gertsch, Karen N. Price, Alan S. Coates, Richard D. Gelber Data analysis and interpretation: Marco Colleoni, Shari Gelber, Aron Goldhirsch, Stefan Aebi, Karen N. Price, Richard D. Gelber Manuscript writing: Marco Colleoni, Shari Gelber, Aron Goldhirsch, Stefan Aebi, Monica Castiglione-Gertsch, Karen N. Price, Alan S. Coates, Richard D. Gelber Final approval of manuscript: Marco Colleoni, Shari Gelber, Aron Goldhirsch, Monica Castiglione-Gertsch, Karen N. Price, Alan S. Coates, Richard D. Gelber

 

View larger version (6K): [in this window] [in a new window]   Fig 4. Disease-free survival comparing chemotherapy-induced amenorrhea (CA) versus no CA for the (A) estrogen receptor (ER) -positive cohort and for the (B) ER-positive cohort who received tamoxifen. (Landmark analyses start at 18 months from random assignment.) Log-rank P values are stratified by gap versus no gap.

	Acknowledgment

	NOTES

 
Supported in part by the Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, National Cancer Institute Grant No. CA-75362, Swedish Cancer Society, Cancer Association of South Africa, and Foundation for Clinical Research of Eastern Switzerland.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

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 Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
1. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International consensus panel on the treatment of primary breast cancer—Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 19:3817-3827, 2001[Free Full Text]

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

3. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline]

4. 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]

5. Bramwell VH, Pritchard KI: Tamoxifen added to adjuvant chemotherapy in premenopausal women with early breast cancer: Is it standard practice or still a subject for study? Eur J Cancer 35:1625-1627, 1999[CrossRef][Medline]

6. Early Breast Cancer Trialists' Collaborative Group: Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: An overview of 61 randomized trials among 28,896 women. N Engl J Med 319:1681-1692, 1988[Abstract]

7. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-15, 1992[Medline]

8. Fisher B, Redmond C, Brown A, et al: Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 305:1-6, 1981[Abstract]

9. Hermanek P, Sobin LH: TNM Classification of Malignant Tumors (ed 4). Berlin, Germany, Springer-Verlag, 1987

10. Davis BW, Zava DT, Locher GW, et al: Receptor heterogeneity of human breast cancer as measured by multiple intratumoral assays of estrogen and progesterone receptor. Eur J Cancer Clin Oncol 20:375-382, 1984[CrossRef][Medline]

11. Berger U, Wilson P, McClelland RA, et al: Correlation of immunocytochemically demonstrated estrogen receptor distribution and histopathologic features in primary breast cancer. Hum Pathol 18:1263-1267, 1987[Medline]

12. Wallgren A, Bernier J, Gelber RD, et al: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer: International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys 35:649-659, 1996[CrossRef][Medline]

13. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, WHO Offset Publication No. 48, 1979

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

15. Greenwood M: The Natural Duration of Cancer. London, United Kingdom, HM Stationary Office, 1926

16. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

17. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972

18. Anderson JR, Cain KC, Gelber RD, et al: Analysis and interpretation of the comparison of survival by treatment outcome variables in cancer clinical trials. Cancer Treat Rep 69:1139-1146, 1985[Medline]

19. Andersson M, Kamby C, Jensen MB, et al: Tamoxifen in high-risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy: Report from the Danish Breast Cancer Co-Operative Group DBCG 82B Trial. Eur J Cancer 35:1659-1666, 1999[CrossRef][Medline]

20. Tormey DC, Gray R, Gilchrist K, et al: Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: An ECOG trial. Cancer 65:200-206, 1990[CrossRef][Medline]

21. Ingle JN, Everson L, Wieand S, et al: Randomized trial to evaluate the addition of tamoxifen to CMFp adjuvant therapy in premenopausal women with node positive breast cancer. Cancer 63:1257-1264, 1989[CrossRef][Medline]

22. Goldhirsch A, Gelber RD, Yothers G, et al: Adjuvant therapy for very young women with breast cancer: Need for tailored treatments. J Natl Cancer Inst Monogr 30:44-51, 2001[Medline]

23. Davidson NE, O'Neill AM, Vukov AM, et al: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 23:5973-5982, 2005[Abstract/Free Full Text]

24. 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]

25. Dardes RD, Horiguchi J, Jordan VC: A pilot study of the effects of short-term tamoxifen therapy on Ki-67 labelling index in women with primary breast cancer. Int J Oncol 16:25-30, 2000[Medline]

26. Wakeling AE, Nicholson RI, Gee JM: Prospects for combining hormonal and nonhormonal growth factor inhibition. Clin Cancer Res 7:S4350-S4355, 2001 (suppl 12)

27. Osborne CK, Schiff R: Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer. Breast 12:362-367, 2003[CrossRef][Medline]

28. Nicholson RI, McClelland RA, Robertson JF, et al: Involvement of steroid hormone and growth factor cross-talk in endocrine response in breast cancer. Endocr Relat Cancer 6:373-387, 1999[Abstract]

29. Lee AV, Cui X, Oesterreich S: Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res 7:S4429-S4435, 2001 (suppl 12)

30. Colleoni M, Gelber S, Coates AS, et al: Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer. J Clin Oncol 19:4141-4149, 2001[Abstract/Free Full Text]

31. Sorlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001[Abstract/Free Full Text]

32. Gruvberger S, Ringner M, Chen Y, et al: Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res 61:5979-5984, 2001[Abstract/Free Full Text]

33. Roila F, Ballatori E, Patoia L, et al: Adjuvant systemic therapies in women with breast cancer: An audit of clinical practice in Italy. Ann Oncol 14:843-848, 2003[Abstract/Free Full Text]

34. Bonadonna G, Rossi A, Valagussa P, et al: The CMF program for operable breast cancer with positive axillary nodes: Updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer 39:2904-2915, 1977[CrossRef][Medline]

35. Fisher B, Sherman B, Rockette H, et al: 1-Phenylalanine mustard (L-PAM) in the management of premenopausal patients with primary breast cancer: Lack of association of disease-free survival with depression of ovarian function—National Surgical Adjuvant Project for Breast and Bowel Cancers. Cancer 44:847-857, 1979[CrossRef][Medline]

36. Goldhirsch A, Gelber RD, Castiglione-Gertsch M: The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients: International Breast Cancer Study Group. Ann Oncol 1:183-188, 1990[Abstract/Free Full Text]

37. Pagani O, O'Neill A, Castiglione-Gertsch M, et al: Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: Results of the International Breast Cancer Study Group (IBCSG) trial VI. Eur J Cancer 34:632-640, 1998[CrossRef][Medline]

38. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628-4635, 2002[Abstract/Free Full Text]

39. Parulekar WR, Day AG, Ottaway JA, et al: Incidence and prognostic impact of amenorrhea during adjuvant therapy in high risk premenopausal breast cancer: Analysis of a National Cancer Institute of Canada Clinical Trials Group Study—NCIC CTG MA 5. J Clin Oncol 23:6002-6008, 2005[Abstract/Free Full Text]

40. Francis P, Fleming G, Nasi ML, et al: Tailored treatment investigations for premenopausal women with endocrine responsive (ER+ and/or PgR+) breast cancer: The SOFT, TEXT, and PERCHE Trials. Breast 12:S44, 2003 (suppl 1, abstr P104)

41. Dellapasqua S, Colleoni M, Gelber RD, et al: Adjuvant endocrine therapy for premenopausal women with early breast cancer. J Clin Oncol 23:1736-1750, 2005[Free Full Text]

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

Related Editorial

• Tales From a Targeted Therapy
  Richard M. Elledge
  JCO 2006 24: 1323-1325 [Full Text]

This article has been cited by other articles:

				M. Colleoni, Z. Sun, G. Martinelli, R. L. Basser, A. S. Coates, R. D. Gelber, M. D. Green, F. Peccatori, S. Cinieri, S. Aebi, et al. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up Ann. Onc., May 25, 2009; (2009) mdp024v1. [Abstract] [Full Text] [PDF]

				A. Merglen, H. M. Verkooijen, G. Fioretta, I. Neyroud-Caspar, V. Vinh-Hung, G. Vlastos, P. O. Chappuis, M. Castiglione, E. Rapiti, and C. Bouchardy Hormonal therapy for oestrogen receptor-negative breast cancer is associated with higher disease-specific mortality Ann. Onc., May 1, 2009; 20(5): 857 - 861. [Abstract] [Full Text] [PDF]

				S. Yao, B. Xu, F. Ma, Y. Liao, and Y. Fan Breast cancer in women younger than 25: clinicopathological features and prognostic factors Ann. Onc., February 1, 2009; 20(2): 387 - 389. [Full Text] [PDF]

				W. G. Newman, K. D. Hadfield, A. Latif, S. A. Roberts, A. Shenton, C. McHague, F. Lalloo, S. Howell, and D. G. Evans Impaired Tamoxifen Metabolism Reduces Survival in Familial Breast Cancer Patients Clin. Cancer Res., September 15, 2008; 14(18): 5913 - 5918. [Abstract] [Full Text] [PDF]

				B. C. Pestalozzi, D. Zahrieh, E. Mallon, B. A. Gusterson, K. N. Price, R. D. Gelber, S. B. Holmberg, J. Lindtner, R. Snyder, B. Thurlimann, et al. Distinct Clinical and Prognostic Features of Infiltrating Lobular Carcinoma of the Breast: Combined Results of 15 International Breast Cancer Study Group Clinical Trials J. Clin. Oncol., June 20, 2008; 26(18): 3006 - 3014. [Abstract] [Full Text] [PDF]

				M. Parton and I. E. Smith Controversies in the Management of Patients With Breast Cancer: Adjuvant Endocrine Therapy in Premenopausal Women J. Clin. Oncol., February 10, 2008; 26(5): 745 - 752. [Full Text] [PDF]

				S. Aebi and M. Rabaglio Overview of Current Approaches to Adjuvant Endocrine Therapy ASCO Educational Book, January 1, 2008; 2008(1): 9 - 13. [Abstract] [Full Text] [PDF]

				V. C. Jordan Tamoxifen or Raloxifene for Breast Cancer Chemoprevention: A Tale of Two Choices Point Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2207 - 2209. [Full Text] [PDF]

				M. J.E. Mourits, E. G.E. de Vries, K. A. ten Hoor, A. G.J. van der Zee, and P. H.B. Willemse Beware of Amenorrhea During Tamoxifen: It May Be a Wolf in Sheep's Clothing J. Clin. Oncol., August 20, 2007; 25(24): 3787 - 3788. [Full Text] [PDF]

				The International Breast Cancer Study Group Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93 Ann. Onc., July 1, 2007; 18(7): 1177 - 1184. [Abstract] [Full Text] [PDF]

				S. S. Ellenberg Discussion Clinical Trials, April 1, 2007; 4(2): 176 - 177. [PDF]

				A Keshaviah, S Dellapasqua, N Rotmensz, J Lindtner, D Crivellari, J Collins, M Colleoni, B Thurlimann, C Mendiola, S Aebi, et al. CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials Ann. Onc., April 1, 2007; 18(4): 701 - 708. [Abstract] [Full Text] [PDF]

				J. M. Walshe, N. Denduluri, and S. M. Swain Amenorrhea in Premenopausal Women After Adjuvant Chemotherapy for Breast Cancer J. Clin. Oncol., December 20, 2006; 24(36): 5769 - 5779. [Abstract] [Full Text] [PDF]

				S Aebi and M Castiglione The enigma of young age. Ann. Onc., October 1, 2006; 17(10): 1475 - 1477. [Full Text] [PDF]

				R. M. Elledge Tales From a Targeted Therapy J. Clin. Oncol., March 20, 2006; 24(9): 1323 - 1325. [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 Search for Related Content PubMed PubMed Citation Related Articles Related Editorial Social Bookmarking                            What's this?