Annals of Oncology Advance Access published online on March 5, 2008
Annals of Oncology, doi:10.1093/annonc/mdn037
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Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?
1 IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA, USA
2 Oncology Institute of Southern Switzerland, Ospedale Italiano, Viganello, Lugano
3 Swiss Group for Clinical Cancer Research, Bern, Switzerland
4 Tom Baker Cancer Centre, Calgary, Alberta, Canada
5 European Institute of Oncology, Milan, Italy
6 Mayo Clinic Jacksonville, Jacksonville, FL, USA
7 Peter MacCallum Cancer Centre, Melbourne, Australia
8 University of Chicago Medical Center, Chicago, IL, USA
9 IBCSG Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA, USA
10 Senology Center of Eastern Switzerland, Kantonsspital, St Gallen, Switzerland
11 IBCSG Coordinating Center, Bern, Switzerland
12 International Breast Cancer Study Group, Bern, Switzerland
13 University of Sydney, Sydney, Australia
14 Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
15 IBCSG Statistical Center, Dana-Farber Cancer Institute, Frontier Science and Technology Research Foundation, Harvard School of Public Health, Boston, MA, USA
* Correspondence to: Dr M. M. Regan, IBCSG Coordinating Center, Effingerstrasse 40, CH-3008 Bern, Switzerland. Tel: +41 31 389 93 91; Fax: +41 31 389 93 92; E-mail: mregan{at}jimmy.harvard.edu
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Abstract |
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Background: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual; TEXT accrued rapidly.
Methods: From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees.
Results: Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not.
Conclusions: The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this population.
chemotherapy, estrogen receptor, exemestane, ovarian ablation, premenopausal, tamoxifen
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAppendixAcknowledgementsReferences |
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Chemotherapy, tamoxifen and ovarian function suppression/ablation (OFS) are individually effective adjuvant treatments for women <50 years of age with estrogen receptor (ER)-positive breast cancer, as shown in several individual trials and confirmed by meta-analyses [1–5]. For patients with endocrine-nonresponsive disease, the effect of adjuvant chemotherapy is independent of endocrine mechanisms [6, 7]. However, for endocrine-responsive [i.e. ER- and/or progesterone receptor (PgR)-positive] breast cancer the benefit of chemotherapy is due to a complex mixture of cytotoxic and endocrine mechanisms. The additional benefit of chemotherapy for premenopausal patients with endocrine-responsive breast cancer who receive combined endocrine treatment with OFS and tamoxifen (or an aromatase inhibitor) remains an open question that prospective randomized clinical trials have been unsuccessful in answering, as diverging opinions regarding its efficacy result in some physicians recommending it while others do not [8].
In 1993, the International Breast Cancer Study Group (IBCSG) activated a randomized clinical trial (IBCSG 11-93) to investigate the role of adjuvant chemotherapy in premenopausal patients with node-positive (N+), hormone receptor-positive invasive breast cancer who receive combined endocrine therapy with OFS and tamoxifen (Figure 1A) [9, 10]. Patients were randomly allocated to receive four cycles of adjuvant anthracycline-based chemotherapy plus long-term OFS and 5 years of tamoxifen (initiated after chemotherapy) or to receive the same combined endocrine therapy without chemotherapy. From May 1993 to November 1998, 174 patients were randomized and the trial closed prematurely because of the low accrual rate. Patients (median age 45 years) tended to be at intermediate risk according to the St Gallen Consensus Criteria [11], with 97% of patients having one to three nodes involved. After a median follow-up of 10 years, 20 of the 89 patients randomized to chemotherapy plus OFS/tamoxifen and 20 of 85 randomized to OFS/tamoxifen without chemotherapy had relapsed; 12 patients had died of cancer in each group. The estimated 10-year disease-free survival was 73% ± 5% for both groups (Hazard ratio = 1.02 for addition of AC doxorubicin or epirubicin plus cyclophosphamide for 4 21-day cycles; 95% CI 0.57–1.83; P = 0.94) [10]. This trial, although clearly underpowered, raises the question of whether chemotherapy is needed in this intermediate-risk population that received combined endocrine treatment [8].
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In 2003, the IBCSG initiated a suite of three complementary tailored treatment investigations, the Suppression of Ovarian Function Trial (SOFT), Tamoxifen and Exemestane Trial (TEXT) and Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial, designed to answer questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer [12, 13]. The TEXT and the PERCHE trials address two questions for women who receive OFS from the start of adjuvant therapy. TEXT (Figure 1C) investigates the role of aromatase inhibitors compared with tamoxifen, and PERCHE (Figure 1B) the value of adding chemotherapy to combined endocrine therapy. These trials involve worldwide participation through the Breast International Group (BIG) network and The Breast Cancer Intergroup of North America.
In PERCHE, whether or not to use adjuvant chemotherapy was determined by random assignment, whereas the oral endocrine agent (tamoxifen or exemestane) combined with OFS was determined by the participating center or by co-enrollment in TEXT. The PERCHE trial had broader eligibility criteria than its predecessor trial IBCSG 11-93 by including patients with node-negative (N–) disease and allowing centers to choose the chemotherapy regimen. Yet from August 2003 to December 2006—at which point the trial was prematurely closed to accrual—only 29 patients were enrolled in PERCHE from 11 centers in seven countries (Australia, Canada, Germany, Hungary, Italy, New Zealand, Switzerland), even though there was widespread consensus among opinion leaders that this was a pivotal study to prospectively determine the role of chemotherapy in patients selected on the basis of clinical criteria. Patients’ median age was 46 years (range 36–54 years). Most patients had intermediate risk disease according to the St Gallen Consensus Criteria [11], and had ER-positive and PgR-positive tumors. Patients were equally divided as lymph N– and N+ disease, with all N+ having one to three positive nodes. Twenty-five of 29 patients were co-enrolled in TEXT.
TEXT has identical eligibility criteria to PERCHE, but the trials have accrued at very different rates. PERCHE, which randomly assigned whether or not to give chemotherapy, accrued on average less than one patient per month. TEXT, which randomly assigned the oral endocrine agent with the center choosing whether to give chemotherapy for individual patients, accrued >40 patients per month. It appears that centers, generally physicians and possibly the patients as well, prefer to make the decision of whether a patient will receive chemotherapy and are unwilling to leave it to chance, but are willing to let chance decide which oral endocrine agent to use. The patients entered in TEXT provide an opportunity to investigate what factors are used in the decision-making process of whether or not to give chemotherapy in addition to combined endocrine therapy in this patient population.
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patients and methods |
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study design
TEXT (IBCSG 25-02) opened for accrual in August 2003 and was designed to enroll 1845 premenopausal women with endocrine-responsive early breast cancer (Figure 1C) who were randomly assigned to receive OFS plus either tamoxifen (20 mg/day) or exemestane (25 mg/day) for 5 years. OFS could be achieved by gonadotropin-releasing hormone (GnRH) analogue (triptorelin 3.75 mg by intramuscular injection every 28 days) until 5 years from randomization; bilateral surgical oophorectomy or bilateral ovarian irradiation was allowed as an alternative after at least 6 months of GnRH analogue. Randomization was stratified by whether or not chemotherapy was planned. The chemotherapy regimen was the center's choice but a planned duration of
2 months was recommended if an anthracycline was included or 4 months if no anthracycline was given. Patients receiving chemotherapy commenced it after randomization, concurrently with the GnRH analogue. Tamoxifen/exemestane started after adjuvant chemotherapy was completed, if given, or 
6–8 weeks after the initiation of GnRH analogue, whichever was later.
The study required that randomization be within 12 weeks after definitive surgery for histologically proven invasive breast cancer with steroid hormone receptor-positive tumors, defined as ER and/or PgR expression 10% of tumor cells by immunohistochemistry.
From 1 November 2003 to 31 December 2006—the period PERCHE was also open to enrollment—1317 patients were enrolled in TEXT. The analysis cohort was comprised of the 890 (68%) patients with complete baseline case report forms in the database as of April 2007, and excluded the 25 patients who were co-enrolled in both TEXT and PERCHE. For both trials, ethical boards of each participating center approved the protocols and all patients provided written informed consent.
data and statistical considerations
Factors of interest included geographic region (cooperative group network and country, with the United States divided into four census regions), patient age, local–regional treatment plan (type of definitive surgery and whether or not radiotherapy was planned) and locally assessed disease characteristics [steroid hormone receptor status (negative for ER or PgR versus positive for both), percentage of cells staining for ER and PgR (among patients treated at institutions reporting this information), axillary lymph node status (negative or positive as well as number of positive nodes), tumor grade, tumor size, presence of peritumoral vascular invasion (PVI) and human epidermal growth factor receptor 2 (HER2) status of the tumor (considered as HER2 positive if amplified by FISH or 3+ by immunohistochemistry and FISH not done)]. Patients were classified into risk categories according to the 2005 St Gallen Consensus Criteria [11], which consider patient age, number of positive lymph nodes, PVI and tumor size, grade and HER2 status.
Descriptive statistics were presented, either as number and percent of patients or as median, interquartile range (IQR) and range of values. Classification and regression tree (CART) analysis [14] examined which combination of factors best classified whether or not chemotherapy was chosen, and investigated combinations of factors that identified groups of patients in which a small or large proportion received chemotherapy. The initial analysis included geographic region, patient age and disease characteristics; a secondary analysis also included levels of hormone receptor expression among the subset of patients with this information available.
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results |
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Among the population of premenopausal patients with endocrine-responsive disease who were enrolled in TEXT and would be receiving 5 years of combined endocrine therapy, additional adjuvant chemotherapy was chosen for 813 of 1317 (62%) patients. Among the subset of 890 in the study cohort, adjuvant chemotherapy was chosen for 569 (64%).
geography
Overall there was no substantial difference in the percentage of patients in the chemotherapy stratum for BIG centers compared with North American centers (62% versus 66%, respectively) (Table 1). Chemotherapy was consistently given more often to patients with lymph node-positive (N+) disease regardless of geographic region. The proportions of patients receiving chemotherapy, however, varied widely according to region, ranging from 64% to 100% of those with N+ disease and from 18% to 83% of those with lymph node-negative (N–) disease. Among patients with N– disease, only 31% from European centers received chemotherapy compared with 52% from North American centers.
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patient age and local–regional treatment
Younger patients were more likely to receive chemotherapy overall and in both lymph node status cohorts (Table 1). The majority of patients who were treated with mastectomy plus radiation therapy received chemotherapy.
disease
Chemotherapy was chosen for 88% of patients with N+ disease compared with 46% with N– disease. The proportion of patients given chemotherapy increased as the number of positive nodes increased, with nearly all patients having four or more positive nodes receiving chemotherapy (Table 2). A clear pattern emerged of choosing chemotherapy according to the 2005 St Gallen risk categories (Table 3) (19% versus 63% versus 96% of low- versus intermediate- versus high-risk patients, respectively), yet the continued role of nodal status within the intermediate category is also apparent (51% of N– intermediate risk versus 83% of N+ intermediate risk). The individual characteristics that comprise the St Gallen criteria are consistent with the overall risk categorization (Tables 3 and 4); patients with more aggressive disease characteristics (presence of PVI, higher grade tumors, >2 cm tumors, HER2-positive tumors) more often received chemotherapy, a pattern particularly apparent among patients with N– disease.
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All patients in TEXT had hormone receptor-positive tumors, of whom only 11% had tumors negative for either ER or PgR (1.5% ER negative and 9.5% PgR negative). Given the caveat of small numbers, higher proportions of N– patients with either ER-negative or PgR-negative tumors received chemotherapy, an observation not apparent in N+ disease (Table 4). For
85% of patients, the continuous percentage of ER and PgR immunostaining cells was reported; higher proportions of patients in the N– cohort with tumors expressing very low levels (
20% expression) of either ER or PgR received chemotherapy (Figure 2).
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all factors
CART analysis explored which factors classified patients into subgroups with low or high chemotherapy prescription. The predominant factor was nodal status (Figure 3). Geographical regions formed the next split for patients with both N– and N+ disease. Among patients with N+ disease, two geographical groupings emerged in which 72% versus 94% of patients received chemotherapy, with patient age or presence of PVI as further determinants among the two groupings, respectively. Among patients with N– disease, 32% versus 60% of patients received chemotherapy in two geographical groupings. Among countries choosing chemotherapy less frequently, tumor size and patient age were determinants: patients with
1 cm tumors least frequently received chemotherapy (13%), whereas patients aged 43 years having >1 cm tumors most frequently received chemotherapy (71%). In the countries where chemotherapy was chosen for 60% of patients with N– disease, tumor grade, size and patient age were determinants. The factors that did not appear to play a major role in decision making were ER status, PgR status or HER2 status of the tumor, neither did the continuous percentage of ER and PgR immunostaining cells appear to play a role in the reanalysis among the subset of patients for whom these percentages were available.
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discussion |
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Clearly there is a group of patients with low to intermediate risk of relapse after surgery for early breast cancer for whom chemotherapy adds little or no benefit to combined endocrine therapy, but the oncology community has not been able to recruit to randomized trials designed to investigate this question despite multiple attempts. The premature closure of PERCHE, and of IBCSG Trial 11-93 10 years earlier, because of inadequate accrual demonstrates that when treating premenopausal endocrine-responsive early breast cancer, physicians and/or patients are not willing to allow random chance to decide whether or not to give chemotherapy. Indeed, the 2007 St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer [15] described the selection of whether to give chemotherapy for patients with endocrine-responsive disease ‘perhaps the most difficult decision in current adjuvant therapy’, mainly because there are only underpowered clinical trial results to aid in this decision. The current absence of sufficient information also challenges decisions to prematurely close trials due to low accrual, with the reason for doing so being that the scientific question will not be relevant long term. However, 10 years after the closure of IBCSG Trial 11-93 the question addressed remains unanswered, and there is no trial planned for the foreseeable future.
We investigated characteristics of patients enrolled in TEXT, where the decision of whether or not to use chemotherapy was determined not by the trial, but at the center, and observed that positive lymph node status was the predominant determinant of chemotherapy choice. Strong geographical patterns were observed also, indicating regional biases, but in spite of preconceived ideas, the United States did not use more chemotherapy in N– populations compared with several other countries. The fact that nodal status was most often used to make the decision reflects a perceived increase in risk of recurrence on the basis of years of research and clinical trials that divided breast cancer patients on the basis of staging. Geographical differences may arise from a variety of sources, including institutional guidelines, national health advisories, insurance coverage, experience with agents such as GnRH analogues, local opinion leaders’ positions and other factors. Randomized clinical trials that remove biases in the perceived value of chemotherapy in the absence of direct evidence of its benefit, however, have been unsuccessful.
Overall, overview analyses and analyses of individual trials have demonstrated a significant benefit for adjuvant chemotherapy compared with no chemotherapy, especially for premenopausal women [1–4]. These analyses have several limitations such as using age <50 years as a proxy for premenopausal status, including a combination of patients with endocrine-responsive and -nonresponsive tumors and sometimes with no hormone receptor assessment, and using possibly less than optimal endocrine treatments. The National Surgical Adjuvant Breast and Bowel Project B-20 trial demonstrated benefit of combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil in addition to tamoxifen versus tamoxifen alone for premenopausal women with endocrine-responsive N– disease [16]. In the recent meta-analysis of adjuvant luteinizing hormone-releasing hormone agonists [5], the addition of OFS plus tamoxifen for patients who receive chemotherapy was beneficial in endocrine-responsive disease with a 26.7% relative reduction in risk of recurrence (95% CI, 38.7% to 12.3% risk reduction; P = 0.001). This meta-analysis, however, did not address the question of adding chemotherapy for patients receiving optimal endocrine treatment (the PERCHE question). IBCSG Trial 11-93 [9, 10], which investigated the addition of chemotherapy to combined OFS plus tamoxifen in a small group of patients (n = 174), has shown neither benefit from adding chemotherapy nor an indication of a detrimental effect on disease control by avoiding chemotherapy. IBCSG Trial 11-93 continues to be the only published study on the role of adding chemotherapy among premenopausal patients with N+ endocrine-responsive disease who receive combined endocrine therapy with OFS plus tamoxifen. This question will become even more important if the results of the ongoing SOFT demonstrate benefit for the addition of OFS to tamoxifen as adjuvant therapy in premenopausal women.
The 2005 St Gallen Consensus endorsed endocrine responsiveness as the primary disease characteristic to consider for selection of adjuvant systemic therapy [11], and the 2007 Consensus reaffirmed and refined this position [15]. The endocrine effects of chemotherapy in young women are also well documented [17], indicating the need to tailor therapies according to their relative endocrine and cytotoxic effects. The 2007 St Gallen Consensus [15] panelists accepted either tamoxifen plus OFS or tamoxifen alone as standard endocrine therapies for premenopausal patients. In premenopausal women with endocrine-responsive disease and a low or intermediate risk of recurrence on average, it is possible that a benefit equivalent to that obtained by chemotherapy plus tamoxifen may be achieved by a combination of OFS plus tamoxifen (or possibly an aromatase inhibitor).
Additional biologic factors such as HER2 expression/amplification and/or measures of proliferation might identify patients with endocrine-responsive disease who possibly derive less benefit from endocrine therapy [18]. Several recent studies have indicated that gene expression profiling can distinguish patient subsets deriving different benefit from endocrine treatment and chemotherapy [19–22]. In our analysis, biological characteristics which may help determine the degree of endocrine responsiveness of the tumor such as ER and PgR expression levels and HER2 status did not appear to be major determinants of chemotherapy choice.
The Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) and Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx) trials were launched in 2006 for women with early-stage breast cancer with the objective of validating the utility of signatures of molecular or gene expression profiles in clinical practice [23, 24]. The trials focus on the question of whether these signatures identify a subset of patients with operable N– breast cancer who may not need chemotherapy. Neither trial will be able to address the question posed in the PERCHE trial, for reasons including the lack of statistical power to examine the premenopausal subgroup and the lack of standardized endocrine therapy, the choice of which may be influenced by whether or not the patient is amenorrheic after chemotherapy.
The role of adjuvant chemotherapy, in addition to optimal endocrine therapy, for premenopausal breast cancer patients with endocrine-responsive disease, and in particular those with limited or no nodal involvement, remains unclear. The inability to directly address the question was once again evidenced by the closure of the PERCHE trial after enrolling only 29 patients over a period of more than 3 years. We conclude that the perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding whether it offers benefit (or degree of benefit) when added to combined endocrine therapy for patients with endocrine-responsive disease.
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funding |
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Pfizer and the US National Cancer Institute to the SOFT, TEXT and PERCHE trials; Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (National Health and Medical Research Council Project Grant 351161), Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, US National Cancer Institute (CA75362, CA25224), Cancer Research Switzerland/Oncosuisse and the Foundation for Clinical Cancer Research of Eastern Switzerland to IBCSG.
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Appendix |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAppendixAcknowledgementsReferences |
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International Breast Cancer Study Group
Participants and Authors in Trial IBCSG 25-02/BIG 3-02/TEXT—SOFT/TEXT/PERCHE (STP) Steering Committee: P. Francis (Chair, SOFT Co-Chair), G. F. Fleming (SOFT Co-Chair), O. Pagani (TEXT Co-Chair), B. Walley (TEXT Co-Chair), R. Torrisi (PERCHE Co-Chair), E. A. Perez (PERCHE Co-Chair), M. M. Regan (STP Statistician), L. Blacher, M. Castiglione-Gertsch, A. S. Coates, R. D. Gelber, A. Goldhirsch, A. Hiltbrunner, R. Maibach, O. Ortmann, K. N. Price, B. Ruepp, G. Viale, J. Burrueco (Pfizer).
IBCSG Scientific Committee: A. Goldhirsch, A. S. Coates (Co-Chairs).
IBCSG Foundation Council: B. Thürlimann (President), M. Castiglione-Gertsch, A. S. Coates, R. D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S. B. Holmberg, D. K. Hossfeld, I. Láng, R. Stahel, M. de Stoppani, A. Veronesi.
IBCSG Coordinating Center, Bern, Switzerland: M. Castiglione-Gertsch (CEO), A. Hiltbrunner (Director), R. Maibach, R. Studer, M. Rabaglio, B. Ruepp, G. Egli, R. Corbascio, S. Roux, E. Streit.
IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA: R. D. Gelber (Group Statistician), M. M. Regan (Trial Statistician), K. N. Price.
Data Management Center, Frontier Science & Technology, Research Foundation, Amherst, NY: L. Blacher (Director), K. Scott, R. Hinkle, J. Swick.
Central Pathology Review Office, European Institute of Oncology, Division of Pathology, Milan, Italy: G. Viale.
Quality of Life Office: J. Bernhard, K. Ribi, D. Gerber.
Breast International Group
International Breast Cancer Study Group: Australian New Zealand Breast Cancer Trials Group (ANZ BCTG)—ANZ BCTG Operations Office, Newcastle, Australia: J. Forbes, D. Lindsay (Head of Data Management), H. Badger (Team Leader), L. Boyes, K. Schmidt, J. Jobling; Coffs Harbour Base Hospital, Coffs Harbour, New South Wales, Australia: K. Briscoe; Liverpool Hospital, Liverpool, New South Wales, Australia: S. Della-Fiorentina; Macarthur Cancer Therapy Centre, Campbelltown, New South Wales, Australia: S. Della-Fiorentina; Calvary Mater Newcastle, Newcastle, New South Wales, Australia: J. Forbes; Riverina Cancer Care Centre, Wagga Wagga, New South Wales, Australia: J. Hill; Tamworth Rural Referral Hospital, Tamworth, New South Wales, Australia: D. Goldstein; Tweed Hospital, Tweed Heads, New South Wales, Australia: E. Abdi; Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia: N. McCarthy; Flinders Medical Centre, Bedford Park, South Australia, Australia: B. Koczwara; Launceston General Hospital, Launceston, Tasmania, Australia: I. Byard; Royal Hobart Hospital, Hobart, Tasmania, Australia: R. Lowenthal; Austin Health, Heidelberg, Victoria, Australia: J. Stewart; Box Hill Hospital, Box Hill, Victoria, Australia: J. Chirgwin; Mercy Private, Box Hill, Victoria, Australia: M. Chipman; Maroondah Hospital, Ringwood East, Victoria, Australia: J. Chirgwin; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia: P. Francis; Royal Perth Hospital, Perth, Western Australia, Australia: E. Bayliss.
Belgium—Institute Jules Bordet, Brussels, Belgium: F. Cardoso; Centre Hospitalier Universitarie Sart Tilman, Liège, Belgium: G. Jerusalem; Centre Hospitalier Peltzer-La Tourelle, Verviers, Belgium: J. P. Salmon.
Egypt—National Cancer Institute, Cairo University, Cairo, Egypt: H. Khaled.
Hungary—National Institute of Oncology, Budapest, Hungary: I. Láng.
Italy—Azienda Ospedaliero-Universitaria di Udine, Udine, Italy: F. Puglisi; Centro di Riferimento Oncologico, Aviano, Italy: D. Crivellari; Fondazione Salvatore Maugeri, Pavia, Italy: L. Pavesi; Istituto Europeo di Oncologia, Milano, Italy: M. Colleoni, A. Goldhirsch; Ospedale degli Infermi, Rimini, Italy: A. Ravaioli; Ospedale di Circolo e Fondazione Macchi, Varese, Italy: G. Pinotti; Ospedali Riuniti di Bergamo, Bergamo, Italy: C. Tondini; Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Prato, Italy: A. Di Leo; Spedali Civili, Brescia, Italy: E. Simoncini; Unita Operativa de Medicina Oncologica, Ospedale Ramazzini, Carpi, Italy: F. Artioli.
Peru—Instituto de Enfermedades Neoplásicas, Lima, Peru: H. Gomez.
Slovenia—Institute of Oncology, Ljubljana, Slovenia: B. Pajk.
South Africa—Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa: E. Murray.
Sweden—West Swedish Breast Cancer Study Group: S. B. Holmberg; Sahlgrenska University Hospital, Göteborg, Sweden: P. Karlsson.
Switzerland—Swiss Association for Clinical Cancer Research: R. Herrmann; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland: K. Zaman; Inselspital, Berne, Switzerland: S. Aebi; Institute of Oncology of Southern Switzerland: O. Pagani (Ospedale San Giovanni, Bellinzona; Ospedale Regionale di Lugano (Civico & Italiano), Lugano; Ospedale Regionale Beata Vergine, Mendrisio; Ospedale Regionale La Carità, Locarno; Istituto Cantonale di Patologia, Locarno); Kantonsspital St Gallen, St Gallen, Switzerland: B. Thürlimann; Rätisches Kantonos-/Regionalspital, Chur, Switzerland: R. von Moos; University Hospital Basel, Basel, Switzerland: C. Rochlitz.
German Exemestane Adjuvant Group
Germany—Caritas-Krankenhaus St Josef, Regensburg, Germany: O. Ortmann; Mammazentrum, Klinikum Deggendorf, Deggendorf, Germany: D. Augustin; St Vincentius Kliniken Karlsruhe, Karlsruhe, Germany: H.-G. Meerpohl.
North America
American College of Surgeons Oncology Group—Hope, A Women's Cancer Center, Asheville, NC: D. J. Hetzel.
Cancer and Leukemia Group B—Dana-Farber Cancer Institute, Boston, MA: H. J. Burstein; Massachusetts General Hospital, Boston, MA: H. J. Burstein; Faulkner Hospital, Boston, MA: H. J. Burstein; Emerson Hospital, Concord, MA: H. J. Burstein; Addison Gilbert, Gloucester, MA: A. P. McIntyre; Mountainview Medical, Burlington, VT: S. Burdette-Radoux; University of Vermont, Burlington, VT: S. Burdette-Radoux; University of Maryland Greenebaum Cancer Center, Pottstown, PA: K. H. Rak Tkaczuk; University of Chicago, Chicago, IL: G. F. Fleming; Walter Reed Army Medical Center, Dayton, OH: T. J. A. Reid; Fort Wayne Medical Oncology/Hematology, Inc., Ft Wayne, IN: S. R. Nattam; Northern Indiana Research Consortium, South Bend, IN: R. H. Ansari; Hematology Oncology Associates/Quad Cities, Bettendorf, IA: S. R. Chitneni; Margaret R. Pardee Memorial Hospital, Hendersonville, NC: J. E. Radford; Greenville Community Clinical Oncology Program (CCOP), Greenville, SC: J. K. Giguere; Washington University School of Medicine, St Louis, MO: M. J. C. Ellis; University of California at San Francisco, San Francisco, CA: H. S. Rugo; University of California at San Diego, San Diego, CA: J. E. Mortimer.
Cancer Trials Support Unit—Portsmouth Regional Hospital, Portsmouth, NH: E. M. Bonnem; United Hospital, St Louis Park, MN: P. J. Flynn; San Francisco General, San Francisco, CA: H. S. Rugo.
Eastern Cooperative Oncology Group—Beth Israel Deaconess Medical Center, Boston, MA: H. J. Burstein; Tufts-New England Medical Center, Boston, MA: J. K. Erban; University of Connecticut, Farmington, CT: S. Tannenbaum; Albert Einstein College of Medicine, Bronx, NY: C. M. Pellegrino; Montefiore Medical Center, Bronx, NY: C. M. Pellegrino; Our Lady of Mercy Medical Center, Bronx, NY: P. H. Wiernik; New York University Medical Center, New York, NY: A. D. Tiersten; Hackensack University Medical CCOP, Hackensack, NJ: R. J. Rosenbluth; Virtua West Jersey Hospitals, Mt Holly, NJ: M. S. Entmacher; South Jersey Hospital System, Vineland, NJ: D. H. Blom; Frederick Memorial Hospital, Frederick, MD: B. M. O'Connor; Aultman Health Foundation, Canton, OH: J. A. Schmotzer Jr; Evanston Northwestern Healthcare, Evanston, IL: D. E. Merkel; Metro-Minnesota CCOP, St Louis Park, MN: P. J. Flynn; Aspirus Wausau Hospital Center, Wausau, WI: U. Gautam; Via Christi Regional Medical Center, Wichita, KS: S. R. Dakhil; West Virginia University, Morgantown, WV: J. Abraham; Erlanger Medical Center, Chattanooga, TN: L. L. Schlabach; University of Miami Sylvester Cancer Center, Miami, FL: S. Gluck, J. Hurley; Comprehensive Cancer Care Specialist at Boca Raton, Boca Raton, FL: I. Wiznitzer, E. Kruglyak.
North Central Cancer Treatment Group—Allan Blair Cancer Center, Regina, Saskatchewan, Canada: M. Salim; Saskatoon Cancer Center, Saskatoon, Saskatchewan, Canada: S. Amer; Mayo Clinic, Rochester, MN: J. N. Ingle, M. Goetz, E. A. Perez; Mayo Clinic Jacksonville, Jacksonville, FL: J. N. Ingle, E. A. Perez, M. P. Goetz; Saint Mary's Medical Center, Ann Arbor, MI: P. J. Stella; Medcenter One Health Systems, Bismarck, ND: E. J. Wos; Billings Clinic, Billings, MT: B. T. Marchello; Geisinger Medical Center, Danville, PA: A. M. Bernath Jr; Oncology-Hematology Associates of Central Illinois, Peoria, IL: J. W. Kugler; Siouxland Hematology-Oncology Associates, Sioux City, IA: D. B. Wender; Sioux Valley Clinic-Oncology, Sioux Falls, SD: L. K. Tschetter; Saint John's Hospital, Springfield, MO: J. W. Goodwin; Metro-Minnesota CCOP, St Louis Park, MN: P. J. Flynn; United Hospital, St Louis Park, MN: P. J. Flynn.
National Cancer Institute of Canada—Tom Baker Cancer Center, Calgary, Alberta, Canada: B. A. Walley; Cross Cancer Institute, Edmonton, Alberta, Canada: K. S. Tonkin; Hospital Charles LeMoyne, Greenfield Park, Quebec, Canada: C. Prady; Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario, Canada: R. G. Tozer; Trillium Health Center, Mississauga, Ontario, Canada: J. A. Gapski; Saskatoon Cancer Center, Saskatoon, Saskatchewan, Canada: S. Amer.
The National Surgical Adjuvant Breast and Bowel Project) Mercy Medical Center, Baltimore, MD: D. A. Riseberg; Suburban Hospital, Bethesda, MD: C. B. Hendricks; Frederick Memorial Hospital, Frederick, MD: B. M. O'Connor; Mission Hospitals, Inc., Asheville, NC: M. J. Messino; Moses H. Cone Memorial, Greensboro, NC: J. E. Feldmann; Presbyterian Hospital, Charlotte, NC: R. B. Reiling; Margaret R. Pardee Memorial Hospital, Hendersonville, NC: J. E. Radford; Forsyth Memorial Hospital, Winston-Salem, NC: J. O. Hopkins; Greenville CCOP, Greenville, SC: J. K. Giguere; Saint Louis University Hospital, St Louis, MO: P. J. Petruska, John H. Stroger Jr; Hospital of Cook County, Chicago, IL: K. A. Dookeran; North Idaho Cancer Center, Coeur D'Alene, ID: H. Tezcan; Desert Regional Medical Center, Palm Springs, CA: C. G. Leichman; Sutter Community Hospital, Sacramento, CA: V. Caggiano; University of California Medical Center at Irvine, Orange, CA: R. S. Mehta.
Southwest Oncology Group—Moses H. Cone Memorial, Greensboro, NC: J. E. Feldmann; Greenville CCOP, Greenville, SC: J. K. Giguere; Northeast Georgia Medical Center, Gainesville, GA: R. J. LoCicero; William Beaumont Hospital, Royal Oak, MI: D. Zakalik; Kansas City CCOP, Kansas City, MO: W. T. Stephenson; University of Arkansas, Little Rock, AR: L. F. Hutchins; University of Colorado, Aurora, CO: A. D. Elias; Montana Cancer Consortium CCOP, Billings, MT: P. W. Cobb; Saint Luke's Mountain States Tumor Institute, Boise, ID: T. A. Walters; Stormont-Vail Regional Health Center, Topeka, KS: S. J. Vogel; Cancer Center of Kansas-Medical Arts Tower, Wichita, KS: S. R. Dakhil; Cancer Center of Kansas-Wichita, Wichita, KS: S. R. Dakhil; Via Christi Regional Medical Center, Wichita, KS: S. R. Dakhil; Doctor's Hospital of Laredo, Laredo, TX: G. W. Unzeitig; Swedish Hospital Medical Center, Seattle, WA: S. E. Rivkin; Madigan Army Medical Center, Tacoma, WA: D. E. McCune; Saint Joseph Medical Center, Burbank, CA: R. L. Friedman, R. R. Mena; Presbyterian Hospital, Whittier, CA: J. H. Freimann Jr.
Radiation Therapy Oncology Group—North Shore Cancer Center, Peabody, MA: K. J. Krag; Aultman Health Foundation, Canton, OH: J. A. Schmotzer Jr.
Participants in Trial IBCSG 26-02/BIG 4-02/PERCHE—Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia: P. Francis; Tweed Hospital, Tweed Heads, New South Wales, Australia: E. Abdi; Auckland Hospital, Auckland, New Zealand: V. Harvey; National Institute of Oncology, Budapest, Hungary: I. Láng; Centro di Riferimento Oncologico, Aviano, Italy: D. Crivellari; Istituto Europeo di Oncologia, Milano, Italy: M. Colleoni, A. Goldhirsch; Azienda Ospedaliero-Universitaria di Udine, Udine, Italy: F. Puglisi; Kantonsspital St Gallen, St Gallen, Switzerland: B. Thürlimann; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland: K. Zaman; Caritas-Krankenhaus St Josef, Regensburg, Germany: O. Ortmann; Hospital Charles LeMoyne, Greenfield Park, Quebec, Canada: C. Prady.
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAppendixAcknowledgementsReferences |
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We thank the patients, physicians, nurses, data managers and pathologists who participated in these trials. This report has not been presented or published elsewhere.
Received for publication October 29, 2007. Accepted for publication January 23, 2008.
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