Annals of Oncology Advance Access originally published online on October 27, 2006
Annals of Oncology 2006 17(12):1772-1776; doi:10.1093/annonc/mdl398
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© 2006 European Society for Medical Oncology
breast cancer |
First—select the target: better choice of adjuvant treatments for breast cancer patients
1 International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Switzerland, and European Institute of Oncology, Milan, Italy
2 FRACP AStat, International Breast Cancer Study Group and University of Sydney, Sydney, Australia
3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA
4 Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA
5 Senology Center of Eastern Switzerland, Kantonsspital, Gallen
6 Zentrum für Tumordiagnostik und Prävention, Silberturm, Grossacker, Rorschacherstrasse Gallen, Switzerland
* Correspondence to: Dr A. Goldhirsch, International Breast Cancer Study Group, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. E-mail: aron.goldhirsch{at}ibcsg.org
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Abstract |
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Abstract
updating St Gallen 2005:...St Gallen Expert Consensus meetings update evidence on treatment of early breast cancer every 2 years and interpret its significance for treatment of individual patients. Such interpretation is controversial. Clinical decisions cannot, however, be postponed, and the harms of failing to tailor treatment must be balanced against those of overinterpretation. Since the ninth meeting in January 2005, an extraordinary year of progress has significantly changed the landscape in breast cancer therapy. The panel in January recommended a fundamental change in selection of adjuvant systemic therapy, giving prime attention to endocrine responsiveness. Primarily, three categories were acknowledged: endocrine responsive in which the primary treatment should be endocrine, endocrine non-responsive in which endocrine therapy should not be used, and an intermediate group for which both endocrine and other therapies should be offered. Secondarily, three risk groups were defined: low, intermediate, and high, slightly modifying the previous classification.
In June 2005, three trials, supported in December by a fourth, demonstrated the additional contribution of targeted therapy with trastuzumab in appropriately selected patients. Reports from several trials strengthened the evidence supporting the inclusion of taxanes, though controversy persists concerning their use in endocrine-responsive disease. This commentary midway between St Gallen meetings, therefore, emphasizes how new information influences algorithms for selecting adjuvant therapy in a rapidly changing environment.
Key words: adjuvant therapy, breast cancer, endocrine responsiveness, tailored therapies
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updating St Gallen 2005: the context |
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Seldom, if ever, have we witnessed such rapid accumulation of new evidence of effective adjuvant therapy as during 2005. It is therefore appropriate, midway between biannually scheduled St Gallen meetings, to consider the implications of this new knowledge. St Gallen Consensus Panels of experts (see Appendix for 2005 Panel) review and interpret evidence on adjuvant systemic treatments in early breast cancer. They propose treatments appropriate for specific patient populations [1], modifying previous guidelines and recommendations [2] on the basis of new evidence. The process is therefore distinct from either the formal meta-analysis undertaken by the Early Breast Cancer Trialists' Collaborative Group or that of a National Institutes of Health (NIH) Consensus Conference, though like the NIH process, the St Gallen Panel aims to provide relevant and contemporary advice for clinical practice. St Gallen recommendations differ from National Comprehensive Cancer Network guidelines [3] which while comprehensive are less explicitly tailored to the needs of specific patient groups.
Successive St Gallen conferences have viewed risk and responsiveness as follows: in 2001 multiple categories of risk were based upon nodal status; 2003 added endocrine responsiveness to define both risk and especially treatment choice. The 2005 treatment recommendations [1] emphasized endocrine responsiveness and modified risk classification. Prognosis per se was considered less relevant for treatment selection. Both the risk of relapse and the endocrine responsiveness of individual tumors are biological continuums, so the creation of categories within either is inevitably arbitrary, but nonetheless useful for application in clinical practice. Younger patients more frequently have tumors lacking hormone receptors, but in those whose tumors are endocrine responsive, the endocrine effects of ovarian suppression by chemotherapy may add to the direct cytotoxic effects.
Laboratory and clinical evidence demonstrates underlying biological heterogeneity among breast cancers with response to endocrine therapy for those tumors expressing high levels of hormone receptors and greater efficacy of chemotherapy among those lacking such receptors [4, 5]. Estimates of average treatment effects based upon clinical trials conducted in cohorts of patients with mixed hormone receptor-positive and -negative tumors are inappropriate to guide treatment of patients whose tumor characteristics are known. Interpretation of retrospective analysis of evidence within patient subpopulations is necessary when selecting optimal treatment for the individual patient. An example is the relatively large benefit of chemotherapy alone observed for postmenopausal women with endocrine non-responsive disease [6], confirmed by an analysis of patients with ER-poor tumors enrolled in randomized trials unconfounded by tamoxifen [7]. Retrospective, exploratory analyses of the SWOG-8814/Intergroup 0100 trial similarly found that the additional benefit from combination chemotherapy with cyclophosphamide, doxorubicin and fluorouracil (CAF) chemotherapy was essentially confined to patients with low and intermediate levels of ER expression, while no benefit from CAF was seen for patients with 1–3 positive axillary nodes, and for patients with high levels of ER in their primary tumors [8]. A recently published retrospective analyses of three Cancer and Leukaemia Group B/Intergroup trials indicated that although various incremental chemotherapy strategies compared with ‘standard’ therapies were more effective across trials in cohorts of patients with endocrine non-responsive disease, this effect was considerably less in the cohorts with endocrine-responsive disease [5]. Choosing treatments according to biological characteristics of responsiveness is further supported by the impressive results from recent trials of adjuvant trastuzumab [9–12].
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endocrine responsiveness |
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In considering this key concept, three tumor categories were defined which depend critically on the availability and appropriate interpretation of high-quality hormone receptor assays.
endocrine responsive
Cells express steroid hormone receptors (assayed with appropriate immunohistological or biochemical methods) and there are no factors calling endocrine response in question (see below). Typically, such patients have both estrogen receptor (ER) and progesterone receptor (PgR) highly positive by immunohistochemistry (ER+ and PgR+), though some cases with one receptor strongly positive may be regarded as endocrine responsive. Endocrine therapies are effective in improving disease-free and overall survival (OS) in patients with such tumors and may be the only adjuvant therapy needed.
endocrine non-responsive
At the other extreme are tumors whose cells have no detectable expression of steroid hormone receptors (ER– and PgR–). Endocrine therapies are not useful. Chemotherapy is effective irrespective of menopausal status, at least for tumors >1cm in size.
endocrine response uncertain
This intermediate group comprises tumors whose cells have some features of endocrine responsiveness, but insufficient to be sure that endocrine therapy alone is adequate. The exact boundary between ‘endocrine responsive’ and ‘endocrine response uncertain’ is necessarily arbitrary, and may vary depending on other clinical features (e.g. according to risk category or menopausal status). Endocrine therapy has useful beneficial effect for patients with >1% cells stained for ER, but is probably useless for patients with 1% or less staining [13]. Patients in the endocrine response-uncertain category therefore require both endocrine therapy and chemotherapy.
Features indicating uncertain endocrine responsiveness include low levels of steroid hormone receptor immunoreactivity (usually considered between >1% and <10% of cells positive) and lack of PgR (irrespective of the expression of ER); findings indicating potential resistance to particular endocrine therapies (e.g. HER2/neu overexpression and tamoxifen) or indicative of increased possibility of emergence of resistant clones associated with a high number of involved lymph nodes.
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risk categories |
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Node-negative status remains the major criterion defining low risk [14], though some patients with node-negative disease are classified as intermediate risk (Table 1). Involvement of four or more nodes in the axilla defines high risk, as does involvement of one to three nodes combined with HER2/neu overexpression or amplification [15]. Other patients with one to three positive axillary nodes are placed in the intermediate-risk category.
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Tumor size >2 cm (measured as the invasive component on the pathological specimen) excludes low risk allocation, even in the absence of other adverse prognostic features. The risk category of tumors <1 cm in size and negative nodes remains controversial. Such patients may have an excellent prognosis regardless of any additional feature (i.e. despite high-grade or negative receptors) [16]. Recent observations indicate that treatment choice for patients with very small tumors (but beyond microinvasive disease) should be based upon endocrine responsiveness [17].
Overexpression of the protein or amplification of the gene for the membrane receptor HER2/neu is recognized as a poor prognostic factor [18], but the primary contribution of HER2 positivity lies in its value as a predictive factor for benefit of trastuzumab [9–12], to indicate a lower probability of response to tamoxifen, and to suggest the use of cytotoxic therapy with taxanes and/or anthracyclines, perhaps dependent on the co-amplification of the topoisomerase II amplicon [11]. The issue of quality assurance of HER2/neu testing [19] is increasingly important as choice of treatment with adjuvant trastuzumab depends on the results of such testing.
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first–select the target |
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Table 1 displays the broad general scheme for treatment choice derived from the above considerations of endocrine responsiveness and risk group. Further details are provided elsewhere [1].
Patient preferences should be elicited by thorough discussion and considered in reaching treatment decisions.
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endocrine therapies for premenopausal women |
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Tamoxifen alone is a standard adjuvant endocrine treatment of premenopausal women with endocrine-responsive disease, with ovarian function suppression (OFS) as an alternative when tamoxifen is contraindicated. The combination of tamoxifen plus OFS may be appropriate for very young patients and for premenopausal patients of any age in whom chemotherapy does not induce OFS, although evidence is awaited from ongoing trials such as SOFT and TEXT [20]. Ovarian ablation plus tamoxifen yielded average results similar to those obtained with chemotherapy [21], but whether both modalities are needed in women with endocrine-responsive disease remains uncertain. Aromatase inhibitor could be justified after tamoxifen in patients who become definitely postmenopausal; this may require biochemical confirmation since simple amenorrhea may be unreliable (especially after chemotherapy or during treatment with tamoxifen).
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endocrine therapies for postmenopausal women |
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The American Society of Clinical Oncology Technology Assessment report concludes that ‘optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer should include an aromatase inhibitor either as initial therapy or after treatment with tamoxifen. Of course, women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options’ [22]. Cost and side effects are important issues. Adjuvant tamoxifen has a long-lasting (‘carry-over’) benefit well beyond 5 years after its cessation, while little such information is available on aromatase inhibitor therapy. Aromatase inhibitors, when compared with tamoxifen, carry less risk of endometrial cancer and thromboembolic events, but more bone fractures, cardiovascular events, and muscle and osteoarticular pain. Much less information is available on the long-term safety of aromatase inhibitors than for tamoxifen.
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chemotherapy regimens |
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The higher the degree of endocrine responsiveness, the lower the likely benefit from adding any chemotherapy [5, 8, 23]. For patients with high-risk disease and uncertain endocrine responsiveness, chemotherapy in addition to endocrine therapy should be considered. Regimens such as doxorubicin plus cyclophosphamide (AC); doxorubicin (A) followed by cyclophosphamide, methotrexate and 5-fluorouracil (CMF); Canadan cyclophosphamide, epirubicin and 5-fluorouracil (CEF); the cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) regimen; dose dense AC with paclitaxel; 5-fluorouracil, epirubicin and cyclophosphamide (FEC) using epirubicin 100 mg/M2 (FEC100); FEC100 followed by docetaxel; tailored FEC; and docetaxel, doxorubicin and cyclophosphamide (TAC) may be appropriate for patients in the high risk category, since they yield superior results, albeit at the price of greater complexity, cost or toxicity. For patients with endocrine-responsive disease and an indication for chemotherapy, treatment with four courses of AC (doxorubicin or epirubicin plus cyclophosphamide) or equivalent regimens such as CMF may be appropriate, while other regimens (i.e. adding taxanes to the regimen or using a dose-dense schedule) may not be more effective [5, 24]. Two trials presented at the December 2005 San Antonio Symposium [25, 26] showed additional benefit for taxane-containing regimens even in predominantly receptor-positive populations. Typically taxanes are administered with high doses of dexamethasone which may itself influence endocrine-responsive disease [27]. Patients with endocrine non-responsive disease and at intermediate or high risk should be offered an anthracycline-based regimen with or without taxanes for 4 or 6 months, with the longer duration offered to those at relatively higher risk.
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trastuzumab |
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The first major studies of adjuvant trastuzumab [9–11] were unanimous in demonstrating substantial reduction in the risk of recurrence early after surgery among patients whose tumors overexpressed HER2/neu and who were treated with trastuzumab as compared with a control group. An OS advantage was also reported in the North American trials [13]. The Breast Cancer International Research Group (BCIRG) study [14] included a treatment arm without anthracycline, offering the possibility of avoiding the risk of cardiac toxicity seen with anthracyclines and trastuzumab. The optimal use of trastuzumab remains uncertain: whether concurrent with or after chemotherapy, and whether or not anthracyclines should be used, especially given the incidence of cardiac toxicity of trastuzumab [28]. Moreover, it should be noted that the majority of the evidence was derived from patients with node-positive disease or those with large tumors. Possibly in future (as with endocrine therapy) groups may be defined in which trastuzumab without cytotoxics may be adequate. At this time, however, it is clear that HER2/neu-positive patients at high risk of early recurrence derive substantial benefit from the use of trastuzumab. Further follow-up will be required to establish the magnitude of any benefit for patients whose disease characteristics indicate a predominant risk of later relapse. While these trials evaluated a 1-year course of trastuzumab, a smaller trial [12] found benefit from a short course of trastuzumab before anthracycline therapy. Results from the 2-year arm of the HERceptin® Adjuvant (HERA trial) [9] are awaited.
Clinical trials designed to exploit therapeutic targets and interpretation of results to generate and test hypotheses within subpopulations of patients will continue to be important strategies in further improvement of the outlook for women with operable breast cancer.
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Acknowledgements |
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The authors thank the Participants of the 9th International Conference on Primary Therapy of Early Breast Cancer for many useful remarks. They acknowledge the substantial contributions of Marco Colleoni, Giuseppe Curigliano, Eric Winer, and Shari Gelber. They also thank Umberto Veronesi, Anne Hamilton, Franco Nolè, and Filippo de Braud for their thoughtful remarks. Partial support was provided by Grant Number CA-75362 from the United States National Cancer Institute.
Members of the panel are listed below. All had a significant input to the discussion and manuscript. Alan S. Coates was unable to attend the conference, but had a major impact on the planning of the meeting and on the final manuscript. Martine Piccart also was unable to attend, but maintained a significant input and was represented by a senior member of her institution. A full summary paper on the St Gallen Meeting 2005 including the news presented, comprehensive references, and detailed recommendations is available elsewhere (Annals of Oncology [1]).
K. S. Albain, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Marywood, IL, USA; J. Bergh, Department of Oncology, Radiumhemmet, Karolinska Institute and Hospital, Stockholm, Sweden; M. Castiglione-Gertsch, International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; A. S. Coates, The Cancer Council Australia and University of Sydney, Sydney, Australia (Absent); A. Costa, Department of Breast Surgery, Fondazione S. Maugeri, Pavia, Italy; J. Cuzick, Cancer Research, UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary College, University of London, Charterhouse Square, London, UK; N. Davidson, Sidney Kimmel Cancer Center of Johns Hopkins, Baltimore, MD, USA; J. F. Forbes, Department of Surgical Oncology, University of Newcastle, Hunter Region Mail Centre, Australia; R. D. Gelber, Departmen of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA, USA; P. E. Goss, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; J. Harris, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; J. H. Glick, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA (Chairman); A. Goldhirsch, International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, and European Institute of Oncology, Milan, Italy (Chairman); A. Howell, CRC, Department of Medical Oncology, Christie Hospital, NHS Trust, Manchester, UK; J. N. Ingle, Mayo Clinic, Rochester, MN, USA; R. Jakesz, University of Vienna, Department of General Surgery, Wien, Austria; J. Jassem. Medical University of Gdansk, Department of Oncology & Radiotherapy, Gdansk, Poland; M. Kaufmann, Department of Gynecology and Obstetrics, Goethe University, Frankfurt am Main, Germany; M. Martin, Servicio de Oncologia Medica, Hospital Universitario San Carlos, Cindad Universitaria s/n, Madrid, Spain; L. Mauriac, Institute Bergonié, Cours d'Argonne, Bordeaux, France; M. Morrow, Lynn Sage Comprehensive Breast Center, Northwestern Memorial Hospital, Chicago, IL, USA; H. T. Mouridsen, Department of Oncology 5074, Rigshospitalet, Copenhagen, Denmark; M. Namer, Centre Antoine Lacassagne, Nice Cedex, France; M. J. Piccart-Gebhart, Department of Chemotherapy, Institut Jules Bordet, Brussels, Belgium (substituted by D. de Valeriola MD, Medical Director, Institut Jules Bordet, Brussels, Belgium); K. Possinger, Universitätsklinikum Charite, Onkologie/Hämatologie, Berlin, Germany; K. Pritchard, Toronto–Sunnybrook Regional Cancer Center, Head Clinical Trials & Epidemiology, Toronto, ON, Canada; E. J. T. Rutgers, The Netherlands Cancer Institute, Department of Surgery, Amsterdam, The Netherlands; B. Thürlimann, Senologie-Zentrum Ostschweiz, Kantonsspital St Gallen, St Gallen, Switzerland; G. Viale, Department of Pathology, European Institute of Oncology and University of Milan, Milan, Italy; A. Wallgren, Sahlgrenska University Hospital, Department of Oncology, Göteborg, Sweden; W. C. Wood, Department of Surgery, Emory University School of Medicine, NE Atlanta, GA, USA.
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Footnotes |
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Participating investigators and institutions are listed in the ‘Acknowledgements’. 
Received for publication September 17, 2006. Accepted for publication September 19, 2006.
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References |
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