© 2007 European Society for Medical Oncology
special article |
Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007
1 International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland and European Institute of Oncology, 20141 Milan, Italy
2 Department of Surgery, Emory University School of Medicine, N. E. Atlanta, GA 30322, USA
3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
4 International Breast Cancer Study Group and University of Sydney, Sydney, NSW 2006, Australia
5 Division of Gynecologic Oncology, Kantonsspital, 9006 St Gallen, Switzerland
6 Tumor-Center ZeTuP (Detection, Treatment, Prevention), 9006 St 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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 Top Abstract introductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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The 10th St Gallen (Switzerland) expert consensus meeting in March 2007 refined and extended a target-oriented approach to adjuvant systemic therapy of early breast cancer. Target definition is inextricably intertwined with the availability of target-specific therapeutic agents. Since 2005, the presence of HER2 on the cell surface has been used as an effective target for trastuzumab much as steroid hormone receptors are targets for endocrine therapies. An expert Panel reaffirmed the primary importance of determining endocrine responsiveness of the cancer as a first approach to selecting systemic therapy. Three categories were acknowledged: highly endocrine responsive, incompletely endocrine responsive and endocrine non-responsive. The Panel accepted HER2-positivity to assign trastuzumab, and noted that adjuvant trastuzumab has only been assessed together with chemotherapy. They largely endorsed previous definitions of risk categories. While recognizing the existence of several molecularly-based tools for risk stratification, the Panel preferred to recommend the use of high-quality standard histopathological assessment for both risk allocation and target identification. Chemotherapy, although largely lacking specific target information, is the only option in cases which are both endocrine receptor-negative and HER2-negative. Chemotherapy is conventionally given with or preceding trastuzumab for patients with HER2-positive disease, and may be used for patients with endocrine responsive disease in cases where the sufficiency of endocrine therapy alone is uncertain. Recommendations are provided not as specific therapy guidelines but rather as a general guidance emphasizing main principles for tailoring therapeutic choice.
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introduction |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Incremental rather than fundamental change in the approach to the management of early breast cancer was the hallmark of the 10th St Gallen conference held in March 2007, attended by more than 4700 participants from 95 countries. Successive St Gallen conferences since 1978 have brought into focus contemporary insights and produced general principles based upon available evidence and expert opinion to provide guidance for the therapy of early breast cancer outside clinical trials [1]. The publication in 2005 of trials of trastuzumab for HER2-positive disease [2–4] represented such an important advance as to necessitate an interim update in 2006 [5].
Some new information presented at the conference is summarized in Table 1. In light of this information, a Panel of 39 experts from around the world (see Appendix) considered specific questions to arrive at recommended principles for the selection of therapies in early breast cancer. Intrinsically different subtypes of breast cancer were clearly recognized based on genetic profile and immunohistochemical (IHC) demonstration of selected targets [18, 73]. Overall treatment strategy stressed the paramount importance of targeted therapies wherever possible, though acknowledging that supplementation with less target-specific chemotherapy may be required. An obvious corollary is the absolute importance of timely, accurate and reliable histopathological assessment including target identification and quantification; an ideal regrettably not yet universally attained. Enhanced partnership between clinicians and pathologists therefore offers the opportunity for substantially improved outcomes.
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A subtle but important clarification of terminology was introduced relative to endocrine responsiveness. The three categories described in 2005 remain essentially unchanged but can more clearly be described as: (i) highly endocrine responsive [high expression of both estrogen receptor (ER) and progesterone receptor (PgR) in a majority of tumor cells]; (ii) incompletely endocrine responsive (lower expression of ER and or PgR); and (iii) endocrine non-responsive (complete absence of both ER and PgR). The degree of endocrine responsiveness varies quantitatively, and will contribute, together with an assessment of the level of risk of relapse, to a decision about whether endocrine therapy alone may be sufficient. While no absolute threshold can be defined, highly endocrine responsive tumors in patients with low risk (Table 2) may be suitable for endocrine therapy alone, while supplementary chemotherapy may be required for patients with highly endocrine responsive tumors in the presence of intermediate- or high-risk factors, and for patients with incompletely endocrine responsive tumors.
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The risk categories as defined in 2005 [1] remained essentially unchanged (Table 2), except that (i) peritumoral vascular invasion should be extensive (i.e. neoplastic emboli seen in two or more blocks of the tumor) to justify incremental risk; (ii) some small tumors and histological types might be at low risk despite the absence of steroid hormone receptors (e.g. medullary carcinoma, apocrine carcinoma, etc.); and (iii) the level of steroid hormone receptor expression and overexpression or amplification of HER2 constitute risk factors as well as therapeutic targets.
The resulting algorithms (Table 3) should serve to assist selection of optimal therapy in the immediate future.
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St Gallen 2007: news and progress |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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St Gallen conferences typically concentrate on breast cancer therapeutics, but various other aspects deserve to be mentioned for completeness, including epidemiology of breast cancer in various geographical areas and across socio economic strata. Reduced breast cancer incidence has been attributed to reduced prescribing of hormone replacement therapies [75]. Adherence to therapeutic guidelines is affected by affordability of systemic therapies in various geographic settings. Table 1 displays selected news in several of these areas.
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categories of endocrine responsiveness |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Three endocrine responsiveness categories were defined. (i) Highly endocrine responsive (previously referred to as endocrine responsive): tumors express high levels of both steroid hormone receptors in a majority of cells (identified with proper immunohistological methods). (ii) Incompletely endocrine responsive (previously referred to as endocrine response uncertain): some expression of steroid hormone receptors but at lower levels or lacking either ER or PgR. (iii) Endocrine non-responsive: tumors having no detectable expression of steroid hormone receptors. While this group is clearly defined in terms of lack of responsiveness to endocrine therapies, it includes tumors of diverse phenotype [76].
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HER2-positivity |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Two technologies are recognized for the determination of HER2-positivity. Either strong IHC staining (3+) of >30% of the tumor cells, or, alternatively, determination of gene amplification by FISH (fluorescence in situ hybridization: ratio of HER2 gene copies to chromosome 17 centromers > 2.2) or CISH (chromogenic in situ hybridization: more than six HER2 signals per cell) [77] is sufficient. The presence of strong IHC staining (3+) is associated with response to trastuzumab in several clinical trials. Theoretically, weaker staining (1+ or 2+) even in the presence of amplification could be associated with a lesser degree of efficacy of trastuzumab. The preliminary data from the N9831 trial are consistent with this hypothesis [78], indicating the urgent need for more research on correlation between specific biological markers and response to anti HER2 agents. It is recognized that these are arbitrary thresholds in a biological continuum, but a pragmatic decision needs to be made particularly because of the high cost of trastuzumab therapy, and the definitions used in the clinical trials upon which such therapy is based.
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risk categories |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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The Panel in 2007 recognized few changes for the risk classification (Table 2). Peritumoral vascular invasion was considered to elevate risk category only if it was extensive [74]. Total absence of steroid hormone receptors and amplification or overexpression of HER2 were each considered sufficient to exclude low risk assignment except for rare tumors such as medullary or apocrine carcinoma (which usually lack any of these receptors). Again, the Panel did not accept the molecularly based tools such as Oncotype DxTM or gene expression profiling by MammaPrintTM as sufficiently established to define risk categories. Both methods are being currently tested within prospective clinical trials [79, 80].
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specific considerations for treatment choice |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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local and regional treatments
Surgical considerations presented during the conference included reaffirmation of breast conservation, sentinel node technology to avoid unnecessary axillary surgery, and the challenging role of surgical treatment in the presence of metastatic disease (see Table 1). These aspects were not subsequently considered by the Panel.
Several aspects of radiation therapy were discussed. In general, recommendations of the American Society for Clinical Oncology (ASCO) or European Society of Mastology (EUSOMA) might be used to guide radiation treatment choice [81, 82]. Current standards for proper irradiation include CT scan simulation for all left-sided cancers, and use of techniques to minimize cardiac irradiation [83]. There was strong agreement to avoid postmastectomy radiation therapy for patients with node-negative disease and T1–T2 tumors, while a slender majority would restrict such treatment to those with 4 or more involved axillary lymph nodes. Publication of the findings from the EBCTCG presented in San Antonio in December 2006 showing an advantage for postmastectomy radiation in women with 1–3 positive nodes is awaited with interest. Postmastectomy irradiation volume should include chest wall and supraclavicular fossa for those with axillary nodes involved. It was agreed that in general axillary radiation should be avoided if proper axillary clearance had been performed. Even following breast conservation, a majority of the Panel would avoid radiation therapy in elderly patients who would receive endocrine therapy. It was the opinion of some of the Panel members, however, that elderly patients should not be denied standard radiation therapy if indicated. No other radiation therapy question commanded majority support among the Panel. These included questions regarding concurrent chemo–radio therapy, delay of endocrine therapy until completion of radiation therapy, partial breast irradiation and shortened courses with hypofractionation.
the systemic adjuvant therapy program
As in 2005, the first consideration is the use of appropriately targeted therapy. For highly and incompletely endocrine responsive disease the selection of endocrine therapy will depend upon menopausal status of the patient. This may be difficult to determine in patients who have recently received cytotoxic chemotherapy, a matter of particular importance if an aromatase inhibitor is being considered: the Panel insisted on ensuring a postmenopausal status before and during the use of an aromatase inhibitor. Other host-related factors governing selection of therapy may include a history of thromboembolic disease contraindicating tamoxifen. Likewise, host factors such as the existence of concomitant cardiac disease might influence the choice of particular chemotherapy agents or the suitability of treatment with trastuzumab. Patient age or co-morbid conditions may further restrict the feasibility of more intensive cytotoxic regimens. Different patterns of expected adverse events may influence patient preference for one or other treatment strategy.
endocrine therapy in postmenopausal patients
Clearly the availability of third generation aromatase inhibitors (AIs) [24, 84–88] has added substantially to the available treatment choice after a quarter century of successful use of tamoxifen. Nevertheless, a clear majority of the Panel felt that 5 years of tamoxifen alone was still a viable option for certain patient categories. Among strategies for the use of AIs, the Panel expressed a clear preference for a switch from tamoxifen to an AI after 2–3 years of tamoxifen, with a substantial minority also supporting an initial use of an AI and very few in favor of a prospective policy of 5 years of tamoxifen followed by an AI. For patients who have completed 5 years of tamoxifen, the majority of the Panel would support the addition of an AI for a further period of time only for patients with node-positive disease. Initial AI was more acceptable in patients at higher risk or with HER2-positive disease. A slim majority also favored initial AIs in patients receiving SSRI anti-depressants.
The Panel clearly preferred sequential rather than concurrent administration of cytotoxic and endocrine therapies. The total duration of optimal adjuvant endocrine treatment was seen as between 5 and 10 years.
Most Panelists considered it wise to check for ovarian function suppression in younger postmenopausal women receiving an AI, though the timing of such an assessment was uncertain.
The Panel supported evaluation of bone mineral density prior to commencement of an AI and the use of calcium, vitamin D and especially physical exercise to reduce the risk of bone loss and treatment-related symptoms.
endocrine therapy for premenopausal patients
The Panel accepted either tamoxifen plus ovarian function suppression or tamoxifen alone as standard endocrine therapies in this group. Ovarian function suppression alone was considered a possibility if subsequent pregnancy is planned, although avoiding tamoxifen for this reason may not be completely justified.
The Panel strongly endorsed a GnRH analogue as a means of ovarian function suppression and a substantial majority also regarded surgical oophorectomy as an appropriate option with the choice of method depending upon disease type and circumstances. Ovarian radiation was overwhelmingly rejected. It is important to recognize that in some patients GnRH analogue alone may not suppress ovarian function completely [89].
While admitting that evidence was lacking about the optimal duration of ovarian function suppression by GnRH analogue for women with hormone receptor positive breast cancer, a clear majority favored a period of 5 years, especially in patients at higher risk of relapse and/or with HER2-positive disease [90]. It was recognized that individual patients would exercise choice regarding the type and duration of ovarian function suppression.
Again without specific evidence, most Panelists preferred to defer GnRH analogue until completion of chemotherapy.
The use of AIs as the sole endocrine therapy for premenopausal patients is not appropriate. The use of AIs together with ovarian function suppression is currently being tested in clinical trials but might be considered outside trials when tamoxifen is contraindicated. Patients who were premenopausal at diagnosis and became postmenopausal after chemotherapy or during adjuvant endocrine therapy may receive AIs [85], but loss of ovarian endocrine function should be verified prior to and during exposure of these drugs, which typically stimulate endocrine ovarian function [91].
trastuzumab
The Panel was prepared to accept strong IHC staining as justifying trastuzumab therapy with only a small minority demanding FISH testing in all cases. The opinion of several Panelists was that, considering the absence of relevant data from randomized trials trastuzumab cannot be viewed as a standard treatment in women with a primary tumor <1 cm of size and with no axillary node involvement. This is particularly true in the setting of endocrine responsive disease. The role of trastuzumab in patients with small, endocrine responsive tumors and no axillary node involvement has not been adequately evaluated.
The standard duration of trastuzumab therapy was accepted as 1 year. A shorter duration (9 weeks) as used in the FinHER study [92] was not generally accepted.
A majority of the Panel found both the sequential HERA model (trastuzumab commencing after completion of all chemotherapy) [2] and the concurrent model (trastuzumab commencing concurrently with a taxane following anthracycline) [3, 4] as equally acceptable. A slim majority found the use of carboplatin and docetaxel administered concurrently with trastuzumab without anthracycline [4] to be an acceptable alternative.
Interestingly, a majority of the Panel was prepared, for selected women, to contemplate trastuzumab with endocrine therapy but without chemotherapy despite the absence of clinical trial evidence to support this approach. The Panel thought it important to avoid trastuzumab in patients with low LVEF (<50%).
chemotherapy
Perhaps the most difficult decision in current adjuvant therapy is selection of patients with highly or incompletely endocrine responsive disease for whom additional chemotherapy should be given. Features that raise doubt about the adequacy of endocrine therapy alone include relatively lower expression of steroid hormone receptor, involvement (and particularly extensive involvement) of axillary lymph nodes, higher grade or proliferative markers, larger tumor size and extensive peri-tumoral vascular invasion. Molecular-based technologies have been proposed to assist in this discrimination (OncotypeDXTM, MammaprintTM) but were not regarded by the Panel as yet sufficiently reliable to make a definitive contribution to the therapeutic decision.
A wide variety of chemotherapy regimens was considered acceptable with little agreement on any particular favorite. Most Panelists supported the use of anthracyclines for all patients and an even greater majority supported anthracycline use for patients with HER2-positive disease. For treatment of patients with triple negative tumors, the Panel was careful to include DNA damaging compounds [33]. Combinations of cyclophosphamide, 5-fluorouracil and an anthracycline (variously abbreviated as CAF, CEF, FEC, FAC [93–96]), commanded relatively wide support, as did the sequence of anthracycline and cyclophosphamide followed by paclitaxel or docetaxel. There was only minority support for dose-dense therapy, while high-dose therapy requiring peripheral blood stem cell support was rejected overwhelmingly.
In general, the Panel was prepared to accept less intensive chemotherapy such as four courses of doxorubicin and cyclophosphamide or six courses of classical CMF in patients with highly (but at high risk of relapse) or incompletely endocrine responsive HER2-negative disease. Other regimens considered suitable for this group included CAF and the combination of docetaxel and cyclophosphamide. Preference for various chemotherapy regimens was geographically heterogeneous, a fact which explains the large range of therapies considered by the Panelists.
The majority of the Panel considered that a shorter duration of chemotherapy (12–16 weeks) might be suitable for elderly patients and that an early initiation of such therapy was important for patients with steroid hormone receptor negative disease. Panel members noted the importance of offering standard chemotherapy to fit elderly patients with sufficient life expectancy. While a clear majority of the Panel supported a role for hematopoietic growth factors in patients with a clinical indication, only a minority supported their routine use. An excess of MDS and acute leukemia has been reported in older recipients of hematopoietic growth factors during adjuvant chemotherapy [97], but this finding is derived from non-randomized series, and no similar excess is evident in prospective randomized trials.
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choice of systemic adjuvant treatment modalities 2007 |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Bringing together these various concepts, Table 3 presents a summary in terms rather simpler than on previous occasions. In 2007 we have two therapeutic targets. Risk plays a minor role and is not a first order consideration in treatment selection, though it may guide selection of patients with endocrine responsive tumors for addition of chemotherapy. All patients receiving trastuzumab should also receive prior or concurrent chemotherapy according to available clinical trial evidence. Patients with triple negative disease are limited to chemotherapy. Thus, the only ambiguity arises in the two boxes describing treatment for patients with HER2-negative disease and at least some degree of endocrine responsiveness. Those with highly endocrine responsive tumors, particularly in the absence of other adverse factors (those at low or intermediate risk of relapse and no indication for trastuzumab), might well receive only endocrine adjuvant therapy, while others may also require at least some chemotherapy. The judgment required in advising such patients on the addition of chemotherapy will involve many factors of risk assessment, degree of endocrine responsiveness, and patient preference. No absolute rules can be defined for this decision which remains a matter for discussion between each patient and her treating clinician. Appendix Table 4 is provided to illustrate treatment decision algorithms incorporating information on therapeutic target and risk category. Current trials on the role of gene profiling in defining efficacy of adjuvant chemotherapy for patients with endocrine responsive disease might provide clinically relevant information [79, 80].
preoperative systemic therapy
Apart from the routine use of such treatment for large tumors, a majority of the Panel supported preoperative systemic therapy to improve resectability and thus cosmesis, while a minority also considered that the assessment of responsiveness constituted a reason to employ this treatment approach. A clear majority supported the inclusion of trastuzumab in the preoperative treatment program for patients with HER2-positive disease.
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special considerations |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Presentations covered at the conference addressed the specific needs of very young patients with particular reference to the preservation of fertility, the avoidance of premature menopause, the safety of pregnancy after the diagnosis of breast cancer and the special therapeutic problems when breast cancer is diagnosed during pregnancy (Table 1). Although not discussed by the Panel, other presentations canvassed the question of cognitive impairment after breast cancer therapy, and the prevention of cancer associated thromboembolic disease (Table 1).
Particular problems recognized in elderly patients included the presence of co-morbidities which might limit the feasibility of particular therapeutic options.
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commentary |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Clearly there has been continued progress in definition of effective systemic adjuvant therapies for early breast cancer. Future studies should define the molecular basis for treatment selection and in particular the definition of patients who might not require chemotherapy [98].
The best way to achieve optimal treatment of today's patients is to ensure the availability of reliable and timely pathological assessment in routine practice including treatment target identification.
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appendix and acknowledgements |
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TopAbstractintroductionSt Gallen 2007: news...categories of endocrine...HER2-positivityrisk categoriesspecific considerations for...choice of systemic adjuvant...special considerationscommentaryappendix and acknowledgementsReferences |
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Members of the Panel are listed below. All had a significant input to the discussion and manuscript. Drs A. Costa and L. Norton were unable to attend the Panel session, but provided input for the planning of the meeting and reviewed and approved the manuscript. Profs H. Mouridsen and A. Wallgren were also unable to attend, but maintained significant input throughout the process and were represented by B. Ejlertsen and P. Karlsson, respectively, senior members of their research teams. For the first time, a patient representative, I. Kössler, joined the Panel.
- M. Aapro, Clinique de Genolier, 1245 Genolier, Switzerland
- K. S. Albain, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL 60153, USA
- J. Bergh, Department of Oncology, Radiumhemmet, Karolinska Institute and Hospital, 17176 Stockholm, Sweden
- H. Burstein, Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- R. Carlson, Division of Oncology and Stanford Medical Informatics, Stanford University, Stanford, CA 94305-5826, USA
- M. Castiglione-Gertsch, International Breast Cancer Study Group Coordinating Center, 3008 Bern, Switzerland
- A. S. Coates, International Breast Cancer Study Group and University of Sydney, Sydney, NSW 2006, Australia
- M. Colleoni, Division of Medical Oncology, European Institute of Oncology, 20141 Milan, Italy
- A. Costa, Maugeri Foundation Breast Unit, Pavia, Italy, and Cantonal Breast Unit, Lugano & Bellinzona, Ospedale San Giovanni, 6500 Bellinzona, Switzerland (Absent)
- J. Cuzick, Cancer Research, UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary College, University of London, London EC1M 6BQ, UK
- N. Davidson, Sidney Kimmel Cancer Center of Johns Hopkins, Baltimore, MD 21231-1000, USA
- A. Di Leo, «Sandro Pitigliani» Medical Oncology Unit, Department of Oncology, Hospital of Prato, 59100 Prato, Italy
- B. Ejlertsen, Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
- J. F. Forbes, Department of Surgical Oncology, University of Newcastle, NSW 2310, Australia
- R. D. Gelber, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- J. H. Glick, University of Pennsylvania Cancer Center, Philadelphia, PA 19104-4283, USA
- J. Gligorov, Medical Oncology, CancerEst, Tenon Hospital, 75970 Paris Cedex 20, France
- A. Goldhirsch, International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland, and European Institute of Oncology, 20141 Milan, Italy (Chairman)
- P. Goss, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- J. Harris, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
- J. N. Ingle, Mayo Clinic, Rochester, MN 55905, USA
- R. Jakesz, University of Vienna, Department of General Surgery, 1090 Wien, Austria
- J. Jassem, Medical University of Gdansk, Department of Oncology & Radiotherapy, 80-211 Gdansk, Poland
- P. Karlsson, Sahlgrenska University Hospital, Department of Oncology, 413 45 Göteborg, Sweden
- M. Kaufmann, Department of Gynecology and Obstetrics, Goethe University, 60596 Frankfurt am Main, Germany
- I. Kössler, President Europa Donna, Bröstcancerföreningarnas Riksorganisation-BRO, 172 27 Sundbyberg, Sweden
- L. Mauriac, Institute Bergonié, 33076 Bordeaux, France
- M. Morrow, Chairman, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA
- H. T. Mouridsen, Department of Oncology 5074, Rigshospitalet, 2100 Copenhagen, Denmark (Absent)
- M. Namer, Centre Antoine Lacassagne, 06189 Nice Cedex, France
- L. Norton, Director of Breast Cancer Programs, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA (Absent)
- M. J. Piccart-Gebhart, Department of Medicine, Institut Jules Bordet, 1000 Brussels, Belgium
- K. Possinger, Universitätsklinikum Charité, Onkologie/Hämatologie, 10098 Berlin, Germany
- K. I. Pritchard, Toronto-Sunnybrook Regional Cancer Center, Head Clinical Trials & Epidemiology, Toronto, ON M4N 3M5, Canada
- E. J. T. Rutgers, The Netherlands Cancer Institute, Department of Surgery, 1066 CX Amsterdam, The Netherlands
- V. F. Semiglazov, Petrov Research Institute of Oncology, Pesochny-2 197758 St Petersburg, Russia
- I. Smith, Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK
- B. Thürlimann, Medizinische Onkologie, Haus 06, Kantonsspital St. Gallen, 9007 St Gallen, Switzerland
- G. Viale, Department of Pathology, European Institute of Oncology and University of Milan, 20141 Milan, Italy
- A. Wallgren, Sahlgrenska University Hospital, Department of Oncology, 413 45 Göteborg, Sweden (Absent)
- T. Watanabe, Department of Medicine, Hamamatsu Oncology Center, Hamamatsu, Shizuoka, Japan
- E. P. Winer, Breast Oncology Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- W. C. Wood, Department of Surgery, Emory University School of Medicine, N.E. Atlanta, GA 30322, USA (Chairman)
The authors thank the Participants in the 10th International Conference on Primary Therapy of Early Breast Cancer for many useful remarks and for substantial contributions to the process. We acknowledge the substantial contributions of Dr Giuseppe Curigliano, Mrs Shari Gelber and Mrs Sabina Briner. We also thank Professor Umberto Veronesi for his guidance and Dr Franco Nolè for his thoughtful remarks. This work is dedicated to the memory of Dr John Bryant who, as senior statistician with the National Surgical Adjuvant Breast and Bowel Project, made significant contributions to the conduct and interpretation of early breast cancer clinical trials.
Appendix Table 4. Treatment allocation by therapeutic target and risk categories. Treatment options in each cell are listed in the order of preference (see text and footnotes)
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Footnotes |
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See Appendix for members of the Panel. 
This is a corrected version of the original article. The corrected version was published on 25 October 2007.
Received for publication April 30, 2007. Accepted for publication May 2, 2007.
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