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Ann Oncol. Aug 2009; 20(8): 1319–1329.
Published online Jun 17, 2009. doi:  10.1093/annonc/mdp322
PMCID: PMC2720818

Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009

Abstract

The 11th St Gallen (Switzerland) expert consensus meeting on the primary treatment of early breast cancer in March 2009 maintained an emphasis on targeting adjuvant systemic therapies according to subgroups defined by predictive markers. Any positive level of estrogen receptor (ER) expression is considered sufficient to justify the use of endocrine adjuvant therapy in almost all patients. Overexpression or amplification of HER2 by standard criteria is an indication for anti-HER2 therapy for all but the very lowest risk invasive tumours. The corollary is that ER and HER2 must be reliably and accurately measured. Indications for cytotoxic adjuvant therapy were refined, acknowledging the role of risk factors with the caveat that risk per se is not a target. Proliferation markers, including those identified in multigene array analyses, were recognised as important in this regard. The threshold for indication of each systemic treatment modality thus depends on different criteria which have been separately listed to clarify the therapeutic decision-making algorithm.

Keywords: early breast cancer, St Gallen Consensus, therapies

introduction

The 11th St Gallen conference held in March 2009, which was attended by >4800 participants from 101 countries, incorporated incremental information but proposed a radically different treatment selection algorithm for the management of early breast cancer. The more we know about the tumour types underlying the heterogeneity of the disease, the greater the opportunity to refine treatment choice. It was recognised that clinical trials are very useful for identifying effective treatments, but fall short of defining the optimal treatment of individual patients. For example, local control is crucial to improve survival on average and especially in patients at low risk, but is overwhelmed by the risk of distant metastases in patients at high risk. Similarly, while cytotoxic chemotherapy improves outcome on average among patients with endocrine-responsive disease receiving endocrine therapy, subgroups can be defined by conventional pathology and by multigene analyses in which little or no additional benefit accrues from chemotherapy. Judgements must be made in the care of individual patients of whether to use or withhold each treatment modality. It is the intention of this report to assist in the rational application of evolving knowledge in reaching these judgements.

St Gallen 2009: news and progress

New information was presented in the areas of genetics, tumour biology, experimental therapeutics, surgery, radiation oncology, and adjuvant systemic therapy. Some of this new information is summarised in Table 1. In the light of this information, a Panel of 43 experts from around the world (see Panel members listed in the appendix) again considered specific questions to arrive at recommended principles for the selection of therapies in early breast cancer.

Table 1.
Recent research findings presented at the 11th International Conference on Primary Therapy of Early Breast Cancer and their implications for patient care

specific considerations for treatment choice

In distilling patient and tumour features to reach patient treatment decisions, the Panel has adopted a fundamentally different approach from that used in previous consensus reports [71, 72]. Clinical decisions in systemic adjuvant therapy of early breast cancer must address three distinct questions: (i) what justifies the use of endocrine therapy, (ii) what justifies the use of anti-HER2 therapy, and (iii) what justifies the use of chemotherapy. Because these decisions are based on quite separate criteria, the previous attempt to produce a single-risk categorization and a separate therapy recommendation are no longer considered appropriate. The new algorithm is summarised in Table 2. As before, the Panel recognised that adherence to therapeutic guidelines is affected by affordability of certain genetic and imaging tests and the costs of some systemic therapies in various geographic settings.

Table 2.
Thresholdsa for treatment modalities

endocrine therapy

The Panel recommends the inclusion of adjuvant endocrine therapy in almost all patients whose tumours show evidence of endocrine responsiveness, now defined as the presence of any detectable estrogen receptor (ER). It questioned the validity of reports of positive progesterone receptor (PgR) in the absence of ER and suggested that such cases be submitted for further pathological review. Whereas previous categories of highly endocrine responsive and incompletely endocrine responsive are not relevant to the decision to use or withhold endocrine therapy, such consideration remains important for the selection of patients with ER-positive disease to receive chemotherapy.

anti-HER2 therapy

Anti-HER2 therapy is indicated in patients with HER2-positive disease as defined by the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelines [74]. The Panel noted that the existing trials used a slightly less restrictive definition of HER2 positivity and acknowledged that patients satisfying the inclusion criteria used in the trials might also be considered for anti-HER2 treatment.

chemotherapy

The threshold for use of cytotoxic chemotherapy is the most difficult to define. Patients receiving anti-HER2 therapy conventionally also receive chemotherapy either preceding or concurrent with the anti-HER2 treatment. Although considered logical by some of the Panel members, the use of adjuvant anti-HER2 therapy without chemotherapy remains unsupported by evidence. Chemotherapy is the mainstay of adjuvant treatment of patients with triple-negative disease who are at sufficient risk of relapse to justify its utilisation. Some rare histological types of breast cancer that fall into the category of triple negative and are diagnosed neither with axillary node involvement nor with other signs of increased metastatic potential do not require adjuvant treatment (e.g. medullary, apocrine, and adenoid cystic breast cancers). Patients with small primary tumours (pT1a pN0 and ER negative) might be spared adjuvant systemic therapy.

The threshold for recommending chemotherapy for patients with ER-positive, HER2-negative disease is particularly difficult to define. These patients include a spectrum from those at low risk [75, 76] for whom there is little evidence supporting the addition of chemotherapy to endocrine therapy and to those with high risk disease and limited ER expression where chemotherapy appears clearly justified. Table 3 summarises the characteristics which favour the use of chemotherapy, those that might justify endocrine therapy alone, and those which are not useful for making this decision. Features indicating increased risk of recurrence and thus indirectly supporting the value of adding chemotherapy to endocrine therapy in such patients include lower expression of steroid hormone receptors, grade 3 tumours, high proliferation as measured by conventional or multigene assays, and the risk factors of four or more axillary lymph nodes involved, extensive peritumoral vascular invasion, and tumour size >5 cm. Emerging data presented but not published indicate that the overall scores from multigene assays may identify patients in these high-risk categories who do not gain benefit from the addition of chemotherapy to endocrine therapy. This represents an important area of research that will likely be clarified over the next several years. Patients with high expression of ERs and PgRs (e.g. >50%), grade 1 tumours, low proliferation, negative axillary lymph nodes, no peritumoral vascular invasion, and tumour size ≤2 cm may be considered for endocrine therapy alone. We note that some features individually provide little guidance in reaching a decision to use chemotherapy. In particular, histological grade 2, intermediate scores on multigene assays, tumour size between 2 and 5 cm, and low numbers of involved lymph nodes (one to three) do not provide definitive indications to either give or withhold chemotherapy. However, if all these intermediate criteria are present, it usually tips the balance towards the use of chemotherapy. The Panel considered the available multigene assays in this context and concluded that a validated assay should be taken into account as an adjunct to high-quality pathology phenotyping if doubt about the indication for chemotherapy persists after consideration of other factors. Considerations of availability and cost determine the current usefulness of multigene assays. The Panel noted that patients with pT1a pN0 and ER-positive disease should be offered endocrine therapy alone even if features which usually indicate chemotherapy are present.

Table 3.
Chemoendocrine therapy in patients with ER-positive, HER2-negative disease

endocrine responsiveness

Based on the philosophy of defining categories according to their implications for treatment selection, the previous three categories of endocrine responsiveness have been simplified so that endocrine therapy is considered indicated if any ER staining is present in the tumour. The majority of Panellists were in favour of indicating the percentage of stained cells on pathology reports rather than merely using scores. Staining for hormone receptors of ≥50% of tumour cells was viewed as indicating highly endocrine-responsive tumours.

HER2 positivity

Two technologies are recognised for the determination of HER2 positivity. These have recently been addressed by a joint working party of the ASCO/CAP [74]. Either immunohistochemical analysis showing uniform, intense membrane staining of >30% of the tumour cells or, alternatively, determination of gene amplification by fluorescence in situ hybridisation (FISH) (ratio of HER2 gene copies to chromosome 17 centromers >2.2) or chromogenic in situ hybridisation (CISH) (more than six HER2 signals per nucleus) is sufficient to define HER2 positivity. Although the definitions used in the pivotal trials of trastuzumab were less restrictive [8184], a substantial minority of the Panellists preferred to use 30% intense and complete staining as a threshold for recommendation of anti-HER2 therapy.

pathological evaluation of characteristics of the disease

In addition to reporting the presence and type of tumour, the Panel considered various additional pathological parameters. Markers of proliferation, and specifically Ki-67-labelling index, were considered important for the determination of prognosis and, importantly, to indicate the potential value of the addition of chemotherapy to patients with receptor-positive disease. Ki-67 specifically was not accepted as the basis for choosing aromatase inhibitors rather than tamoxifen in postmenopausal patients with receptor-positive disease [85] as further validation of findings in this regard was felt to be necessary [86]. Reporting of ER generated considerable discussion. The Panel strongly endorsed the reporting of percentage of stained cells but was evenly divided on whether other scoring methods should also be reported. PgR was considered valuable for prognosis, but less important for predicting response to treatment (e.g. tamoxifen).

The majority of the Panel considered that high grade was a sufficient indication for chemotherapy and that genomic grade could be considered as an adjunct to histological grade if readily available. Gene expression signatures are likely to indicate a prognostically relevant dichotomy (low grade versus high grade), though the implications of this observation for therapy require further study [87, 88]. uPA/PAI-1 was not accepted by a majority of the Panel as a useful prognostic factor.

In an important change from the previous St Gallen conference and after a long debate, the Panel supported the use of a validated multigene-profiling assay, if readily available, as an adjunct to high-quality phenotyping of breast cancer in cases in which the indication for adjuvant chemotherapy remained uncertain.

local and regional treatments

The aspects considered by the Panel included surgical margins, indications for sentinel node biopsy, and the role of prophylactic mastectomy. Re-excision was considered mandatory if invasive cancer or DCIS is present at the inked surgical margin, but is not required for lobular carcinoma in situ (LCIS). The Panel was divided about the need for surgical margins greater than “not on ink” in DCIS, although no detailed specific recommendation was given beside avoiding the need to insist on a large (e.g. 1 cm) free margin. The use of surgical procedures developed to allow a wide excision with satisfactory results (oncoplastic surgery) was also endorsed. The Panel considered that sentinel node biopsy is the standard of care for patients with a clinically negative axilla and that axillary node dissection could be avoided in all patients with a negative sentinel node and in selected patients with micrometastatic disease or isolated tumour cells in the sentinel node. A trend to increasing use of prophylactic contralateral mastectomy was reported, though it was acknowledged that this procedure was not associated with any proven survival advantage.

Radiation therapy after local excision of DCIS was considered to be standard by the Panel members, though most members considered that it could be avoided in elderly patients and those with low-grade DCIS and clearly negative margins. For patients with invasive cancer, postmastectomy radiation therapy was indicated for those with four or more involved axillary lymph nodes, but indications for its use in patients with one to three nodes were considered more restricted and particularly applicable for young patients and those with other poor prognostic features. The majority of the Panel considered that accelerated whole-breast radiation after conservative surgery was an acceptable option for patients aged ≥60 with cancers with favourable patterns, but that partial breast radiation should still be considered experimental. The Panel considered that endocrine therapy without radiation might be considered in elderly patients with small tumours, clinically node-negative and -positive ERs.

adjuvant systemic therapies

The Panel considered targeted therapies against the steroid hormone receptors and overexpressed HER2 as of prime importance. In patients whose tumours lack these targets or in those at higher risk despite the presence of steroid hormone receptors, the use of chemotherapy requires consideration as set out in Tables 2 and and33.

endocrine therapy for premenopausal patients

The Panel accepted either tamoxifen or tamoxifen plus ovarian function suppression as standard endocrine therapies in this group. Ovarian function suppression alone or ovarian ablation was considered a possibility only in extraordinary circumstances. Aromatase inhibitors alone are contraindicated in premenopausal patients. In case tamoxifen is contraindicated, aromatase inhibitors may be administered to premenopausal women together with ovarian function suppression. Verification of ovarian function suppression to postmenopausal levels is important also in patients under the age of 60 who are receiving aromatase inhibitors.

Pharmacogenetic determination of tamoxifen metabolism status as influenced by CYP2D6 was not considered ready for routine application in selecting patients for tamoxifen therapy by the majority of the Panellists.

endocrine therapy in postmenopausal patients

A majority of the Panel considered that an aromatase inhibitor should form part of standard endocrine therapy for postmenopausal women with receptor-positive breast cancer, though acknowledging that there were certain patients for whom tamoxifen alone can be considered adequate. There was division about the proper duration of treatment with aromatase inhibitors, though it was pointed out that safety data beyond 5 years are not yet available. The majority of the Panel preferred aromatase inhibitors as up-front endocrine treatment particularly in patients at higher risk of early relapse.

anti-HER2 therapy

Updated results from two of the trastuzumab trials were presented continuing to demonstrate the value of this therapy for patients with HER2-positive disease. The FinHER trial evaluated a short course of trastuzumab, which is currently being compared with a conventional 1-year duration. Meanwhile, the standard duration of trastuzumab therapy remains 1 year. The Panel noted that no results are yet available from the 2-year trastuzumab group in the HERA trial. 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. Finally, the limited evidence of increased risk among patients with HER2-positive tumours <1 cm in size without axillary nodal involvement does not allow definitive recommendation regarding anti-HER2 therapy in this group.

adjuvant chemotherapy

Two situations were recognised in which the decision to use adjuvant chemotherapy was relatively clear-cut. First, adjuvant systemic therapy for patients with triple-negative disease is essentially limited to chemotherapy, and most such patients are at sufficient risk to justify this treatment. Secondly, as noted above, chemotherapy is conventionally given with or preceding trastuzumab for patients with HER2-positive invasive breast cancer. The remaining patients—those with ER-positive, HER2-negative disease—are the group in whom decisions about adjuvant chemotherapy are most difficult (Table 3). The Panel recognised that patients whose tumours contained high levels of ER derived less benefit from addition of chemotherapy to endocrine therapy. There was no agreement about the definition of a standard chemotherapy regimen for any disease subset. Taxane-containing regimens were discussed and combinations containing docetaxel and cyclophosphamide as well as dose-dense doxorubicin and cyclophosphamide followed by paclitaxel were viewed as standard therapies among several other regimens.

neoadjuvant systemic therapy

Neoadjuvant systemic therapy was considered justified primarily to enhance the possibility of breast-conserving surgery. If indicated, the majority of the Panel considered that the neoadjuvant chemotherapy regimen should include both a taxane and an anthracycline and (for HER2-positive disease) an anti-HER2 drug. Thus, the choice of a regimen for adjuvant or neoadjuvant chemotherapy might be made using similar criteria. Neoadjuvant endocrine therapy without chemotherapy was considered reasonable for postmenopausal patients with strongly receptor-positive disease. If used, such treatment should be considered for a duration of 5–8 months or until maximum tumour response.

preservation of fertility

Pregnancy after diagnosis of breast cancer has not been shown to negatively impact prognosis. Women should be counselled about options for preserving fertility. The Panel did not consider that any currently available methods for preservation of fertility following chemotherapy were of proven value, though gonadotropin-releasing hormone agonists are used occasionally. These are being tested in an ongoing clinical trial for women with endocrine nonresponsive disease who are receiving alkylating agents. Cryoconservation and retransplantation of ovarian tissue are also experimental.

use of bisphosphonates

Emerging information on bone protection from demineralisation and tumour by bisphosphonates was viewed as interesting, but the Panel did not consider that routine use of bisphosphonates was indicated for women with normal bone health receiving adjuvant endocrine therapy.

male breast cancer

The Panel considered that adjuvant tamoxifen was standard therapy and did not endorse the use of adjuvant aromatase inhibitors in men with breast cancer.

commentary

The present report proposes a new approach to the separate selection of each treatment modality according to its most relevant indications. We look forward to future studies more accurately defining the value of various high-throughput technologies in assessing the level of risk and likelihood of response to specific therapies. Meanwhile, careful application of the presently available therapies described in this report offers great value to women with early breast cancer.

Acknowledgments

Members of the Panel are listed below. All had a significant input to the discussion and manuscript. John Forbes and Stella Kyriakides were unable to attend the Panel session, but provided input for the planning of the meeting and reviewed and approved the manuscript.

Matti Aapro, Clinique de Genolier, 1 Route du Muids, 1245 Genolier, Switzerland; Kathy S. Albain, Loyola University Medical Center, Cardinal Bernardin Cancer Center, 2160 S First Avenue, Room 109, Maywood, IL 60153, USA; Jonas Bergh, Department of Oncology, Karolinska Institute and University Hospital, 17176 Stockholm, Sweden; Harold Burstein, Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA; Robert Carlson, Medical Oncology, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA; Monica Castiglione-Gertsch, MHA ISPM/RGT University of Geneva, Boulevard de la Cluse 55, 1205 Geneva, Switzerland; Alan S. Coates, International Breast Cancer Study Group and University of Sydney, Sydney, 40 Cook Road, Centennial Park NSW 2021, Australia; Marco Colleoni, Research Unit Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; Alberto Costa, European School of Oncology, Via del Bollo 4, 20123 Milan, Italy; Jack Cuzick, Cancer Research, UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary College, University of London, Charterhouse Square, London EC1M 6BQ, UK; Nancy Davidson, Director, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, UPMC Cancer Pavilion, 5th Floor, Suite 500, Pittsburgh, PA 15232, USA; Angelo Di Leo, Sandro Pitigliani Medical Oncology Unit, Department of Oncology, Hospital of Prato, Piazza dell'Ospedale, 59100 Prato, Italy; John F. Forbes, ANZ Breast Cancer Trials Group, University of Newcastle, Locked Bag 7, Hunter Region Mail Centre, NSW 2310, Newcastle, Australia (Absent); Richard D. Gelber, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA; John H. Glick, University of Pennsylvania, Abramson Cancer Center, 16 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA; Joseph Gligorov, APHP Tenon, Cancer Est, 4 Rue de la Chine, 75020 Paris, France; Michael Gnant, Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Wien, Austria; Aron Goldhirsch, International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland and European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy (Chairman); Paul E. Goss, Director, Breast Cancer Research, MGH Cancer Center, 55 Fruit Street, Boston, MA 02114, USA; Jay Harris, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Room 1622, 44 Binney Street, Boston, MA 02115, USA; James N. Ingle, Mayo Clinic Cancer Center, Breast Cancer Research Program, 200 First Street, S.W., Rochester, MN 55905, USA (Chairman); Jacek Jassem, Department of Oncology & Radiotherapy, Medical University of Gdansk, Debinki Street 7, 80-211 Gdansk, Poland; Per Karlsson, Department of Oncology, Sahlgrenska University Hospital, 41345 Göteborg, Sweden; Manfred Kaufmann, Director, Department Gynecology, Obstetrics and Breast Unit, J.W. Goethe University Hospital, Theodor Stern Kai 7, 60596 Frankfurt a. M., Germany; Stella Kyriakides, Europa Donna Cyprus, 28 Prodromou Street, 2406 Nicosia, Cyprus (Absent); Louis Mauriac, Institute Bergonié, Regional Cancer Center, 229 Cours d'Argonne, 33076 Bordeaux, France; Gunter von Minckwitz, GBG Forschungs GmbH, Schleussnerstrasse 42, 63263 Neu Isenburg, Germany; Monica Morrow, Breast Surgery Service, Anne Burnett Windfohr Chair of Clinical Oncology, Memorial Sloan-Kettering Cancer Center, Department of Surgery, 1275 York Avenue MRI 1026, New York, NY 10065, USA; Henning T. Mouridsen, Department of Oncology, Finsen Center 5074, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; Moise Namer, Head, Medical Oncology, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice Cedex 2, France; Larry Norton, Director of Breast Cancer Program, Memorial Sloan-Kettering Cancer Center, Room H 901, 205 East 64th Street, Concourse Level, New York, NY 10021-6007, USA; Soonmyung Paik, National Surgical Adjuvant Breast and Bowel Project, 4929 Bayard Street, Pittsburgh, PA 15213, USA; Martine J. Piccart-Gebhart, Internal Medicine, Oncology, Institut Jules Bordet, Rue Héger-Bordet 1, 1000 Brussels, Belgium; Kurt Possinger, Universitätsklinikum Charité Campus Mitte, Centrum 14, M.S. Onkologie/Hämatologie, Charitéplatz 1, 10117 Berlin, Germany; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre, Ontario Clinical Oncology Group, 2075 Bayview Avenue, Toronto, Ontario M4N 1H6, Canada; Emiel J.T. Rutgers, The Netherlands Cancer Institute, Department of Surgery, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Vladimir F. Semiglazov, N.N. Petrov Research Institute of Oncology, 68 Leningradskaya Street, Pesochny-2, 197758 St. Petersburg, Russia; Ian Smith, Department of Medicine, Royal Marsden Hospital and Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK; Beat Thürlimann, Breast Center, Kantonsspital St Gallen, 9007 St Gallen, Switzerland; Giuseppe Viale, Department of Pathology, European Institute of Oncology and University of Milan, Via Ripamonti 435, 20141 Milan, Italy; Toru Watanabe, Department of Medicine, Hamamatsu Oncology Center, 3-6-13 Chuo Naka-Ku, 430-0929 Hamamatsu, Japan; Eric P. Winer, Breast Oncology Center, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA, 02115, USA; William C. Wood, Department of Surgery, Suite B 206, Emory University Hospital, 1364 Clifton Road, Atlanta, GA 30322, USA.

The authors thank the Participants in the 11th 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 Giuseppe Curigliano, Shari Gelber, and Sabina Briner. We also thank Professor Umberto Veronesi for his guidance and Franco Nolè for his thoughtful remarks.

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