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Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer

From the International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Lugano, and Zentrum für Tumordiagnostik und Prävention, St Gallen, Switzerland; European Institute of Oncology, Milan, Italy; University of Pennsylvania Cancer Center, Philadelphia, PA; Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; and Australian Cancer Society and University of Sydney, East Sydney, Australia.

Address reprint requests to Aron Goldhirsch, MD, International Breast Cancer Study Group, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; e-mail: agoldhirsch{at}sakk.ch

	INTRODUCTION

TOP INTRODUCTION PROGNOSIS AND PREDICTION OF... APPENDIX REFERENCES

 
DEVELOPMENT OF treatment guidelines for early breast cancer requires comprehensive analysis of the results of randomized clinical trials and the interpretation of their biologic, clinical, and social relevance for individual patients. Several successive worldwide meta-analyses, using available data from individual randomized trials, have been presented by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).^1-5 Conferences such as the series that have been held in St Gallen, Switzerland, since 1978 provide an opportunity to reach expert consensus about the implications of these and other relevant data to guide women and their doctors in the selection of appropriate treatment.

In February 2001, the Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer was held in St Gallen, Switzerland. Knowledge on breast cancer genetics, diagnosis, treatment, and prevention has evolved since the Sixth International Conference, held in February 1998.⁶ Some important areas highlighted at the recent meeting include recognition of the increased role of endocrine therapy in properly selected patient groups, the loss of enthusiasm for high-dose therapy and incorporation of new agents to be reflected in improved outcomes, the avoidance of unnecessarily extensive surgery by development of sentinel lymph node biopsy, a better definition of the role of postmastectomy radiation therapy, and the importance of factoring patient preferences into treatment decisions. Table 1 describes some examples of findings presented at the meeting and their implications or status relative to patient care.

	PROGNOSIS AND PREDICTION OF RESPONSE

TOP INTRODUCTION PROGNOSIS AND PREDICTION OF... APPENDIX REFERENCES

 
An important change from previous years is that the Panel no longer defines a group of patients who should not be offered adjuvant systemic therapy. Even among patients who are at minimal or low risk of recurrence (10% recurrence at 10 years; Table 2), a case can be made for adjuvant tamoxifen to prevent a second primary breast cancer by analogy with the Breast Cancer Prevention Trial (National Surgical Adjuvant Breast and Bowel Project P-1)¹⁷ and the overview by the EBCTCG.³ Reduced incidence of second breast cancers in women receiving tamoxifen was confined to the cohorts with tumors expressing steroid hormone receptors, whereas no reduction in incidence was observed for patients who had tumors without such receptors.

An additional fundamental change from the previous consensus is that treatment selection is based primarily on assessment of endocrine-responsive or endocrine-nonresponsive disease according to the presence of estrogen and progesterone receptors in the primary tumor. The threshold defining endocrine-responsive disease has also changed in that tumors containing as few as 1% of cells staining for steroid hormone receptors are regarded as potentially endocrine-responsive (ie, might benefit from the addition of endocrine therapies to the adjuvant treatment program). Selection of endocrine therapy alone, chemotherapy alone, or of the combination of these modalities depends upon a complex integration of factors, including assessment of risk of recurrence and the probability of endocrine responsiveness. Thus, for example, a patient with uninvolved or only a few involved lymph nodes and a strongly positive receptor tumor (eg, 90% of cells stained), might best be treated with endocrine therapy alone, whereas a patient with multiple involved nodes and a low level of detectable receptor (eg, 9% of cells stained) would probably be a candidate for combined chemoendocrine therapy. Uncertainty remains regarding the value of factors such as overexpression of HER2/neu, p53 mutation, and high level of proliferative markers for selecting patients for combined therapy.⁶⁹ Patients with endocrine-nonresponsive disease (absence of detectable steroid hormone receptors) should be offered adjuvant chemotherapy alone. Such patients do not benefit from adjuvant endocrine therapy. Indeed they should not receive endocrine therapy, because this may in some circumstances reduce the efficacy of their adjuvant chemotherapy.

CONSENSUS PANEL RECOMMENDATIONS AND GUIDELINES
This section and Tables 2 and 3 summarize the recommendations and guidelines for postoperative adjuvant systemic therapy of early breast cancer proposed by the International Consensus Panel during the St Gallen Conference, 2001. The Panel emphasized that these guidelines are based on evidence from clinical trials demonstrating that various adjuvant therapies can reduce the risk of relapse and increase survival duration. They are not intended to be used to define required treatment for all patients, as circumstances and attitudes toward treatment and resources may vary both between individuals and systematically in different parts of the world. Discussions on postoperative radiation therapy, preoperative systemic therapy, biologic therapies, and choice of chemotherapy regimen are described within sections of Table 1.

As in previous editions of the Experts’ Consensus, the format used to construct Table 3 reflects the four issues that are considered during treatment decision made outside of the framework of clinical trials: prognosis, prediction of treatment response, extrapolation of results on treatment effects obtained from randomized trials, and consideration of patient’s preference concerning absolute and relative risks and benefits of effective therapies. Aspects related to availability of national resources (for offering every type of adjuvant treatment to all in each country), and the involvement of well women in designing educational strategies (for a more extensive participation of patients in clinical research programs) were discussed but were not reflected in the recommendations.

Within the body of Table 3, we distinguish between therapies for which direct evidence is available demonstrating treatment effect based on results of randomized trials and therapies that are still investigational, the latter being indicated with brackets. Finally, footnotes to Table 3 indicate specific areas in which patient preference should be considered to define appropriate treatment. As previously emphasized, physicians should elicit preferences of patients concerning aversion to side effects and attitudes toward disease recurrence and weigh these preferences against the uncertainty about prognosis and treatment effectiveness in terms of the absolute magnitude of the benefit to be achieved. The recommendation to consider patient preference does not mean that when physicians are uncertain about what to do they should invite the patient to decide. Rather, the footnotes emphasize that physician’s judgment based on patient preference is an acceptable way to help in the selection of adjuvant treatment.

NODE-NEGATIVE BREAST CANCER
Treatment for patients with node-negative disease varies substantially according to the baseline prognosis. For patients considered at high risk, the treatment choice follows an algorithm similar to that for node-positive disease, considering mainly resistance or responsiveness to endocrine therapies (ie, the latter requires presence of positive estrogen and/or progesterone receptor staining at the histopathologic evaluation of the primary tumor). Chemotherapy for approximately six courses was considered to be the treatment of choice for those patients whose tumors did not express estrogen and progesterone receptors, especially those at higher risk of relapse. For those with tumors expressing estrogen and/or progesterone receptors, endocrine therapy alone (adapted to the menopausal status) or combined chemotherapy in association with (usually followed by) endocrine therapy were both considered appropriate treatment options.

• Data from individual clinical trials on the treatment of patients with node-negative disease indicate that the addition of classical CMF (cyclophosphamide, 100 mg/m² orally, daily on days 1 through 14; methotrexate 40 mg/m² administered intravenously [IV] and fluorouracil 600 mg/m² IV, both on days 1 and 8, repeated every 4 weeks⁴⁹) or of methotrexate followed by fluorouracil (M-F) to tamoxifen benefited the patients as compared with tamoxifen alone.⁷⁰
  
• Additional information from a trial conducted specifically in postmenopausal patients leads to the conclusion that much of the effect of chemotherapy (three courses of classical CMF) is seen in patients with low or no estrogen receptor expression in the primary tumor.⁷¹
  
• The use of an adjuvant anthracycline-based regimen is probably indicated in the high-risk, node-negative setting. The choice of the regimen should especially account for the results from two trials in which classical CMF was compared with an anthracycline combination. In one trial, a CMF-like anthracycline regimen (CAF, in which cyclophosphamide is given orally on days 1 through 14, and doxorubicin and fluorouracil, both IV, are given on days 1 and 8 of a 28-day course) was shown to improve outcome when compared with classical CMF,⁷² whereas in the other, in which AC (doxorubicin plus cyclophosphamide IV on day 1 every 21 days) was used, no difference in treatment outcome was seen.⁷³
  
• The use of tamoxifen is not indicated for patients with hormone receptor status defined as negative.^3,73
  

For patients with minimal/low-risk disease, the question of whether to treat with tamoxifen depends on a risk-benefit analysis, in which the low relapse rate within the first 10 years and the potential reduction of the incidence of breast cancer in the conserved breast and in the contralateral breast should be taken into account and weighed against risks of endocrine treatment.

• The use of ovarian function suppression for a limited period of time (eg, 2 years of gonadotropin-releasing hormone [GnRH] analog) is being investigated, and preliminary results are encouraging.⁷⁴
  
• The use of chemotherapy was not considered a reasonable option for this group of patients, although information is available on the efficacy of adjuvant chemotherapy in reducing the risk of relapse, mainly in premenopausal patients.⁷⁵ How much of this benefit is due to the endocrine effects of chemotherapy is still a matter for research.^76,77
  

NODE-POSITIVE BREAST CANCER
The increased risk of relapse and death associated with tumor metastasis to the ipsilateral axilla had in the past significantly influenced the choice of treatment. More intensive cytotoxic courses of treatment were used to attempt a more extensive tumor cell kill. The higher risk of relapse represents, in fact, a larger opportunity for a greater absolute benefit, because most evidence supports a similar proportional benefit in higher- and lower-risk groups. Some areas of research provided useful information for making treatment recommendations for patients who are at an increased risk of relapse.

• The use of anthracycline-based regimens led, on average, to improved treatment results compared with CMF-type regimens.⁴ Direct comparison of an anthracycline-based regimen with classical CMF showed a significant improvement in disease-free survival favoring the former almost exclusively in trials in which the schedule of the anthracycline-based regimen was similar to classical CMF (eg, CEF, which is a 4-epidoxorubicine–containing regimen, and CAF, which is a doxorubicin-containing regimen).^72,78 These data are the basis for indicating a preference for anthracycline regimens in this setting.
  
• Several trials of high-dose chemotherapy with marrow or peripheral-blood progenitor-cell support failed to show a significant improvement in treatment outcome.^56-59 Some studies of high-dose chemotherapy are still under evaluation and their results will become available shortly. At this stage it is unknown whether clinically relevant reduction of relapse rates or mortality will derive from high doses of cytotoxics requiring stem-cell support, and the use of this modality should be exclusively confined to the framework of randomized clinical trials.
  
• An initial wave of enthusiasm followed the early results of a large trial investigating the introduction of taxanes, specifically paclitaxel, as part of a standard adjuvant therapy for node-positive breast cancer.⁵³ Further follow-up of that trial and the presentation of a second trial, with a similar design and size, suggested that the addition of paclitaxel after four courses of AC might be effective only in patients with endocrine-nonresponsive disease. There was no apparent benefit of paclitaxel among patients who were treated also with tamoxifen. Furthermore, because paclitaxel extended the duration of adjuvant chemotherapy, doubt remains in terms of whether a taxane would add benefit if comparing two cytotoxic regimens of the same duration (ie, four courses of AC followed by four courses of paclitaxel v AC followed by another effective regimen of similar duration) for patients with endocrine-nonresponsive disease.⁵⁴ Investigations on the role of taxanes (paclitaxel and docetaxel) in adjuvant cytotoxic regimens are ongoing and will provide useful information on the use of these drugs. The most important information from the first trial of paclitaxel as part of the adjuvant chemotherapy program⁵³ is probably related to the essential role of endocrine treatment in addition to a short course (AC for four cycles) for patients who are at high risk of relapse but who have endocrine-responsive disease.
  
• Combined chemotherapy and tamoxifen was proven to be superior to tamoxifen alone in several individual trials of patients with tumors expressing estrogen and/or progesterone receptors, and this is well reflected in the overview.^3,4 The higher the risk of relapse, the larger might be the advantage of the chemotherapy plus tamoxifen over tamoxifen alone. The recommendation on the use of tamoxifen alone in postmenopausal women with node-positive disease may be justified on the basis of individual considerations related to risk of relapse, age, and assessment of patient’s preference.
  

SPECIFIC ASPECTS OF TREATMENT
Ovarian Ablation and Ovarian Endocrine Function Suppression The overview results² indicated the beneficial effect of ovarian ablation. This treatment significantly improved long-term survival for women younger than 50 years, at least in the absence of chemotherapy. Long-term side effects are still a significant issue when offering this treatment mainly to very young women, especially because the safety of treatments for menopausal symptoms is unknown for this cohort of patients.

Seven trials (most with only preliminary data) tested the use of goserelin to suppress ovarian function (with or without the addition of tamoxifen), comparing it with chemotherapy alone.^{43-46,74,79,80} The addition of goserelin to chemotherapy, with or without tamoxifen, was tested in the Intergroup Trial 0101.⁷⁹ The results led to the conclusion that, after chemotherapy, the combination of goserelin with tamoxifen is more effective than goserelin alone in terms of disease-free survival (but not in terms of overall survival). Tamoxifen alone was not tested. The most relevant question remains, in fact, whether premenopausal patients who maintain ovarian endocrine function after chemotherapy should be offered tamoxifen alone, or tamoxifen plus ovarian suppression. Data from randomized trials in advanced disease suggest that combined tamoxifen and GnRH analog is indeed more beneficial than each of the modalities alone.⁴⁷ On the basis of available information from the randomized trials in the adjuvant setting, it is clear that combined tamoxifen and GnRH analog may be regarded as a proper treatment option for premenopausal women with endocrine-responsive disease. The duration of GnRH analog treatment has not been critically studied, and in the various trials, the drug was given for 2, 3, or 5 years.

Tamoxifen Tamoxifen is the most established adjuvant treatment for patients with tumors expressing steroid hormone receptors.³ Its use for the duration of 5 years seems to reduce relapse and death, with benefit accruing for several years after its cessation (the term of carry-over effect has been conceived at the EBCTCG secretariat to describe this observation). The question of whether a longer duration of treatment with the drug will improve treatment outcome is under investigation in at least two large randomized trials. The late use of tamoxifen (beginning treatment some years after diagnosis) has been shown in a randomized controlled trial⁸¹ to be effective in women with endocrine-responsive disease who did not start the drug shortly after surgery.

Despite the fact that tamoxifen has been widely used for almost three decades, the relevance of its endocrine effects also on other target tissues has not been completely elucidated. As described above, it is as yet unknown whether ovarian function suppression in premenopausal patients treated with adjuvant tamoxifen significantly improves treatment outcome. In postmenopausal patients, an important question is whether the association of tamoxifen with aromatase inhibitors, especially their sequential use, improves treatment results. This has been suggested in a small trial in which aminogluthetimide in sequence after tamoxifen was used.⁸² This information, together with the data of efficacy of newer aromatase inhibitors, such as anastrozole, letrozole, and exemestane, on measurable disease (mostly advanced disease; in one trial of letrozole was tested as a neoadjuvant treatment), awaits confirmation in ongoing trials in the adjuvant setting. Their use is not indicated outside the framework of clinical trials. The Panel stressed that the use of other selective estrogen receptor modulators instead of tamoxifen or after the treatment of this drug is currently not justified, given available data.

Chemotherapy Regimen Anthracycline-based regimens have been increasingly introduced to clinical practice, motivated by the evidence that, on average, their use is more effective in terms of relapse-free and overall survival than several CMF-based regimens (see also discussion within the sections on treatment of node-negative and node-positive disease).⁴ The optimal dose of anthracyclines (doxorubicin and epirubicin) for inclusion in such regimens is unknown, although some information on reduced treatment effects with a lower anthracycline dose is available.^83,84 Increasing the dose of doxorubicin did not improve treatment results in a trial in which the role of paclitaxel was also investigated.⁵³ An important observation related to the use of intensive regimens containing anthracyclines and alkylating agents, often with the support of hemopoietic growth factors, is the increased incidence of leukemia.^57,78

The failure to show a clinically relevant treatment effect using high-dose chemotherapy (with marrow or peripheral-blood progenitor-cell support) represents a challenge for development of newer regimens, with particular attention on predictive factors and focusing on patients with disease likely to have less interference with endocrine effects of chemotherapy. Also the inconclusive evidence on the usefulness of taxanes in the adjuvant setting leads to similar conclusions.

Progress in cytotoxic adjuvant therapy has been limited. Indeed, an old regimen such as classical CMF remains a valid treatment alternative for patients with lower risk of relapse. One potentially promising approach is the combined use of trastuzumab and chemotherapy,³⁸ which is being investigated in at least five clinical trials in the adjuvant setting. The use of trastuzumab as part of an adjuvant therapy in patients whose tumors overexpress HER2/neu should be strictly limited to the context of clinical trials

In conclusion, the international Panel attempted to answer many questions related to the best use of treatments investigated in randomized clinical trials. New available information from clinical trials enhanced the role of endocrine treatments, especially in premenopausal women, for whom the endocrine effects of cytotoxic agents became more evident. The Panel members were more than ever convinced that much more can be achieved to increase knowledge about the disease and improve patient care if participation in clinical trials becomes more acceptable to the public as well as to the medical community. International cooperation on trials and their evaluation must lead to the investigation of critical biologic principles rather than establish the superiority of particular pharmaceuticals for regulatory purposes. A collaborative approach involving the development of new agents and investigation of their optimal integration into adjuvant therapy programs will best ensure progress for improved patient care.

	APPENDIX

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Members of the Panel are as follows; all had a significant input to the discussion and manuscript:Jeffrey S. Abrams, MD, Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, Bethesda, MD; Michael Baum, MD, Department of Surgery, University College London, Charles Bell House, London, United Kingdom; Jonas Bergh, MD, Department of Oncology, Radiumhemmet, Karolinska Institute and Hospital, Stockholm, Sweden; Monica Castiglione-Gertsch, MD, International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; Alan S. Coates, MD, Australian Cancer Society and University of Sydney, Sydney, Australia; John Forbes, MD, Department of Surgical Oncology, University of Newcastle, Newcastle Mater Hospital, Newcastle, Australia; Richard D. Gelber, PhD, Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; John H. Glick, MD, University of Pennsylvania Cancer Center, Philadelphia, PA (Chairman); Aron Goldhirsch, MD, International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Lugano, Switzerland, and European Institute of Oncology, Milan, Italy (Chairman); Anthony Howell, MD, Cancer Research Campaign Department of Medical Oncology, Christie Hospital, National Health Service Trust, Manchester, United Kingdom; Raimund Jakesz, MD, University of Vienna, Department of General Surgery, Wien, Austria; Manfred Kaufmann, MD, Department of Gynecology and Obstetrics, Goethe University, Frankfurt am Main, Germany; Henning T. Mouridsen, MD, Department of Oncology, Rigshospitalet, Copenhagen, Denmark; Monica Morrow, MD, Lynn Sage Comprehensive Breast Center, Northwestern Memorial Hospital, Chicago, IL; Moise Namer, MD, Centre Antoine Lacassagne, Nice, France; Martine J. Piccart-Gebhart, MD, Department of Chemotherapy, Institut Jules Bordet, Brussels, Belgium; Maureen E. Trudeau, MD, Toronto Sunnybrook Regional Cancer Center, Toronto, Ontario, Canada; Arne Wallgren, MD, Department of Oncology, Sahlgrenska University Hospital, Goeteborg, Sweden; and William C. Wood, MD, Department of Surgery, Emory University School of Medicine, Atlanta, GA.

	ACKNOWLEDGMENTS

 
We thank the participants of the Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer for many useful remarks. We also thank Umberto Veronesi, MD; Bernard Fisher, MD; Marco Colleoni, MD; Franco Nolé, MD; Elisabetta Munzone, MD; Kathleen Pritchard, MD; Daniel Vorobiof, MD; Matti Aapro, MD; and Shari Gelber for their thoughtful contributions.

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Submitted April 3, 2001; accepted July 25, 2001.

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