Originally published as JCO Early Release 10.1200/JCO.2003.04.576 on July 7 2003

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldhirsch, A. Articles by Senn, H.-J. Search for Related Content PubMed PubMed Citation Articles by Goldhirsch, A. Articles by Senn, H.-J.

Meeting Highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer

From the International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Lugano; Division of Gynecologic Oncology, Kantonsspital; Zentrum für Tumordiagnostik und Prävention, Silberturm, Grossacker, St Gallen, Switzerland; European Institute of Oncology, Milan, Italy; Department of Surgery, Emory University, Atlanta, GA; Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA; and The Cancer Council Australia, Sydney, New South Wales, 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.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor–absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer—both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
DEVELOPMENT OF expert consensus treatment guidelines for early breast cancer requires comprehensive analysis of the results of randomized clinical trials and the interpretation of their biologic, clinical, social, and personal relevance for individual patients. The series of conferences held in St Gallen (Switzerland) since 1978 has specifically focused on reaching expert consensus on the implications of evidence for patient treatment selection.¹ The eighth such meeting, with 3,200 participants from 75 countries, was held in March 2003.

New insight into prognosis and prediction of response has come from the extensive work on the urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 system,^2,3 and recently introduced technologies including gene profiling^4–7 and cyclin E determination.^8,9 However, the exact application of each of these technologies remains to be properly defined.

We finally have reliable evidence that sequential administration of tamoxifen after chemotherapy is superior to concurrent use of these modalities.^10,11 Additional analyses of the National Surgical Adjuvant Breast and Bowel Project (NSABP) study B-20 in node-negative women¹² and the publication of International Breast Cancer Study Group (IBCSG) study IX¹³ have clarified that tamoxifen alone may be adequate adjuvant therapy for postmenopausal women with node-negative, endocrine-responsive disease.

Although much useful information will come from new technologies, there is also a valuable resource of information already available from current studies. Subset analysis is inevitable in deriving information with which to tailor treatment to individual patients. Such analysis is statistically proper provided sufficient numbers of patients are available and provided hypotheses generated in one data set can be independently confirmed. This recently has been done to substantiate greater responsiveness to cytotoxic chemotherapy in tumors lacking estrogen receptors,^14,15 and the inadequacy of cytotoxic therapy alone in young patients with endocrine-responsive disease.^16,17 Indeed, concentration exclusively on overall average effects produced by pooling biologically different disease entities can result in dangerously misleading advice for individual patients. Within the Early Breast Cancer Trialists’ Collaborative Group Overview of adjuvant cytotoxic therapy,¹⁸ the greater magnitude of benefit observed among older patients with node-negative as distinct from node-positive disease may reflect relative selection into the node-negative cohorts of higher-risk patients with a more chemotherapy-responsive disease associated with lack of steroid hormone receptor expression.¹⁹

Although preliminary evidence and laboratory models suggest that overexpression of HER2 may indicate a lower probability of responsiveness to tamoxifen²⁰ and perhaps cyclophosphamide, methotrexate, and fluorouracil (CMF),²¹ the Panel was not ready to accept this information as currently useful for patient care. Table 1 describes additional examples of findings presented at the meeting and their implications or status relative to patient care.

	PROGNOSIS AND PREDICTION OF RESPONSE

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
Estrogen and progesterone receptor content in the primary tumor are powerful markers to predict endocrine responsiveness in their presence⁷⁴ and cytotoxic responsiveness in their absence.^{15,19,20,51,75–77} This does not mean that patients with tumors expressing hormone receptors do not benefit from chemotherapy.

Gene expression profiling studies^4–7 support a clear separation of steroid hormone receptor–absent disease as an entity distinct from disease showing low or high levels of receptors, whereas some clinical studies already provide empirical data that receptor-absent disease is different from that with even low levels of receptor expression.^51,75 Most clinical data, however, use a different grouping that combines receptor-absent disease with that expressing low receptor levels (so-called receptor-negative disease). Recognition of the importance of the receptor-absent group will require a change to current practices in many laboratories from reporting merely positive or negative receptor status (often adopting arbitrary cutoffs) in favor of more quantitative reporting of routine receptor determinations.

The implication for tailored treatment advice today depends on the degree of certainty that either modality alone will be sufficient for an individual patient. At one extreme, patients with both receptors absent can only be treated effectively with chemotherapy. The addition of endocrine agents in this population is at best useless and may be actively harmful either by the direct toxicity of the endocrine agent^22,78,79 or by interference with cytotoxics.^77,80–82 At the other extreme, some patients may have such strong receptor expression that the probability of control with endocrine therapy alone is considered sufficiently high that no cytotoxic treatment is required, especially among patients with low risk for recurrence.^12,13,83 Between these extremes, there is a gradation in level of uncertainty that endocrine therapy alone will be sufficient. In this in-between group, measures of absolute risk (eg, increased nodal involvement), and factors that might predict resistance to tamoxifen (HER2 overexpression) are relative (although imprecise) indications for the addition of cytotoxic therapy. For patients in lower risk groups such as postmenopausal patients in NSABP Trial B-20¹² and IBCSG Trial IX,¹³ and premenopausal patients in IBCSG Trial 11–93,⁸⁴ endocrine therapy alone may suffice. The Panel considered that, in circumstances in which the need for cytotoxics is uncertain, the addition of other agents such as trastuzumab or the substitution of endocrine agents not affected by a particular form of presumed resistance might reduce the indication for cytotoxics.

In considering stage as a factor that modulates the tailoring of treatment, it is noteworthy that the staging itself is being refined and altered by techniques such as sentinel lymph node biopsy and immunohistochemical identification of tumor cells within lymph nodes (both axillary and other nodes), bone marrow, and circulating blood. The new American Joint Committee on Cancer classification includes patients with isolated tumor cells in lymph nodes as having node-negative status.⁸⁵ This may lead to uncertainty about the proper risk category for such patients.

Patient Preferences, Advocacy, and Psychosocial Considerations
As in the previous meeting,¹ the Panel recognized the importance of ascertaining and allowing for patient preferences in defining the threshold of expected benefit at which treatment should be undertaken.^73,86,87 The increasing importance of patient advocacy groups^88–90 and the availability of information on the Internet emphasize the need to incorporate this aspect into decision making. Individual patient’s decisions will involve their preferences with regard to the additional benefit that could reasonably be expected from additional effective therapy. Patients should be involved in the decision-making process to the extent they desire⁹¹ and may be assisted by specific decision-making aids.^73,92–94

	CONSENSUS PANEL RECOMMENDATIONS AND GUIDELINES

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
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, 2003. 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, and include expert interpretation of the implications of this evidence for clinical decision making. The guidelines are not intended to be used to define required treatment for all patients because circumstances and attitudes toward treatment and availability of resources may vary both among 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.

The most important feature for determination of baseline prognosis remains the nodal status. For women presenting with node-negative disease, two patient populations have been defined on the basis of the risk for relapse (prognosis). These are described in the rows of Table 2 (Minimal risk and Average risk). A subtle but important change introduced to the classification refers to the influence of receptor levels. Only receptor-absent disease is now considered sufficient to constitute a criterion to remove an otherwise suitable patient from the minimal-risk group. This reclassification will avoid placing patients with low levels of receptor expression and otherwise low-risk features into a group for which only chemotherapy would be recommended.¹⁰²

Table 3 lists the categories of therapy considered to be appropriate for each of the groups defined according to treatment response (or predictive) factors. Within the body of Table 3, we distinguish among therapies for which direct evidence is available demonstrating treatment effect on the basis of results of randomized trials and therapies that are still investigational, the latter being indicated with brackets. Footnotes to Table 3 indicate specific additional aspects.

	NODE-NEGATIVE BREAST CANCER

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
Treatment for patients with node-negative disease varies substantially according to the baseline prognosis. For patients considered to be at average risk, the treatment choice follows an algorithm similar to that for node-positive disease. 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. Definition of the threshold at which combined-modality treatment is preferred may involve consideration of the level of receptor expression and the presence of factors such as HER2 overexpression (and to some extent also high tumor grade or high proliferation rate), which may reduce confidence in the efficacy of endocrine therapy alone.

For patients with minimal-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 reappearance of breast cancer in the conserved breast and in the contralateral breast should be taken into account and weighed against risks of endocrine treatment.

	NODE-POSITIVE BREAST CANCER

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
The increased risk of relapse and death associated with tumor metastasis to the ipsilateral axilla has 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. Even with endocrine-responsive disease, the higher risk of relapse and the presence of endocrine-resistant clones within the tumor, in general, have been taken as indications for the inclusion of cytotoxic chemotherapy in the treatment regimen.

The Panel recognized two general levels of cytotoxic therapy regimens, as discussed in Table 1. Treatment with four courses of doxorubicin and cyclophosphamide was shown to be equivalent to six courses of classical CMF.⁵⁹ Several regimens and schedules, such as Canadian cyclophosphamide, epirubicin, and fluorouracil (Canadian CEF)⁶⁰; the cyclophosphamide, doxorubicin, and fluorouracil (CAF) regimen⁶¹; dose-dense administration of doxorubicin, paclitaxel, and cyclophosphamide⁶⁸; and also to some extent, tailored fluorouracil, epirubicin, and cyclophosphamide (FEC),⁶² and docetaxel, doxorubicin, and cyclophosphamide (TAC)⁶⁷ have been shown in comparative trials to yield superior results, though at the cost of greater complexity, economic cost, or toxicity (Table 1). These more effective regimens may be preferred in patients at higher risk.

	SPECIFIC ASPECTS OF TREATMENT

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
Ovarian Ablation and Ovarian Endocrine Function Suppression
The Early Breast Cancer Trialists’ Collaborative Group Overview results¹⁰³ indicated a beneficial effect of ovarian ablation. This treatment significantly improved long-term survival for women younger than 50 years of age, at least in the absence of chemotherapy.⁵⁶ Long-term side effects, mainly for young women, are still a significant issue when this treatment is offered especially because the safety of treatments for menopausal symptoms is unknown.

For premenopausal women with endocrine-responsive disease, ovarian function suppression (goserelin) with⁵⁴ or without⁵⁵ tamoxifen appeared to be at least as effective as CMF chemotherapy alone, and information is available that the addition of tamoxifen to goserelin is more effective than goserelin alone, at least in the presence of chemotherapy.⁵⁶ The sequential use of goserelin after CMF appeared better than either modality alone in patients with node-negative disease, at least in subset analyses for women with estrogen receptor–positive breast cancer and those younger than 40 years.⁵⁷ The combination of bilateral oophorectomy followed by tamoxifen was effective compared with no adjuvant treatment even among patients with tumors overexpressing HER2.³² Chemotherapy alone was insufficient for younger patients (< 35 years of age) with steroid hormone receptor–positive tumors in retrospective analyses conducted in parallel across multiple cooperative groups,¹⁷ presumably because such patients received inadequate endocrine therapy from the ovarian effects of their cytotoxic treatment.

Aromatase Inhibitors in Postmenopausal Patients
A large randomized clinical trial (ATAC: Anastrozole, Tamoxifen Alone, or in Combination) has shown preliminary evidence that anastrozole is superior to tamoxifen as adjuvant therapy for postmenopausal women, 84% of whom had disease recorded as receptor-positive.⁵² The combination was no more effective than tamoxifen alone. The toxicity profile was more favorable with anastrozole with the exception of an increased risk of musculoskeletal disorders and bone fractures. Tamoxifen has a long-lasting (carryover) benefit,⁷⁴ so that the ultimate comparison between these two agents must await additional follow-up. Thus, long-term superiority of anastrozole is uncertain. An additional concern is that unplanned subset analyses within the ATAC trial have indicated less effect for anastrozole among groups defined by prior radiation therapy (63% of patients) or chemotherapy (21% of patients). Results from retrospective studies, on material from two distinct trials comparing tamoxifen with letrozole³⁰ or anastrozole,³¹ indicate that aromatase inhibitors are more effective than tamoxifen in patients with disease expressing estrogen receptors or progesterone receptors in the presence of overexpressed HER2. This observation must still be prospectively confirmed. Accordingly, the American Society of Clinical Oncology Technology Assessment Report⁵³ has recommended that anastrozole be used only for postmenopausal patients in whom tamoxifen is contraindicated or not tolerated, and the St Gallen Panel agreed with this statement. In making this assessment, it is noteworthy that the NSABP P-1 and the International Breast Cancer Intervention Study (IBIS-I) chemoprevention trials found that tamoxifen increased deep venous thrombosis and pulmonary embolism, especially among patients immobilized by surgery or bone fracture.^78,79

Radiation Therapy in Early Breast Cancer
Recent analysis of the Danish and the European Organization for Research and Treatment of Cancer trials has cast doubt on the traditional perception that radiotherapy is relatively of most benefit to patients with higher risk of relapse (eg, four or more positive nodes). In these trials the highest survival benefit was seen predominantly among patients with one to three positive nodes, whereas the reduction in locoregional recurrences was largest in patients with more advanced cancer.¹⁰⁴ Tailoring postmastectomy radiation therapy treatment recommendations for individual patients remains a priority for additional research.

	COMMENTARY

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
The International Consensus 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 cytotoxics was also 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 were to become more acceptable to the public and the medical community.¹⁰⁵ International cooperation on trials and their evaluation must concentrate on the investigation of critical biologic principles rather than merely establishing the superiority of particular pharmaceuticals for regulatory purposes. A collaborative approach involving the development of new agents and their careful scientific study by investigator-controlled clinical trials groups to determine their optimal integration into adjuvant therapy programs will best ensure progress for improved patient care. Patients with early breast cancer deserve no less.

	APPENDIX

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
Members of the International Consensus Panelare listed below. All members had a significant input to the discussion and manuscript. Kathy S. Albain, MD, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL; Harry Bartelink, MD, the Netherlands Cancer Institute, Radiation Therapy, Amsterdam, the Netherlands; 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, The Cancer Council Australia and University of Sydney, Sydney, Australia; Alberto Costa, MD, Department of Breast Surgery, Fondazione S. Maugeri, Pavia, Italy; Jack Cuzick, PhD, Imperial Cancer Research Fund, Mathematics, Statistics, and Epidemiology, London, United Kingdom; Nancy Davidson, MD, Sidney Kimmel Cancer Center of Johns Hopkins, Baltimore, MD; 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; Aron Goldhirsch, MD, International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Lugano, Switzerland, and European Institute of Oncology, Milan, Italy (Chairperson); Anthony Howell, MD, CRC Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom; James N. Ingle, MD, Mayo Clinic, Rochester, MN; Raimund Jakesz, MD, University of Vienna, Department of General Surgery, Vienna, Austria; Jacek Jassem, MD, Medical University of Gdansk, Department of Oncology and Radiotherapy, Gdansk, Poland; Manfred Kaufmann, MD, Department of Gynecology and Obstetrics, Goethe University, Frankfurt am Main, Germany; Monica Marrow, MD, Lynn Sage Comprehensive Breast Center, Northwestern Memorial Hospital, Chicago, IL; Henning T. Mouridsen, MD, Department of Oncology, Rigshospitalet, Copenhagen, Denmark; Moise Namer, MD, Centre Antoine Lacassagne, Nice Cedex, France; Martine J. Piccart-Gebhart, MD, PhD, Department of Chemotherapy, Institut Jules Bordet, Brussels, Belgium; Trevor Powles, MD, the Royal Marsden Hospital, Surrey, United Kingdom; Beat Thürlimann, MD, Medizinische Onkologie Kantonsspital, St Gallen, Switzerland; Giuseppe Viale, MD, Department of Pathology, European Institute of Oncology and University of Milan, Milan, Italy; William C. Wood, MD, Department of Surgery, Emory University School of Medicine, Atlanta, GA (Chairperson).

	ACKNOWLEDGMENTS

 
We thank the Participants of the Eighth International Conference on Primary Therapy of Early Breast Cancer; Professor Umberto Veronesi, Professor Bernard Fisher, Dr Marco Colleoni, Dr Daniel Vorobiof, Dr Angelo DiLeo, Dr Anne Hamilton, Dr Franco Nolè, Dr Silvia Dellapasqua, Dr Matti Aapro, and Shari Gelber for their thoughtful contributions.

	REFERENCES

TOP ABSTRACT INTRODUCTION PROGNOSIS AND PREDICTION OF... CONSENSUS PANEL RECOMMENDATIONS... NODE-NEGATIVE BREAST CANCER NODE-POSITIVE BREAST CANCER SPECIFIC ASPECTS OF TREATMENT COMMENTARY APPENDIX REFERENCES

 
1. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Clin Oncol 19:3817–3827, 2001[Free Full Text]

2. Harbeck N, Kates RE, Look MP, et al: Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). Cancer Res 62:4617–4622, 2002[Abstract/Free Full Text]

3. Look MP, van Putten WL, Duffy MJ, et al: Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94:116–128, 2002[Abstract/Free Full Text]

4. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747–752, 2000[CrossRef][Medline]

5. van’t Veer LJ, De Jong D: The microarray way to tailored cancer treatment. Nat Med 8:13–14, 2002[CrossRef][Medline]

6. Bartelink H, Begg AC, Martin JC, et al: Translational research offers individually tailored treatments for cancer patients. Cancer J Sci Am 6:2–10, 2000[Medline]

7. van De Vijver MJ, He YD, van’t Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009, 2002[Abstract/Free Full Text]

8. Keyomarsi K, Tucker SL, Buchholz TA, et al: Cyclin E and survival in patients with breast cancer. N Engl J Med 347:1566–1575, 2002[Abstract/Free Full Text]

9. Keyomarsi K, Tucker SL, Bedrosian I: Cyclin E is a more powerful predictor of breast cancer outcome than proliferation. Nat Med 9:152, 2003[CrossRef][Medline]

10. Albain KS, Green SJ, Ravdin PM, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143)

11. Albain KS: Adjuvant chemo-endocrine therapy for breast cancer: Combined or sequential? Breast 12:S13, 2003 (suppl 1, abstr S36)

12. Fisher B, Jeong J-H, Bryant J, et al: Findings from two decades of National Surgical Adjuvant Breast and Bowel Project clinical trials involving breast cancer patients with negative axillary nodes. Proceedings of the San Antonio Breast Cancer Symposium, December 11–14, 2002, San Antonio, TX (abstr 16)

13. International Breast Cancer Study Group: Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 94:1054–1065, 2002[Abstract/Free Full Text]

14. Coates AS, Gelber RD, Goldhirsch A: Subsets within the chemotherapy overview: International Breast Cancer Study Group. Lancet 352:1783–1784, 1998[Medline]

15. Coates AS, Goldhirsch A, Gelber RD: Overhauling the breast cancer overview: Are subsets subversive? Lancet Oncol 3:525–526, 2002[CrossRef][Medline]

16. Aebi S, Gelber S, Castiglione-Gertsch M, et al: Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 355:1869–1874, 2000[CrossRef][Medline]

17. Goldhirsch A, Gelber RD, Yothers G, et al: Adjuvant therapy for very young women with breast cancer: Need for tailored treatments. J Natl Cancer Inst Monogr 30:44–51, 2001

18. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930–942, 1998[CrossRef][Medline]

19. Cole BF, Gelber RD, Gelber S, et al: Polychemotherapy for early breast cancer: An overview of the randomised clinical trials with quality-adjusted survival analysis. Lancet 358:277–286, 2001[CrossRef][Medline]

20. Osborne CK, Bardou V, Hopp TA, et al: Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95:353–361, 2003[Abstract/Free Full Text]

21. Paik S, Bryant J, Tan-Chiu E, et al: HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92:1991–1998, 2000[Abstract/Free Full Text]

22. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296–300, 2003[CrossRef][Medline]

23. Veronesi U, Maisonneuve P, Rotmensz N, et al: Italian randomized trial among women with hysterectomy: Tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 95:160–165, 2003[Abstract/Free Full Text]

24. Zheng L, Li S, Boyer TG, et al: Lessons learned from BRCA1 and BRCA2. Oncogene 19:6159–6175, 2000[CrossRef][Medline]

25. Contant CM, Menke-Pluijmers MB, Seynaeve C, et al: Clinical experience of prophylactic mastectomy followed by immediate breast reconstruction in women at hereditary risk of breast cancer (HB(O)C) or a proven BRCA1 and BRCA2 germ-line mutation. Eur J Surg Oncol 28:627–632, 2002[CrossRef][Medline]

26. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616–1622, 2002[Abstract/Free Full Text]

27. Cuzick J, Forbes J, Howell A: Tamoxifen for breast-cancer prevention. Lancet 361:178, 2003[Medline]

28. National Comprehensive Cancer Network. http://www.nccn.org

29. Jordan VC: Is tamoxifen the rosetta stone for breast cancer? J Natl Cancer Inst 95:338–340, 2003[Free Full Text]

30. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808–3816, 2001[Abstract/Free Full Text]

31. Dixon JM, Jackson J, Hills M, et al: Anastrozole demonstrates clinical and biological effectiveness in erbB2 ER positive breast cancers. Proceedings of the San Antonio Breast Cancer Symposium, December 11–14, 2002, San Antonio, TX (abstr 263)

32. Love RR, Duc NB, Havighurst TC, et al: HER-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. J Clin Oncol 21:453–457, 2003[Abstract/Free Full Text]

33. Bryant J, Land S, Allred C, et al: DCIS: NSABP evidence from randomized trials. Breast 12:S9, 2003 (suppl 1, abstr S24)

34. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227–1232, 2002[Abstract/Free Full Text]

35. Fisher B, Jeong JH, Anderson S, et al: Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567–575, 2002[Abstract/Free Full Text]

36. Galimberti V: Evaluation of regional lymphnodes: New standards? Breast 12:S5, 2003 (suppl 1, abstr S9)

37. van der Ent FW, Kengen RA, van der Pol HA, et al: Halsted revisited: Internal mammary sentinel lymph node biopsy in breast cancer. Ann Surg 234:79–84, 2001[CrossRef][Medline]

38. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378–1387, 2001[Abstract/Free Full Text]

39. Koc M, Polat P, Suma S: Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol 64:171–175, 2002[CrossRef][Medline]

40. Bentzen SM, Skoczylas JZ, Overgaard M, et al: Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst 88:918–922, 1996[Abstract/Free Full Text]

41. Pierce LJ: Treatment guidelines and techniques in delivery of postmastectomy radiotherapy in management of operable breast cancer. J Natl Cancer Inst Monogr 30:117–124, 2001

42. Intra M, Gatti G, Luini A, et al: Surgical technique of intraoperative radiotherapy in conservative treatment of limited-stage breast cancer. Arch Surg 137:737–740, 2002[Abstract/Free Full Text]

43. Keisch M, Vicini F, Kuske RR, et al: Initial clinical experience with the MammoSite breast brachytherapy applicator in women with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 55:289–293, 2003[CrossRef][Medline]

44. Vicini F, Baglan K, Kestin L, et al: The emerging role of brachytherapy in the management of patients with breast cancer. Semin Radiat Oncol 12:31–39, 2002[CrossRef][Medline]

45. Bankhead C: Accelerated partial breast irradiation: More data needed, researchers say. J Natl Cancer Inst 95:259–261, 2003[Free Full Text]

46. Hayes DF: Markers of increased risk for failure of adjuvant therapies. Breast 12:S14, 2003 (suppl 1, abstr S37)

47. Viale G: Histopathology of primary breast cancer 2003. Breast 12:S4, 2003 (suppl 1, abstr S8)

48. Braun S, Pantel K, Muller P, et al: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342:525–533, 2000[Abstract/Free Full Text]

49. Piccart MJ: New data on chemotherapy in the adjuvant setting. Breast 12:S4, 2003 (suppl 1, abstr S5)

50. Colleoni M: Preoperative systemic treatment: Prediction of responsiveness. Breast 12:S13, 2003 (suppl 1, abstr S35)

51. Colleoni M, Gelber S, Coates AS, et al: Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer. J Clin Oncol 19:4141–4149, 2001[Abstract/Free Full Text]

52. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131–2139, 2002[CrossRef][Medline]

53. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: Status report 2002. J Clin Oncol 20:3317–3327, 2002[Abstract/Free Full Text]

54. Jakesz R, Hausmaninger H, Kubista E, et al: Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: Evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 20:4621–4627, 2002[Abstract/Free Full Text]

55. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628–4635, 2002[Abstract/Free Full Text]

56. Davidson NE: Ovarian ablation as adjuvant therapy for breast cancer. J Natl Cancer Inst Monogr 30:67–71, 2001

57. Castiglione-Gertsch M, O’Neill A, Gelber RD, et al: Is the addition of adjuvant chemotherapy always necessary in node negative (N-) pre/perimenopausal breast cancer patients (pts) who receive goserelin? First results of IBCSG trial VIII. Proc Am Soc Clin Oncol 21:38a, 2002 (abstr 149)

58. Castiglione-Gertsch M: Chemo-endocrine therapy: Any need to combine? Breast 12:S11, 2003 (suppl 1, abstr S30)

59. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483–1496, 1990[Abstract]

60. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651–2658, 1998[Abstract]

61. Hutchins L, Green S, Ravdin P, et al: CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: First results of Intergroup trial INT 0102. Proc Am Soc Clin Oncol 17:1a, 1998 (abstr 2)

62. Bergh J, Wiklund T, Erikstein B, et al: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: A randomised trial—Scandinavian Breast Group 9401 study. Lancet 356:1384–1391, 2000[CrossRef][Medline]

63. Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: Are all CMFs alike? Ann Oncol 9:489–493, 1998[Abstract/Free Full Text]

64. Adlard JW, Dodwell DJ: Optimum anthracycline-based chemotherapy for early breast cancer. Lancet Oncol 2:469–474, 2001[CrossRef][Medline]

65. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983, 2003[Abstract/Free Full Text]

66. Mamounas EP: Evaluating the use of paclitaxel following doxorubicin/cyclophosphamide in patients with breast cancer and positive axillary nodes. NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer, November 1–3, 2000, Bethesda, MD

67. Nabholtz J-M, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:36a, 2002 (abstr 141)

68. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431–1439, 2003[Abstract/Free Full Text]

69. Fumoleau P, Kerbrat P, Romestaing P, et al: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21:298–305, 2003[Abstract/Free Full Text]

70. Colleoni M, Litman HJ, Castiglione-Gertsch M, et al: Duration of adjuvant chemotherapy for breast cancer: A joint analysis of two randomised trials investigating three versus six courses of CMF. Br J Cancer 86:1705–1714, 2002[CrossRef][Medline]

71. Pico C, Martin M, Jara C, et al: Epirubicin-cyclophosphamide (EC) chemotherapy plus tamoxifen (T) administered concurrent (Con) versus sequential (Sec): Randomized phase III trial in postmenopausal node-positive breast cancer (BC) patients—GEICAM 9401 study. Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 144)

72. Sertoli MR, Pronzato P, Venturini M, et al: A randomized study of concurrent versus sequential adjuvant chemotherapy and tamoxifen in stage II breast cancer. Proc Am Soc Clin Oncol 21:46a, 2002 (abstr 182)

73. Simes RJ, Coates AS: Patient preferences for adjuvant chemotherapy of early breast cancer: How much benefit is needed? J Natl Cancer Inst Monogr 30:146–152, 2001

74. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451–1467, 1998[CrossRef][Medline]

75. Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. J Clin Oncol 18:584–590, 2000[Abstract/Free Full Text]

76. Colleoni M, Minchella I, Mazzarol G, et al: Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors. Ann Oncol 11:1057–1059, 2000[Abstract/Free Full Text]

77. Lippman ME, Allegra JC: Quantitative estrogen receptor analyses: The response to endocrine and cytotoxic chemotherapy in human breast cancer and the disease-free interval. Cancer 46:2859–2868, 1980 (12 suppl)[CrossRef][Medline]

78. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388, 1998[Abstract/Free Full Text]

79. IBIS Investigators: First results of the International Breast Cancer Intervention Study (IBIS-1). Lancet 360:817–824, 2002[CrossRef][Medline]

80. Fisher B: Treatment of primary breast cancer with L-PAM/5-FU and tamoxifen: An interim report. Breast Cancer Res Treat 3:S7–S17, 1983 (suppl)

81. Osborne CK, Kitten L, Arteaga CL: Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens. J Clin Oncol 7:710–717, 1989[Abstract]

82. International Breast Cancer Study Group: Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. J Clin Oncol 15:1385–1394, 1997[Abstract]

83. Wolff AC, Abeloff MD: Adjuvant chemotherapy for postmenopausal lymph node-negative breast cancer: It ain’t necessarily so. J Natl Cancer Inst 94:1041–1043, 2002[Free Full Text]

84. International Breast Cancer Study Group: Randomized controlled trial of ovarian function suppression plus tamoxifen versus the same endocrine therapy plus chemotherapy: Is chemotherapy necessary for premenopausal women with node-positive breast cancer? First results of International Breast Cancer Study Group Trial 11–93. Breast 10:130–138, 2001 (suppl 3)

85. Singletary SE, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer Staging System for Breast Cancer. J Clin Oncol 20:3628–3636, 2002[Abstract/Free Full Text]

86. Ravdin PM, Siminoff IA, Harvey JA: Survey of breast cancer patients concerning their knowledge and expectations of adjuvant therapy. J Clin Oncol 16:515–521, 1998[Abstract]

87. Lindley C, Vasa S, Sawyer WT, et al: Quality of life and preferences for treatment following systemic adjuvant therapy for early breast cancer. J Clin Oncol 16:1380–1387, 1998[Abstract/Free Full Text]

88. Langer AS: Side effects, quality-of-life issues, and trade-offs: The patient perspective. J Natl Cancer Inst Monogr 30:125–129, 2001

89. Brussels Statement. http://www.mindfully.org/Health/Brussels-Statement-Oct2000.htm

90. National Breast Cancer Coalition. http://www.natlbcc.org/

91. Jefford M, Tattersall MHN: Informing and involving cancer patients in their own care. Lancet Oncol 3:629–637, 2002[CrossRef][Medline]

92. Molenaar S, Sprangers MA, Rutgers EJT, et al: Decision support for patients with early-stage breast cancer: Effects of an interactive breast cancer CDROM on treatment decision, satisfaction, and quality of life. J Clin Oncol 19:1676–1687, 2001[Abstract/Free Full Text]

93. Ravdin PM, Siminoff LA, Davis GJ, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19:980–991, 2001[Abstract/Free Full Text]

94. Levine M, Whelan T: Decision-making process: Communicating risk/benefits—Is there an ideal technique? J Natl Cancer Inst Monogr 30:143–145, 2001

95. Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481, 1999[Abstract/Free Full Text]

96. Adami HO, Malker B, Holmberg L, et al: The relation between survival and age at diagnosis in breast cancer. N Engl J Med 315:559–563, 1986[Abstract]

97. Chung M, Chang HR, Bland KI, et al: Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 77:97–103, 1996[CrossRef][Medline]

98. Kroman N, Jensen MB, Wohlfahrt J, et al: Factors influencing the effect of age on prognosis in breast cancer: Population based study. BMJ 320:474–478, 2000[Abstract/Free Full Text]

99. Colleoni M, Rotmensz N, Robertson C, et al: Very young women (<35 years) with operable breast cancer: Features of disease at presentation. Ann Oncol 13:273–279, 2002[CrossRef][Medline]

100. Mintzer D, Glassburn J, Mason BA, et al: Breast cancer in the very young patient: A multidisciplinary case presentation. Oncologist 7:547–554, 2002[Abstract/Free Full Text]

101. Love RR, Duc NB, Allred DC, et al: Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 20:2559–2566, 2002[Abstract/Free Full Text]

102. Morrow M, Krontiras H: Who should not receive chemotherapy? Data from American databases and trials. J Natl Cancer Inst Monogr 30:109–113, 2001

103. Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189–1196, 1996[CrossRef][Medline]

104. Bartelink H: Radiotherapy to the conserved breast, chest wall, and regional nodes: Is there a standard? Breast 12:S9, 2003 (suppl 1, abstr S24)

105. Ellis PM, Butow PN, Tattersall MHN, et al: Randomized clinical trials in oncology: Understanding and attitudes predict willingness to participate. J Clin Oncol 19:3554–3561, 2001[Abstract/Free Full Text]

Submitted April 28, 2003; accepted June 11, 2003.

This article has been cited by other articles:

				P. D. Gobardhan, S. G. Elias, E. V. E. Madsen, V. Bongers, H. J. M. Ruitenberg, C. I. Perre, and T. van Dalen Prognostic value of micrometastases in sentinel lymph nodes of patients with breast carcinoma: a cohort study Ann. Onc., July 24, 2008; (2008) mdn535v1. [Abstract] [Full Text] [PDF]

				H. Fiegl, A. Jones, C. Hauser-Kronberger, G. Hutarew, R. Reitsamer, R. L. Jones, M. Dowsett, E. Mueller-Holzner, G. Windbichler, G. Daxenbichler, et al. Methylated NEUROD1 Promoter is a Marker for Chemosensitivity in Breast Cancer Clin. Cancer Res., June 1, 2008; 14(11): 3494 - 3502. [Abstract] [Full Text] [PDF]

				M. Derenzini, G. Donati, G. Mazzini, L. Montanaro, M. Vici, C. Ceccarelli, D. Santini, M. Taffurelli, and D. Trere Loss of Retinoblastoma Tumor Suppressor Protein Makes Human Breast Cancer Cells More Sensitive to Antimetabolite Exposure Clin. Cancer Res., April 1, 2008; 14(7): 2199 - 2209. [Abstract] [Full Text] [PDF]

				M. Kyndi, F. B. Sorensen, H. Knudsen, M. Overgaard, H. M. Nielsen, and J. Overgaard Estrogen Receptor, Progesterone Receptor, HER-2, and Response to Postmastectomy Radiotherapy in High-Risk Breast Cancer: The Danish Breast Cancer Cooperative Group J. Clin. Oncol., March 20, 2008; 26(9): 1419 - 1426. [Abstract] [Full Text] [PDF]