Meeting Highlights: International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005

A. Goldhirsch1,2,*, J. H. Glick3, R. D. Gelber4, A. S. Coates5, B. Thürlimann6, H.-J. Senn7 and Panel Members{dagger}

1 International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 2 European Institute of Oncology, Milan, Italy; 3 Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 4 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; 5 The Cancer Council Australia and University of Sydney, Sydney, NSW, Australia; 6 Division of Gynecologic Oncology, Kantonsspital, St Gallen, Switzerland; 7 Zentrum für Tumordiagnostik und Prävention, Silberturm, Grossacker, St Gallen, Switzerland

* Correspondence to: Dr A. Goldhirsch, International Breast Cancer Study Group, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. E-mail: aron.goldhirsch{at}ibcsg.org


    Abstract
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
The ninth St Gallen (Switzerland) expert consensus meeting in January 2005 made a fundamental change in the algorithm for selection of adjuvant systemic therapy for early breast cancer. Rather than the earlier approach commencing with risk assessment, the Panel affirmed that the first consideration was endocrine responsiveness. Three categories were acknowledged: endocrine responsive, endocrine non-responsive and tumors of uncertain endocrine responsiveness. The three categories were further divided according to menopausal status. Only then did the Panel divide patients into low-, intermediate- and high-risk categories. It agreed that axillary lymph node involvement did not automatically define high risk. Intermediate risk included both node-negative disease (if some features of the primary tumor indicated elevated risk) and patients with one to three involved lymph nodes without additional high-risk features such as HER2/neu gene overexpression. The Panel recommended that patients be offered chemotherapy for endocrine non-responsive disease; endocrine therapy as the primary therapy for endocrine responsive disease, adding chemotherapy for some intermediate- and all high-risk groups in this category; and both chemotherapy and endocrine therapy for all patients in the uncertain endocrine response category except those in the low-risk group.


    St Gallen 2005: news and progress
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
Since 1978, St Gallen (Switzerland) conferences have consistently focused on reaching expert consensus on the implications of evidence for patient treatment selection [1Go]. The ninth such meeting, in January 2005, attracted 4166 participants from 78 countries. Highlights reported here reflect information that has emerged since the last such meeting in 2003.

A Consensus Panel of experts (see Appendix), developed a series of guidelines and recommendations for selection of adjuvant systemic treatments in specific patient populations, modifying its previous guidelines and recommendations [1Go] based on the new evidence that has emerged since 2003. The declaration of consensus was based on best available evidence as presented at the St Gallen and other recent meetings and reflected by votes recorded at the Panel session. The manuscript was subsequently reviewed by all members of the Panel, and by other opinion leaders as acknowledged. The new treatment recommendations stress endocrine responsiveness and modify risk classification, since prognosis per se is now less of an issue influencing treatment choice.

This report concentrates on new aspects. Its recommendations are evidence-based to the extent possible, so recent evidence is critical, as summarized in Table 1. Breast cancer mortality is decreasing in many countries, despite a rising incidence. Care for patients with breast cancer is essentially multidisciplinary, and there is an important general trend to more selective interventions to minimize acute and late toxicity without compromising efficacy. Just as limited surgery allows conservation of the breast and unaffected lymph nodes and limited radiation therapy is being studied, so appropriate adjuvant systemic therapy involves choosing treatments tailored to individual patients according to assessment of endocrine responsiveness. This last aspect is perhaps the most important innovation for the 2005 conference.


View this table:
[in this window]
[in a new window]
 
Table 1. Recent research findings presented at the 9th International Conference on Primary Therapy of Early Breast Cancer and their implications for patient care

 
Endocrine responsiveness
Three disease responsiveness categories were defined:
(i) Endocrine responsive: the cells express steroid hormone receptors (diagnosed with proper immunohistological or biochemical methods) and for which it is probable that endocrine therapies are effective in improving disease-free and overall survival.
(ii) Endocrine response uncertain: some expression of steroid hormone receptors either quantitatively low or qualitatively insufficient to indicate a substantial chance for response to endocrine therapies alone, thus suggesting the need for chemotherapy. The exact boundary between ‘endocrine responsive’ and ‘endocrine response uncertain’ is undecided, and may well be different in different clinical settings (e.g. according to number of involved axillary lymph nodes or menopausal status).
(iii) Endocrine non-responsive: cells have no detectable expression of steroid hormone receptors.
The value of this primary classification is that endocrine therapies may be offered alone to selected patients with clearly endocrine responsive disease, while chemotherapy alone is offered to patients with endocrine non-responsive disease. The newly defined category of uncertain endocrine responsiveness is suited to combinations of chemotherapy and endocrine therapy.

Features indicative of uncertainty of endocrine responsiveness include low levels of steroid hormone receptor immunoreactivity (usually considered as <10% of cells positive), lack of progesterone receptors (PgR) [irrespective of the expression of estrogen receptors (ER)], features suggesting potential resistance to particular endocrine therapies (e.g. HER2/neu overexpression and tamoxifen), a high number of involved lymph nodes, high tumor levels of urokinase-type plasminogen activator/plasminogen activator inhibitor type 1 (uPA/PAI-1) [91Go] and increased proliferation markers. Since any detectable steroid hormone receptor indicates some degree of endocrine responsiveness, such patients should receive endocrine therapy, but the doubtful adequacy of such treatment alone suggests a need also for adjuvant chemotherapy.


As biological understanding of factors influencing treatment response improves, it is likely that the language used to describe various aspects of discussion on treatment choice will evolve. Currently, the terms endocrine responsive, uncertain endocrine response (see text), and endocrine non-responsive refer to the groups of tumors that are responsive to endocrine therapies alone, chemotherapy and endocrine therapy combinations, and chemotherapy alone, respectively. Endocrine responsiveness may not in future be the most precise way to describe the continuum of therapeutic targets against which new biological agents are effective.

 

Research findings summarized in Table 1 bring together and interpret recent data, and lead to re-interpretion of some older observations according to newer hypotheses (generated by clinical observations). While much useful information will come from new technologies, there is also a valuable resource of information in data from current and past studies. Subset analysis is extremely helpful as we try to tailor treatment to individual patients. Such analysis is statistically proper provided sufficient numbers of patients are available and provided hypotheses generated in one dataset can be independently confirmed [92Go]. An important finding from this approach was the large benefit of chemotherapy alone for postmenopausal women with endocrine non-responsive disease [93Go], which was confirmed by an analysis of patients with ER-poor tumors enrolled in randomized trials unconfounded by tamoxifen [information derived from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Overview] [82Go]. Retrospective, exploratory analysis of the SWOG 8814/Intergroup 0100 trial similarly indicated little additional benefit from CAF (cyclophosphamide, adriamycin and 5-fluorouracil) chemotherapy among patients with high ER levels who also received tamoxifen [78Go, 94Go, 95Go], in contrast to the benefit of CAF in sequence with tamoxifen in patients with low and intermediate levels of ER expression. Similarly, although more intensive chemotherapy (compared with a less intensive ‘standard’) is reproducibly more effective across trials in cohorts of patients with endocrine non-responsive disease, this effect is almost imperceptible in the cohorts with endocrine responsive disease [81Go].

Risk categories
Nodal status remains the most important feature for defining risk category. Node-negative status, including sentinel node negative, was accepted overwhelmingly to be the major condition defining low risk [96Go]. Although nodal micrometastases were prognostically relevant in several studies [31Go, 32Go], the Panel considered that neither they nor isolated tumor cells in lymph nodes should influence risk allocation and treatment choice. Involvement of four or more nodes in the axilla by itself indicated high risk, but patients with one to three nodes involved required significant HER2/neu overexpression or amplification [58Go] to be included in the high-risk group, with other patients with one to three nodes included in the intermediate-risk category. The reproducibility of HER2/neu testing was recognized as a significant methodological problem [97Go], but was not directly addressed by the Panel. Fluorescence in situ hybridization (FISH) testing was viewed as more reliable if HER2/neu was to dictate risk group or treatment choice.

Tumors larger than 2 cm (measured as the invasive component on the pathological specimen), indicated intermediate- or high-risk allocation, even in the absence of other adverse prognostic features. The risk allocation of tumors below 1 cm in size and negative nodes remained controversial. Some but not all Panel members viewed all such patients as having an excellent prognosis regardless of any additional feature (i.e. despite high-grade histology or the absence of steroid hormone receptor expression) [98Go]. Recent observations indicate that treatment choice for patients with very small tumors (but not including microinvasive disease) should be based upon endocrine responsiveness [99Go].

While tumor (histological or nuclear) grade was accepted as useful for risk allocation, quantitative Ki67 expression was not. Other tumor features (Table 1) were not viewed by the panelists as sufficiently established to guide responsiveness or prognosis.

Gene expression profiling studies of several types were reviewed (Table 1). The Panel overwhelmingly endorsed the need for further prospective studies of gene profiling both for prognostic estimation, and especially to aid treatment choice. Such trials are being discussed and hopefully will soon be activated [33Go, 100Go].

The Panel modified classification of risk, defining three categories: low-, intermediate- and high-risk groups (Table 2). Risk is a continuum, so distinction between risk categories is inevitably arbitrary and indeed less important now that endocrine responsiveness is the primary consideration in treatment choice. The new risk groups departed from the traditional node-positive/node-negative boundary, by including some patients with node-negative, low-grade disease but with features conferring a worse prognosis and patients with one to three involved axillary lymph nodes but no other adverse features in an intermediate-risk group (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 2. Definition of risk categories for patients with operated breast cancer

 
The Panel added two features not previously accepted as sufficiently reliable to define risk category. The first was overexpession or amplification of the HER2/neu gene. Despite issues related to reproducibility of immunohistochemistry staining or FISH testing for HER2/neu, it was felt that HER2/neu status should be regarded as useful for patient care, with overexpression indicating a worsened prognosis [101Go]. Overexpressed or amplified HER2/neu may also have predictive value. It may indicate a lower probability of response to tamoxifen [21Go] and perhaps suggest treatment with taxanes or anthracyclines [102Go], rather than CMF (cyclophosphamide, methotrexate and 5-fluorouracil).

The second new adverse prognostic feature was peritumoral vessel invasion [103Go–105Go], especially lymphovascular invasion [106Go]. This proved somewhat controversial, but was accepted by the majority of panelists for patients with node-negative disease [107Go]. Its value in patients with one or few positive axillary lymph nodes was considered uncertain, and insufficient at the present time to influence the hierarchical risk allocation (e.g. a patient with one positive axillary node, no HER2/neu overexpression should remain in the intermediate-risk category despite peritumoral vascular invasion).

Several instruments are available to help estimate the risk of breast cancer-related events and the reduction of these risks by given therapies, as well as their costs in terms of side-effects [108Go, 109Go]. Adjuvant! On line was independently validated by Olivotto et al. [110Go] and provides simplified (average) estimates for various clinical scenarios allowing graphical presentation of risks and benefits during consultations. The appeal of these instruments lies in their simplified and averaged format, but this is also their major drawback.

The historical evolution of thinking about risk and responsiveness may be summarized as follows: in 2001 multiple categories of risk were based upon nodal status (three risk categories for node-negative and a fourth for the node-positive group); 2003 added endocrine responsiveness to define both risk and treatment choice leading to only two categories of risk for node-negative disease plus one for node-positive; in 2005 endocrine responsiveness is removed from determination of risk since it is the primary factor determining treatment choice (Table 3). The 2005 edition defines three risk categories including a group merging higher risk node-negative disease and lower risk node-positive disease into an intermediate-risk group ‘across nodal status’.


View this table:
[in this window]
[in a new window]
 
Table 3. Choice of treatment modalities 2005 (see text)

 

    Panel recommendations and guidelines
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
This section and Tables 3 and 4 summarize the recommendations and guidelines for post-operative adjuvant systemic therapies of early breast cancer as updated by the International Consensus Panel during the St Gallen Conference, 2005. 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. Clinical trial evidence applies only on average for a patient population. Selection of treatment for an individual typically involves attempts to relate clinical trial findings to specific subgroups, despite the uncertainties inherent in this step.


View this table:
[in this window]
[in a new window]
 
Table 4. Adjuvant systemic treatment regimens for patients with operable breast cancera

 
Patient preferences will frequently influence treatment choice. A thorough discussion of the potential benefits and risks of each therapeutic option is required for each patient. Therefore, these recommendations are not intended as prescriptive for all patients, since circumstances, attitudes toward treatment and availability of resources may vary both among individuals and across health care systems in different parts of the world.

Emerging evidence on postoperative radiation therapy, preoperative systemic therapy, biological therapies, choice, timing and duration of endocrine treatments and chemotherapy regimen are also described within sections of Table 1.


    Systemic treatment regimens
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
Choice of modalities
Treatment allocation follows considerations related to endocrine responsiveness, which are summarized in Table 3. Patients with tumors that express some level of steroid hormone receptors but with characteristics indicating a potential clinically relevant (slight to substantial) benefit from adding chemotherapy to endocrine therapy were defined as having an uncertain degree of endocrine responsiveness. While such patients should receive endocrine therapy, adding four to six courses of chemotherapy to the adjuvant program was viewed as appropriate. The endocrine components of these therapies should be tailored according to menopausal status.

Low-risk group
In the low-risk category there are by definition no endocrine non-responsive cancers. Patients with endocrine responsive low-risk disease should be offered an endocrine treatment according to menopausal status (Table 3). If endocrine treatment is contra-indicated (e.g. known intolerance, co-morbid condition) or rejected, the alternative of no adjuvant systemic treatment is a reasonable option.

Intermediate-risk group
Intermediate-risk (Table 3) includes patients with endocrine responsive disease for whom endocrine therapy alone is reasonable, as well as patients with endocrine non-responsive disease for whom chemotherapy alone is indicated. Between these extremes, some patients with endocrine responsive disease or disease of uncertain endocrine responsiveness should receive chemotherapy in addition to endocrine treatment. Experimental and clinical experience has shown that tamoxifen, and probably other selective estrogen receptor modulators (e.g. toremifene), should not be administered concurrently with chemotherapy, especially for patients in whom the disease is of uncertain endocrine responsiveness [78Go, 113Go]. It is not known whether concurrent use of chemotherapy and other types of endocrine therapies (e.g. GnRH analog for premenopausal patients) should be similarly avoided, though concurrent treatment works well in advanced disease [111Go] and in the preoperative treatment setting [112Go].

High-risk group
Most patients in the high-risk group (Table 3) are likely to receive chemotherapy unless it is contraindicated (owing to a co-morbid condition) or rejected by patient preference. Elderly patients at high risk of relapse and without significant co-morbidity should be offered chemotherapy. EBCTCG Overview analyses for the ER-poor cohort in trials not confounded by tamoxifen show that the benefits of adjuvant chemotherapy are substantial and unrelated to age in such patients. Elderly patients with co-morbidities, but with a sufficiently long life expectancy, require difficult individualized decisions about adjuvant systemic therapy outside clinical trials.

Endocrine therapies for premenopausal women
Published EBCTCG Overview results indicated a beneficial effect of tamoxifen [114Go] and of ovarian ablation [115Go], the latter only in trials without chemotherapy [116Go]. Ovarian ablation and tamoxifen yielded results similar to those obtained with chemotherapy, while the need for both modalities in women with endocrine responsive disease remains unclear [117Go].

The 2005 Panel again viewed tamoxifen as a standard adjuvant treatment for premenopausal women with endocrine responsive disease who have an indication for endocrine therapy alone. Ovarian function suppression (OFS) was accepted as an alternative where tamoxifen was contraindicated [118Go]. While admitting the lack of conclusive data favoring the combination of tamoxifen plus ovarian function suppression, this was accepted as reasonable for very young patients, especially in intermediate- and high-risk groups, and for premenopausal patients of any age at high risk, especially if chemotherapy did not induce OFS. The lack of evidence on the combination of OFS and tamoxifen in patients with intermediate risk and those for whom endocrine therapy alone is prescribed emphasizes the strategic importance of the ongoing trials such as SOFT and TEXT [75Go]. The Panel was reluctant to recommend the use of aromatase inhibitors plus GnRH analog for premenopausal patients outside clinical trials, although the majority accepted the combination as an option for women with contraindications to adjuvant tamoxifen especially for those with node-positive disease. Tamoxifen should be avoided in pregnancy owing to its teratogencity [119Go].

Optimal duration of ovarian function suppression is unknown. Patients with tumors overexpressing HER2/neu [120Go] may benefit if the entire period of tamoxifen were covered with a GnRH analog.

Most panelists agreed that tamoxifen should be given sequentially after adjuvant chemotherapy, but timing of OFS in relation to chemotherapy was less clearly defined. Sequential use of any indicated chemotherapy before OFS allows assessment of chemotherapy-induced amenorrhea [121Go].

Patients who received adjuvant tamoxifen when they were premenopausal for node positive, endocrine responsive disease, might consider later continuation of the adjuvant endocrine treatment with letrozole if they become postmenopausal in the interim. Almost 14% of the patients in the MA-17 trial were premenopausal at diagnosis and postmenopausal before randomization [122Go].

Endocrine therapies for postmenopausal women
Several trials comparing aromatase inhibitors either versus standard tamoxifen or versus placebo after completion of about 5 years of tamoxifen have reported results during the past 2 years. The ATAC trial results indicated that 5 years of anastrozole increased disease-free though not overall survival compared with tamoxifen [66Go]. Joint, muscle and bone pain, especially bone fractures, were more frequent with anastrozole, while gynecological and vascular events were more frequent with tamoxifen. In the BIG 1-98 trial, letrozole was shown to improve disease-free survival, especially systemic disease-free survival [67Go], as compared with tamoxifen. Cardio- and cerebro-vascular events, as well as bone fractures, were more frequent with letrozole, while gynecological and venous thromboembolic complications were more frequent with tamoxifen.

Five trials have examined a switch to an aromatase inhibitor after 2–3 years of adjuvant tamoxifen compared with continuing tamoxifen alone to complete 5 years. The first trial (380 patients) tested low-dose aminogluthethimide and resulted in comparable event-free survival, but longer overall survival [123Go]. In an Italian trial (426 patients), switch to anastrozole after 2 years of tamoxifen yielded a significant reduction in recurrences [124Go]. A joint analysis combined an Austrian and a German trial (total of 3123 patients) of anastrozole treatment after 2 years of tamoxifen. The group treated with anastrozole had significantly improved relapse-free survival compared with continuing on tamoxifen, regardless of nodal status [69Go]. IES, the largest such trial (4742 patients), tested switch to the aromatase inhibitor exemestane after 2–3 years of tamoxifen. There was a significant improvement of disease-free survival, but not survival within the first 30 months of follow-up [68Go]. The MA-17 trial compared letrozole with placebo after completion of about 5 years of tamoxifen in 5157 women. Letrozole improved disease-free and overall survival in patients with node-positive disease at diagnosis. Patients with node-negative disease at diagnosis experienced improved disease-free but not overall survival compared with placebo [122Go].

The ASCO Technology Assessment report recently recommended that ‘optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer should include an aromatase inhibitor either as initial therapy or after treatment with tamoxifen. Of course, women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options’ [72Go]. Is tamoxifen alone still an acceptable therapy? Cost and side-effects are important issues when choosing a treatment for an individual patient. Adjuvant tamoxifen has a long-lasting (‘carry-over’) benefit well beyond 5 years after its cessation, while no information is available on similar long-term follow up of patients after aromatase inhibitor therapy. Treatment with aromatase inhibitors compared with tamoxifen is associated with a decreased risk of endometrial cancer and thromboembolic events, but with increased cardiovascular events as well as bone fractures, muscle and osteoarticular pain. Knowledge of long-term side-effects of aromatase inhibitors is much less extensive than that for tamoxifen, an issue of concern for several panelists.

In summary, recent trials support several options for postmenopausal women who require endocrine therapy, while lacking evidence to choose between them: (i) an aromatase inhibitor (anastrozole, letrozole) alone for 5 years; (ii) tamoxifen for 2–3 years followed by an aromatase inhibitor (exemestane, anastrozole) to complete 5 years of therapy; or (iii) switch to an aromatase inhibitor (letrozole) after completing 5 years of tamoxifen. (iv) Finally, selected patients at low risk or with co-morbid musculo-skeletal or cardiovascular risk factors may be considered suitable for tamoxifen alone, and this may be the only option available on economic grounds in many cases [125Go, 126Go].

An additional area of uncertainty was whether adjuvant chemotherapy should be given concurrently with aromatase inhibitors. The majority of the panelists supported sequential use, but data directly addressing this question are lacking.

Chemotherapy regimens
The Panel recognized several types and levels of chemotherapy regimens, but acknowledged the possibility that the higher the degree of endocrine responsiveness, the lower the likely benefit from adding chemotherapy. For patients with endocrine responsive high-risk disease, chemotherapy in addition to endocrine therapy was considered indicated by most panelists. In such cases, however, the more intensive regimens (i.e. adding taxanes to the regimen or using a dose-dense schedule) may not be more effective than ‘basic’, once every 3 weeks anthracycline-based regimens like AC (doxorubicin or epirubicin plus cyclophosphamide), FEC100 (5-fluorouracil, epirubicin 100 mg/m2 and cyclophosphamide) or CAF (Table 1). The degree of perceived benefit led to the various categories of chemotherapy displayed in Table 4.

Recent references describe current use of chemotherapy in clinical practice. Less intensive regimens like AC or classical CMF [127Go, 128Go] are typically used for node-negative disease, while more intensive regimens such as AC or A followed by CMF [129Go], Canadian CEF [130Go], the CAF regimen [131Go, 132Go], dose-dense cyclophosphamide, doxorubicin and paclitaxel [133Go], FEC100 followed by docetaxel [134Go], tailored FEC [135Go], FEC100 [136Go] and TAC (docetaxel, doxorubicin, cyclophosphamide) [137Go] are more frequently offered to patients with node-positive disease. These have been shown in comparative trials to yield superior results, though at the cost of greater complexity, cost or toxicity.

For patients with endocrine responsive disease and an indication for chemotherapy, treatment with four courses of AC was considered to be appropriate. Most panelists did not support taxane-containing treatments in this population regardless of their nodal status.

The Panel favored anthracycline-containing regimens for patients with endocrine non-responsive disease and intermediate risk. Duration was controversial, with roughly equal Panel support for 4 or 6 months for patients with node-negative disease. Six courses of 3 or 4 weeks duration were clearly favored for patients at higher range of risk of relapse. Most but not all Panel members agreed that chemotherapy should start within 3–4 weeks from operation for patients with endocrine non-responsive disease [138Go]. Taxanes were supported for patients at higher risk. Most Panel members did not advocate dose-dense regimens even for patients with endocrine non-responsive disease notwithstanding results from one large study [133Go]. Panel members could not agree on the use of hematopoietic growth factors to avoid dose reduction or delay.


    Radiation therapy
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
The Panel members reviewed recent changes in practice related to the developments described in Table 1. Radiation therapy, whether after breast conservation or mastectomy, should follow chemotherapy. Concurrent chemotherapy and radiation therapy might be feasible with CMF, perhaps requiring alteration to the schedule or dose of radiation [139Go, 140Go]. Concurrent radiation with anthracycline-based regimes or taxanes is not recommended since it increases the risk of symptomatic radiation-induced damage to normal tissue. Tamoxifen and radiotherapy can be given concurrently without significant altered efficacy or increased toxicity [141Go, 142Go].

Radiation therapy may not be necessary after conservative surgery in selected elderly patients (over 70 years) with small endocrine responsive cancer whose tumor excision was complete and who receive tamoxifen, although long-term follow up is not yet available [143Go, 144Go]. Thus, for example, an 80-year-old patient with significant co-morbid conditions and a small endocrine responsive breast cancer, endocrine therapy alone following proper local tumor excision is appropriate. However, for a healthy 70 year old patient (with life expectancy that might exceed 15 years), radiation therapy to the conserved breast might be preferred.

Radiotherapy variations
A boost may be particularly useful in premenopausal patients [145Go]. Accelerated partial breast irradiation (APBI) lacks data from phase III trials. Outside trials, the Panel recommended that APBI should be limited to defined patient groups (e.g. older age, low or intermediate risk, negative margins) with informed consent on lack of data on long-term outcome [55Go].

Although shorter radiotherapy fractionation schemes are popular due to logistical and patient convenience [146Go], data are lacking on long-term efficacy and toxicity.

Indications for radiation therapy after mastectomy are unchanged from previous St Gallen Meeting highlights [1Go], although computed tomography scan-based simulation, especially for left-sided cancers, may ensure that the heart is not included in the radiation fields [1Go, 147Go, 148Go].


    Specific aspects of treatments
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
Patient preferences and quality of life considerations
Quality of life during treatment is important, but not the dominant factor for patients with operable breast cancer since the adverse effects of treatments are transient [149Go, 150Go]. Patients' preferences assessed post hoc were found to support this attitude [151Go, 152Go]. Long-term effects may be important. Special considerations may apply to underserved minority groups, younger women, elderly women, those in difficult relationships or who are rendered prematurely menopausal by adjuvant chemotherapy [153Go]. Endocrine-related symptoms usually worsened initially and recovered partially during 2 years [1Go].


    Commentary
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
The Panel tried to apply answers derived from randomized clinical trials. Trials are usually designed to test the value of one or more treatments in a defined group, but tailoring treatment for an individual patient requires an additional step. Extrapolation of information from clinical trials, focusing upon patterns of response of different subpopulations, yielded important answers for several groups, especially contrasting those with endocrine responsive and endocrine non-responsive disease. Panel members were convinced that increased participation in clinical trials would increase knowledge about the disease and improve patient care [154Go]. International trial cooperation should be focused on questions relevant for patient care and biological principles, rather than regulatory requirements for the marketing of a new drug. Substudies focusing on safety, quality of life and subjective side-effects, and on economic and personal costs should be routinely incorporated in cooperative group trials.

Definition of appropriate niches for tailored research is perhaps the key achievement of this St Gallen Conference. Such an approach brings clinical research closer to the individual patient. Women with breast cancer deserve no less.


    Appendix
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
Members of the Panel are listed below. All had a significant input to the discussion and manuscript. Professor Alan S. Coates was unable to attend the conference, but had a major impact on the planning of the meeting and on the final manuscript. Professor Martine Piccart also was unable to attend, but maintained a significant input and was represented by a senior member of her institution.

Kathy S. Albain MD, Loyola University Medical Center, Cardinal Bernardin Cancer Center, Marywood, IL 60153, USA.
Jonas Bergh MD, Department of Oncology, Radiumhemmet, Karolinska Institute and Hospital 17176 Stockholm, Sweden.
Monica Castiglione-Gertsch MD, International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, 3008 Bern, Switzerland.
Alan S. Coates MD, The Cancer Council Australia and University of Sydney, GPO Box 4708, Sydney, NSW 2001 Australia (absent).
Alberto Costa MD, Department of Breast Surgery, Fondazione S. Maugeri, Via A. Ferrata 8, 27100 Pavia, Italy.
Jack Cuzick PhD, 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 MD, Sidney Kimmel Cancer Center of Johns Hopkins, 1650 Orleans Street, Room 409, Baltimore, MD 21231-1000, USA.
John F. Forbes MD, Department of Surgical Oncology, University of Newcastle, Locked Bag 7, Hunter Region Mail Centre, NSW 2310, Australia.
Richard D. Gelber PhD, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Paul Goss MD, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
Jay Harris MD, Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
John H. Glick MD, Abramson Cancer Center of the University of Pennsylvania Cancer Center, 16 Penn Tower, 3400 Spruce Street, Philadelphia PA 19104-4283, USA (Chairman).
Aron Goldhirsch MD, International Breast Cancer Study Group, Oncology Institute of Southern Switzerland, 6903 Lugano, Switzerland, and European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy (Chairman).
Anthony Howell MD, CRC, Department of Medical Oncology, Christie Hospital, NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
James N. Ingle MD, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA.
Raimund Jakesz MD, University of Vienna, Department of General Surgery, Waehringer Guertel 18–20, 1090 Wien, Austria.
Jacek Jassem MD Medical University of Gdansk, Department of Oncology & Radiotherapy, Debinki Street 7, 80-211 Gdansk, Poland.
Manfred Kaufmann MD, Department of Gynecology and Obstetrics, Goethe University, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany.
Miguel Martin MD, Servicio de Oncologia Medica, Hospital Universitario San Carlos, Cindad Universitaria s/n, 28040 Madrid, Spain.
Louis Mauriac MD, Institute Bergonié, 229, Cours d'Argonne, 33076 Bordeaux, France.
Monica Morrow MD, Lynn Sage Comprehensive Breast Center, Northwestern Memorial Hospital, 251 East Huron Street, Galter 13-174, Chicago, IL 60611, USA.
Henning T. Mouridsen MD, Department of Oncology 5074, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Moise Namer MD, Centre Antoine Lacassagne, 33 Av. Valombrose, 06189 Nice Cedex, France.
Martine J. Piccart-Gebhart MD, PhD, Department of Chemotherapy, Institut Jules Bordet, Rue Héger-Bordet 1, 1000 Brussels, Belgium (substituted by Dominique de Valeriola MD, Medical Director, Institut Jules Bordet, Rue Héger-Bordet 1, 1000 Brussels, Belgium).
Kurt Possinger MD, Universitätsklinikum Charite, Onkologie/Hämatologie, Schumannstrasse 20–21, 10098 Berlin, Germany.
Kathleen Pritchard MD, Toronto-Sunnybrook Regional Cancer Center, Head Clinical Trials & Epidemiology, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
Emiel JT Rutgers MD, The Netherlands Cancer Institute, Department of Surgery, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Beat Thürlimann MD, Medizinische Onkologie, Haus 06, Kantonsspital St Gallen, 9007 St Gallen, Switzerland.
Giuseppe Viale MD, Department of Pathology, European Institute of Oncology and University of Milan, Via Ripamonti 435, 20141 Milan, Italy.
Arne Wallgren MD, Sahlgrenska University Hospital, Department of Oncology, 413 45 Göteborg, Sweden.
William C. Wood MD, Department of Surgery, Emory University School of Medicine, 1364 Clifton Road, N.E. Atlanta, GA 30322, USA.


    Acknowledgements
 
The authors thank the Participants of the 9th International Conference on Primary Therapy of Early Breast Cancer for many useful remarks. They acknowledge substantial contribution of Dr. Marco Colleoni, Dr. Giuseppe Curigliano, Dr. Eric Winer, and Mrs. Shari Gelber. They also thank Professor Umberto Veronesi, Dr. Anne Hamilton, Dr. Franco Nolè, and Dr. Filippo de Braud for their thoughtful remarks. Partial support was provided by grant number CA-75362 from the United States National Cancer Institute. This work is dedicated to the memories of Joan Coates, Harold Frankel and Carlo Stucchi.


    Notes
 
{dagger} Panel Members are listed in the Appendix. Back


    References
 Top
 Abstract
 St Gallen 2005: news...
 Panel recommendations and...
 Systemic treatment regimens
 Radiation therapy
 Specific aspects of treatments
 Commentary
 Appendix
 References
 
1. Goldhirsch A, Wood WC, Gelber RD et al. Meeting Highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer. J Clin Oncol 2003; 21: 3357–3365.[Abstract/Free Full Text]

2. Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol 2005; 16: 481–488.[Abstract/Free Full Text]

3. Thomson CS, Brewster DH, Dewar JA et al. Improvements in survival for women with breast cancer in Scotland between 1987 and 1993: impact of earlier diagnosis and changes in treatment. Eur J Cancer 2004; 40: 743–753.[CrossRef][ISI][Medline]

4. Martino S, Cauley JA, Barrett-Connor E et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomised trial of raloxifene. J Natl Cancer Inst 2004; 96: 1751–1761.[Abstract/Free Full Text]

5. Goss PE, Strasser-Weippl K. Prevention strategies with aromatase inhibitors. Clin Cancer Res 2004; 10: 372–379.

6. Garber J. Genetic counseling: therapeutic consequences. Breast 2005; 14 (Suppl): S3.

7. Sorlie T, Tibshirani R, Parker J et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003; 100: 8418–8423.[Abstract/Free Full Text]

8. Foulkes WD, Brunet JS, Stefansson IM et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 2004; 64: 830–835.[Abstract/Free Full Text]

9. Kriege M, Brekelmans CT, Boetes C et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 2004; 351: 427–437.[Abstract/Free Full Text]

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

11. Schwartz MD, Kaufman E, Peshkin BN et al. Bilateral prophylactic oophorectomy and ovarian cancer screening following BRCA1/BRCA2 mutation testing. J Clin Oncol 2003; 21: 4034–4041.[Abstract/Free Full Text]

12. Rebbeck TR, Friebel T, Lynch HT et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2004; 22: 1055–1062.[Abstract/Free Full Text]

13. Garber J, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005; 23: 276–292.[Abstract/Free Full Text]

14. Tassone P, Tagliaferri P, Perricelli A et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 2003; 88: 1285–1291.[CrossRef][ISI][Medline]

15. Borg A. The biology of BRCA1/2 and beyond. Breast 2005; 14 (Suppl): S5.

16. Al-Hajj M, Wicha MS, Benito-Hernandez A et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.[Abstract/Free Full Text]

17. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004; 23: 7274–7282.[CrossRef][ISI][Medline]

18. Minn AJ, Kang Y, Serganova I et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 2005; 115: 44–55.[Abstract/Free Full Text]

19. Klijn JG, Blamey RW, Boccardo F et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomised trials. J Clin Oncol 2001; 19: 343–353.[Abstract/Free Full Text]

20. Dowsett M. The biology of steroid hormones and endocrine therapies. Breast 2005; 14 (Suppl): S5.

21. Shou J, Massarweh S, Osborne CK et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004; 96: 926–935.[Abstract/Free Full Text]

22. 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 randomised trial. J Clin Oncol 2001; 19: 3808–3816.[Abstract/Free Full Text]

23. Lipton A, Ali SM, Leitzel K et al. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 2003; 21: 1967–1972.[Abstract/Free Full Text]

24. Osborne CK. Endocrine responsiveness: understanding how progesterone receptor can be used to select endocrine therapy. Breast 2005; 14 (Suppl): S5.

25. van de Vijver MJ. Biological variables and prognosis of DCIS. Breast 2005; 14 (Suppl): S7.

26. Cornfield DB, Palazzo JP, Schwartz GF et al. The prognostic significance of multiple morphologic features and biologic markers in ductal carcinoma in situ of the breast: a study of a large cohort of patients treated with surgery alone. Cancer 2004; 100: 2317–2327.[CrossRef][ISI][Medline]

27. Roka S, Rudas M, Taucher S et al. High nuclear grade and negative estrogen receptor are significant risk factors for recurrence in DCIS. Eur J Surg Oncol 2004; 30: 243–247.[CrossRef][Medline]

28. Ceilley E, Jagsi R, Goldberg S et al. The management of ductal carcinoma in situ in North America and Europe. Results of a survey. Cancer 2004; 101: 1958–1967.[CrossRef][ISI][Medline]

29. Veronesi P, Intra M, Vento AR et al. Sentinel lymph nodes for localized DCIS? Breast 2005; 14 (Suppl): S7.

30. Viale G. Histopathology of primary breast cancer 2005. Breast 2005; 14 (Suppl): S6.

31. Cserni G, Gregori D, Merletti F et al. Meta-analysis of non-sentinel node metastases associated with micrometastatic sentinel nodes in breast cancer. Br J Surg 2004; 91: 1245–1252.[CrossRef][ISI][Medline]

32. Colleoni M, Rotmensz N, Perruzzotti G et al. Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement. J Clin Oncol 2005; 23: 1379–1389.[Abstract/Free Full Text]

33. Hayes D. Prognostic and predictive factors revisited. Breast 2005; 14 (Suppl): S6.

34. Colleoni M, Viale G, Zahrieh D et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res 2004; 10: 6622–6628.[Abstract/Free Full Text]

35. Naume B, Wiedswang G, Borgen E et al. The prognostic value of isolated tumor cells in bone marrow in breast cancer patients: evaluation of morphologic categories and the number of clinically significant cells. Clin Cancer Res 2004; 10: 3091–3097.[Abstract/Free Full Text]

36. Wiedswang G, Borgen E, Kareson R et al. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavourable clinical outcome. Clin Cancer Res 2004; 10: 5342–5348.[Abstract/Free Full Text]

37. Harbeck N, Kates RE, Schmitt M et al. Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer. Clin Breast Cancer 2004; 5: 348–352.[Medline]

38. Harbeck N. Pooled analysis validates predictive impact of uPA and PAI-1 for response to adjuvant chemotherapy in breast cancer. Breast 2005; 14 (Suppl): S27.

39. Norberg T, Klaar S, Karf G et al. Increased p53 mutation frequency during tumor progression—results from a breast cancer cohort. Cancer Res 2001; 61: 8317–8321.[Abstract/Free Full Text]

40. Poelman SM, Heimann R, Fleming GF et al. Invariant p53 immunostaining in primary and recurrent breast cancer. Eur J Cancer 2004; 40: 28–32.[CrossRef][ISI][Medline]

41. 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 2002; 347: 1999–2009.[Abstract/Free Full Text]

42. Sotiriou C, Neo SY, McShane LM et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 2003; 100: 10393–10398.[Abstract/Free Full Text]

43. Paik S, Shak S, Tang G et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351: 2817–2826.[Abstract/Free Full Text]

44. Kaufmann M. Preoperative (neoadjuvant) systemic treatment of breast cancer. Breast 2005; 14 (Suppl): S11.

45. Chen AM, Meric-Bernstam F, Hunt KK et al. Breast conservation after neoadjuvant chemotherapy: the MD Anderson cancer center experience. J Clin Oncol 2004; 22: 2303–2312.[Abstract/Free Full Text]

46. Buzdar AU, Ibrahim NK, Francis D et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005; 23: 3676–3685.[Abstract/Free Full Text]

47. Dixon JM. Role of endocrine therapy in the neoadjuvant surgical setting. Ann Surg Oncol 2004; 11: 18–23.

48. Semiglazov VF, Semiglazov V, Ivanov V et al. The relative efficacy of neoadjuvant endocrine therapy vs chemotherapy in postmenopausal women with ER-positive breast cancer. J Clin Oncol 2004; 23: 7.

49. Morrow M. Limiting breast surgery to the proper minimum. Breast 2005; 14 (Suppl): S7–S8.

50. Petit JY. Nipple sparing mastectomy in association with intraoperative radiotherapy: a new type of mastectomy for breast cancer treatment. Breast 2005; 14 (Suppl): S8.

51. Bellon J, Harris J. Which extent of adjuvant radiotherapy is standard? Breast 2005; 14 (Suppl): S8–S9.

52. Hughes KS, Schnaper LA, Berry D et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004; 351: 971–977.[Abstract/Free Full Text]

53. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with 4 or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b & c randomized trials. ESTRO 2004, Amsterdam (Abstr 33). (http://www.estroweb.org/ESTRO/upload/abstractbooks/2AbstractbookESTRO23.pdf Available on August 20th, 2005).

54. Ragaz J, Olivotto IA, Spinelli JJ et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005; 97: 116–126.[Abstract/Free Full Text]

55. Wallner P, Arthur D, Bartelink H et al. Workshop on partial breast irradiation: state of the art and the science, Bethesda, MD, December 8–10, 2002. J Natl Cancer Inst 2004; 96: 175–184.[Abstract/Free Full Text]

56. Orecchia R. Intraoperative radiation therapy to the breast. Breast 2005; 14 (Suppl): S8.

57. Huang J, Barbera L, Brouwers M et al. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 2003; 21: 555–563.[Abstract/Free Full Text]

58. Baselga J, Gianni L, Geyer C et al. Future options with trastuzumab for primary systemic and adjuvant therapy. Semin Oncol 2004; 31: 51–57.[ISI][Medline]

59. Disis ML, Salazar LG, Knutson KL. Peptide-based vaccines in breast cancer. Breast Dis 2004; 20: 3–11.[Medline]

60. Ropero S, Menendez JA, Vazquez-Martin A et al. Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. Breast Cancer Res Treat 2004; 86: 125–137.[CrossRef][ISI][Medline]

61. Gennari R, Menard S, Fagnoni F et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 2004; 10: 5650–5655.[Abstract/Free Full Text]

62. Burstein HJ, Harris LN, Gelman R et al. Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. J Clin Oncol 2003; 21: 46–53.[Abstract/Free Full Text]

63. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792–799.[Abstract/Free Full Text]

64. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 2004; 4: 423–436.[CrossRef][ISI][Medline]

65. Orlando L, Colleoni M, Bertolini F et al. Metronomic oral chemotherapy (CT) versus the same regimen in association with Thalidomide (TLM): Results of a randomised trial in patients (pts) with advanced breast cancer (ABC). J Clin Oncol 2004; 22: 3015 (Abstr).

66. Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005; 365: 60–62.[CrossRef][ISI][Medline]

67. International Breast Cancer Study Group (IBCSG), on behalf of the Breast International Group (BIG). Letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. BIG 1-98: A prospective randomised double-blind phase III study. The Primary Therapy of Early Breast Cancer 9th International Conference in St Gallen, Switzerland, 26 January 2005. Also available as: Thurlimann BJ, Keshaviah A, Mouridsen H et al. BIG 1-98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer (Abstract). J Clin Oncol (Annual Meeting Proceedings) 23: 511, 2005.

68. Coombes RC, Hall E, Gibson LJ et al. A randomised trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081–1092.[Abstract/Free Full Text]

69. Jakesz R, Kaufmann M, Gnant M et al. Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results from 3123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial. Breast Cancer Res Treat 2004; 88: 7.

70. Goss PE. The rise and current status of aromatase inhibitors in breast cancer treatment. Breast Cancer Res Treat 2004; 88: 1.[ISI][Medline]

71. Castiglione-Gertsch M. Adjuvant endocrine therapies for postmenopausal women: standards and not. Breast 2005; 14 (Suppl): S9.

72. 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 postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23: 619–629.[Abstract/Free Full Text]

73. Ravdin PM, Davis GJ. A method for making estimates of the benefit of the late use of letrozole in patients completing 5 years of tamoxifen. Clin Breast Cancer 2004; 5: 313–316.[Medline]

74. Pritchard K. Adjuvant endocrine therapies for pre/perimenopausal women. Breast 2005; 14 (Suppl): S9.

75. Dellapasqua S, Colleoni M, Gelber RD et al. Adjuvant endocrine therapy for premenopausal women with early breast cancer. J Clin Oncol 2005; 23: 1736–1750.[Free Full Text]

76. Colleoni M, Gelber S, Snyder R et al. Randomized comparison of adjuvant tamoxifen (Tam) versus no hormonal treatment for premenopausal women with node-positive (N+), early stage breast cancer: First results of International Breast Cancer Study Group Trial 13-93. J Clin Oncol 2004; 22: 532 (Abstr).

77. Fallowfield L. Acceptance of adjuvant endocrine therapies and quality of life issues. Breast 2005; 14 (Suppl): S13.

78. Albain KS, Green SJ, Ravdin PM et al. for SWOG, ECOG, CALGB, NCCTG and NCIC-CTG: 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 2002; 21: 37a.

79. Albain K, Barlow W, O'Malley F et al. Mature outcomes and new biologic correlates on phase III intergroup trial 0100 (INT-0100, SWOG-8814): Concurrent (CAFT) vs sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) vs T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone PgR receptor-positive breast cancer. Proc SABCS 2004 (Abstr 37). (http://www.abstracts2view.com/sabcs/sessionindex.php Available on August 20th, 2005).

80. Albain KS. Do all patients with endocrine-responsive early breast cancer need adjuvant chemotherapy before endocrine treatment? Breast 2005; 14 (Suppl): S9–S10.

81. Berry DA, Cirrincione C, Henderson IC et al. Effects of improvements in chemotherapy on disease-free and overall survival of estrogen-receptor negative, node-positive breast cancer: 20-year experience of the CALGB & U.S. Breast Intergroup. Breast Cancer Res Treat 2004; 88: 17.[CrossRef][ISI][Medline]

82. Gelber RD, Goldhirsch A. Predicting response to systemic treatments: learning from the past to plan for the future. Breast 2005; 14 (Suppl): S11.

83. Aebi S. Special issues related to adjuvant therapy in very young women. Breast 2005; 14 (Suppl): S12.

84. 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 2001; 30: 44–51.[Medline]

85. Muss H. Special issues related to adjuvant therapy in elderly women. Breast 2005; 14 (Suppl): S12–S13.

86. Crivellari D, Price K, Gelber RD et al. Adjuvant endocrine therapy compared with no systemic therapy for elderly women with early breast cancer: 21-year results of International Breast Cancer Study Group Trial IV. J Clin Oncol 2003; 21: 4517–4523.[Abstract/Free Full Text]

87. Fargeot P, Bonneterre J, Roche H et al. Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French adjuvant study group 08 trial. J Clin Oncol 2004; 22: 4622–4630.[Medline]

88. Biganzoli L, Aapro M, Balducci L et al. Adjuvant therapy in elderly patients with breast cancer. Clin Breast Cancer 2004; 5: 188–195.[Medline]

89. Winer EP. Standards of follow-up for primary breast cancer. Breast 2005; 14 (Suppl): S6–S7.

90. Rutgers EJ. Follow-up care in breast cancer. Expert Rev Anticancer Ther 2004; 4: 212–218.[CrossRef][Medline]

91. Meijer-van Gelder ME, Look MP, Peters HA et al. Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease. Cancer Res 2004; 64: 4563–4568.[Abstract/Free Full Text]

92. Coates A, Goldhirsch A, Gelber R, International Breast Cancer Study Group. Overhauling the breast cancer overview: are subsets subversive? Lancet Oncol 2002; 3: 525–526.[CrossRef][ISI][Medline]

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

94. Allred DC, Harvey JM, Berardo M et al. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Modern Pathol 1998; 11: 155–168.[ISI][Medline]

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 1999; 17: 1474–1481.[Abstract/Free Full Text]

96. Cody HS 3rd, Borgen PI, Tan LK. Redefining prognosis in node-negative breast cancer: can sentinel lymph node biopsy raise the threshold for systemic adjuvant therapy? Ann Surg Oncol 2004; 11: 227–230.[CrossRef]

97. Bofin AM, Ytterhus B, Martin C et al. Detection and quantitation of HER-2 gene amplification and protein expression in breast carcinoma. Am J Clin Pathol 2004; 122: 110–119.[CrossRef][ISI][Medline]

98. Wood WC, Anderson M, Lyles RH et al. Can we select which patients with small breast cancers should receive adjuvant chemotherapy? Ann Surg 2002; 235: 859–862.[CrossRef][ISI][Medline]

99. Colleoni M, Rotmensz N, Peruzzotti G et al. Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies. Ann Oncol 2004; 15: 1633–1639.[Abstract/Free Full Text]

100. Cufer T, Piccart-Gebhart M. Adjuvant chemotherapy: standards and beyond. Breast 2005; 14 (Suppl): S3–S4.

101. Ross JS, Fletcher JA, Linette GP et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 2003; 8: 307–325.[Abstract/Free Full Text]

102. Konecny GE, Thomssen C, Luck HJ et al. Her-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancer. J Natl Cancer Inst 2004; 96: 1141–1151.[Abstract/Free Full Text]

103. Pinder SE, Ellis IO, Galea M et al. Pathological prognostic factors in breast cancer. III. Vascular invasion: relationship with recurrence and survival in a large study with long-term follow-up. Histopathology 1994; 24: 41–47.[ISI][Medline]

104. Kato T, Kameoka S, Kimura T et al. The combination of angiogenesis and blood vessel invasion as a prognostic indicator in primary breast cancer. Br J Cancer 2003; 88: 1900–1908.[CrossRef][ISI][Medline]

105. Hasebe T, Sasaki S, Imoto S et al. Histological characteristics of tumor in vessels and lymph nodes are significant predictors of progression of invasive ductal carcinoma of the breast: a prospective study. Hum Pathol 2004; 35: 298–308.[CrossRef][ISI][Medline]

106. Schoppmann SF, Bayer G, Aumayr K et al. Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer. Ann Surg 2004; 240: 306–312.[CrossRef][ISI][Medline]

107. de Mascarel I, Bonichon F, Durand M et al. Obvious peritumoral emboli: an elusive prognostic factor reappraised. Multivariate analysis of 1320 node-negative breast cancers. Eur J Cancer 1998; 34: 58–65.[CrossRef][ISI][Medline]

108. Adjuvant! Online. http://www.adjuvantonline.com/ (August 20th, 2005; date last accessed).

109. Mayo Clinic. http://www.mayoclinic.com/calcs/ The "adjuvant systemic therapy for breast cancer" tool has been removed indefinitely after January 2005 (St. Gallen Conference) due to the availability of adjuvantonline.

110. Olivotto IA, Bajdik C, Ravdin PM et al. An independent population-based validation of the adjuvant decision-aid for stage I–II breast cancer. J Clin Oncol 2004; 22 (Suppl): 522.

111. Falkson G, Falkson HC. CAF and nasal buserelin in the treatment of premenopausal women with metastatic breast cancer. Eur J Cancer Clin Oncol 1989; 25: 737–741.[CrossRef][ISI][Medline]

112. Torrisi R, Colleoni M, Magni E et al. Endocrine and chemoendocrine primary therapy in premenopausal women with endocrine responsive breast cancer: a feasibility study. Breast Cancer Res Treat 2004; 88: 110–111.

113. Colleoni M, Li S, Gelber RD et al. Timing of CMF chemotherapy in combination with tamoxifen in postmenopausal women with breast cancer: role of endocrine responsiveness of the tumor. Ann Oncol 2005; 16: 716–725.[Abstract/Free Full Text]

114. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–1467.[CrossRef][ISI][Medline]

115. Early Breast Cancer Trialists' Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 1189–1196.[CrossRef][ISI][Medline]

116. Davidson NE. Ovarian ablation as adjuvant therapy for breast cancer. J Natl Cancer Inst Monogr 2001; 30: 67–71.[Medline]

117. Prowell TM, Davidson NE. What is the role of ovarian ablation in the management of primary and metastatic breast cancer today? Oncologist 2004; 9: 507–517.[Abstract/Free Full Text]

118. International Breast Cancer Study Group. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003; 95: 1833–1846.[Abstract/Free Full Text]

119. Barthelmes L, Gateley CA. Tamoxifen and pregnancy. Breast 2004; 13: 446–451.[CrossRef][ISI][Medline]

120. 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 2003; 21: 453–457.[Abstract/Free Full Text]

121. Arriagada R, Le MG, Spielmann M et al. Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol 2005; 16: 389–396.[Abstract/Free Full Text]

122. Goss PE, Ingle JN, Martino S et al. A randomised trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349: 1793–1802.[Abstract/Free Full Text]

123. Boccardo F, Rubagotti A, Amoroso D et al. Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study. J Clin Oncol 2001; 19: 4209–4215.[Abstract/Free Full Text]

124. Boccardo F, Rubagotti A, Amoroso D et al. Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat 2003; 82: 6–7.

125. Hillner BE. Benefit and projected cost-effectiveness of anastrozole versus tamoxifen as initial adjuvant therapy for patients with early-stage estrogen receptor-positive breast cancer. Cancer 2004; 101: 1311–1322.[CrossRef][ISI][Medline]

126. Carlson RW, Anderson BO, Chopra R et al. Treatment of breast cancer in countries with limited resources. Breast J 2003; 9: 67–74.[CrossRef]

127. Fisher B, Jeong JH, Anderson S et al. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 2004; 96: 1823–1831.[Abstract/Free Full Text]

128. Bonadonna G, Moliterni A, Zambetti M et al. 30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 2005; 330: 217.[Abstract/Free Full Text]

129. Cameron DA, Anderson A, Toy E et al. Block sequential adriamycin CMF – optimal non-myeloablative chemotherapy for high risk adjuvant breast cancer? Br J Cancer 2002; 87: 1365–1369.[CrossRef][ISI][Medline]

130. Therasse P, Mauriac L, Welnicka-Jaskiewicz M et al. Final results of a randomised phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol 2003; 21: 843–850.[Abstract/Free Full Text]

131. Bull JM, Tormey DC, Li SH et al. A randomised comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer 1978; 41: 1649–1657.[ISI][Medline]

132. Guidi AJ, Berry DA, Broadwater G et al. Association of angiogenesis and disease outcome in node-positive breast cancer patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil: a Cancer and Leukemia Group B correlative science study from protocols 8541/8869. J Clin Oncol 2002; 20: 732–742.[Abstract/Free Full Text]

133. 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 2003; 21: 1431–1439.[Abstract/Free Full Text]

134. Roché H, Fumoleau P, Spielmann M et al. Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. Breast Cancer Res Treat 2004; 88: 27.[CrossRef]

135. 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 2000; 356: 1384–1391.[CrossRef][ISI][Medline]

136. Bonneterre J, Roche H, Kerbrat P et al. Long-term cardiac follow-up in relapse free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group. J Clin Oncol 2004; 22: 3070–3079.[Abstract/Free Full Text]

137. Martin M, Pienkoswki T, Mackey J et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005; 352: 2302–2313.[Abstract/Free Full Text]

138. 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. The International Breast Cancer Study Group. J Clin Oncol 2000; 18: 584–590.[Abstract/Free Full Text]

139. Lamb D, Atkinson C, Joseph D et al. Simultaneous adjuvant radiotherapy and chemotherapy for stage I and II breast cancer. Australas Radiol 1999; 43: 220–226.[CrossRef][Medline]

140. Bellon JR, Shulman LN, Come SE et al. A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma. Cancer 2004; 100: 1358–1364.[CrossRef][ISI][Medline]

141. Ahn PH, Vu HT, Lannin D et al. Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol 2005; 23: 17–23.[Abstract/Free Full Text]

142. Harris EE, Christensen VJ, Hwang WT et al. Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol 2005; 23: 11–16.[Abstract/Free Full Text]

143. Harris EE, Solin LJ. Treatment of early-stage breast cancer in elderly women. Med Pediatr Oncol 2000; 34: 48–52.[CrossRef][ISI][Medline]

144. Fyles AW, McCready DR, Manchul LA et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004; 351: 963–970.[Abstract/Free Full Text]

145. 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 2001; 345: 1378–1387.[Abstract/Free Full Text]

146. Troung MT, Hirsch AE, Formenti SC. Novel approaches to postoperative radiation therapy as part of breast-conserving therapy for early-stage breast cancer. Clin Breast Cancer 2003; 4: 253–263.[Medline]

147. Remouchamps VM, Vicini FA, Sharpe MB et al. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol Biol Phys 2003; 55: 392–406.[CrossRef][ISI][Medline]

148. Pedersen AN, Korreman S, Nystrom H et al. Breathing adapted radiotherapy of breast cancer: reduction of cardiac and pulmonary doses using voluntary inspiration breath-hold. Radiother Oncol 2004; 72: 53–60.[CrossRef][ISI][Medline]

149. Hurny C, Bernhard J, Coates AS et al. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. International Breast Cancer Study Group. Lancet 1996; 347: 1279–1284.[CrossRef][ISI][Medline]

150. Fallowfield L, McGurk R, Dixon M. Same gain, less pain: potential patient preferences for adjuvant treatment in premenopausal women with early breast cancer. Eur J Cancer 2004; 40: 2403–2410.[CrossRef][ISI][Medline]

151. Studts JL, Abell TD, Roetzer LM et al. Preferences for different methods of communicating information regarding adjuvant chemotherapy for breast cancer. Psychooncology 2005; 14: 647–660.[ISI][Medline]

152. Duric V, Stockler M. Patients' preferences for adjuvant chemotherapy in early breast cancer: a review of what makes it worthwile. Lancet Oncol 2001; 2: 691–697.[CrossRef][ISI][Medline]

153. Schover LR. Myth-busters: telling the true story of breast cancer survivorship. J Natl Cancer Inst 2004; 96: 1800–1801.[Free Full Text]

154. Simon MS, Du W, Flaherty L et al. Factors associated with breast cancer clinical trials participation and enrollment at a large academic medical center. J Clin Oncol 2004; 22: 2046–2052.[Abstract/Free Full Text]