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
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Abstract |
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St Gallen 2005: news and progress |
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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 [1] 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.
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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) [91] 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.
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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 [92]. An important finding from this approach was the large benefit of chemotherapy alone for postmenopausal women with endocrine non-responsive disease [93
], 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] [82
]. 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 [78
, 94
, 95
], 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 [81
].
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 [96]. Although nodal micrometastases were prognostically relevant in several studies [31
, 32
], 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 [58
] 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 [97
], 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) [98]. Recent observations indicate that treatment choice for patients with very small tumors (but not including microinvasive disease) should be based upon endocrine responsiveness [99
].
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 [33, 100
].
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).
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The second new adverse prognostic feature was peritumoral vessel invasion [103105
], especially lymphovascular invasion [106
]. This proved somewhat controversial, but was accepted by the majority of panelists for patients with node-negative disease [107
]. 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 [108, 109
]. Adjuvant! On line was independently validated by Olivotto et al. [110
] 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.
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Panel recommendations and guidelines |
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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.
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Systemic treatment regimens |
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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 [78, 113
]. 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 [111
] and in the preoperative treatment setting [112
].
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 [114] and of ovarian ablation [115
], the latter only in trials without chemotherapy [116
]. 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 [117
].
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 [118]. 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 [75
]. 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 [119
].
Optimal duration of ovarian function suppression is unknown. Patients with tumors overexpressing HER2/neu [120] 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 [121].
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 [122].
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 [66]. 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 [67
], 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 23 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 [123]. In an Italian trial (426 patients), switch to anastrozole after 2 years of tamoxifen yielded a significant reduction in recurrences [124
]. 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 [69
]. IES, the largest such trial (4742 patients), tested switch to the aromatase inhibitor exemestane after 23 years of tamoxifen. There was a significant improvement of disease-free survival, but not survival within the first 30 months of follow-up [68
]. 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 [122
].
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 [72]. 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 23 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 [125, 126
].
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 [127, 128
] are typically used for node-negative disease, while more intensive regimens such as AC or A followed by CMF [129
], Canadian CEF [130
], the CAF regimen [131
, 132
], dose-dense cyclophosphamide, doxorubicin and paclitaxel [133
], FEC100 followed by docetaxel [134
], tailored FEC [135
], FEC100 [136
] and TAC (docetaxel, doxorubicin, cyclophosphamide) [137
] 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 34 weeks from operation for patients with endocrine non-responsive disease [138]. 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 [133
]. Panel members could not agree on the use of hematopoietic growth factors to avoid dose reduction or delay.
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Radiation therapy |
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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 [143, 144
]. 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 [145]. 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 [55
].
Although shorter radiotherapy fractionation schemes are popular due to logistical and patient convenience [146], data are lacking on long-term efficacy and toxicity.
Indications for radiation therapy after mastectomy are unchanged from previous St Gallen Meeting highlights [1], although computed tomography scan-based simulation, especially for left-sided cancers, may ensure that the heart is not included in the radiation fields [1
, 147
, 148
].
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Specific aspects of treatments |
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Commentary |
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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.
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Appendix |
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Acknowledgements |
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Notes |
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References |
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