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The Oncologist, Vol. 6, No. 4, 376-385, August 2001
© 2001 AlphaMed Press

MEETING REPORT

Adjuvant Therapy of Primary Breast Cancer: A Review of Key Findings from the 7th International Conference, St. Gallen, February 2001

Matti S. Aapro

Correspondence: Matti S. Aapro, M.D., Clinique de Genolier, 1 Route de Muids, Genolier CH-1272 Switzerland. Telephone: 41-22-366-9134; Fax: 41-22-366-9131; e-mail: aapro{at}cdg.ch


   ABSTRACT
Top
 Abstract
Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
Breast cancer research has developed at a rapid pace over the last decades. Recent discoveries promise to provide individualized treatment options, increased long-term survival for women with breast cancer, and the possibility of moving toward curative intent in the treatment of advanced breast cancer. Age, race, tumor size, histological tumor type, axillary nodal status, standardized pathological grade, and hormone-receptor status are accepted as established prognostic and/or predictive factors for selection of systemic adjuvant treatment of breast cancer. The role of other promising new factors, such as p53 mutations, HER-2 status, plasminogen activator system, histological evidence of vascular invasion, and quantitative parameters of angiogenesis will be determined in ongoing prospective studies. Currently, 5 years' treatment with adjuvant tamoxifen in women with hormone-positive receptor status, is regarded as the optimal duration of treatment. Long-term follow-up on the randomized trials will determine the added benefit of treatment beyond 5 years. Ovarian ablation has shown a reduction in recurrence and death, and the exact role and extent of adjuvant chemotherapy in premenopausal women with hormone-responsive tumors is under discussion. Combination hormonal and chemo-hormonal therapies are also being evaluated. There are no convincing data on the survival impact of tamoxifen as a preventative therapy for breast cancer: longer-term follow-up is required, and the planned meta-analyses in 2005 should help shed light on this issue. Statistically significant benefits have been observed with adjuvant chemotherapy (particularly with anthracycline-containing regimens in premenopausal women) versus no adjuvant chemotherapy. The optimal length of adjuvant anthracycline/cyclophosphamide (AC) regimens needs further evaluation as do randomized comparisons of AC to cyclophosphamide/ doxorubicin/5-fluorouracil (5-FU) and cyclophosphamide/epirubicin/5-FU. Although taxanes promise to provide an additive benefit to adjuvant chemotherapy regimens, the Cancer and Leukemia Group B 9344 and the National Surgical Adjuvant Breast and Bowel Project B-28 studies evaluating paclitaxel in the adjuvant setting have not yet demonstrated statistically significant benefits on disease-free survival and overall survival. In the year 2000, all adjuvant therapy studies conducted by the Co-operative Groups in both node-negative and node-positive disease involve a taxane. High-dose chemotherapy evaluations are still ongoing. The numerous prospective adjuvant therapy trials (hormonal; selective estrogen-receptor modulators; aromatase inhibitors; chemotherapy, involving anthracyclines/taxanes/platinum/trastuzumab; biological factors; elderly women (>70 years); high-risk patients; radiotherapy in 1-3 positive lymph nodes), and neoadjuvant studies might further define the chances to enhance cure rates in the treatment of primary breast cancer.

Key Words. Adjuvant chemotherapy • Neoadjuvant chemotherapy • Primary breast cancer • Consensus • St. Gallen


   INTRODUCTION
Top
 Abstract
 Introduction
The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
Breast cancer is one of the most frequently diagnosed cancers, with a lifetime risk in the more developed countries of one in eight women presenting with breast cancer [1]. In the world, there are more than 1,000,000 cases each year, and almost half of these are in countries defined as "less developed" by the World Health Organization. However, over the last 5 decades, our understanding of breast cancer has progressed considerably through continued research, and its mortality has started to decline [2].

Up until the 1950s, breast cancer was believed to be a locoregional disease, and hence, surgery was the primary form of treatment [3]. In the 1960s, animal models lead to the hypothesis of breast cancer rapidly evolving into a systemic disease, which supported the role of systemic therapy [3, 4]. Trials evaluating systemic treatment approaches with hormonal therapy, chemotherapy (mono- and polychemotherapy), and combined hormonal and chemotherapy, resulted in a plethora of sometimes contradictory data. Local therapy (surgery and radiation therapy) continued to play an important role as integral components of breast cancer treatment. In the 1990s, the Early Breast Cancer Trialists' Collaborative Group published overviews, consolidating data from the randomized trials, with an adequate methodology allowing for sufficient numbers of patients and avoiding pitfalls of small, insufficiently powered studies. This information provided additional insights on effective treatments for breast cancer. Tamoxifen was accepted as the standard treatment for patients whose tumors expressed the estrogen and/or progesterone receptors [5, 6]. Chemotherapy, consisting of an anthracycline- or cyclophosphamide-based regimen, was included for patients who were younger, had a higher risk, or administered in patients who had a receptor-negative status [5]. The 1990s also saw the introduction of many active novel treatments for breast cancer (i.e., taxanes) and the identification of factors that would predict response to systemic therapy, or subgroups of patients that would benefit from specific treatments.

The rapid pace of discovery, which took place at the turn of the last century, has generated information that holds great promise to provide better treatment options and increase the long-term survival for women with breast cancer.

The 7th International Conference on Adjuvant Chemotherapy of Primary Breast Cancer, which took place in St. Gallen, Switzerland in February 2001, updated participants on recent adjuvant trial data and established an international consensus on adjuvant therapy of primary breast cancer.

This paper will review a number of key areas addressed by the meeting: A) the role of prognostic and predictive factors on the selection of systemic adjuvant therapy; B) the selection of hormonal adjuvant therapy, the duration of treatment, the role of ovarian ablation, and the value of combined hormonal-chemotherapy treatment; C) the selection of adjuvant chemotherapy; the use of taxanes and anthracyclines or nonanthracyclines for adjuvant treatment; optimal dose, timing, and duration of adjuvant therapy; the impact of side effects and quality of life on the choice of adjuvant treatment; D) innovative treatment strategies; E) the role of adjuvant breast radiation, and F) neoadjuvant therapy.


   THE ROLE OF PROGNOSTIC AND PREDICTIVE FACTORS ON THE SELECTION OF SYSTEMIC ADJUVANT THERAPY
Top
 Abstract
 Introduction
 The Role of Prognostic...
Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
As hormonal therapy, chemotherapy, and local treatment have proved to be effective treatments in the overview analyses, the challenge remains to optimize the use of these treatments. In a move toward treatments customized to individual patients, the selection of systemic adjuvant therapy may be based on predictive and prognostic factors. It is well accepted that prognostic factors are measurements at diagnosis associated with outcome (i.e., recurrence rate, death rate, and other clinical outcomes), while predictive factors are associated with the degree of response to specific therapy. These factors need to be accurate and reproducible.

Established prognostic and predictive factors are shown in Table 1Go [6-10]. Adjuvant hormonal therapy is recommended for women whose tumors express hormone receptors, regardless of age, menopausal status, axillary node involvement, or tumor size [8, 9, 12]. Tamoxifen should not be used in women with estrogen-receptor (ER)-negative tumors, as they appear not to benefit from adjuvant hormonal therapy [6, 8, 9, 12]. Actually, tamoxifen may be harmful in some of these patients as it will increase the risk of other events while providing no antitumor effect.


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  		Table 1. Established prognostic and predictive factors for selective systemic adjuvant therapy [6-10]
 
Promising prognostic and/or predictive factors are shown in Table 2Go. These include HER-2, p53, vascular invasion, invasiveness, and angiogenesis parameters [9, 12, 13]. However, these have not yet been adequately proven and are, therefore, not regarded as established predictive and/or prognostic factors. Results from prospective clinical trials are required, which incorporate these promising factors, before altering patient management. Such studies are ongoing and include the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 and the American College of Surgeons-Oncology Group (ACOS) sentinel node trials.


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  		Table 2. Promising prognostic and predictive factors for selective systemic adjuvant therapy [6-11, 13]
 

   ADJUVANT HORMONAL THERAPY
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
Tamoxifen is an extensively studied adjuvant hormonal therapy. Data from trials and the 1992 overview data set resulted in tamoxifen 20 mg being recommended as the standard dose in postmenopausal women with ER-rich tumors [5, 7, 14]. The results from the overview were less conclusive concerning the use of tamoxifen in premenopausal and ER-negative disease. Questions were raised whether 2 years, 5 years, or longer than 5 years of tamoxifen treatment would be optimal. Several large studies addressed these questions. Multicenter trials also addressed the possible preventative effects of tamoxifen in reducing the incidence of breast cancer. Updated overview data were provided in 1998 and 2000, which formed an important base for the discussions at the St. Gallen Conference, and some of these results are summarized in Table 3Go.


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  		Table 3. Effects of adjuvant therapy [6, 8]
 
Best Type of Endocrine Treatment and Duration of Endocrine Treatment
The value of endocrine therapy was confirmed in the 2000 overview. The main effects of tamoxifen were observed in women with ER-positive tumors with little effect observed in ER negative tumors. Five years of tamoxifen treatment appeared superior to 2 years of treatment (Table 4Go) [15].


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  		Table 4. Absolute improvement in 15-year outcome for women with ER-positive disease [15]
 
To date, outside of clinical trials there are no conclusive data to justify the use of tamoxifen for a period longer than 5 years [6, 9, 15, 16]. No conclusions could be drawn in the comparison of the 5- with the 10-year data, as the follow-up was short and there were few events [15]. Trials are still ongoing to address the question of the benefits of tamoxifen treatment beyond 5 years.

While tamoxifen has been associated with a slightly increased risk of endometrial cancer and venous thromboembolism, it appears the benefits outweigh the risks in women with endocrine-responsive tumors.

Value of Combined Hormonal/Chemotherapy Treatment
Tamoxifen combined with chemotherapy further reduces the risk of disease recurrence, particularly in premenopausal women [6, 9, 11]. Thus, all patients with hormone-receptor-positive tumors receiving adjuvant chemotherapy should also receive tamoxifen [6, 9]. The timing of tamoxifen, during or after chemotherapy, is still being discussed.

Ovarian Ablation and Combined Treatments
In the absence of chemotherapy, trials with ovarian ablation resulted in a reduction in recurrence by an absolute value of 12.2% at 10 years and 13.3% at 15 years [15]. Deaths were reduced by 8.3% at 10 years and 10.4% at 15 years. In ER-positive premenopausal patients, alternative strategies with ovarian ablation and chemotherapy have been explored. However, in the trials with ovarian ablation in the presence of chemotherapy, the results to date have shown no additional advantages, and the value of ovarian ablation in combination with chemotherapy needs to be further explored [9, 15, 17, 18]. It may be that chemotherapy will play a decreased role for adjuvant therapy of premenopausal women with hormone-receptor-positive tumors [19]. Longer follow-up on the Zoladex Early Breast Cancer Research Association (ZEBRA) study might provide further insights, and the United States (U.S.) Intergroup might explore the use of ovarian ablation following chemotherapy in women with maintained ovarian function.

Adjuvant Hormonal Treatment Options in Development
The combination of hormonal therapies is being evaluated, especially in studies involving selective estrogen-receptor modulators (SERMs) and aromatase inhibitors.

Ongoing cooperative group and multinational studies are comparing tamoxifen x 5 years followed either by placebo x 5 years or letrozole x 5 years; tamoxifen x 5 years followed either by placebo x 5 years or exemestane x 5 years; tamoxifen x 5 years versus letrozole x 5 years versus tamoxifen x 2 years followed by letrozole x 3 years versus letrozole x 2 years followed by tamoxifen x 3; tamoxifen x 5 years versus tamoxifen for 2-3 years followed by exemestane for 2-3 years; and the Arimidex, Tamoxifen and Combined (ATAC) Trial Group study compares tamoxifen x 5 years versus anastrozole x 2-5 years, versus tamoxifen + anastrozole x 5 years. Results of this latter study should be available by the end of 2002.


   ADJUVANT CHEMOTHERAPY
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
Statistically significant benefits have been observed in patients receiving adjuvant chemotherapy versus those receiving no adjuvant chemotherapy (Table 5Go) [9, 20]. Moreover, anthracycline-containing adjuvant chemotherapy regimens have resulted in a small but statistically significant increase in survival compared to non-anthracycline-containing adjuvant regimens (Table 5Go) [9, 20]. However, as discussed later, the extent of anthracycline therapy is still under discussion.


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  		Table 5. Adjuvant chemotherapy [9, 20]
 
Chemotherapy has been demonstrated to provide survival benefit in premenopausal and postmenopausal women up to the age of 70 years and in most tumor subsets, except for small node-negative tumors less than 1 cm in diameter [9, 12]. It is possible that adjuvant chemotherapy for older patients will also provide a survival advantage, provided it is possible to give it at a sufficient dose-intensity, which has not been the case for the most frequently tested regimen, cyclophosphamide/methotrexate/5-fluorouracil (5-FU) (CMF) [21].

Progress with Chemotherapy for Primary Breast Cancer
The Oxford overview data confirm that polychemotherapy (>2 agents) offers a survival advantage compared to single agents in the adjuvant setting, with four to six courses (3-6 months) providing optimal benefits [9, 12, 20, 22]. Generally, randomized trials have shown a threshold effect for the doxorubicin and cyclophosphamide combination, with doses of 60 mg/m2 and 600 mg/m2, respectively, seeming optimal [5, 23]. While the NSABP-B15 trial found an equivalence between four cycles of anthracycline/cyclophosphamide (AC) and six cycles of CMF, other randomized trials have shown better disease-free survival and overall survival with more intensive anthracycline regimens versus CMF or longer versus shorter durations of anthracycline-based adjuvant regimens [22, 24]. Such data call into question the optimal length of treatment of the AC regimen. Additionally, AC has not been compared with cyclophosphamide/doxorubicin/5-FU or cyclophosphamide/epirubicin/5-FU in randomized trials as adjuvant treatment for primary breast cancer. Future trials are needed to define the optimal use of adjuvant anthracycline-based regimens. While waiting for results from such studies, the decision to use an anthracycline-based adjuvant therapy, and the type of such therapy, should be made on individual patients taking into consideration the potential survival benefits versus toxicity risks.

The Use of Taxanes and Anthracyclines as Adjuvant Chemotherapy
As anthracyclines and taxanes (paclitaxel and docetaxel) are the most active cytotoxic treatments available for advanced breast cancer, the evaluation of these agents in the adjuvant setting was logical [25]. Several trials have assessed the efficacy and safety of the addition of a taxane to standard anthracycline adjuvant chemotherapy in node-positive breast cancer [26-29]. Two strategies have been used for the administration of the anthracycline/taxane regimen: A) combination and B) sequential administration. Prospective phase III adjuvant trials with docetaxel, either in combination or in sequential administration to the anthracycline, are ongoing. Whereas, adjuvant studies with paclitaxel are evaluating the combination in a sequential strategy [30]. The sequential strategy with paclitaxel is an attempt to reduce the possible increased incidence of cardiotoxicity that is associated with the paclitaxel/anthracycline combination (which may be linked to the pharmacokinetic interaction of the drugs), a potential problem which is not observed with the docetaxel/anthracycline combination [30-35].

Currently available data with adjuvant paclitaxel/anthracycline combinations in node-positive breast cancer do not permit definitive recommendations of the use of taxanes in the adjuvant setting [9, 12, 22]. This conclusion is based on the results of the Cancer and Leukemia Group B (CALGB) 9344 and NSABP B-28 trial, which did not demonstrate statistically significant benefits on disease-free and overall survival [9, 12, 22, 35, 36]. However, it is hoped that mature data from the ongoing or recently closed taxane/anthracycline adjuvant trials will clearly demonstrate their role in the adjuvant setting.

Patients in the CALGB 9344 (n = 3,170) study were randomized to receive either four cycles of AC or four cycles of AC followed by four cycles of paclitaxel (175 mg/m2 over 3 hours) [9, 12, 22, 25, 37]. In 1998, preliminary data at a median follow-up of 21 months showed the AC followed by paclitaxel arm was associated with a 22% reduction in disease recurrence and a 26% reduction in mortality [37]. However, the 52-month follow-up showed a reduction in the benefit in the risk of recurrence (13%) and death (14%) with the addition of paclitaxel to anthracycline. Additionally, the improvement in survival with AC followed by paclitaxel was no longer statistically significant when compared to the AC arm alone (p = 0.0745) [9, 22, 25, 37]. There remains a possibility that paclitaxel provides some survival advantage to hormone-unresponsive patients, but the study design does not allow a firm conclusion because the potential advantage might be related simply to a longer exposure to chemotherapy.

The NSABP B-28 (n = 3,060) enrolled patients with operable breast cancer and pathologically positive nodes. Patients were randomized to receive either AC x four cycles or AC x four cycles followed by four cycles of paclitaxel (225 mg/m2) over 3 hours [8, 11, 18, 21, 33]. Patients were stratified according to number of positive axillary nodes, tamoxifen administration, and type of surgery. The third interim analysis of this study, with a median follow-up of 34 months, estimated median disease-free survival to be 81% in both groups; median overall survival was 92% in the AC group and 90% in the AC followed by paclitaxel group. The number of deaths was 133 in the AC group and 136 in the AC followed by paclitaxel group (p = 0.98) [9, 12, 22, 25, 36]. To date, no difference with regard to steroid hormone-receptor status has emerged. Further follow-up of this trial is required, but the same problem on duration of treatment remains.

The use of taxanes in node-negative breast cancer should be restricted to clinical trials as there are no data available yet to support the use of taxanes outside clinical trials.

The Role of High-Dose Adjuvant Chemotherapy
There is no convincing evidence yet that high-dose chemotherapy with peripheral stem cell support is superior to standard therapy in the adjuvant setting [9, 12, 22, 38-42]. Randomized trials are continuing to evaluate the value of high-dose chemotherapy, but it should not be offered outside of clinical trials.


   ONGOING TRIALS AND INNOVATIVE ADJUVANT CHEMOTHERAPY STRATEGIES
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
Although at present there are no convincing data to justify the use of biological factors in selecting specific adjuvant chemotherapy, the predictive roles of p53 mutations and HER-2 overexpression are being explored in prospective studies. Additionally, the role of high-dose chemotherapy in the adjuvant setting, the definition of the contribution offered by the taxanes, and the integration of novel agents (i.e., trastuzumab) are also under evaluation in prospective trials. A summary of some of the sequential versus combination adjuvant trials is shown in Figure 1Go.



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  		Figure 1. Planned, ongoing, and completed selected adjuvant studies comparing sequential to combination chemotherapy.

 
Based on the NSABP B-15 (AC x 4, AC x 4 followed by CMF x 3 or CMF x 6) and NSABP B-11 (melphalan plus 5-FU to melphalan plus 5-FU plus doxorubicin) trials, HER-2/neu overexpression appears to predict a benefit with an anthracycline treatment. To further investigate the predictive ability of HER-2/neu overexpression, the NSABP B-31 trial will randomize node-positive and HER-2/neu-positive patients to either AC x four cycles followed by paclitaxel x four cycles or AC x four cycles followed by four cycles of paclitaxel plus trastuzumab for 1 year. Given the concern of the additive cardiotoxicity of doxorubicin and trastuzumab [43], the North Central Cancer Treatment Group (NCCTG) 9831 will randomize patients to receive either: paclitaxel plus concomitant trastuzumab; paclitaxel followed by trastuzumab; or weekly paclitaxel alone for 12 weeks. The Breast Cancer International Research Group (BCIRG) 006 study will randomize patients to four cycles of AC followed by four cycles of docetaxel, or to four cycles of AC followed by four cycles of docetaxel plus trastuzumab for 1 year, or an intriguing triple regimen of docetaxel plus platinum salts plus trastuzumab [44, 45].

Side Effects and Quality of Life: The Impact on the Choice of Adjuvant Therapy
Concerns on the toxicity associated with the use of adjuvant chemotherapy are reasonable. Most acute side effects (i.e., nausea, vomiting, alopecia, neutropenia) resolve on completion of treatment. Longer-term side effects with hormonal therapy (small increase in risk of second malignancies, thromboembolism), chemotherapy (i.e., cardiac disease), or a combination of tamoxifen and chemotherapy need to be carefully considered on an individual patient basis. At the cumulative doses utilized in standard anthracycline adjuvant programs in patients with no preexisting heart disease, excessive cardiac toxicity seems to be restricted [9, 12].

Limited data are available on the use of adjuvant chemotherapy in elderly women (>70 years) and high-risk patients. Further studies are being conducted on these specific patient populations. In the clinic, benefit/risk ratios and patients' needs should be considered when treating these patients. Clear communications of the risks/benefits to the patients are essential [9, 12, 22].


   ROLE OF NEO-ADJUVANT THERAPY
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
Controversies in Breast...
 Conclusions
 References
 
The St. Gallen Conference focused on adjuvant therapy for primary breast cancer; however, neoadjuvant therapy provides several advantages, namely it allows for in vivo tumor response to new anticancer agent assessments; reduces the likelihood of drug resistance as it allows a switch to non-cross-resistant regimens; takes advantage of the less favorable growth kinetics for micrometastases, and may increase the rate of breast conservation and achieve nodal downstaging [46-50].

In the past, randomized neoadjuvant studies produced inconclusive results, with some showing disease-free survival benefits at 5 years and others showing no difference versus adjuvant therapy [47, 50-53]. Since then, however, biological determinants have been introduced and promise to enhance our understanding of particular characteristics of an individual tumor and best treatment options. It may be that neoadjuvant therapy will prove of interest in terms of survival for younger endocrine-unresponsive patients as an early start of chemotherapy seems to play a role only for this subset of patients [54].

The correlation between p53 and HER-2 expression as possible predictors of response to neoadjuvant chemotherapy is under investigation [55].

The NSABP B-18 study showed significantly better disease-free and overall survival among patients achieving a pathological complete response [9]. It is hoped that the NSABP B-27 trial will confirm these results. Phase II neoadjuvant trials with the taxanes have produced encouraging results, which has prompted further evaluation in the phase III setting [56-62]. The NSABP B-27 study randomized patients to receive either AC x four cycles followed by surgery, AC x four cycles followed by docetaxel x four cycles and then followed by surgery, or AC x four cycles followed by surgery and then docetaxel x four cycles. All patients received 5 years tamoxifen treatment. This study has recently closed, with 2,411 patients enrolled. The results from this study will help define the role of docetaxel in the neoadjuvant setting.

Studies will also need to address the issue of whether the inclusion of an anthracycline is essential in neoadjuvant regimens.


   CONTROVERSIES IN BREAST RADIATION
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
Conclusions
 References
 
With the establishment of adjuvant systemic therapy, the role of locoregional therapy has changed and moved toward less aggressive surgery combined with radiotherapy [63]. Randomized trials showed mastectomy, plus radiotherapy produced similar results to extensive radical mastectomy and the role of postoperative irradiation in breast-conserving therapy has been confirmed [63, 64]. Analyses have shown that radiotherapy can significantly reduce the locoregional recurrence rate but does not significantly improve the long-term survival of the patient [63, 65, 66]. More recent studies in patients with well-defined pathologically staged high-risk breast cancer have demonstrated a clinically relevant improvement in survival in some patients receiving radiotherapy and systemic therapy [63]. From these studies, it was concluded that improving locoregional tumor control could improve overall survival rates and that radiotherapy was an important part of the multimodality approach to the treatment of high-risk breast cancer [9, 12, 63].

Women with a high risk (>=4 axillary nodes or an advanced primary tumor) of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy (administered within 6 months following the mastectomy) [9, 12]. However, radiotherapy should not be delivered concurrently with anthracycline chemotherapy [9, 12].

It is uncertain whether women with only one to three positive lymph nodes would benefit from postmastectomy radiotherapy. This is being addressed in ongoing randomized trials.


   CONCLUSIONS
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
References
 
Breast cancer mortality rates are decreasing, and this is due in part to the progress made in the adjuvant treatment of primary breast cancer and efficient earlier screening programs [1].

It is hoped that the novel predictive and prognostic factors will be confirmed, through the randomized trials, as reliable and accurate factors for predicting patient outcomes or response to specific treatments. These, together with currently established factors, will enhance the ability to customize patient treatments.

Prospective adjuvant tamoxifen trials will provide insight to the value of continuing treatment beyond 5 years, of combined hormonal therapy, and of the benefits of SERMs and aromatase inhibitors. The jury is still out on the role of tamoxifen as prevention for breast cancer. The NSABP P-1 study, comparing tamoxifen versus placebo, showed almost a 50% reduction in the early incidence of breast cancer; however, the study was then stopped and unblinded [67]. Neither this study, nor the Multiple Outcomes of Raloxifene Evaluation study (comparing raloxifene to placebo) established a reduction in breast cancer mortality. The Royal Marsden trial and the Italian trial demonstrated no effect of tamoxifen on the early incidence of breast cancer [67]. The risk/benefit ratio of chemoprevention has also not been demonstrated. The International Breast Cancer Intervention Study (IBIS) trial enrolled 7,000 women with an increased risk of breast cancer; this study is now closed and an interim analysis is expected this year. Further follow-up of the Royal Marsden, IBIS, and Italian studies are ongoing and a meta-analysis is planned for 2005 [67]. This may shed light on the role of tamoxifen in a preventative role. Additional studies are also under way: IBIS-II compares tamoxifen to anastrozole to placebo in healthy postmenopausal women (aged 40-70 years); the PROPLAC study will compare the naturally occurring dietary SERM (phytoestrogen) to placebo in healthy pre- and postmenopausal women. The raloxifene Zoladex (RAZOR) study will compare raloxifene plus goserelin to placebo in premenopausal women likely to be a BCRA-type gene mutation [67]. Long follow-ups are needed on these trials in order to demonstrate a clinical benefit or reduction in breast cancer mortality.

The use of vaccines as an adjuvant therapy for breast cancer is in the early stage of evaluation [68]. As our knowledge on breast tumor cellular biology improves, potential targets for antigen-specific immunotherapy might have an important role to play in the management of this disease.

With our increasing options for early treatment of breast cancer, we should achieve enhanced cure rates in primary breast cancer in the near future while avoiding overtreatment.


Photo by Swiss-Image.ch


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 
M.S.A. acknowledges relationships with the following corporate sponsors: Aventis, Roche, Novartis, Pharmacia, Merck, Helsinn, Wyeth, and AstraZeneca. The editors gratefully acknowledge an unrestricted educational grant from Aventis Oncology.


   References
Top
 Abstract
 Introduction
 The Role of Prognostic...
 Adjuvant Hormonal Therapy
 Adjuvant Chemotherapy
 Ongoing Trials and Innovative...
 Role of Neo-Adjuvant Therapy
 Controversies in Breast...
 Conclusions
 References
 

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Received July 10, 2001; accepted for publication July 13, 2001.




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