Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cristofanilli, M.
Right arrow Articles by Hortobágyi, G. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cristofanilli, M.
Right arrow Articles by Hortobágyi, G. N.
The Oncologist, Vol. 9, No. 4, 471–478, July 2004
© 2004 AlphaMed Press

Breast Cancer Highlights: Key Findings from the San Antonio Breast Cancer Symposium: A U.S. Perspective

Massimo Cristofanilli, Gabriel N. Hortobágyi

Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Massimo Cristofanilli, M.D., Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: mcristof{at}mdanderson.org


   ABSTRACT
Top
 Abstract
Introduction
 Aromatase Inhibitors: The New...
 Adjuvant Chemotherapy:...
 Novel Treatments for Breast...
 Conclusions
 References
 
The San Antonio Breast Cancer Symposium has become one of the leading forums for communication of important discoveries in breast cancer research. Over the past couple of years, seminal, practice-changing results have been presented at this meeting. The aromatase inhibitors represent the most effective endocrine interventions for postmenopausal women with hormone receptor-positive breast cancer. Their introduction into the adjuvant therapy of primary breast cancer was prompted by evidence from the ATAC trial. Progress in adjuvant chemotherapy included the introduction to taxanes, and more recently, the demonstration that the dose-dense administration of paclitaxel in association with doxorubicin and cyclophosphamide resulted in significant improvements in relapse-free and overall survival rates. Molecular targets have become accepted as rational targets, and targeted therapies are proceeding through clinical trials. The success of trastuzumab elicited much excitement, but a number of theoretical and practical hurdles must be overcome before other molecularly targeted agents are incorporated into standard therapy of primary and metastatic breast cancer.

Key Words. Breast cancer • Endocrine therapy • Dose-dense chemotherapy • Trastuzumab • Targeted therapies


   INTRODUCTION
Top
 Abstract
 Introduction
Aromatase Inhibitors: The New...
 Adjuvant Chemotherapy:...
 Novel Treatments for Breast...
 Conclusions
 References
 
As one in eight North American women is destined to develop breast cancer during her lifetime, and the incidence continues to rise, breast cancer has become an extremely important social and economic issue in developed countries. The expanded use of systemic adjuvant therapies has been associated with a significant reduction in mortality over the past decade [1]. Similarly, diagnostic technologies are now providing the information necessary to describe the biological molecular determinants of breast carcinogenesis and progression [2]. The proliferation of molecular targets has inspired academic institutions and the pharmaceutical industry to spend considerable effort on the discovery and development of novel molecularly targeted drugs to be used alone or in combination with cytotoxic agents in the management of breast cancer.

These events bring into even sharper focus the need to understand the biology of breast cancer and to develop more effective methods of prevention, adjuvant treatments, and targeted treatments. Always dedicated to balancing translational research with the clinical management of breast cancer, the 25th San Antonio Breast Cancer Symposium once again was an ideal arena for presenting the results of several important trials, as well as for the education of clinical oncologists in the community. This review is intended to provide some critical discussion of the highlights of the meeting.


   AROMATASE INHIBITORS: THE NEW STANDARD OF CARE FOR ADJUVANT HORMONAL TREATMENT OF POSTMENOPAUSAL WOMEN?
Top
 Abstract
 Introduction
 Aromatase Inhibitors: The New...
Adjuvant Chemotherapy:...
 Novel Treatments for Breast...
 Conclusions
 References
 
Aromatase inhibitors (AIs) have been shown to have an overall superior efficacy to tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE) in managing hormone-receptor-positive metastatic breast cancer in postmenopausal women [3, 4]. Several clinical trials have been designed to investigate the role of AIs in the adjuvant treatment of breast cancer in postmenopausal women over the past few years. The first analysis of the Arimidex, Tamoxifen, alone or in combination (ATAC) trial, the largest adjuvant hormonal study ever conducted, involving over 9,000 women recruited between 1996 and 2000, was presented with a median follow-up of 33 months at the 2001 San Antonio Breast Cancer Symposium and the results were published shortly thereafter [5, 6]. These preliminary results, demonstrating a significant therapeutic advantage for patients treated with anastrozole (Arimidex®; AstraZeneca Pharmaceuticals) over those treated with tamoxifen, were reviewed by an expert panel at the 2002 American Society of Clinical Oncology (ASCO) meeting, which recommended that tamoxifen remain the standard of care until additional follow-up data were available [7].

For these reasons, we believe that the update of the ATAC trial presented by Dr. Buzdar was one of the most important presentations at the 2002 San Antonio Breast Cancer Symposium [8]. The updated analysis at a median follow-up of 47 months continued to demonstrate a significant advantage for women treated with anastrozole. An overall lower recurrence rate was seen with anastrozole compared with tamoxifen (13.2% versus 15.1%). At 48 months, an absolute 2.4% difference in the probability of first recurrence was seen in the overall study population favoring anastrozole; this difference was even greater (2.9%), in receptor-positive patients. Interestingly, the incidence of new contralateral primary breast cancer was lower in the anastrozole-treated group than in the tamoxifen-treated group, reaching statistical significance in receptor-positive patients (p = 0.042 OR = 0.56, 95% confidence interval [CI] = 0.32–0.98). These data reaffirmed the superiority of anastrozole over tamoxifen with even longer follow-up and suggested that this selective AI could be considered the new standard of care for the adjuvant treatment of receptor-positive postmenopausal breast cancer patients. Additionally, since these data suggested a similarly beneficial effect in reducing contralateral breast cancer, the AIs are exciting candidates for trials of chemoprevention of breast cancer. While several additional clinical trials are exploring the roles of all three selective AIs in the adjuvant setting, two clinical trials have been designed to explore the role of anastrozole as adjuvant therapy of noninvasive breast cancer and as chemoprevention in high-risk individuals (International Breast Cancer Intervention Study II [IBIS II]), and NSABP B-35.

Tamoxifen remains the drug of choice for chemoprevention studies in high-risk women based on the results of the P-1 trial [9]. A more detailed knowledge of the pathophysiology of breast disease might contribute to a more accurate risk assessment and a better definition of high-risk populations. In this context, a significant contribution came from the analysis presented by Allred et al. on the predictive value of estrogen receptor (ER) expression in tamoxifen-treated women with ductal carcinoma in situ (DCIS) [10]. This analysis included 1,804 women that were recruited in the National Surgical Adjuvant Breast Project (NSABP) protocol B24 trial, a randomized study evaluating the role of radiotherapy with or without tamoxifen in women with DCIS treated with lumpectomy [11]. The study already showed a lower risk for developing invasive disease in women with DCIS receiving tamoxifen, and this analysis was intended to evaluate whether the determination of ER expression in DCIS specimens could contribute to further select patients who would benefit from tamoxifen or other selective estrogen receptor modulators. Of the 628 patients included in this analysis, 428 (77%) had ER-positive DCIS. This group of women demonstrated a significant reduction in both ipsilateral and contralateral breast cancer (all breast cancer: RR = 0.41, 95% CI = 0.25–0.65, p = 0.0002). The magnitude of benefit was much lower in the ER-negative group (RR = 0.80, p = 0.51), suggesting that ER expression represents an important predictor of efficacy in women with DCIS, similar to the predictive value in invasive disease.


   ADJUVANT CHEMOTHERAPY: DISCOVERING THE CRITICAL ROLE OF SCHEDULE OF ADMINISTRATION
Top
 Abstract
 Introduction
 Aromatase Inhibitors: The New...
 Adjuvant Chemotherapy:...
Novel Treatments for Breast...
 Conclusions
 References
 
The use of systemic chemotherapy in women with primary breast cancer in association with definitive local/regional therapy has been advocated since the early 1960s [12]. Adjuvant systemic chemotherapy was subsequently demonstrated to be associated with definitively superior disease-free survival (DFS) and overall survival (OS) compared with placebo [13, 14]. These early trials using either L-phenylalanine mustard (L-PAM) or cyclophosphamide, methotrexate, 5-fluorouracil (CMF) changed the treatment of women with node-positive primary breast cancer. Subsequently, the introduction of anthracyclines added significant incremental benefits, and anthracycline-containing regimens have become the standard of care over the past decade or so. Additional clinical trials have also extended the indications of adjuvant systemic treatments to women with lymph-node-negative breast cancer [15, 16].

In recent years, the taxanes have been investigated in several trials of adjuvant therapy of women with node-positive breast cancer. The two major trials reported to date, NSABP-B28 and CALGB-9344, provided conflicting evidence about the role of taxanes in adjuvant therapy [16]. The Cancer and Leukemia Group B (CALGB) 9344 trial was reported to show a benefit for patients treated with paclitaxel following four cycles of doxorubicin-cyclophosphamide (AC) chemotherapy when compared with the standard anthracycline-containing regimen alone [16]. A recent update of that trial, with a follow-up approaching 8 years, demonstrated significantly better DFS and OS rates for paclitaxel-treated women [17]. The initial analysis of the NSABP B28 trial showed no difference in outcome between patients treated with AC alone and those treated with AC and paclitaxel [16]. A more recent update confirmed a significant reduction in recurrences with paclitaxel (RR = 0.83, p = 0.008). A triple-drug combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) was shown to be superior, in terms of DFS, to standard 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy in a randomized comparison [18]. There was also a nonsignificant trend toward better survival in the TAC-treated patients (p = 0.11).

Preclinical investigation has demonstrated that paclitaxel has schedule-dependent therapeutic activity. Uncontrolled clinical trials of weekly paclitaxel suggested that this schedule was associated with a different toxicity profile than the U.S. Food and Drug Administration-approved every-3-week schedule of administration. The only reported comparison of these two schedules of administration was performed in a study by the University of Texas M.D. Anderson Cancer Center investigators and reported at the 2002 ASCO meeting [19]. Women with newly diagnosed primary breast cancer were randomized to receive preoperative chemotherapy consisting of either paclitaxel given on a "standard" every-3-week schedule or a more frequent weekly schedule. Both groups received additional chemotherapy with FAC before undergoing surgery. The primary end point of the study was efficacy, represented by comparing the two regimens in their abilities to produce pathologic complete remission (pCR). The weekly schedule resulted in an almost double pCR rate compared with that achieved with the every-three-week schedule (28% versus 15%). An update of this study with information about DFS and OS is awaited with interest. The study stimulated a series of questions on the biological underpinnings of these findings. Two concepts in support of the greater benefit of this approach are: A) the concept of dose density based on the Norton-Simon model [20, 21], which assumes that a Gompertzian model of growth is more applicable to human breast cancer proliferation, and B) the concept of antiangiogenic or metronomic chemotherapy, which consists of the use of more frequent, low-dose chemotherapy administration to affect proliferating endothelial cells that support tumor neoangiogenesis [22, 23]. The concept of dose density was tested in protocol CALGB 9741, which was initially reported by Citron and colleagues [24]. The study was a randomized, phase III adjuvant trial of sequential chemotherapy using doxorubicin, paclitaxel, and cyclophosphamide or concurrent doxorubicin and cyclophosphamide, followed by paclitaxel at 14-day (dose-dense) or 21-day (conventional) intervals in women with node-positive stage II-IIIA breast cancer. The 14-day schedule required the use of prophylactic growth-factor support (filgrastim). The study had a 2 x 2 factorial design. The primary end point was DFS; OS and toxicity were secondary end points. Approximately 2,000 women were assigned to the four study arms. Toxicities were primarily bone-marrow related; the conventional schedule was associated with more significant neutropenia; moderate-to-severe anemia was more frequent in the concomitant arm given every 2 weeks, with 13% of women requiring red cell transfusions. The median follow-up at the time of this analysis was 36 months. When the data were analyzed based on schedule of administration, women receiving the dose-dense schedule experienced significantly better DFS and OS than those on the conventional schedule (p = 0.010 and 0.013, respectively). This is an important study, and the significant survival advantage makes these results quite compelling. The conclusions from this report also suggest that women with primary breast cancer receiving either the sequential or the concurrent regimen used in this trial should strongly consider G-CSF support to achieve the dose-dense administration associated with superior results. However, the trial also raises several important questions. Does the dose-dense approach apply to all adjuvant chemotherapy regimens? Or should it be applied only to the regimens used in this trial? Are the improvements in outcome related to the dose-dense administration or simply to the optimal schedule for one of the drugs, that is, paclitaxel? Which regimen should oncologists consider the most appropriate standard? Furthermore, which of the regimens investigated should be proposed as the standard arm in future comparative clinical trials? Should we consider the results of this trial a validation of the dose-dense administration or can we discriminate the effect of the schedule of administration from the effect of the dose? The next generation of clinical trials should answer questions of whether a more frequent administration schedule at lower doses (e.g., weekly paclitaxel or metronomic chemotherapy) can achieve results similar to those of the dose-dense schedule with less toxicity, and probably fewer costs. It is noteworthy that the results of this intriguing trial refocused our attention on the importance of optimizing chemotherapy regimens and opened new directions for future trials.


   NOVEL TREATMENTS FOR BREAST CANCER: VALUE OF TARGET, IMPORTANCE OF MODEL
Top
 Abstract
 Introduction
 Aromatase Inhibitors: The New...
 Adjuvant Chemotherapy:...
 Novel Treatments for Breast...
Conclusions
 References
 
The proliferation of knowledge about the pathophysiologic mechanisms of breast cancer has stimulated rapid growth in the number of biomolecular markers and the development of targeted therapeutic agents [2]. The most compelling evidence for the benefit associated with targeted treatments is represented by the use of trastuzumab- (Herceptin®; Genentech, Inc.; South San Francisco, CA) based regimens that have been demonstrated to significantly prolong survival in women with HER-2/neu overexpressing metastatic breast cancer [25]. Preclinical studies have demonstrated synergistic interactions between platinum salts and taxanes and, more importantly, between platinum compounds and trastuzumab [26]. These data provided the rationale for a randomized phase III trial conducted by Robert et al. comparing the standard trastuzumab-paclitaxel (TP) combination with trastuzumab-paclitaxel-carboplatin (TPC) [27]. A total of 194 newly diagnosed HER-2-overexpressing women were randomized. There was a higher frequency of hematologic toxicity in women treated with TPC. The objective response rate was greater with TPC than with TP (52% versus 36%, respectively) and was associated with a significant improvement in DFS. Results were similar in HER-2-overexpressing tumors when confirmed by fluorescence in situ hybridization. Preliminary estimates also suggest a longer overall survival in women treated with TPC. This important study validated preclinical observations and identified an additional effective regimen for the treatment of women with HER-2/neu-overexpressing breast cancer.

At the San Antonio Symposium, two studies were presented in which two of the most promising new agents for the management of cancer were tested [28, 29]. The first agent was gefitinib (Iressa®; AstraZeneca Pharmaceuticals), a potent, small-molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, which demonstrated activity in preclinical studies of breast cancer tumor models [30, 31]. Albain et al. presented the findings of a phase II trial for patients with heavily pretreated metastatic breast cancer [28]. The primary objective of the study was to evaluate the safety and clinical benefit of gefitinib; secondary end points included progression-free survival (PFS) and OS. Molecular studies of tissue biopsies of metastatic lesions (e.g., EGFR and EGFR-p) and/or of circulating tumor cells (e.g., EGFR, HER-2) were planned as optional procedures, but EGFR expression was not a requirement for entry into the protocol. Patients with measurable disease and unlimited previous chemotherapy or hormonal therapy were eligible for the study. The statistical design required 58 patients in order to detect a clinical benefit superior to 5% with an 80% power. Of 63 patients enrolled, 31 (approximately 50%) had received more than three previous chemotherapy regimens. Overall, the treatment was well tolerated, with only 28 patients (44%) experiencing reversible acneiform grade 3–4 skin rashes. Three patients obtained clinical benefit: one partial response and two stable disease, a 4.8% response rate (95% CI = 0%–12%). Among the 12 patients with symptomatic bone pain, symptoms improved in five patients (42%), with reduced narcotic requirements. Fifteen patients (24%) continued treatment beyond 2 months (the time of clinical assessment of efficacy), the median PFS time was 57 days (95% CI = 56–58 days), and the median survival time was 144 days (95% CI = 110–242 days).

Are these results surprising? Should we interpret them with optimism and try to look ahead to future combinations? As already mentioned, approximately 50% of the patients had received three or more previous chemotherapy regimens for metastatic disease. Forty-five patients had received therapy with a taxane, 32 had received an anthracycline, and 19 had received trastuzumab. With this history of extensive prior treatment, the probability of response to additional therapy would already have been 20% or less [32–34]. Additionally, the presence of visceral disease in 50 patients (79%) may have had a negative impact on prognosis [35, 36]. The low response rate in an unselected patient population is in keeping with the response rate one would expect from other targeted therapies, for example, trastuzumab, in a group of patients with breast cancer unselected by HER-2 status.

Symptomatic improvement in patients with bone disease might suggest that gefitinib interferes with angiogenic factors, for example, vascular endothelial growth factor (VEGF), and possibly such bone-resorbing factors, as parathyroid hormone-related protein [37, 38]. Although a modulation of VEGF expression also has been documented in other tumor types, the latter biological function remains to be demonstrated in breast cancer. In summary, the results of this early clinical trial suggest that additional research is needed to determine the optimal use of these novel targeted agents. The development of reliable methods to select patients likely to benefit from gefitinib or other EGFR-targeted interventions is clearly of paramount importance. Consideration should also be given to designing trials for specific, highly selected patient groups. For instance, preclinical experiments suggest that gefitinib in combination with tamoxifen results in additive or synergistic effects and delays the emergence of resistance to endocrine therapy. Clinical trials in less heavily pretreated patient populations would also be more likely to demonstrate the antitumor activity of this drug, and preclinical experiments also suggest developing combination regimens with endocrine agents or other methods of targeting specific signaling pathways (e.g., AIs or ER modulators in ER-positive disease and cytotoxic agents in ER negative disease) [39].

The second targeted agent presented was bevacizumab (AvastinTM; Genentech, Inc.), a recombinant humanized monoclonal antibody (rHumAb) to VEGF, one of the many factors involved in the modulation of tumor angiogenesis [40, 41]. Increasing evidence supports the hypothesis that tumor angiogenesis is controlled by an "angiogenic switch," a physiologic mechanism that involves a dynamic balance of angiogenic factors (i.e., inhibitors and inducers). Binding of VEGF to its receptors, known as VEGF receptor 1 (Flt-1) and 2 (KDR/Flk-1), begins the signaling cascade that regulates cellular events involved in new blood vessel formation. The major receptor for VEGF, Flk-1, is one of a number of endothelial cell growth-factor receptors believed to be involved directly or indirectly in angiogenesis [40]. The cascade triggered by receptor tyrosine kinase activation modulates cellular events such as proliferation, differentiation, and morphogenesis [42].

VEGF is a strong endothelial-cell-specific mitogen and a potent vascular permeabilizing agent. Retrospective clinical data have clearly established that higher levels of cytosolic VEGF are a strong independent prognostic factor in node-negative as well as node-positive breast cancer patients [43, 44].

Bevacizumab has demonstrated clinical activity in phase I and phase II early clinical trials [45, 46], which prompted the design of a phase III trial comparing capecitabine with (arm A) or without (arm B) bevacizumab in women with measurable metastatic breast cancer who had already been exposed to anthracyclines and taxanes. The primary end point was time to progression; secondary objectives were safety and objective response. Four hundred sixty-two patients were randomized; the majority had visceral metastases (A, 73.7%; B, 77.8%) and had received more than one regimen for metastatic disease (A, 85%; B, 84%). Patients who received the combination therapy had a higher incidence of cardiovascular complications (e.g., hypertension, bleeding) and proteinuria. The investigators observed a statistically significant difference in overall response rate (ORR) in favor of the combination regimen (A, 30.2% versus B, 19.2%, p = 0.006); this result was confirmed by an independent review (A, 19.8% versus B, 9.1%, p = 0.001). No complete remission was obtained with either treatment. The duration of response was longer in the single-agent arm than in the combination arm (A, 4.96 months versus B, 6.7 months), indicating that, in the patient group treated, the addition of bevacizumab failed to prolong progression-free survival.

The results of that trial raised many questions, the first concerning the possible benefits of antiangiogeneic modulators that specifically target VEGF in the context of metastatic breast cancer. One must remember that tumor microcirculation differs profoundly from that of normal organs in three ways: first, the flow characteristics and, sometimes, blood volume, of the microcirculation; second, the microvascular permeability; and third, the increased fractional volume of the extravascular extracellular space [47]. VEGF seems to be the major regulator of vascular permeability. It has been postulated (and subsequently confirmed in animal models) that the growth of tumor vascularity depends on blood flow and capillary and arterial pressures [48]. Furthermore, tumor cell death seems to be associated with an additional paracrine stimulation of neovascularization through tumor-related release of VEGF. Treatment with specific VEGF inhibitors was reported to produce a characteristic reduction in tumor vessel density, mainly microvascular density [49, 50] (Fig. 1Go). This phenomenon is associated with an increase in tumor blood volume (because of the predominance of large vessels) and a significant reduction in tumor vessel permeability without a change in leakage space [50]. To summarize these findings, VEGF modulators are able to affect only microvessels; they lack antivascular effects, and the resultant changes in tumor blood volume increase the partial pressure of oxygen (pO2) and reduce hypoxia.



View larger version (49K):
[in this window]
[in a new window]
  		Figure 1. Characteristic histopathologic features in tumor tissue pre- and post-treatment with an angiogenic modulator. The treatment is associated with changes in the expression level of angiogenic molecules (e.g., VEGF, interleukin [IL]-8, basic fibroblast growth factor [bFGF]) and microvessel density (MVD). These changes result in increased blood flow (BF) and blood volume (BV), reduced vascular permeability, and increased pO2 (reduced hypoxia).

 
Less-advanced stage disease (e.g., primary breast cancer) probably represents a more appropriate model for clinical testing of VEGF modulators, because cytotoxic agents would be more likely to produce optimal cytoreduction (or debulking). The pathophysiologic changes resulting from cancer cell death and increased VEGF secretion affect tumor microcirculation and may increase the efficacy of VEGF modulators. Among the cytotoxic agents, the taxanes have already demonstrated interesting antiangiogenic properties and appear to be the most appropriate agents to be combined with VEGF modulators in future trials [51]. In fact, there is an ongoing randomized trial in patients with metastatic breast cancer and no prior exposure to chemotherapy for metastatic disease comparing paclitaxel alone with paclitaxel plus bevacizumab.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Aromatase Inhibitors: The New...
 Adjuvant Chemotherapy:...
 Novel Treatments for Breast...
 Conclusions
References
 
The 25th San Antonio Breast Cancer Meeting was an opportunity to present interesting results from clinical trials in the adjuvant and metastatic settings. The additional follow-up information of the ATAC trial provided at this meeting reinforced the superior therapeutic efficacy and favorable safety profile of anastrozole over tamoxifen. These results bring stronger support to the use of AIs in hormone-sensitive postmenopausal women with early breast cancer. The lower incidence of contralateral breast cancers in anastrozole-treated patients suggests potential preventive properties and indicates that this agent (as well as the other selective AIs) should be tested as chemopreventive agents in high-risk women.

The choice of the optimal adjuvant chemotherapy regimen remains controversial. The results of the CALGB 9741 trial clearly indicate that the dose density and schedule of administration of doxorubicin, cyclophosphamide, and paclitaxel are important factors in determining prognosis. Based on that trial, investigators who utilize these three drugs as their adjuvant chemotherapy treatment of choice should strongly consider adopting one of the two dose-dense regimens used in the CALGB 9741 trial. These are compelling results, although how widely applicable they are remains to be determined. Future trials are necessary to assess whether dose-dense strategies apply to all three drugs used in the CALGB 9741 trial and whether these concepts also apply to other drugs without such exquisite schedule-dependent effects as paclitaxel.

We had the opportunity to look in some detail at the disappointing results of two trials of novel biological agents. These are probably the first of a series of negative studies testing novel classes of agents in breast cancer patients. This first generation of clinical trials suffered from our overenthusiastic but uncritical approach to clinical testing. A careful review of the results and a better understanding of the biology of the disease will be translated into a more rational approach to careful patient selection and appropriate trial design in order to contribute progress to the management of breast cancer. In fact, despite the apparently disappointing results with gefitinib and bevacizumab in breast cancer, these two agents have shown efficacy in other malignancies [52–54], suggesting that organ-site-specific research must take place to reveal the roles of various systemic targeted approaches in the management of different tumor types. We hope that future clinical investigations will consider the integration of novel targeted treatments as a high priority in the management of patients with metastatic and, more importantly, primary breast cancer.


   References
Top
 Abstract
 Introduction
 Aromatase Inhibitors: The New...
 Adjuvant Chemotherapy:...
 Novel Treatments for Breast...
 Conclusions
 References
 

  1. Jemal A, Murray T, Samuels A et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.[Abstract/Free Full Text]
  2. Cristofanilli M, Hortobagyi GN. Molecular targets in breast cancer: current status and future directions. Endocr Relat Cancer 2002;9:249–266.[Abstract]
  3. Nabholtz JM, Buzdar A, Pollak M et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women. Results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 2000:18;3758–3767.[Abstract/Free Full Text]
  4. Mouridsen H, Gershanovich M, Sun Y et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596–2606.[Abstract/Free Full Text]
  5. ATAC Trialists’ Group. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in post-menopausal women. Breast Cancer Res Treat 2001;69:210.
  6. Baum M, Buzdar AU, Cuzick J et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first result of the ATAC randomised trial. Lancet 2002;359:2131–2139.[CrossRef][Medline]
  7. Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol 2002;20:3317–3327[Abstract/Free Full Text]
  8. ATAC Trialists’ Group. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial in post-menopausal women with early breast cancer. Update efficacy results based on a median follow-up of 47 months. Breast Cancer Res Treat 2002;76(suppl):S32.
  9. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–1388.[Abstract/Free Full Text]
  10. Allred DC, Bryant J, Land S et al. Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP Protocol B-24. Breast Cancer Res Treat 2002;76(suppl):S36.
  11. Fisher B, Dignam J, Wolmark N et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993–2000.[CrossRef][Medline]
  12. Fisher B, Ravdin RG, Ausman RK et al. Surgical adjuvant chemotherapy in cancer of the breast: results of a decade of cooperative investigation. Ann Surg 1968;168:337–356.[Medline]
  13. Fisher B, Carbone P, Economou SG et al. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N Engl J Med 1975;292:117–122.[Abstract]
  14. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405–410.[Abstract]
  15. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1998;352:930–942.[CrossRef][Medline]
  16. Eifel P, Axelson JA, Costa J et al. National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst 2001;93:979–989.[Abstract/Free Full Text]
  17. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976–983.[Abstract/Free Full Text]
  18. Nabholtz JM, Pienkowsky T, Mackey J et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 2002;21:36a.
  19. Green MC, Buzdar AU, Smith T et al. Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC—final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 2002;21:35a.
  20. Norton L, Simon R. Growth curve of an experimental solid tumor following radiotherapy. J Natl Cancer Inst 1977;58:1735–1741.
  21. Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977:61:1307–1317.[Medline]
  22. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045–1047.[Medline]
  23. Miller KD, Sweeney CJ, Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 2001;19:1195–1206.[Abstract/Free Full Text]
  24. Citron M, Berry D, Cirrincione C et al. Superiority of dose-dense (D-D) over conventional scheduling (CS) and equivalence of sequential (SC) vs. combination adjuvant chemotherapy (CC) for node-positive breast cancer (CALGB 9741, INT C9741). Breast Cancer Res Treat 2002;76(suppl 1):S32.
  25. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
  26. Arteaga CL, Winnier AR, Poirier MC et al. p185c-erbB-2 signal enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. Cancer Res 1994;54:3758–3765.[Abstract/Free Full Text]
  27. Robert N, Leyland-Jones B, Asmar L et al. Phase III comparative study of trastuzumab and paclitaxel with or without carboplatin in patients with Her-2/neu positive advanced cancer. Breast Cancer Res Treat 2002;76(suppl):S37.[CrossRef]
  28. Albain K, Elledge R, Gradishar WJ et al. Open-label, phase II, multicenter trial of ZD1839 (‘Iressa’) in patients with advanced breast cancer. Breast Cancer Res Treat 2002;76(suppl 1):S33.
  29. Miller KD, Rugo HS, Cobleigh MA et al. Phase III trial of capecitabine (Xeloda®) plus bevacizumab (AvastinTM) versus capecitabine alone in women with metastatic breast cancer (MBC) previously treated with an anthracycline and a taxane. Breast Cancer Res Treat 2002;76(suppl 1):S37.
  30. Chan KC, Knox WF, Gee JM et al. Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast. Cancer Res 2002;62:122–128.[Abstract/Free Full Text]
  31. Wakeling AE, Guy SP, Woodburn JR et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002;62:5749–5754.[Abstract/Free Full Text]
  32. Pivot X, Asmar L, Hortobagyi GN. The efficacy of chemotherapy with docetaxel and paclitaxel in anthracycline-resistant breast cancer. Int J Oncol 1999;15:381–386.[Medline]
  33. Blum JL, Dieras V, Lo Russo PM et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001;92:1759–1768.[CrossRef][Medline]
  34. Zelek L, Barthier S, Riofrio M et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer 2001;92:2267–2272.[CrossRef][Medline]
  35. Kramer JA, Curran D, Piccart M et al. Identification and interpretation of clinical and quality of life prognostic factors for survival and response to treatment in first-line chemotherapy in advanced breast cancer. Eur J Cancer 2000;36:1498–1506.
  36. Pritchard KI. Liver metastases: can our understanding of their biology and prognostic value contribute to a strategy for optimum therapeutic management? Eur J Cancer 1997;33(suppl 7):S11–S14.
  37. van der Pluijm G, Sijmons B, Vloedgraven H et al. Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. J Bone Miner Res 2001;16:1077–1091.[CrossRef][Medline]
  38. Ravindranath N, Wion D, Brachet P et al. Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl 2001;22:432–443.[Abstract]
  39. Marquez DC, Lee J, Lin T et al. Epidermal growth factor receptor and tyrosine phosphorylation of estrogen receptor. Endocrine 2001;16:73–81.[CrossRef][Medline]
  40. Strawn LM, McMahon G, App H et al. Flk-1 as a target for tumor growth inhibition. Cancer Res 1996;56:3540–3545.[Abstract/Free Full Text]
  41. Presta LG, Chen H, O’Connor SJ et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593–4599.[Abstract/Free Full Text]
  42. Shawver LK, Lipson KE, Fong TAT et al. Receptor tyrosine kinases as targets for inhibition of angiogenesis. Drug Discovery Today 1997;2:50–63.
  43. Gasparini G, Harris AL. Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol 1995;13:765–782.[Abstract/Free Full Text]
  44. Linderholm B, Tavelin B, Grankvist K et al. Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J Clin Oncol 1998;16:3121–3128.[Abstract/Free Full Text]
  45. Gordon MS, Margolin K, Talpaz M et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843–850.[Abstract/Free Full Text]
  46. Margolin K, Gordon MS, Holmgren E et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol 2001;19:851–856.[Abstract/Free Full Text]
  47. Galmarini FC, Galmarini CM, Sarchi MI et al. Heterogeneous distribution of tumor blood supply affects the response to chemotherapy in patients with head and neck cancer. Microcirculation 2000;7:405–410.[CrossRef][Medline]
  48. Denekamp J, Dasu A, Waites A. Vasculature and microenviromental gradients: The missing links in novel approaches to cancer therapy? Adv Enzyme Regul 1998:38:281–299.[CrossRef][Medline]
  49. Vajkoczy P, Menger MD, Vollmar B et al. Inhibition of tumor growth, angiogenesis, and microcirculation by the novel Flk-1 inhibitor SU5416 as assessed by intracavital multi-fluorescence videomicroscopy. Neoplasia 1999;1:31–41.[CrossRef][Medline]
  50. Bhujwalla ZM, Artemov D, Natarajan K et al. Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470. Clin Cancer Res 2003;9:355–362.[Abstract/Free Full Text]
  51. Sweeney CJ, Miller KD, Sissons SE et al. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res 2001;61:3369–3372.[Abstract/Free Full Text]
  52. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237–2246.[Abstract/Free Full Text]
  53. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–434.[Abstract/Free Full Text]
  54. Kabbinavar F, Hurwitz HI, Fehrenbacher L et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60–65.[Abstract/Free Full Text]
Received May 23, 2003; accepted for publication March 12, 2004.




This article has been cited by other articles:


Home page
 CarcinogenesisHome page
A. Calcabrini, J. M. Garcia-Martinez, L. Gonzalez, M. J. Tendero, M. T. A. Ortuno, P. Crateri, A. Lopez-Rivas, G. Arancia, P. Gonzalez-Porque, and J. Martin-Perez
Inhibition of proliferation and induction of apoptosis in human breast cancer cells by lauryl gallate
Carcinogenesis, August 1, 2006; 27(8): 1699 - 1712.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
K. Collett, G. E. Eide, J. Arnes, I. M. Stefansson, J. Eide, A. Braaten, T. Aas, A. P. Otte, and L. A. Akslen
Expression of Enhancer of Zeste Homologue 2 Is Significantly Associated with Increased Tumor Cell Proliferation and Is a Marker of Aggressive Breast Cancer
Clin. Cancer Res., February 15, 2006; 12(4): 1168 - 1174.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cristofanilli, M.
Right arrow Articles by Hortobágyi, G. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cristofanilli, M.
Right arrow Articles by Hortobágyi, G. N.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS