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The Oncologist, Vol. 10, No. suppl_2, 9-17, October 2005; doi:10.1634/theoncologist.10-90002-9
© 2005 AlphaMed Press

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 Can We Approach Zero Relapse in Breast Cancer?
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Can We Approach Zero Relapse in Breast Cancer?

Eleftherios P. Mamounas

Northeastern Ohio Universities College of Medicine, Aultman Cancer Center, Canton, Ohio, USA

Key Words. Adjuvant therapy • Neoadjuvant therapy • Aromatase inhibitors • Taxanes • Trastuzumab • Genomic profiling

Correspondence: Eleftherios P. Mamounas, M.D., M.P.H., F.A.C.S., Northeastern Ohio Universities College of Medicine, Aultman Cancer Center, 2600 6th Street SW, Canton, Ohio 44710, USA. Telephone: 330-438-6281; Fax: 330-363-7367; e-mail: tmamounas{at}aultman.com

Received September 6, 2005; accepted for publication September 6, 2005.


   LEARNING OBJECTIVES
Top
 Learning objectives
Abstract
 Introduction
 Adjuvant hormonal therapy
 Adjuvant chemotherapy
 Disclosure of potential...
 References
 
After completing this course, the reader will be able to:

  1. Discuss the factor most likely to contribute to further decreases in breast cancer mortality.
  2. Describe the achievments made in the adjuvant treatment of node-negative and node-positive breast cancer.
  3. Explain the evolving role of targeted therapies and genomics in breast cancer.

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   ABSTRACT
Top
 Learning objectives
 Abstract
Introduction
 Adjuvant hormonal therapy
 Adjuvant chemotherapy
 Disclosure of potential...
 References
 
Adjuvant hormonal therapy and adjuvant chemotherapy have contributed significantly to the falling rates of breast cancer mortality. The introduction of taxanes and aromatase inhibitors in the adjuvant setting represents recent important improvements. More recently, the demonstration of significant benefit in the adjuvant setting with novel molecular targeted therapies (such as trastuzumab [Herceptin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com]) is already beginning to have a substantial impact on the adjuvant treatment of patients with certain tumor characteristics (i.e., HER-2 positivity). Neoadjuvant treatment represents an approach that offers an intermediate end point (i.e., pathologic complete response) that can be used as a marker of therapeutic activity. Furthermore, the use of genomic profiling is starting to replace the traditional prognostic and predictive factors currently used to estimate risks for recurrence and response to particular adjuvant therapies. These recent developments have demonstrated that the notion of approaching zero relapse in breast cancer patients is now within our reach.


   INTRODUCTION
Top
 Learning objectives
 Abstract
 Introduction
Adjuvant hormonal therapy
 Adjuvant chemotherapy
 Disclosure of potential...
 References
 
In recent years, considerable progress in the treatment of breast cancer has been made. Breast cancer mortality represents one objective measure of such progress. Prior to the 1990s, mortality from the disease was stubbornly stable in the U.S. and was actually rising in the United Kingdom [1]. However, during the past 10–15 years, breast cancer mortality has started to decline considerably on both sides of the Atlantic [1]. The reason for this decline is probably multifactorial, with earlier detection of the disease by the widespread use of mammography and more effective treatment of advanced disease clearly deserving some of the credit. However, there is a general agreement that adjuvant systemic therapy (adjuvant hormonal therapy and adjuvant chemotherapy) deserves the lion’s share of the credit for the reduction in breast cancer mortality [2].

As we move into the 21st century, the real question and challenge is whether we can continue to achieve reductions in breast cancer mortality and, if so, which factors will be responsible for these reductions. It is likely that screening and early detection will continue to play important—albeit, in the short term, diminished—roles. The introduction of breast magnetic resonance imaging for selected groups of high-risk patients and the potential for using proteomics in the future represent important leads (Fig. 1Go). Chemoprevention represents a very promising approach. The proof of principle that a proportion of breast cancers can be prevented with the use of tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals, Wilmington, DE, http://www.astrazeneca-us.com) has been clearly established. Newer selective estrogen receptor modulators and aromatase inhibitors (AIs) represent promising leads in the future of chemoprevention. We can certainly expect that the continuing development of novel agents for the treatment of advanced breast cancer will continue to improve the outcome of these patients, but whether this will result in a meaningful reduction in breast cancer mortality will depend on how effective these agents will be in delaying progression. It is quite probable, however, that such novel agents will exert most of their influence on reducing breast cancer mortality through their effectiveness in the adjuvant setting. Important recent developments in the adjuvant field include the demonstration of benefit with AIs in postmenopausal hormone receptor (HR)-positive patients [3], with taxanes in node-positive patients [4–8], and with trastuzumab (Herceptin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) in patients whose tumors overexpress the HER-2/neu oncogene [9–11].



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  		Figure 1. Factors likely to further reduce breast cancer mortality in the future. Abbreviations: AIs, aromatase inhibitors; MRI, magnetic resonance imaging; SERMS, selective estrogen receptor modulators.

 
The trastuzumab example clearly portrays the principle that the efficacy of adjuvant therapy is not only dependent on the treatment used but also on the proper identification of the selected group of patients that is more likely to benefit from the particular treatment. Considerable interest has developed recently in the use of gene-expression profiling as a means for estimating risk for recurrence and, perhaps more importantly, as a means for identifying selected subgroups of patients that receive more/less benefit from certain adjuvant interventions [12–15]. Alternatively, the approach of administering the adjuvant treatment before surgery (neoadjuvant therapy), offers a direct clinical method for testing the sensitivity of the tumor to the agent/regimen in question and offers the ability to identify patients who have a high likelihood of achieving a pathologic complete response (pCR) [16, 17].


   ADJUVANT HORMONAL THERAPY
Top
 Learning objectives
 Abstract
 Introduction
 Adjuvant hormonal therapy
Adjuvant chemotherapy
 Disclosure of potential...
 References
 
Even as recently as the 2000 National Institutes of Health Consensus Development Conference, 5 years of tamoxifen was the undisputable gold standard for adjuvant hormonal therapy. Recent results from the pivotal National Surgical Adjuvant Breast and Bowel Project (NSABP)-B14 trial continue to show the value of adjuvant tamoxifen in estrogen receptor (ER)-positive, node-negative women [18]. Compared with patients randomized to placebo, those taking adjuvant tamoxifen were significantly more likely to be alive (15-year overall survival rate, 71% versus 65%; p = .0008) and to be alive without recurrence (15-year recurrence-free survival rate, 78% versus 65%; p < .0001). That study also demonstrated that longer treatment with tamoxifen is not necessarily better, with 5 years of treatment providing the optimum benefit [19].

AIs as Adjuvant Therapy
The introduction of AIs as adjuvant hormonal therapy for postmenopausal patients with HR-positive tumors represents an important advancement in adjuvant therapy. Three distinct approaches have been employed for the incorporation of AIs into the adjuvant setting as a means of improving on the current gold standard of 5 years of tamoxifen (Fig. 2Go). The first approach was to give the AI from the start and compare it with continuing tamoxifen for a total of 5 years. The second approach was to introduce the AI following 2–3 years of tamoxifen and to compare it with a total of 5 years of tamoxifen. Finally, the third approach was to evaluate AIs as extended adjuvant therapy after 5 years of adjuvant tamoxifen.



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  		Figure 2. Strategies for the evaluation of aromatase inhibitors (AIs) in the adjuvant setting. Abbreviations: PLAC, placebo; TAM, tamoxifen.

 
Seven randomized trials have been reported to date evaluating AIs in the adjuvant setting and using the three approaches discussed above. All these trials have demonstrated a significantly higher disease- or event-free survival rate in the group treated with the AI (Fig. 3Go). In the Arimidex®, Tamoxifen®, Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, which both used the aromatase inhibitor as up-front therapy (anastrozole [Arimidex®; AstraZeneca Pharmaceuticals] in the ATAC trial and letrozole [Femara®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com] in the BIG 1-98 trial), the relative risks for disease-free survival event were 13% and 19% lower, respectively, compared with tamoxifen [20, 21].



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  		Figure 3. Relative reductions in disease-free survival event in seven reported aromatase inhibitor (AI) adjuvant trials. Abbreviations: ABCSG/ARNO, Austrian Breast Cancer Study Group/Arimidex®-Nolvadex®; IES, International Exemestane Study; ITA, Italian Trial of Anastrozole; m, months; MA.17, National Cancer Institute of Canada MA.17 trial; TAM, tamoxifen.

 
The Italian Trial of Anastrozole (ITA), International Exemestane Study (IES), and Austrian Breast Cancer Study Group (ABCSG)-6/Arimidex®-Nolvadex® (ARNO)-95 trials, which started the aromatase inhibitor after 2–3 years of tamoxifen (anastrozole in the ITA and ABCSG-6/ARNO-95 trials and exemestane [Aromasin®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com] in the IES trial), have reported disease-free survival events of 58%, 27%, and 40%, respectively, with follow-up from 28–52 months [22–24]. Finally, in the National Cancer Institute of Canada (NCIC) MA.17 trial and the ABCSG-6a trial, which compared letrozole and anastrozole, respectively, with placebo in patients who had completed 5 years of adjuvant tamoxifen (with or without aminoglutethimide in the ABCSG trial), the disease-free survival event rates were 42% and 36% lower, respectively [25, 26] None of the above trials has, so far, demonstrated a significant improvement in overall survival for the total cohort of trial patients. Longer follow-up is required before the observed significant differences in disease-free survival and distant disease-free survival could translate into significant overall survival differences.

A very important and consistent observation in all the adjuvant AI trials, with significant clinical ramifications, is the finding of a lower risk for contralateral breast cancer in the group treated with the AI versus the group receiving tamoxifen or placebo. This risk reduction was in the range of 40%–50% in the trials comparing an AI with tamoxifen and around40%in the NCICMA.17 trial that compared letrozole with placebo [20–25]. This finding gives us considerable hope that the AIs will be useful in patients with noninvasive breast cancer and, more important, in the chemoprevention setting. Clinical trials to test these hypotheses are currently under way or in the planning stage.

Despite the substantial progress with AIs in the adjuvant setting, several unanswered questions remain. These are being addressed in recently completed, currently ongoing, or planned clinical trials and include the following. Are there significant differences among the different AIs in efficacy or toxicity? Are there subgroups of patients that benefit more or less from therapy with AIs? What is the optimal time to initiate an AI: up-front, after 2–3 years of tamoxifen, or after 5 years of tamoxifen? To ask this question differently, is there a priming effect of tamoxifen that may make subsequent treatment with an AI more effective? What is the optimal duration of AI therapy? What is the role for AIs in premenopausal women who undergo ovarian function suppression? And finally, what is the role of AIs in patients with noninvasive breast cancer and in the setting of chemoprevention?


   ADJUVANT CHEMOTHERAPY
Top
 Learning objectives
 Abstract
 Introduction
 Adjuvant hormonal therapy
 Adjuvant chemotherapy
Disclosure of potential...
 References
 
Over the past 20 years, significant progress has occurred with the use of adjuvant chemotherapy in the treatment of node-negative as well as node-positive breast cancer patients.

Progress in Patients with Negative Axillary Nodes
Examples of the continuous progress with adjuvant chemotherapy in the node-negative setting can be witnessed in a series of NSABP trials in women with negative axillary nodes. A recent update of NSABP protocol B-13, which compared surgery alone with a two-drug combination of methotrexate and 5-fluorouracil (MF) in node-negative patients with ER-negative tumors, continues to show at 16 years that chemotherapy produces a significantly higher relapse-free survival rate (77% versus 63%; p < .001) and overall survival rate (74% versus 65%; p = .03) [27]. Similarly, a recent update of the successor NSABP trial in the same group of patients (protocol B-19), continues to demonstrate the superiority of the three-drug combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) over MF (13-year relapse-free survival rate, 83% versus 73%; p < .01; 13-year overall survival rate, 82% versus 74%; p = .01) [27]. Furthermore, NSABP protocol B-23 subsequently demonstrated that four cycles of doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) plus cyclophosphamide (AC) were equivalent to six cycles of CMF and that adding tamoxifen did not improve outcome in this population of ER-negative patients [27]. In node-negative, ER-positive patients, a recent update of the NSABP B-20 trial continues to demonstrate significantly better disease-free survival and overall survival with the addition of chemotherapy to tamoxifen compared with tamoxifen alone [18]. NSABP B-20 randomized patients to receive either tamoxifen alone or MF plus tamoxifen or CMF plus tamoxifen. At 12 years, the addition of chemotherapy to tamoxifen produced an absolute 10% higher disease-free survival rate (89% with chemotherapy plus tamoxifen versus 79% with tamoxifen alone; p < .0001) and an absolute 4% higher overall survival rate (87% versus 83%, respectively; p = .063) [18].

Despite the aforementioned progress in node-negative patients, there is still considerable room for improvement. Some of the remaining issues that have been or are currently being addressed in research studies include the optimization of anthracycline-based regimens, the role for taxanes, the possible contribution of biologics, and the better selection of candidates for adjuvant chemotherapy.

The question of the optimization of anthracycline-based regimens is currently being addressed in two cooperative group trials in the U.S., both in high-risk, node-negative breast cancer patients. NSABP B-36 is comparing four cycles of doxorubicin/cyclophosphamide (AC) with six cycles of 5-fluorouracil/epirubicin/Ellence® (Pfizer Pharmaceuticals)/cyclophosphamide (FEC100). That study started initially as a 2–2 factorial design with the addition of the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib (Celebrex®; Pfizer Pharmaceuticals), to chemotherapy. However, given the recently disclosed increased rate of cardiac events with COX-2 inhibitors, the celecoxib comparison has been dropped from the protocol. The U.S. Intergroup, under the leadership of the Cancer and Leukemia Group B (CALGB) is currently comparing four cycles of AC with six cycles of AC and is further evaluating paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) (four cycles versus six cycles), all given in an every-2-week, dose-dense schedule.

Another important question, which was addressed in a recently reported Eastern Cooperative Oncology Group (ECOG) trial (ECOG 2197), is whether the incorporation of a taxane in this population of patients can further improve outcome. ECOG 2197 randomized 3,200 patients with zero to three positive nodes to receive either four cycles of AC or four cycles of doxorubicin/docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) (AT) [28]. However, despite the higher rate of hematologic toxicity with the AT regimen than with the AC regimen, no significant difference in disease-free survival or overall survival was observed.

Value of Gene-Expression Profiling for Assessing Prognosis and Benefit from Adjuvant Therapy
As outcome for breast cancer patients continues to improve with more effective adjuvant therapy (particularly in node-negative patients), one issue of increasing importance is that only a minority of patients benefits from treatment. Thus, continuing to investigate biomarkers that will predict risk for recurrence and magnitude of benefit from adjuvant therapy is an important goal that is beginning to become clinical reality.

In Europe, a group from the Netherlands Cancer Institute has used DNA microarrays to develop and validate a 70-gene prognostic index in both node-negative and node-positive patients. van de Vijver et al. reported that this prognostic profile can clearly distinguish patients with a good prognosis from those with a poor prognosis [12]. Patients with a good gene signature had a greater than 90% survival rate at 12 years, as opposed to those with a poor signature (either node-negative or node-positive) who had around a 50% survival rate at 12 years. One potential limitation of these data, particularly for the node-positive cohort, is that the majority of node-positive patients in that study were treated with adjuvant chemotherapy, making it difficult to distinguish whether the good outcome in patients with the good signature was a result of favorable biology or a result of good response to adjuvant chemotherapy. This issue limits the utility of this index in node-positive patients. The second potential clinical limitation of this test is that it requires fresh tissue that may not always be available following surgery. The test is currently being prospectively validated in a large, randomized trial (Microarray for Node-Negative Disease May Avoid Chemotherapy [MINDACT] trial) that seeks to determine whether the use of this test in order to decide which patients receive adjuvant chemotherapy will result in a decrease in chemotherapy use without adversely affecting outcome.

Another significant development in the field of gene-expression profiling is the recent demonstration that reverse transcriptase–polymerase chain reaction (RT-PCR) technology can be used to quantify gene expression levels in paraffin-embedded tissue. Data originally presented at the 2003 San Antonio Breast Cancer Symposium and eventually published in 2004 validated a 21-gene recurrence score as a significant predictor of outcome in node-negative, ER-positive patients [13]. Perhaps more importantly, however, this 21-gene recurrence score was recently shown to significantly predict which node-negative, ER-positive patients benefit from the addition of adjuvant chemotherapy to hormonal therapy [14]. The benefit from adjuvant chemotherapy in addition to tamoxifen was dramatic for patients who had a high recurrence score but was negligible for patients with low recurrence score. These findings were consistent with those from a smaller study from the Milan Cancer Institute that showed that increasing values in the 21-gene recurrence score were associated with increasing rates of pCR to neoadjuvant chemotherapy [15].

The above findings provide hope that, with the use of genomic technology, we are now starting to isolate subgroups of patients that are approaching zero relapse either because of this inherently good prognosis or because of this responsiveness to adjuvant therapy.

Progress in Patients with Positive Axillary Nodes: Incorporating Taxanes into the Adjuvant Setting
For patients with positive axillary nodes, the most important development in adjuvant chemotherapy during the past decade was the demonstration of benefit with the use of taxanes. There have been three distinct strategies used to evaluate taxanes in randomized clinical trials in the adjuvant setting (Fig. 4Go).



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  		Figure 4. First-generation trials evaluating taxanes in the adjuvant setting. Abbreviations: AC, doxorubicin/cyclophosphamide; AT, doxorubicin/docetaxel; FEC, fluorouracil/epirubicin/cyclophosphamide; T, docetaxel; TAC, docetaxel/doxorubicin/cyclophosphamide; TCH, docetaxel/carboplatin/trastuzumab; TH, docetaxel/trastuzumab.

 
The initial strategy was to incorporate taxanes as sequential therapy following an anthracycline-containing regimen. Four clinical trials have been reported evaluating sequential therapy with either paclitaxel or docetaxel following either AC or FEC (CALGB 9344, NSABP B-28, [PACS] 01, and NSABP B-27 [in the neoadjuvant setting]). All these trials have shown significant reductions in disease-free survival or relapse-free survival events (in the range of 14%–17%), and in the case of two of these trials (CALGB 9344 and PACS 01), significant reductions in mortality were also seen with the taxane-containing regimen. (18%–23%) (Fig. 5Go) [4–6, 29].



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  		Figure 5. Relative reductions in recurrence with the sequential addition of taxanes to anthracycline-containing regimens. Abbreviations: AC, doxorubicin/cyclophosphamide; CALGB, Cancer and Leukemia Group B; DFS, disease-free survival; FEC, fluorouracil/epirubicin/cyclophosphamide; NSABP, National Surgical Adjuvant Breast and Bowel Project; T, docetaxel; T*, paclitaxel.

 
When toxicity data with the combination of taxanes and anthracyclines became available, combination studies with anthracyclines/taxanes were performed in the adjuvant setting. These compared either the triple combination of docetaxel/doxorubicin/cyclophosphamide (TAC) with 5-fluorouracil/doxorubicin/cyclophosphamide (FAC) (each for six cycles [Breast Cancer International Research Group (BCIRG) 001]) or the double combination of AT with AC (each for four cycles [see above discussion of ECOG 2197]). The BCIRG 001 trial demonstrated significantly longer disease-free and overall survival with six cycles of the TAC regimen compared with six cycles of the FAC regimen (7% absolute improvement in disease-free survival and 6% absolute improvement in overall survival) [7], yet another demonstration of the activity of taxanes in the adjuvant setting.

The initial results with the incorporation of taxanes either sequentially or in combination into anthracycline-based treatments have generated new hypotheses that have been tested in second-generation adjuvant taxane trials. These trials have compared sequential versus combination anthracycline-taxane regimens (NSABP B-30, BCIRG 005) [7, 30] and have also evaluated the concept of delivering chemotherapy in a more dose-dense fashion [31]. Results from the NSABP B-30 trial and the BCIRG 005 trial are not available as of yet. However, the dose-dense approach of delivering chemotherapy was found to be effective in significantly improving disease-free and overall survival in early results from the CALGB 9741 trial that compared the administration of sequential anthracycline–taxane chemotherapy every 2 weeks with every 3 weeks [31].

Currently, the NSABP B-38 trial is comparing the TAC regimen (as used in the NSABP B-30 and the BCIRG 001 trials) with the sequential regimen of dose-dense AC followed by paclitaxel (AC->T), as used in the CALGB 9741 trial, and with a third regimen in which gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, http://www.lilly.com) is added to paclitaxel as part of the dose-dense AC->T regimen (AC->TG) (Fig. 6Go).



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  		Figure 6. Schema of the National Surgical Adjuvant Breast and Bowel Project B-38 trial. Abbreviations: AC, doxorubicin/cyclophosphamide; q, every; TAC, docetaxel/doxorubicin/cyclophosphamide.

 
Finally, a third strategy has been the use of taxanes instead of anthracyclines in situations in which anthracyclines need to be avoided because of potential toxicity (as is the case, for example, with cardiotoxicity when trastuzumab is part of the regimen). This strategy was investigated in the BCIRG 006 trial comparing AC followed by docetaxel with AC followed by docetaxel plus trastuzumab with docetaxel plus carboplatin (Paraplatin®; Bristol-Myers Squibb) plus trastuzumab in patients overexpressing the HER-2/neu oncogene (Fig. 4Go).

Trastuzumab in Patients Overexpressing HER-2/neu
As mentioned earlier, one of the most important recent developments in the adjuvant treatment of breast cancer is the demonstration of a clinically and statistically significant improvement in disease-free survival and overall survival with the addition of trastuzumab to adjuvant chemotherapy (either in combination or in sequence). Results of the joint analysis of the NSABP B-31/North Central Cancer Treatment Group (NCCTG) N9831 trials, presented at the 2005 meeting of the American Society of Clinical Oncology, demonstrated a 52% reduction in recurrence in favor of the trastuzumab-containing arm [9]. In addition, a 53% reduction in distant recurrence, leading to a 33% reduction in mortality, was also observed. Similar results were also reported at the same meeting from the Herceptin® Adjuvant (HERA) trial that evaluated the addition of trastuzumab to chemotherapy in a sequential fashion (46% lower recurrence) [11]. Whether combining trastuzumab with taxane-based chemotherapy or administering it in a sequential fashion following the completion of chemotherapy is preferable is still an open question. The only results that are based on a direct comparison from a randomized trial come from the NCCTG 9831 trial, which demonstrated that the combination approach is superior [10]. Finally, the optimal duration of trastuzumab therapy is also an open question. Results from the HERA trial will provide information on this question when they become available.

Neoadjuvant Chemotherapy and the Role of pCR
Neoadjuvant chemotherapy has emerged as an important alternative to adjuvant chemotherapy with some significant potential advantages. Results from the first-generation randomized clinical trials comparing neoadjuvant with adjuvant chemotherapy have shown that the use of neoadjuvant chemotherapy produces a higher rate of lumpectomy and a lower rate of axillary positivity and results in similar improvements in disease-free survival and overall survival as adjuvant chemotherapy. In addition, neoadjuvant therapy has the important advantage of offering insights into individual tumor chemosensitivity, and particularly into the significance of achieving a pCR. The NSABP B-18 trial—among several others—has demonstrated that women with a pCR following four cycles of AC have substantially higher rates of disease-free survival and overall survival than women who have any other type of tumor response [32].

With the introduction of taxanes into the adjuvant setting, clinical rationale developed for the conduct of second-generation trials that aimed to evaluate whether more effective regimens could further reduce the extent of locoregional therapy in the breast, and perhaps more importantly, in the axilla, with the use of sentinel node biopsy. Furthermore, it became important to evaluate whether achievement of a pCR with the more active regimens would continue to correlate with better outcome and, as a result, whether pCR could be used as a guide for further locoregional and systemic therapy.

Several randomized neoadjuvant trials have evaluated the addition of taxanes to anthracycline-containing regimens in the neoadjuvant setting and have demonstrated significant increases in pCR rates [33–38]. NSABP protocol B-27 was the largest randomized trial that evaluated the addition of preoperative and postoperative docetaxel after preoperative AC in patients with operable breast cancer. That trial demonstrated a doubling of the pCR rate in the breast as well as an additional significant reduction in the rate of axillary positivity with the sequential addition of preoperative docetaxel [38]. Although there was a modest, nonsignificant improvement in disease-free survival and no significant improvement in overall survival with the addition of docetaxel in that study, outcome results according to pCR and treatment confirmed that the significant correlation between the achievement of a pCR and better outcome, observed in previous studies, remained intact despite the doubling in the number of patients who achieved a pCR with preoperative docetaxel [29].

Thus, there is currently justification for the adoption of pCR as a correlate of chemotherapy efficacy in order to test new drugs and regimens in the neoadjuvant setting. More importantly, high-throughput technology is increasingly being used to identify genomic profiles associated with pCR to specific drugs or combinations, thus helping us to better select patients for particular neoadjuvant regimens in the future.

The next NSABP neoadjuvant trial (NSABP B-40) will randomize patients with operable breast cancer to receive neoadjuvant AC followed by docetaxel or AC followed by docetaxel plus capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com) or AC followed by docetaxel plus gemcitabine (Fig. 7Go). Tissue for biomarker assessment will be collected before randomization and again at the time of surgery, after neoadjuvant chemotherapy. The primary end points are pCR, clinical complete response, and gene expression patterns. Arguably, the most important part of this trial is the battery of ancillary studies examining gene-expression profiling as a potential method for identifying patients likely to achieve or not achieve a pCR.



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  		Figure 7. Schema of the National Surgical Adjuvant Breast and Bowel Project B-40 trial. Abbreviations: AC, doxorubicin/cyclophosphamide; cCR, clinical complete response; pCR, pathologic complete response; T, docetaxel; TG, docetaxel/gemcitabine; TX, docetaxel/capecitabine.

 
Finally, a recently disclosed, small, randomized trial from MD Anderson Cancer Center combined anthracycline/taxane-based neoadjuvant chemotherapy with trastuzumab in HER-2/neu–positive patients and demonstrated a pCR rate of 65% with the trastuzumab-based regimen [39]. Although larger trials are being designed to confirm these findings, these data have provided a great deal of enthusiasm regarding the value of trastuzumab in the early breast cancer setting, a value that was recently demonstrated in the adjuvant setting by randomized trials (see above). Furthermore, these results support that the correlation between pCR and outcome should extent to regimens containing targeted agents in combination with chemotherapy. If these findings can be replicated, and if the allocation of patients to particular forms of therapy can be further refined through the use of genomic profiles, then we will indeed be getting close to the goal of zero relapse in selected groups of breast cancer patients.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning objectives
 Abstract
 Introduction
 Adjuvant hormonal therapy
 Adjuvant chemotherapy
 Disclosure of potential...
References
 
Dr. Mamounas has acted as a consultant for sanofi-aventis, Pfizer, AstraZeneca, Novartis, Genentech, Eli Lilly, and Bristol-Myers Squibb. He has received honoraria from sanofi-aventis, Pfizer, AstraZeneca, Novartis, Genentech, and Genomic Health.


   REFERENCES
Top
 Learning objectives
 Abstract
 Introduction
 Adjuvant hormonal therapy
 Adjuvant chemotherapy
 Disclosure of potential...
 References
 

  1. Peto R, Boreham J, Clarke M et al. UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 2000;355:1822.[Medline]
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  3. Chung CT, Carlson RW. Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know? Clin Breast Cancer 2004;5(suppl 1):S18–S23.
  4. 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]
  5. Mamounas EP, Bryant J, Lembersky B et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005;23:3686–3696.[Abstract/Free Full Text]
  6. Roche H, Fumoleau P, Speilmann M et al. Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. Breast Cancer Res Treat 2004;88(suppl 1):S16.
  7. Martin M, Pienkowski T, Mackey J et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352:2302–2313.[Abstract/Free Full Text]
  8. Aapro MS. Adjuvant therapy of primary breast cancer: a review of key findings from the 7th international conference, St. Gallen, February 2001. The Oncologist 2001;6:376–385.[Abstract/Free Full Text]
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Provocative Optimism in the Treatment of Early Stage Disease
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