| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Letter to the Editor |
1 Surgical Oncology Research Unit Section of Surgery, Ioannina University School of Medicine, Ioannina, Greece, E-mail: droukos{at}cc.uoi.gr
2 Department of Gynecology & Obstetrics, Ioannina University School of Medicine, Ioannina, Greece
3 Department of Surgery, Ioannina University School of Medicine, Ioannina, Greece
To the Editor:
Most of the 20th century has been required to move from radical, extensive Halsted mastectomy to breast-conserving therapy (BCT). However, it was not until 2002 that the 20-year results of two pioneering randomized controlled trials (RCTs)1,2 demonstrating equal survival after mastectomy and BCT led to high-quality evidence-based clinical practice recommendations.3 If BCT was substantial progress for a better quality of life of patients by the end of the past century, what will be the next step a multidisciplinary, individualized, therapeutic concept without surgery in the next decades?4
Even though BCT has been established as a safe oncological treatment, it tends to be underutilized in the United States, with rates ranging from <10% to 45%.5 This fact underlines the gap between research developments and translation into clinical practice and reveals that a long time is needed for a wide application of a new surgical treatment. The low BCT rate may however also reflect concerns about an increased risk of both inadequate margin control6 and local recurrence.7 This local failure in long-term follow-up is 10% to 20% in RCTs despite postoperative radiation. For an optimal application of BCT, a careful selection of stage I/II breast cancer patients8 and lumpectomy margin control,5 regardless of the type of postsurgical adjuvant therapy,9 are essential.
The increasing incidence of breast cancer—about 1,200,000 new cases each year worldwide—coupled with improved therapeutic strategies and long-term survival have increased the number of women who desire a potentially intact conservation of the breast without surgery. This will undoubtedly be the greatest achievement toward an excellent quality of life. Cancer will be the biggest health problem in the next decades in the industrialized world, according to World Health Organization estimates. Breast cancer currently accounts for >32% for all female malignancies in the United States. Breast cancer research has attracted the largest funding proportion of all cancers by both the private and public sectors in the industrialized world.10 As a result, important research developments have been made in better understanding the primary tumor growth and its ability to spread and recur, identifying factors affecting treatment failure, application of new targeted therapies, and prediction of outcomes and response to specific therapies. Could all these advances lead to an individualized neoadjuvant multitherapy without surgery?
Adjuvant systemic therapy has traditionally been administered postoperatively, but preoperative (neoadjuvant) therapy is increasingly utilized.11 Primary systemic (neoadjuvant) treatment has been recommended for patients with locally advanced breast cancer.12 The role of neoadjuvant therapy for operable breast cancer, however, has not yet been clarified. Because screening programs are now widely available and contribute to increased rates of early detection and because most patients are diagnosed with early-stage cancer, there is increasing interest on neoadjuvant therapy for these patients.
In response to our improved understanding of the early dissemination of tumor cells, the concept of early systemic therapy has evolved. However, despite intensive research, comprehensive reviews of RCTs demonstrate no significant increase in survival for preoperative versus postoperative chemotherapy.11,12 A recent careful and methodologically sound meta-analysis of 9 RCTs in a total of 3861 patients confirmed an equal survival rate with preoperative and postoperative adjuvant therapy.13 Mauri et al.13 described an increased risk of locoregional recurrence with preoperative treatment, particularly in the subgroup without surgery, and they highlighted the key role of surgery even when a complete clinical response occurs.
Should we forget neoadjuvant therapy for women with operable breast cancer? Clearly not. In contrast to the low mean pathologic complete response (pCR) rate of 10% to 15% in this meta-analysis,13 results from more recent trials with more effective agents and specific therapies indicate the achievement of much higher response rates. Because the pCR is a key predictor of long-term outcome, it is not surprising that with low rates of pCR in the meta-analysis, no survival benefit can be demonstrated. Even if larger trials are conducted, such low pCR rates cannot lead to significant survival improvements. What we need is not very large trials, but studies with more effective specific therapies targeted to specific subsets of patients and accurate prediction of pCR. If these two key research achievements—namely, high rates of pCR and accurate prediction—could be realized, then it is rational to suppose that neoadjuvant therapy will proven highly effective to improve both survival and quality of life.
HETEROGENEITY
Breast cancer is a heterogeneous disease. We all have experienced that among our patients with the same clinical (age) and pathologic (nodal status; tumor size and grade) criteria and the same treatment strategy, some have recurrence and die while others live disease-free long-term. The addition of estrogen receptors and HER-2 as predictive factors14 has improved the classification system and tailored treatment. Recently, studies using gene expression profiling have revealed distinct genetic subtypes within the estrogen receptor–positive and HER-2-positive or -negative tumors.15
Given this heterogeneity of breast cancer, it has now become clear that the key to future progress is to move away from the "one shoe fits all" strategy either in chemotherapy16 or endocrine therapy.17 Primary medical therapy is a major challenge, and we think that efforts should be focused on two principal key directions aimed at improving (1) the pCR rate and (2) individualized pCR prediction. By identifying patients who will experience pCR before initiation of the specific treatment, we will then be able to design relatively small trials with survival as the end point.
IMPROVED pCR
There is consensus that pCR after neoadjuvant therapy is a powerful prognostic marker for both disease-free and overall survival, and it is considered an extremely valuable end point in trials of preoperative chemotherapy regimens.11 By adding a taxane to standard doxorubicin and cyclophosphamide in the National Surgical Adjuvant Breast and Bowel Project B27 trial with 2411 patients, the pCR rate was significantly improved (13.7% vs. 26.1%; P < .001).18 This study complements the Cancer and Leukemia Group B 9344 and National Surgical Adjuvant Breast and Bowel Project B28 trials and confirms the incremental benefit of adding a taxane.11
Even higher and very impressive pCR rates are currently reported by tailoring neoadjuvant therapy. In a more recent RCT, the pCR rate was significantly increased to 67% when trastuzumab was added to chemotherapy (25% pCR rate with paclitaxel and epirubicin) in the neoadjuvant setting of patients with operable, HER-2–positive breast tumors.19 Despite the small size, the trial’s Data Monitoring Committee stopped the trial because of the superiority of the trastuzumab arm: Buzdar et al.19 from the M. D. Anderson Cancer Center (Houston, TX) demonstrated the significant increase in pCR without clinical congestive heart failure. These results confirm the importance of specific therapies if they causatively target a selected subset of tumors on the basis of the heterogeneity.
IDENTIFYING INDIVIDUALS WITH pCR
The most exciting challenge for this century will be in advancing individualized care on the basis of personalized prediction of outcome and responses to specific therapy. Prediction of pCR to specific neoadjuvant chemotherapy, hormonal therapy, and HER-2–targeted therapy alone or in combination now appears feasible with techniques such as microarrays and real-time polymerase chain reaction.
Assays that evaluate the expression of multiple genes simultaneously by using sophisticated statistical analyses have been developed in the United States (21-gene profiler) and in Europe (70-gene profiler). More recently, investigators from the National Surgical Adjuvant Breast and Bowel Project and Genomic Health demonstrated that a 21-gene assay can help predict which estrogen receptor–positive, node-negative tumors are at a low, intermediate, or high risk of distance recurrence in the setting of tamoxifen therapy.20 A 70-gene profiler assay developed in The Netherlands can more accurately predict outcomes than more classically accepted clinical criteria.21 The TransBIG group has applied the 70-signature profiler to a series of 350 patients from 5 European centers and 1 US center and, again, have observed a dramatic difference in outcomes between those with favorable and unfavorable profiles.22 These advances and validation studies are so dramatic in a short time that the first prospective randomized trial to test the efficacy of a 70-gene prognostic profiler is scheduled to begin the enrollment of 6000 women in the Microarray for Node-Negative Disease May Avoid Chemotherapy (MINDACT) trial.23 We have previously reported that gene expression array as new tumor marker to avoid chemotherapy will first be clinically tested in women with node-negative disease compared with node-positive disease because of the higher risk of recurrence among node-positive breast cancer.24 In the neoadjuvant setting, a recent study suggested that gene expression profiling of cellular material collected by fine-needle aspiration before neoadjuvant chemotherapy may identify women who are least likely to achieve a pCR.25 We think that the dramatic advances in both high pCR and accurate prediction open the way for future trials with neoadjuvant therapy with and without surgery that will have the statistical power for demonstrating a significant survival benefit without the need for enrollment of a very large number of patients.
In summary, pCR is a key predictor of long-term outcome. This objective response rate, translated into improved survival, is dramatically increasing with specific therapies, including chemotherapy, endocrine therapy, and targeted therapy (trastuzumab). Novel promising combined therapies targeting signaling cancer pathways, coupled with standard therapy tailored to molecular subsets of patients, are undergoing clinical testing in the neoadjuvant setting. With improved new combined therapy-based objective response rates and prediction of objective responses (pCR) by using gene expression assays, the time for a randomized trial comparing standard current therapy including surgery with the model of combined therapy without surgery or chemotherapy seems near. Avoiding surgery or chemotherapy when they are unnecessary or treating patients with appropriate specific therapies on an individualized basis will maximize the benefits of our patients regarding both survival and quality of life. Although the research way for the gold standard—randomized clinical trials—of testing new therapeutic approaches has been opened, optimal application of this concept in routine clinical practice will require a long time.
REFERENCES
This article has been cited by other articles:
 |
|
 |
|
  M. Fatouros, G. Baltoyiannis, and D. H. Roukos The Predominant Role of Surgery in the Prevention and New Trends in the Surgical Treatment of Women With BRCA1/2 Mutations Ann. Surg. Oncol., January 1, 2008; 15(1): 21 - 33. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
