Journal of the National Cancer Institute Advance Access originally published online on April 8, 2008
JNCI Journal of the National Cancer Institute 2008 100(8):521-523; doi:10.1093/jnci/djn098
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© The Author 2008. Published by Oxford University Press.
EDITORIALS |
Can Early Response Assessment Guide Neoadjuvant Chemotherapy in Early-Stage Breast Cancer?
Affiliation of authors: Department of Breast Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Francisco J. Esteva, MD, PhD, Department of Breast Medical Oncology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd—Unit 1354, Houston, TX 77030 (e-mail: festeva{at}mdanderson.org).
Randomized clinical trials conducted over the last three decades have shown that systemic adjuvant therapy reduces the risk of recurrence and death in patients with early-stage breast cancer. In patients with locally advanced and inflammatory breast cancer, the use of chemotherapy before surgery (neoadjuvant or preoperative approach) is the standard of care. A clinical and/or radiological response is achieved in most patients, and this response facilitates optimal surgery and radiation therapy. The success of neoadjuvant chemotherapy for locally advanced breast cancer, combined with emerging data on the use of adjuvant chemotherapy, led to studies investigating neoadjuvant chemotherapy among women with operable breast cancer. Randomized clinical trials of adjuvant vs neoadjuvant chemotherapy in patients with early-stage operable breast cancer showed no difference in disease-free or overall survival rates. Potential advantages of the neoadjuvant approach include surgical downstaging among women who might otherwise have required a mastectomy, increasing rates of breast conservation, and in vivo testing of sensitivity of cancer cells to the systemic therapy used.
Anthracyclines and taxanes are the most effective cytotoxic agents in breast cancer and form the backbone of most regimens used in the neoadjuvant setting. The GeparTrio trial, whose results are presented in this issue of the Journal, evaluated the role of early response for selecting subsequent therapy in patients initially treated with neoadjuvant anthracycline- and taxane-based chemotherapy (1,2). Patients with stage II or III breast cancer who were candidates for neoadjuvant chemotherapy received two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC). Patients who achieved a clinical or sonographic response were randomly assigned to receive either four additional cycles of TAC or six additional cycles of TAC. Patients who did not achieve a clinical or radiological response were randomly assigned to either four additional cycles of TAC or four cycles of vinorelbine in combination with capecitabine (NX). In responding patients, the pathologic complete response rates were similar in patients receiving six or eight cycles of TAC. In the nonresponder patients, using four cycles of NX after two cycles of TAC was as ineffective as using six cycles of TAC. The use of non–cross-resistant chemotherapy regimens is based on the hypothesis that cancer cells surviving a particular chemotherapy regimen ("resistant" cells) may be more sensitive to a second regimen. However, randomized clinical trials failed to confirm this hypothesis in breast cancer patients undergoing neoadjuvant chemotherapy. In the Aberdeen trial (3), patients with large or locally advanced breast cancer who were not responding to an anthracycline-based regimen were switched to single-agent docetaxel. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial (4), patients were randomly assigned to doxorubicin–cyclophosphamide (AC) vs AC followed by docetaxel before surgery, regardless of response to AC. In both studies, the resistant population did not derive much benefit from the sequential administration of the taxane after anthracycline-based chemotherapy. Although the GeparTrio trial was powered to show noninferiority between TAC and NX in TAC-refractory patients, the results do not support the hypothesis that NX is a non–cross-resistant regimen after TAC chemotherapy. Some of the drugs administered may share mechanisms of resistance developed by breast cancer cells, and the TAC and NX regimens may not be truly non–cross-resistant. For example, expression of the multidrug resistance protein has been associated with resistance to taxanes and vinca alkaloids, and the activity of capecitabine is clearly much lower in tumors refractory to anthracyclines and taxanes than in untreated tumors (5,6). More research is needed to understand specific mechanisms of resistance for the different chemotherapeutic agents and to develop drugs that are truly non–cross-resistant.
The Aberdeen trial and the GeparTrio trial both showed that, among patients with early response to therapy, continuation of the same treatment results in additional response. However, the GeparTrio trial indicates that most of the additional benefit is obtained with just a few (in this case, four) additional cycles of treatment. The Aberdeen trial showed that crossing over to a taxane produced more benefit in the responding population than continuing on the regimen that produced the initial response. The NSABP B-27 study simply confirmed the additional response to a crossover regimen and, in subset analysis, indicated that the additional benefit is largely limited to patients with a partial (therefore, incomplete) clinical response, with little apparent benefit to nonresponders and complete responders. In contrast to the Aberdeen study, patients who were responders were not switched to an alternate treatment in the GeparTrio trial. The pathologic complete response rate in the nonresponders was low (5%–6%) and was not improved by switching to a non–cross-resistant chemotherapy regimen. Although different in design and drugs used, these studies support the idea that some breast cancers are sensitive to cytotoxic chemotherapy whereas others may be intrinsically resistant. Administering the full course of anthracycline and taxane chemotherapy seems appropriate in patients who are responding by physical examination and imaging studies. However, patients who do not respond to the initial chemotherapy should be considered for alternative treatment approaches, if possible as part of a clinical trial.
The primary endpoints in the GeparTrio trial were pathologic complete response for patients who were initially responding to TAC chemotherapy (1) and radiological response as assessed by ultrasound for the nonresponders (2). The role of pathologic complete response as a predictor of disease-free and overall survival has been established in prospective clinical trials (7). However, the assessment of pathologic complete response is not uniform across studies. The NSABP investigators defined pathologic complete response as no evidence of invasive cancer cells in the breast (7), whereas our group (8) and others (9) consider pathologic complete response only when there is no evidence of invasive breast cancer in the breast and the axillary lymph nodes. Because a residual cancer burden has been shown to be predictive of distant relapse–free survival in patients treated with neoadjuvant chemotherapy (10), developing uniform criteria to define a pathologic complete response would help the interpretation of clinical trials testing novel therapeutics in future neoadjuvant trials. The choice of sonographic response before surgery in nonresponders in the GeparTrio trial is problematic because the correlation between ultrasound response and pathologic complete response is low. The sonographic overall response was approximately 50%, whereas the pathologic complete response rate was 5%–6%. Promising data are emerging with functional imaging modalities (eg, positron emission tomography) that may reflect the biological response of the tumor and probably will be more appropriate than anatomical changes detected by ultrasound. Clinical trials should be conducted to validate the predictive role of molecular imaging in breast cancer patients undergoing neoadjuvant chemotherapy.
Traditional cytotoxic agents target general biological processes such as DNA repair and the cell cycle. Better understanding of breast cancer biology has led to a more rational development of drugs targeting growth factor receptors (eg, trastuzumab and lapatinib) and other molecules that play a critical role in cancer cell growth, invasion, and metastasis (11). Another revolutionary aspect of cell biology that is changing the direction of drug development is the interactive communication between tumor and host. A recent example is the improvement in disease-free survival observed in patients with metastatic breast cancer who received monoclonal antibody therapy against vascular endothelial growth factor (12). Perhaps the most dramatic conceptual change in the approach to breast cancer treatment is the realization that breast cancer is a conglomerate of several molecularly defined syndromes, with distinct prognoses, clinical courses, and sensitivity profiles to existing therapeutics. The most common breast cancer type, which expresses estrogen receptor but with a normal component of HER2, should be treated predominantly with endocrine interventions. HER2-amplified tumors, with or without estrogen receptor expression require HER2-directed therapies, whereas those lacking both types of receptor expression are best managed with chemotherapy. Future clinical trials of neoadjuvant systemic therapy should be designed with molecular subsets of breast cancer in mind.
REFERENCES
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8. Gralow JR, Burstein HJ, Wood W, et al. Preoperative therapy in invasive breast cancer: pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol (2008) 26(5):814–819.
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