EDITORIAL Preoperative Chemotherapy for Breast Cancer: Lessons Learned and Future Prospects George W. Sledge, Jr Indiana University School of Medicine, Indianapolis, IN In a previous issue of the Journal of Clinical Oncology, Bear et al1 report the results of National Surgical Adjuvant Breast and Bowel Project Protocol B-27 (NSABP B-27), a large, well-conducted trial that compared preoperative chemotherapy with doxorubicin and cyclophosphamide (AC), with the same regimen followed by four cycles of docetaxel (ACT) in early-stage breast cancer. This important article serves as the basis for asking several questions: What do the results of this trial tell us about preoperative chemotherapy? What does NSABP B-27 tell us about the role of the taxanes in adjuvant therapy for breast cancer? And finally, how do we go forward? The Place of Preoperative Chemotherapy in Early-Stage Breast Cancer Preoperative chemotherapy, also known as primary chemotherapy or neoadjuvant chemotherapy, was initially given to patients with inflammatory and noninflammatory locally advanced breast cancer. To summarize a large and mature literature, preoperative chemotherapy is capable of shrinking large primary tumors, rendering many inoperable patients operable and improving the survival of patients with inflammatory breast cancer. Following these initial studies, investigators began asking whether preoperative chemotherapy might perform additional tasks in patients with operable breast cancer. The first task was pragmatic: Would preoperative chemotherapy, by shrinking large (but operable) breast cancers, allow more patients to undergo breast-preserving surgery? Several nonrandomized trials suggested that this might be the case, and subsequent randomized trials (eg, NSABP B-18 and European Organization for Research and Treatment of Cancer study 10902) proved the case.2,3 A second goal was suggested by preclinical studies: Might the early administration of chemotherapy (earlier, at least, than standard postoperative adjuvant chemotherapy) improve the survival of patients with operable breast cancer? Here, unfortunately, preoperative chemotherapy showed its limits—randomized trials have failed to demonstrate a survival benefit for preoperative treatment as compared with standard adjuvant chemotherapy.2,3 NSABP B-27 should be read in the context of these previous studies. The addition of docetaxel to the preoperative chemotherapy roughly doubled the percentage of patients undergoing a pathologic complete response, and increased the percentage of patients with a clinical complete response from 40.1% to 63.6% (P < .001). It is therefore disappointing that preoperative docetaxel did not increase the rate of breast preservation, which was identical for both groups. Several factors may explain this disparity, including the personal preferences of patients and the innate conservatism of their surgeons, the ready availability of breast reconstructive surgery for many patients, the real difficulties in confirming response preoperatively, and the fact that the overall response rate reported for patients receiving preoperative AC chemotherapy is already quite high (85.5%). It is nevertheless disappointing, as breast preservation is the one truly proven benefit of preoperative chemotherapy. What Is the Role of Taxanes in Early-Stage Breast Cancer? NSABP B-18 conclusively demonstrated that preoperative chemotherapy and standard postoperative adjuvant chemotherapy result in equivalent long-term survival, a finding subsequently confirmed in other randomized trials. In this sense, the article by Bear et al1 should be viewed within the larger context of adjuvant taxane trials for early stage breast cancer. NSABP B-27 is not sufficiently mature regarding either disease-free or overall survival of patients receiving ACT, and therefore cannot be considered to represent a new standard of care. Having said this, the trial does suggest a role for adjuvant taxane use. The pathologic complete response rate (pCR) for patients receiving ACT was 26.1%, compared with the 13.7% rate seen for AC alone (P < .001). As pCR seems to be associated with improved long-term outcome in many trials of preoperative chemotherapy,2,4,5 the addition of docetaxel to AC may ultimately add real, if modest, long-term benefit. Might this increased pCR rate merely reflect additional duration of therapy? Another preoperative chemotherapy trial, performed by a group in Scotland, compared continuing doxorubicin-based chemotherapy alone, with doxorubicin-based chemotherapy followed by docetaxel-based chemotherapy, in patients undergoing an initial complete or partial response. While not strongly statistically powered, the initial results of this trial suggest that switching from an anthracycline-based regimen to a taxane-based regimen improves both the pCR rate and the 3-year survival rate.6 The use of pCR rates in preoperative chemotherapy trials as a study end point has other implications. First, it serves as our ultimate goal for response. Complete disappearance of tumor is a worthy end point for systemic chemotherapy, and one that we still accomplish all too infrequently. Breast pCR is our best current surrogate for elimination of microscopic metastatic disease, as evidenced by long-term survival data. Second, in an era in which adjuvant trials have grown progressively larger, and follow-up is lengthy, the use of pCR rates as surrogate end points might allow investigators to design new trials with greater speed. In this sense, an improved pCR rate for a novel therapy would suggest that such an agent could result in ultimate clinical benefits. Finally, pCR might be used as an end point allowing earlier approval of new agents by the US Food and Drug Administration, compared with classical study end points. The Future of Primary Chemotherapy The increase in pCR rate seen in the docetaxel-containing arm of NSABP B-27 is an encouraging result. However, we do not know to what degree the improved pCR rate brought about by the addition of docetaxel will translate into an improvement in overall survival. But we do know that this systemic chemotherapy still fails to induce a pCR in three-fourths of treated patients. This suggests that we have a long way to go, therapeutically. What are reasonable future directions for primary therapy trials? Some directions will necessarily involve chemotherapeutic approaches. The recent presentation of C9741, an intergroup trial testing the dose-density hypothesis, suggests that the use of granulocyte-colony-stimulating factor to narrow the interval between treatments may result in improved relapse-free and overall survival in the adjuvant setting.7 This approach certainly might be used in a primary chemotherapy setting, shortening the time before definitive surgery and perhaps increasing operability. Pilot dose-dense trials have been performed in the preoperative setting.7 Another approach would be to utilize docetaxel as a platform on to which other chemotherapeutic agents might be added. The obvious agent to consider in this context is capecitabine. In the setting of metastatic disease, the addition of capecitabine to docetaxel has been shown to improve overall survival9; it is reasonable to expect that its addition in the adjuvant setting might improve the cure rate of patients with early disease. There is a certain poignancy to this approach. In the United States during the 1990s, fluorouracil was widely dropped from adjuvant regimens in cooperative group trials, based on convenience factors rather any data suggesting inactivity in the adjuvant setting. Now we may see the return of the fluoropyrimidines in another guise. The primary chemotherapy setting also offers nonchemotherapeutic possibilities. Preoperative trastuzumab–based regimens (in combination with chemotherapy) have already been piloted in the primary chemotherapy setting in patients with HER-2 positive disease,10 and are certainly worthy of consideration for confirmatory randomized trials. And while the vast majority of the preoperative therapy literature has examined the use of systemic chemotherapy, more recent trials have suggested a place for preoperative hormonal therapy for estrogen receptor–positive breast cancer.11 While we have no direct comparisons of preoperative hormonal therapy to preoperative chemotherapy, data from the adjuvant setting certainly suggests that this would be a reasonable approach for some patients. Finally, the preoperative therapy setting offers us some useful possibilities with regard to therapeutic targeting and treatment individualization. The preoperative setting represents a potentially useful clinical laboratory for exploring surrogate markers of response. When one can obtain tissue before therapy, treat a patient, and then obtain residual tissue at the time of definitive surgery, the possibility exists for analysis of this tissue to evaluate molecular markers of response and resistance. As in every other aspect of oncology, novel technologies such as cDNA microarrays ("gene chips") have the potential to revolutionize our understanding of response and resistance. A cDNA microarray analysis of tumor samples obtained before primary chemotherapy has recently been presented,12 and suggests that this technology may soon be able to predict who will benefit from such therapy. NSABP B-27 has several important correlative trials that will be reported in coming years. There is no doubt that this important trial will continue to teach us new lessons about the biology and treatment of breast cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: George W. Sledge, Aventis. REFERENCES 1. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165–4174, 2003[Abstract/Free Full Text] 2. van der Hage J, van de Velde C, Julien J-P, et al: Preoperative chemotherapy in primary breast cancer: Results from the European Organization for Research and Treatment of Cancer Trial 10902. J Clin Oncol 19:4224–4237, 2001[Abstract/Free Full Text] 3. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672–2685, 1998[Abstract] 4. Fisher E, Wang JQ, Bryant J, et al: Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95:681–695, 2002[CrossRef][Medline] 5. Chollet P, Amat S, Cure H, et al: Prognostic significance of a complete pathological response after induction chemotherapy in operable breast cancer. Br J Cancer 86:1041–1046, 2002[CrossRef][Medline] 6. Heys S: Neoadjuvant docetaxel in breast cancer: 3-year survival results from the Aberdeen trial. Clin Breast Cancer 3:69–74, 2002 (suppl 2) 7. Citron M, Berry D, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431–1439, 2003[Abstract/Free Full Text] 8. Miller K, McCaskill-Stevens W, Sisk J, et al: Combination versus sequential doxorubicin and taxotere as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol 17:3033–3037, 1999[Abstract/Free Full Text] 9. O’Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812–2823, 2002[Abstract/Free Full Text] 10. Burstein H, Harris L, Kaelin C, et al: Preoperative Herceptin and paclitaxel for HER-2 overexpressing stage I/II breast cancer. Proc Am Soc Clin Oncol 20:26, 2001 (abstr 100) 11. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808–3816, 2001[Abstract/Free Full Text] 12. Ayers M, Symmans W, Stec J, et al: Gene expression profiling of fine needle aspirates of breast cancer identifies genes associated with complete pathologic response to neoadjuvant taxol/FAC chemotherapy. Breast Cancer Res Treat 76:64, 2002 Journal of Clinical Oncology, Vol 21, Issue 24 (December), 2003: 4481-4482 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.