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Originally published as JCO Early Release 10.1200/JCO.2006.09.9796 on April 2 2007 © 2007 American Society of Clinical Oncology.
Adjuvant Chemotherapy for High-Risk Operable Breast Cancer
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX In this issue of the Journal of Clinical Oncology, results are reported from the Southwest Oncology Group (SWOG)/Intergroup phase III randomized study of dose-dense chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide compared with four cycles of high-dose chemotherapy (HDCT) with doxorubicin and cyclophosphamide and autologous hematopoietic progenitor cell support.1 All 536 patients treated in this study had four or more involved axillary lymph nodes. The authors found no evidence that high-dose chemotherapy with autologous stem-cell support was superior to dose-dense chemotherapy. In fact, HDCT was associated with a higher rate of toxic effects and with an insignificant inferior outcome. The past three decades of research into using adjuvant therapies to improve the outcome of patients with high-risk breast cancer has resulted in several approaches that have significantly altered the natural history of the disease and improved our understanding of the biology of breast cancer.2,3 Breast cancer comprises a group of biologically different diseases, and our knowledge and understanding of these subsets of disease are evolving. To provide our patients with optimal clinical management, we need to be familiar with some of the distinct subsets of breast cancer and different therapeutic approaches. A high proportion of breast cancers are invasive ductal carcinomas, with or without steroid hormone receptors or HER2 overexpression. For the small number of patients with squamous, myoepithelial, or spindle cell histologies, the disease does not express hormone or HER2 receptors and it also does not respond to current adjuvant therapies. Current adjuvant therapy options for patients with hormone-receptor–positive disease include ovarian ablation, ovarian suppression, or antiestrogens for premenopausal patients and antiestrogens3 or aromatase inhibitors for postmenopausal patients.3,4 For patients with hormone-receptor–negative disease, endocrine therapies have no favorable impact on the risk of recurrence or the risk of a second primary breast cancer.2 Adjuvant Chemotherapy in Breast Cancer Because single-agent chemotherapeutic drugs have resulted in no benefit or only modest benefits as adjuvant therapies, combination chemotherapy regimens have been established as standard care.5 Studies comparing anthracycline-containing combinations with nonanthracycline combinations have shown that the inclusion of an anthracycline reduces the risk of recurrence and also has a favorable impact on survival.2 However, not all anthracycline-containing regimens are superior; the combination of doxorubicin (or epirubicin) and cyclophosphamide administered over four cycles seems at best equivalent to six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF).6 Three-drug anthracycline combinations that include fluorouracil administered for six or more cycles have been shown to be clearly superior to CMF, as have sequential regimens of an anthracycline followed by CMF.7 At present, it is not feasible to identify the subset of patients who would most benefit from anthracycline-containing combinations, although amplification of the topoisomerase II gene is of particular interest because it is the target of anthracyclines.8 Taxanes—such as paclitaxel and docetaxel—with significant antitumoral activity in metastatic disease have been evaluated in the adjuvant setting, and their inclusion can further modify the natural history of the disease by reducing the risk of recurrence and death.9,10 Some clinical trials have assessed the sequential contribution of taxanes to adjuvant chemotherapy, using four cycles of doxorubicin plus cyclophosphamide (AC) as the control arm; these results suggest that taxanes improve on the results obtained with AC or CMF alone. Trial designs that used more effective control regimens (fluorouracil, doxorubicin, and cyclophosphamide or doxorubicin followed by CMF) provide even more compelling data that support the inclusion of taxanes in the adjuvant setting. The recent presentation of the early results of the National Cancer Institute of Canada Clinical Trial Group MA21 study confirm long-held suspicions about the differences in the efficacy of various anthracycline-containing regimens.11 In this study, six cycles of fluorouracil, epirubicin, and cyclophsphamide were clearly superior to standard AC followed by paclitaxel, and were equivalent to a dose-dense regimen of epirubicin plus cyclophosphamide followed by paclitaxel. These data suggest that standard AC followed by paclitaxel may not be an appropriate standard of care. Data from clinical trials have illustrated that the benefit of taxane-based chemotherapy is independent of the hormone-receptor status of the tumor. However, the reductions in risk of recurrence and death have been more striking in patients with hormone receptor–negative disease.12 At present, it is not feasible to define a subset of patients with hormone receptor–positive disease who would not achieve additional benefit from adjuvant chemotherapy. In the near future, however, we may be able to define this subset of patients using a molecular profile of tumors that takes into account other novel prognostic markers. Optimal Dose and Schedule of Chemotherapy Studies evaluating escalated doses of anthracycline or cyclophosphamide compared with conventional doses have shown no additional benefit from dose escalation,9,13 although there are minimal threshold doses below which the benefit is significantly reduced. High-dose chemotherapy with hematopoietic stem-cell support has been evaluated in a number of randomized trials.14-17 The data from the HDCT arm of the SWOG/Intergroup 9623 study1 are consistent with the results of most other randomized trials, which have failed to demonstrate the superiority of high-dose chemotherapy. In a number of trials, patients treated with high-dose chemotherapy have had insignificantly inferior outcomes compared with those in the standard treatment arms. Despite improved supportive care, a small fraction of patients die from toxicity during high-dose therapies. A few prospective studies of high-dose chemotherapy with autologous hematopoietic progenitor cell support have reported improved outcomes.15,18 These studies included predominantly younger patients, a larger-than-usual proportion of whom had hormone-receptor–positive disease. It is possible that the benefits observed in these trials may be related to premature ovarian failure caused by the intensive chemotherapy in a higher proportion of patients; thus, the resulting benefit might be a function of the endocrine mechanism rather than the cytotoxic effect of high-dose chemotherapy. Nevertheless, the encouraging positive results of these trials may lead to additional studies. To date, studies have failed to consistently identify a subset of patients who might benefit from high-dose chemotherapy. Therefore, one cannot recommend high-dose chemotherapy for any subset of breast cancer patients outside the context of a well-designed clinical trial addressing a novel question. In the dose-dense arm of the SWOG/Intergroup 9623 study, the doses of drugs were also unconventional,1 and these higher doses of anthracyclines and cyclophosphamide have been previously shown to offer no additional benefit over standard doses.9,13 Experimental mathematical models have suggested that dose-dense therapy may result in a better outcome, and one study done by the Cancer and Leukemia Group B (CALGB) 9741 has shown superiority of this approach over the conventional schedule.19 However, several other studies have not shown similar findings. Several studies have not demonstrated any superiority of this approach,19,20 and some trials have reported additional toxicities which were not observed with conventional doses of these drugs. For example, there has been an increased risk of hand-foot syndrome with dose-dense anthracycline and docetaxel combinations.21 In a phase II study of dose-dense FEC followed by alternating weekly taxanes, novel toxicities (pericardial or pleural effusions and pneumonitis) were seen.22 In CALGB 9741, chemotherapy drugs administered as single agents sequentially in a dose-dense manner resulted in an outcome similar to that of the same agents administered concomitantly.23 In that study, paclitaxel was administered at the dose of 175 mg/m2. Subsequent trials have established that paclitaxel has schedule-dependent efficacy. Its antitumor activity is significantly enhanced with weekly administration compared with a once-every-3-weeks schedule, and it can be administered on a weekly schedule without growth factor support. Paclitaxel given on a weekly schedule in the neoadjuvant setting resulted in a higher complete pathologic response rate,24 a high overall response rate, and longer control of metastatic disease.25 It is possible that the benefit of dose-dense therapy in CALGB 9741 may have been due to the altered schedule of paclitaxel. Biologics in Adjuvant Therapy In previous decades, several biologic therapies were evaluated as adjuvant therapy, including Bacillus Calmette-Guérin, interferon, and levamisole.26-28 The data of these trials illustrated no benefit from the inclusion of these nonspecific biologics in the treatment of patients with high-risk disease. The identification of HER2-overexpressing breast cancer as a separate subset of disease with a high risk of recurrence and death has brought a better understanding of this disease. Subsequent development of an antibody against HER2 (trastuzumab) has substantially improved the prognosis of patients with this disease.29 Inclusion of trastuzumab in the treatment of metastatic disease has resulted in objective responses in a high proportion of patients, with longer time to disease progression and longer survival. The initial data in the adjuvant setting regarding trastuzumab illustrate a significant reduction in the risk of recurrence and improved survival. This drug has become an important component of effective therapy for patients with HER2-positive disease. The optimal schedule (concurrently v sequentially with chemotherapy) and duration of therapy remain to be further defined. Retrospective data from one study suggest that patients with tumors that overexpressed the cMYC gene had the greatest benefit from trastuzumab therapy, although cMYC nonoverexpressing tumors that were treated with trastuzumab also benefited from this therapy.30 Initial data from another study suggested that patients with tumors that had coamplification of HER2 and topoisomerase II, at a median follow-up of 23 months, achieved greater benefit from trastuzumab- and anthracycline-containing therapies.31 With additional follow-up of the same trial (median follow-up of 36 months), the estimated 3-year disease-free survival rate was 89% for patients treated with trastuzumab and anthracycline-containing therapy, and 87% for patients treated with anthracycline-containing therapy without trastuzumab and for patients treated with nonanthracycline-containing therapy with trastuzumab.32 These results need further confirmation in other trials of trastuzumab. Current Status of Adjuvant Therapy So what is the current optimal adjuvant chemotherapy regimen? It could be stated that anthracycline-based therapies are superior to nonanthracycline-based therapy. Inclusion of taxanes can further reduce the risk of recurrence, independent of the hormone-receptor status of the tumor. Dose-dense therapies have shown a benefit in patients with hormone-receptor–negative disease in some studies. But, several other studies showed no such benefit, and additional studies are needed to define the value of dose-dense chemotherapy, which can be associated with significant toxicities and additional costs. High-dose chemotherapy in early-stage breast cancer is not an established therapy. Despite the current data, although there may be a benefit in a subset of patients, this has yet to be identified. Dose-dense chemotherapy drugs scheduled as evaluated in the SWOG/Intergroup 9623 protocol cannot be recommended for clinical use; however, the doses and schedule of these same drugs (doxorubicin, cyclophosphamide, and paclitaxel) as evaluated in the CALGB 9741 study may be appropriate, although the benefits of these regimens over the conventional every-3-week schedule may be due to the schedule of administration of paclitaxel. Endocrine therapies can substantially reduce the risk of recurrence and death in patients with hormone-receptor–positive disease. In patients with high-risk HER2-positive disease, inclusion of trastuzumab can result in a lower risk of recurrence and improved survival. Progress in pharmacogenomics provides us with tools to determine which subgroup of patients might benefit from which combinations of drugs. We need to assess prospectively which patients benefit from the inclusion of an anthracycline or a taxane in their treatment regimen. Prospective studies should also explore which patients benefit from dose-dense administration of chemotherapy and whether such scheduling is applicable to all drugs used in the adjuvant treatment of breast cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Aman U. Buzdar, AstraZeneca, Genentech, Pfizer Research Funds: Aman U. Buzdar, AstraZeneca, Genentech, Pfizer, Tiaho Testimony: N/A Other: N/A NOTES published online ahead of print at www.jco.org on April 2, 2007. REFERENCES 1. Moore HCF, Green SJ, Gralow J, et al: Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup Study 9623. J Clin Oncol 25:1677-1682, 2007 2. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 3. The Breast International Group (BIG) 1-98 Collaborative Group: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 4. ATAC Trialists' Group: Results of the ATAC (Arimidex, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 356:60-62, 2006 5. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339:1-15, 1992[Medline] 6. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990[Abstract] 7. Gianni L, Baselga J, Eiermann W, et al: European Cooperative Trial in Operable Breast Cancer (ECTO): Improved freedom from progression (FFP) from adding paclitaxel (T) to doxorubicin (A) followed by cyclophosphamide methotrexate and fluorouracil (CMF). J Clin Oncol 23:7S, 2005 (suppl; abstr 513) 8. Buzdar AJ: Topoisomerase II alpha gene amplification and response to anthracycline-containing adjuvant chemotherapy in breast cancer. J Clin Oncol 24:2409-2411, 2006 9. 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 21:976-983, 2003 10. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005 11. Burnell M, Levine MN, Chapman JA, et al: A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA. 21: Results of an interim analysis. Presented at the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-16, 2006 (abstr 53) 12. Berry DA: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:2356-2367, 2006 13. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374-3388, 1999 14. Antman KH, Rowlings PA, Vaughan WP, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 15:1870-1879, 1997 15. Rodenhuis S, Bontenbal M, Beex LVAM, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 349:7-16, 2003 16. Roche H, Viens P, Biron P, et al: High-dose chemotherapy for breast cancer: The French PEGASE Experience. Cancer Control 10:42-47, 2006 17. Zander AR, Kroger N, Schmoor C, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: First results of a randomized trial. J Clin Oncol 22:2273-2283, 2004 18. Nitz UA, Mohrmann S, Fischer J, et al: Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: Results of a multicentre phase III trial. Lancet 366:1935-1944, 2005[CrossRef][Medline] 19. Venturini M, Del Mastro L, Aitini E, et al: Dose-dense adjuvant chemotherapy in early breast cancer patients: Results from a randomized trial. J Natl Cancer Inst 97:1724-1733, 2005 20. Fountzilas G, Skarlos D, Dafni U, et al: Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: A randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 16:1762-1771, 2005 21. Bardia A, Loprinzi CL, Goetz MP: Hand-foot syndrome after dose-dense adjuvant chemotherapy for breast cancer: A case series. J Clin Oncol 24:e18-e19, 2006 (e-correspondence) 22. Dang CT, D'Andrea GM, Moynahan ME, et al: Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer. Clin Cancer Res 10:5754-5761, 2004 23. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent 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 24. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983-5992, 2005 25. Seidman AD, Hudis CA, Raptis G, et al: Paclitaxel for breast cancer: The Memorial Sloan-Kettering Cancer Center experience. Oncology 11:20-28, 1997 (suppl 2)[CrossRef][Medline] 26. Buzdar AU, Blumenschein GR, Smith TL, et al: Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast-cancer: A prospective randomized trial. Cancer 53:384-389, 1984[CrossRef][Medline] 27. Buzdar AU, Hortobagyi GN, Kau SW, et al: Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer. J Clin Oncol 10:1540-1546, 1992 28. Kay RG, Mason BH, Stephens EJ, et al: Levamisole in primary breast-cancer: A controlled-study in conjunction with L-phenylalanine mustard. Cancer 51:1992-1997, 1983[CrossRef][Medline] 29. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 30. Kim C, Bryant J, Horne Z, et al: Trastuzumab sensitivity of breast cancer with co-amplification of HER2 and cMYC suggests pro-apoptotic function of dysregulated cMYC in vivo. Breast Cancer Res Treat 94:S6-S7, 2005 (suppl 1) 31. Slamon D, Eiermann W, Robert N, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 94:S5, 2005 (suppl 1) 32. Slamon D, Eiermann W, Robert N, et al: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC
