Over the past 20 years we have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. In addition, the list of cytotoxic chemotherapeutic agents useful in the control of breast cancer has grown considerably. The emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, and the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that disrupt specific cellular targets and pathways. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select patients who could forgo adjuvant chemotherapy. Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. This review will highlight some of the landmark accomplishments during this time, and offer a glimpse at where we might be 20 years from now.
The first observations of hormone-dependency of breast cancer were made over a century ago, when ovarian ablation was observed to cause regression of systemic disease. The past 2 decades have witnessed the emergence of a new generation of aromatase inhibitors as valuable antiestrogens in the management of both advanced and early-stage breast cancer. The role of ovarian function suppression in the adjuvant treatment of premenopausal women with hormone-sensitive breast cancer is only now being prospectively investigated in randomized trials, after Beatson's early observation. Progress in the development of effective nonantiestrogen therapy (eg, cytotoxics and targeted agents) for breast cancer has been indeed much more contemporary. The past 2 decades constitutes about one-half of what most would consider to represent the "chemotherapy era."
The list of cytotoxic chemotherapeutic agents useful in the control and cure of breast cancer is long, and growing (Table 1). A high level of evidence-based medicine supports the use of sequential single-agent chemotherapy for metastatic disease, with judicious use of combination chemotherapy arguably indicated for selected patients. Just as the emergence of anthracyclines was a major chemotherapeutic step forward in the 1980s, the taxanes have clearly been the agents with the greatest impact on breast cancer treatment over the past decade. Dose escalation of cytotoxic chemotherapeutic agents into the realm of myelosuppression requiring autologous bone marrow and peripheral blood stem cell support did not improve survival for patients with either metastatic or early-stage disease[3-5]—this was a lesson learned the hard way. More modest dose escalation of agents such as paclitaxel and docetaxel (Taxotere) has not prolonged time to disease progression.[6,7] More frequent dosing of paclitaxel has proven superior to standard every-3-week dosing, and indeed dose-dense chemotherapy with anthracycline and taxane improves disease-free and overall survival as compared to conventional every-3-week dosing.
The end of the past 2 decades has been characterized by a greater understanding of the molecular biology of breast cancer, rational drug design, and the development of agents that perturb specific, often premeditated cellular targets and pathways. The emergence of trastuzumab (Herceptin)[10-12] and, in the near future, lapatinib (Tykerb),[13,14] agents that improve outcomes for patients with HER2-overexpressing breast cancers, is one obvious example. The benefit observed for the addition of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to weekly paclitaxel in metastatic breast cancer as reported in Eastern Cooperative Oncology Group (ECOG) 2100 represents another. Whether the target is angiogenesis, HER-family signaling, apoptosis, or other pathways, numerous agents in development are likely to emerge from ongoing clinical trials, and optimizing their use in combinations with both cytotoxics and other targeted agents will remain a challenge as we begin to morph beyond the chemotherapy era.
It is well recognized that in the effort to cure early-stage breast cancer, many women will receive adjuvant chemotherapy without deriving benefit. The development of better prognostic and predictive assays that employ a panel of genes involved in the malignant and metastatic phenotype promises to allow clinicians to better select those patients who cold forego adjuvant chemotherapy.[16-19] One such assay, the Oncotype DX 21-gene reverse transcriptase polymerase chain reaction assay is already used in the clinic and is being further studied in a randomized phase III trial.[19,20]
Finally, adjunctive and supportive therapy of breast cancer has evolved substantially over the past 20 years. The use of granulocyte colony-stimulating factor (G-CSF, Neupogen) has ameliorated neutropenic complications of chemotherapy (and facilitated dose-dense chemotherapy), erythropoietin has mitigated against anemia, and bisphosphonates have reduced skeletal complications. Newer generation antiemetics have lessened chemotherapy-induced nausea and vomiting. Ongoing trials are examining pharmacologic means of preventing peripheral neuropathy, mucositis, and cognitive dysfunction.
This review will highlight some of the landmark accomplishments of the past 20 years, and offer a glimpse at where we might be 20 years from now.
Over the past 2 decades, numerous clinical trials have established the benefit of anthracycline-based chemotherapy over non-anthracycline-containing chemotherapy, a finding that has been substantiated by a meta-analysis showing a decline in breast cancer mortality during that time (Figure 1). More recent analysis of outcomes from several of these trials suggests that the differential benefit of anthracycline-containing chemotherapy may be confined to or largely derived in those patients with HER2-overexpressing tumors.[22,23] Current investigation focuses on whether amplification of the topoisomerase II-alpha gene may be a useful aid in predicting for greater anthracycline benefit.
Numerous trials have demonstrated the benefit of the addition of paclitaxel and docetaxel in improving disease-free and overall survival in early breast cancer,[25-28] and these agents have become standard components in the adjuvant and neoadjuvant therapy of early-stage disease. The recently reported ECOG 1199 adjuvant trial showed no significant difference in efficacy between these two taxanes, with less toxicity noted for paclitaxel (Table 2).
A recent report indicates the feasibility of integrating nanoparticle albumin-bound paclitaxel (Abraxane) into dose-dense adjuvant chemotherapy. Ongoing Intergroup studies are comparing paclitaxel to doxorubicin-cyclophosphamide for lower-risk early-stage disease, and weekly to every-2-week paclitaxel. Examination of the potential contribution of agents not currently considered standard in the adjuvant setting, such as gemcitabine (Gemzar) and capecitabine (Xeloda), is also ongoing.
Dr. Seidman is a member of the speakers' bureau and has received honoraria from Abraxis, Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Amgen, Pfizer, Novartis, and Merck. He has also served as a consultant for Pharmion, Sonus, and Cephalon.
1. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet 2:104-107, 162-167, 1896.
2. Seidman A: Sequential single-agent chemotherapy for metastatic breast cancer: Therapeutic nihilism or realism? J Clin Oncol 21(4):577-579, 2003.
3. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 13:1069-1076, 2000.
4. Berry DA, Broadwater G, Klein JP, et al: High-dose versus standard chemotherapy in metastatic breast cancer: Comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 20(3):743-750, 2002.
5. Peters WP, Rosner GL, Vredenburgh JJ, et al: Prospective, randomized comparison of high-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: A report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol 23(10):2191-2200, 2005.
6. Winer EP, Berry DA, Woolf S, et al: Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol 22(11):2061-2068, 2004.
7. Mourisden H, et al: Phase III study of docetaxel 100 versus 75 versus 60 mg/m2 as second line chemotherapy in advanced breast cancer (abstract 327). Breast Cancer Res Treat 76 (suppl 1):S88, 2002.
8. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: Phase III study of weekly paclitaxel via 1-hour infusion vs. standard 3-hour infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2-positive MBC and randomized for T in HER2 normal MBC. J Clin Oncol 22(14S July 15 suppl):512, 2004.
9. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy ads 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(8):1431-1439, 2003.
10. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783-792, 2001.
11. Marty M, Cognetti F, Maraninchi D, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 23(19):4265-4274, 2005.
12. Robert N, Leyland Jones B, Asmar L, et al: Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer.
J Clin Oncol 24(18):2786-2792, 2006.
13. Konecny GE, Pegram MD, Venkatesan N, et al: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 66(3):1630-1639, 2006.
14. Geyer CE, Cameron D, Chan S, et al: A phase III randomized, open-label international study comparing lapatinib and capecitabine vs. capecitabine in women with refractory advanced or metastatic breast cancer (EGF100151) (LBA). J Clin Oncol 24(suppl 18S):2006.
15. Miller KD, Wang M, Gralow J, et al. Randomized phase III trial of paclitaxel vs. paclitaxel plus bevacizumab as first-line treatment for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100) (abstract 3). Proc SABCS 2005.
16. van de Vijver MJ, He YD, van't Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002.
17. van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002.
18. Wang Y, Klijn JGM, Zhang Y, et al: Gene-expression profiles to predict distant metastasis of lymph-node negative primary breast cancer. Lancet 365:671-679, 2005.
19. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol May 23, 2006 (e-pub ahead of print).
20. Sparano J, Hayes D, Dees E, et al: Phase III randomized study of adjuvant combination chemotherapy and hormonal therapy versus adjuvant hormonal therapy alone in women with previously resected axillary node-negative breast cancer with various levels of risk for recurrence. http://www.cancer.gov/clinicaltrials/ECOG-PACCT-1
21. Early Breast Cancer Trialists' Collaborative Group (EBCTG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and survival: An overview of randomized trials. Lancet 365:1687-1717, 2005.
22. Paik S, Bryant J, Tan-Chiu, et al: HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92(24):1991-1998, 2000.
23. Pritchard KI, Shepherd LE, O'Malley FP, et al: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354(20):2177-2179, 2006.
24. Park K, Kim J, Lim S, et al: Topo-isomerase II-alpha and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. Eur J Cancer 39(5):631-634, 2003.
25. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in adjuvant chemotherapy for patients with node-positive primary breast cancer. J Clin Oncol 21(6):976-983, 2003.
26. Martin M, Pienkowski T, Mackey J et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352(22):2302-2313, 2005.
27. Mamounas EP, Bryant J, Lembersky B, et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSAPB B-28. J Clin Oncol 23(16):3686-3696, 2005.
28. Roche H, Fumoleau P, Spielmann M, et al: Five years analysis of the PACS-01 trial: 6 cycles of FEC 100 vs. 3 cycles of FEC 100 followed by 3 cycles of docetaxel for the adjuvant treatment of node positive breast cancer (abstract 24). Proc SABCS 2004.
29. Sparano JA, Wang M, Martino D, et al: Phase III study of doxorubicin and cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node positive or high-risk node negative breast cancer: Results of North American Breast Cancer Intergroup trial E1199 (abstract 48). Proc SABCS 2005.
30. Robert N, Ambro S, Krekow L, et al. Pilot study of dose-dense doxorubicin plus cyclophosphamide followed by ABI-007 in patients with early-stage breast cancer (abstract 2073). Proc SABCS 2005.
31. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673-1684, 2005.
32. Piccart-Gebhart M, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer.
N Engl J Med 353(16):659-672, 2005.
33. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354(8):809-820, 2006.
34. Seidman AD: Is trastuzumab active following conventional adjuvant chemotherapy in HER-2 positive early breast cancer? Natl Clin Pract Oncol 3(4):178-179, 2006.
35. Miller KD, Burstein HJ, Elias AD, et al: Phase II study of SU11248, a multitargeted tyrosine kinase inhibitor in patients with previously treated metastatic breast cancer (abstract 563). J Clin Oncol 23(16S):19s, 2005.
36. Albain K, Barlow W, O'Malley F, et al: Concurrent versus sequential chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for post-menopausal, node-positive, estrogen and/or progesterone receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814) (abstract 37). Breast Cancer Res Treat 2004.
37. Pierce LJ, Hutchins LF, Green SR, et al: Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol 23(1):24-29, 2005.
38. Hughes KS, Schnaper LA, Berry D, et al: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351(10):971-977, 2004.
39. Seidman AD: e-mail survey, March 2005.
40. 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(12):2812-2823, 2002.
41. Sledge GW, Neuberg D, Bernardo P, et al: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An Intergroup trial (E1193). J Clin Oncol 21(4):588-592, 2003.
42. Vogl DT, Stadtmauer EA: High dose chemotherapy and autologous hematopoietic stem cell transplantation for metastatic breast cancer: A therapy whose time has passed. Bone Marrow Transplant 37(11):985-987, 2006.
43. Bezwoda WR, Seymour L, Dansey RD: High dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13(10):2483-2489, 1995.
44. Weiss RB, Rifkin RM, Stewart FM, et al: High-dose chemotherapy for high-risk primary breast cancer: An on-site review of Bezwoda study. Lancet 355(9208):999-1003, 2000.
45. Forbes JF, Kennedy J, Pienkowski T, et al: BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer: Main time to progression analysis (LBA 516). J Clin Oncol 24(suppl 18S): 7s, 2006.
46. Slamon D, Eiermann W, Pienkowski T, et al. Phase III randomized trial of doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 Study (abstract 1). Proc SABCS 2005.
47. Modi S, Stopeck A, Gordon MS, et al: Phase I trial of KOS-953, a heat-shock protein 90 inhibitor, and trastuzumab (abstract 501).
J Clin Oncol 24(18S):3s, 2006.
48. Seidman AD, Hudis CA, Albanell J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16(10):3353-3361, 1998.
49. Press MF, Sauter G, Bernstein L, et al: Diagnostic evaluation of HER2 as a molecular target: An assessment of accuracy and reproducibility of laboratory testing in large, prospective randomized clinical trials. Clin Cancer Res 11(18):6598-6607, 2005.
50. Johnson ML, Seidman AD: Emerging targeted therapies for breast cancer. Oncology 19(5):611-618, 2005.