Metastatic breast cancer is a devastating
problem, with only a small percentage of patients surviving 5 years
or longer. In 1999, about 45,000 women died of metastatic breast
cancera mortality statistic that has not changed appreciably in
decades. The median survival after the detection of distant
metastases is about 3 years for all patients and about 2 years for
patients whose disease is endocrine refractory. Thus, metastatic
breast cancer remains an essentially incurable disease.
Until recently, little progress had been made in treatment. However,
the development of newer endocrine, chemotherapeutic, and, most
recently, biological agents, may lead to modest but definite
improvements in these grim statistics. Except for clinical trials
that use high-dose therapies, palliation remains the major goal of therapy.
Nevertheless, several highly debated, controversial treatment-related
issues remain. These include: (1) whether initial treatment should
consist of endocrine therapy or chemotherapy; (2) whether combination
chemotherapy (polychemotherapy) is superior to
single-agent chemotherapy; (3) the optimal sequence of administration
of chemotherapeutic agents and regimens; (4) whether dose
intensification is superior to standard-dose treatment; and (5) what
constitutes the optimal duration of treatment.
The most important therapeutic issue is whether treatment is being
initiated with curative or palliative intent. Despite the aggressive
trimodality efforts of medical oncology, radiation oncology, and
surgical oncology, almost all patients with metastatic breast cancer
eventually succumb to the disease. Physicians and patients should
discuss and clarify the intent of treatment and decide how they wish
to navigate the delicate balance among relief of symptoms,
prolongation of survival, and toxicity.
An awareness of the natural history of untreated breast cancer is
also important. In a series of 250 patients with breast cancer who
opted for no treatment at diagnosis, median survival was 2.7 years,
and 10% of patients lived 10 years or longer. These data indicate
that, in a small percentage of patients, breast cancer may behave as
a chronic disease, even without treatment.
Prolonged remissions have been well documented in patients treated
with endocrine therapy. In one study of 156 patients treated with
tamoxifen (Nolvadex) for estrogen receptorpositive metastatic
breast cancer, 15% were alive and 7.6% were progression free after 5 years.
The potential for cure using state-of-the-art
polychemotherapy is well illustrated by a review of 1,581 patients
with metastatic breast cancer treated between 1973 and 1982 with a
doxorubicin-containing induction regimen followed by
cyclophosphamide, methotrexate, and fluorouracil (CMF) maintenance
therapy. Complete responses occurred in 16.6% of patients, but
only 3.1% remained in complete remission for more than 5 years. With
a median follow-up of 16 years, only 1.6% (26 of the 1,581 initial
patients) were still alive and disease free. Favorable
characteristics of these remarkable long-term survivors included
younger age, premenopausal status, good performance status, and a low
tumor burden at the time of treatment. These sobering statistics are
characteristic of the results of current chemotherapeutic regimens
used in the metastatic setting.
Is it better to initiate treatment with endocrine therapy or
chemotherapy? Two randomized trials have addressed this question. In
the first trial, 339 postmenopausal women with metastatic breast
cancer, 75% of whom had unknown hormone receptor status, were
randomized to receive tamoxifen alone, tamoxifen and concurrent
cyclophosphamide and Adriamycin (CA), or CA alone. Although the
response rates ranged from 51% in patients treated with tamoxifen
plus CA to 22% in those given tamoxifen alone, overall survival rates
were virtually identical among the three groups. Of the tamoxifen
treated patients, 35% responded to CA as a second-line therapy. In
no subgroup was initial chemotherapy associated with superior
survival when compared with endocrine therapy.
A similar trial compared initial therapy with CMF vs tamoxifen in
patients 65 years of age and older. Complete and partial response
rates were 45% for patients treated with tamoxifen and 38% for those
given CMF, with median response durations of 10.4 and 7.9 months,
respectively. Overall survival data favored tamoxifen as initial
therapy, even in estrogen receptornegative patients.
Currently, most patients with receptor-positive invasive breast
cancer receive systemic therapy with tamoxifen at the time of initial
diagnosis, and it is uncertain as to whether such patients may do as
well with initial endocrine therapy in the metastatic setting. In our
view, patients who relapse within 1 to 2 years after the initiation
of adjuvant tamoxifen or oophorectomy are more likely to benefit from
chemotherapy than from further endocrine therapy, but this decision
is unlikely to have any major effect on survival. In all other
patients, with the exception of patients with rapidly progressive
visceral metastatic disease, initial treatment in the metastatic
setting should consist of endocrine therapy.
In patients who are receptor positive and seriously ill, chemotherapy
combined with endocrine therapy is a reasonable option so as to
maximize the patients chance for a rapid response. Numerous
trials comparing concurrent chemotherapy and endocrine therapy with
chemotherapy alone have failed to show a survival benefit for
Endocrine therapies should be continued indefinitely in patients with
stable disease and until disease progression in responding patients.
Individuals who have displayed stable disease for 4 to 6 months or
longer should be observed for a withdrawal response at the time of
disease progression and prior to initiation of further therapies.
Agents that should be considered for hormonal therapy are described below.
Selective Estrogen Receptor Modulators
There is major interest in the development of new selective estrogen
receptor modulators (SERMs). Tamoxifen, the first SERM widely
available for the treatment of breast cancer, has demonstrated
efficacy in both the metastatic and adjuvant settings and has served
as the prototype for the development of newer SERMs.
The search for the ideal SERM continues. This agent should have
estrogen antagonistic effects on breast and endometrial tissues (less
breast and endometrial cancer), estrogen agonistic effects on the
hypothalamus (cessation or decrease in vasomotor symptoms), skeleton
(maintenance of bone density), and liver (lowering of cholesterol),
and no effect on the coagulation system. To date, no agent has met
all of these goals.
Toremifene (Fareston) is currently available for the treatment of
metastatic breast cancer and appears to have less estrogen agonistic
effects on the endometrium compared with tamoxifen. In the metastatic
setting, toremifene offers no advantages over tamoxifen.
Raloxifene (Evista) has been approved by the Food and Drug
Administration (FDA) for the treatment of osteoporosis in
postmenopausal women and may decrease the risk of breast cancer.
Although raloxifene has shown activity in patients with metastatic
breast cancer, no trials have directly compared it with tamoxifen or
other hormonal agents. As a result, raloxifene should not be used in
patients with metastatic breast cancer outside of a clinical trial.
Other SERMs, including droloxifene and idoxifene, are
unlikely to be associated with a better therapeutic index than
available agents. Newer SERMs with potentially superior therapeutic
indices are currently in clinical trials.
1. Bloom HJG, Richardson WW, Harries EJ: Natural history of untreated
breast cancer (1805-1933): Comparison of untreated and treated cases
according to histological grade of malignancy. Br Med J 2:213-221, 1962.
2. Kuss JT, Muss HB, Hoen H, et al: Tamoxifen as initial endocrine
therapy for metastatic breast cancer: Long-term follow-up of two
Piedmont Oncology Association (POA) trials. Breast Cancer Res Treat
3. Greenberg PA, Hortobagyi GN, Smith TL, et al: Long-term follow-up
of patients with complete remission following combination
chemotherapy for metastatic breast cancer. J Clin Oncol 14:2197-2205, 1996.
4. The Australian and New Zealand Breast Cancer Trials Group,
Clinical Oncological Society of Australia: A randomized trial in
postmenopausal patients with advanced breast cancer comparing
endocrine and cytotoxic therapy given sequentially or in combination.
J Clin Oncol 4:186-193, 1986.
5. Taylor SG, Gelman RS, Falkson G, et al: Combination chemotherapy
compared to tamoxifen as initial therapy for stage IV breast cancer
in elderly women. Ann Intern Med 104:455-461, 1986.
6. Ellis MJ, Hayes DF, Lippman ME: Treatment of metastatic breast
cancer, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of
the Breast, 2nd ed, pp. 749-797. Philadelphia, Lippincott, Williams
and Wilkins, 1999.
7. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J
Med 339:1609-1618, 1998.
8. Hayes DF, van Zyl JA, Hacking A, et al: Randomized comparison of
tamoxifen and two separate doses of toremifene in postmenopausal
patients with metastatic breast cancer. J Clin Oncol 13:2556-2566, 1995.
9. Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene
on risk of breast cancer in postmenopausal women: Results from the
MORE randomized trial: Multiple Outcomes of Raloxifene Evaluation.
JAMA 281:2189-2197, 1999.
10. Rauschning W, Pritchard KI: Droloxifene, a new antiestrogen: Its
role in metastatic breast cancer. Breast Cancer Res Treat 31:83-94, 1994.
11. Coombes RC, Haynes BP, Dowsett M, et al: Idoxifene: Report of a
phase I study in patients with metastatic breast cancer. Cancer Res
12. Howell A, DeFriend D, Robertson J, et al: Response to a specific
antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer.
Lancet 345:29-30, 1995.
13. Kimmick GG, Muss HB: Endocrine therapy in metastatic breast
cancer. Cancer Treat Res 94:231-254, 1998.
14. Boccardo F, Rubagotti A, Perrotta A, et al: Ovarian ablation vs
goserelin with or without tamoxifen in preperimenopausal patients
with advanced breast cancer: Results of a multicentric Italian study.
Ann Oncol 5:337-342, 1994.
15. Klijn JG, Seynaeve C, Beex L, et al: Combined treatment with
buserelin (LHRH-A) and tamoxifen (TAM) vs single treatment with each
drug alone in premenopausal metastatic breast cancer: Preliminary
results of EORTC study 10881 (abstract). Proc Am Soc Clin Oncol
16. Jonat W, Kaufmann M, Blamey RW, et al: A randomized study to
compare the effect of the luteinizing hormone-releasing hormone
(LHRH) analogue goserelin with or without tamoxifen in pre- and
perimenopausal patients with advanced breast cancer. Eur J Cancer
17. Buzdar AU, Plourde PV, Hortobagyi GN: Aromatase inhibitors in
metastatic breast cancer. Semin Oncol 23:28-32, 1996.
18. Buzdar AU, Jonat W, Howell A, et al: Anastrozole vs megestrol
acetate in the treatment of postmenopausal women with advanced breast
carcinoma: Results of a survival update based on a combined analysis
of data from two mature phase III trials: Arimidex Study Group.
Cancer 83(6):1142-1152, 1998.
19. Dombernowsky P, Smith I, Falkson G, et al: Letrozole, a new oral
aromatase inhibitor for advanced breast cancer: Double-blind
randomized trial showing a dose effect and improved efficacy and
tolerability compared with megestrol acetate. J Clin Oncol
20. Kaufman M, Bajetta E, Dirix LY et al: Survival advantage of
exemestane [Aromasin] over megestrol acetate in postmenopausal women
with advanced breast cancer refractory to tamoxifen: Results of a
phase II randomized double-blind study (abstract). Proc Am Soc Clin
Oncol 18:109a, 1999.
21. Fossati R, Confalonieri C, Torri V, et al: Cytotoxic and hormonal
treatment for metastatic breast cancer: A systematic review of
published randomized trials involving 31,510 women. J Clin Oncol
22. Joensuu H, Holli K, Heikkinen M, et al: Combination chemotherapy
vs single-agent therapy as first- and second-line treatment in
metastatic breast cancer: A prospective randomized trial. J Clin
Oncol 16:3720-3730, 1998.
23. Gianni L: Paclitaxel plus doxorubicin in metastatic breast
cancer: The Milan experience. Oncology 12:13-15, 1998.
24. Sledge GW: First-line chemotherapy for advanced breast cancer.
Cancer Control 6(suppl 5):17-21, 1999.
25. Bishop JF, Dewar J, Toner GC, et al: Initial paclitaxel improves
outcome compared with CMFP combination chemotherapy as front-line
therapy in untreated metastatic breast cancer. J Clin Oncol
26. Smith GA: Current status of vinorelbine for breast cancer.
Oncology 9:767-773, 1995.
27. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with
dexrazoxane for doxorubicin-containing therapy in advanced breast
cancer. J Clin Oncol 15:1318-1332, 1997.
28. Ranson MR, Carmichael J, OByrne K, et al: Treatment of
advanced breast cancer with sterically stabilized liposomal
doxorubicin: Results of a multicenter phase II trial. J Clin Oncol
29. Batist G, Rao SC, Ramakrishnan G, et al: Phase III study of
liposome-encapsulated doxorubicin (TLC D-99) vs doxorubicin (DOX) in
combination with cyclophosphamide (CPA) in patients with metastatic
breast cancer (abstract). Proc Am Soc Clin Oncol 18:127a, 1999.
30. Seidman AD: Single-agent paclitaxel in the treatment of breast
cancer: Phase I and II development. Semin Oncol 26:14-20, 1999.
31. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of
Taxol, an active drug in the treatment of metastatic breast cancer. J
Natl Cancer Inst 83:1797-1805, 1991.
32. Miller KD, Sledge GW: Taxanes in the treatment of breast cancer:
A prodigy comes of age. Cancer Invest 17:121-136, 1999.
33. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with
weekly 1-hour paclitaxel infusions in the treatment of metastatic
breast cancer. J Clin Oncol 16:3353-3361, 1998.
34. Trudeau ME: Phase I-II studies of docetaxel as a single agent in
the treatment of metastatic breast cancer. Semin Oncol 26:21-26, 1999.
35. Ravdin PM: The international experience with docetaxel in the
treatment of breast cancer. Oncology 11:38-42, 1997.
36. Valero V, Jones SE, Von Hoff DD, et al: A phase II study of
docetaxel in patients with paclitaxel-resistant metastatic breast
cancer. J Clin Oncol 16:3362-3368, 1998.
37. Burstein HJ, Younger J, Bunnell CA et al: Weekly docetaxel
(Taxotere) for metastatic breast cancer: A phase II trial (abstract).
Proc Am Soc Clin Oncol 18:127a, 1999.
38. Loffler TM, Freund W, Droge C, et al: Activity of weekly taxotere
in patients with metastatic breast cancer. Proc Am Soc Clin Oncol
39. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial
of docetaxel vs doxorubicin in patients with metastatic breast
cancer. J Clin Oncol 17:2341-2354, 1999.
40. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized
trial of docetaxel vs mitomycin plus vinblastine in patients with
metastatic breast cancer progressing despite previous
anthracycline-containing chemotherapy. J Clin Oncol 17:1413-1424, 1999.
41. Nabholtz JM, Smylie M, Mackey J, et al: Docetaxel and
anthracycline polychemotherapy in the treatment of breast cancer.
Semin Oncol 26:47-52, 1999.
42. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensive
vinorelbine with concurrent granulocyte colony-stimulating factor
support in paclitaxel-refractory metastatic breast cancer. J Clin
Oncol 15:1395-1400, 1997.
43. Spielmann M, Dorval T, Turpin F, et al: Phase II trial of
vinorelbine/doxorubicin as first-line therapy of advanced breast
cancer. J Clin Oncol 12:1764-1770, 1994.
44. Carmichael J, Possinger K, Phillip P, et al: Advanced breast
cancer: A phase II trial with gemcitabine. J Clin Oncol 13:2731-2736, 1995.
45. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study
of capecitabine in paclitaxel-refractory metastatic breast cancer. J
Clin Oncol 17:485-493, 1999.
46. OShaughnessy J, Moiseyenko V, Bell D et al: A randomized
phase II study of Xeloda (capecitabine) vs CMF as first-line
chemotherapy of breast cancer in women aged ³
55 years (abstract). Proc Am Soc Clin Oncol 17: 398a, 1998.
47. OReilly SM, Moiseyenko V, Talbot DC, et al: A randomized
phase II study of Xeloda (capecitabine) vs paclitaxel in breast
cancer patients failing previous anthracycline therapy (abstract).
Proc Am Soc Clin Oncol 17: 627a, 1998.
48. Bunnell CA, Winer EP: Oral 5-FU analogues in the treatment of
breast cancer. Oncology 12(10;suppl 7):39-43, 1998.
49. Hryniuk W, Bush H: The importance of dose intensity in
chemotherapy of metastatic breast cancer. J Clin Oncol 11:1281-1288, 1984.
50. Savarese DM, Hsieh C, Stewart FM: Clinical impact of chemotherapy
dose escalation in patients with hematologic malignancies and solid
tumors. J Clin Oncol 15:2981-2995, 1997.
51. Lotz JP, Cure H, Janvier M, et al: High-dose chemotherapy (HD-CT)
with hematopoietic stem cells transplantation (HSCT) for metastatic
breast cancer: Results of the French protocol PEGASE 04 (abstract).
Proc Am Soc Clin Oncol 18:43a, 1999.
52. Vahdat L, Antman K: High-dose chemotherapy for breast cancer.
Clin Oncol Updates 2:1-15, 1999.
53. Peter WP, Jones RB, Vredenburgh J, et al: A large, prospective,
randomized trial of high-dose combination alkylating agents with
autologous cellular support (ABMS) as consolidation for patients with
metastatic breast cancer achieving complete remission after intensive
doxorubicin-based induction therapy (AFM) (abstract). Proc Am Soc
Clin Oncol 15:121, 1996.
54. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with
hematopoietic rescue as primary treatment for metastatic breast
cancer: A randomized trial (abstract). J Clin Oncol 13:2483-2489, 1995.
54a. Weiss RB, Rifkin RM, Stewart FM, et al: High-dose chemotherapy
for high-risk primary breast cancer: An on-site review of the Bezwoda
study. Lancet 355:999-1003, 2000.
55. Stadtmauer EA, ONeill A, Goldstein LJ, et al: Phase III
randomized trial of high-dose chemotherapy (HDC) and stem cell
support (SCT) shows no difference in overall survival or severe
toxicity compared to maintenance chemotherapy with cyclophosphamide,
methotrexate, and 5-fluorouracil (CMF) for women with metastatic
breast cancer who are responding to conventional induction
chemotherapy: The Philadelphia Intergroup Study (PBT-1)
(abstract). Proc Am Soc Clin Oncol 18:1a, 1999.
56. Livingston R, Crowley J. Commentary on PBT-1 study of high-dose
consolidation vs standard chemotherapy in metastatic breast cancer. J
Clin Oncol 17:22-24, 1999.
57. Miller KD, Sledge GW: The role of chemotherapy for metastatic
breast cancer. Hematol Oncol Clin North Am 13:415-434, 1999.
58. Rahman ZU, Frye DK, Buzdar AU, et al: Impact of selection process
on response rate and long-term survival of potential high-dose
chemotherapy candidates treated with standard-dose
doxorubicin-containing chemotherapy in patients with metastatic
breast cancer. J Clin Oncol 15:3171-3177, 1997.
59. 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.
60. Berry DA, Broadwater G, Perry MC, et al: Conventional vs
high-dose therapy for metastatic breast cancer: Comparison of Cancer
and Leukemia Group B (CALGB) and blood and bone marrow transplant
registry patients (abstract). Proc Am Soc Clin Oncol 18:128a, 1999.
61. Jaiyesimi IA, Buzdar AU, Decker DA, et al: Use of tamoxifen for
breast cancer: 28 Years later. J Clin Oncol 13:513-529, 1995.
62. Janicek MJ, Hayes DF, Kaplan WD: Healing flare in skeletal
metastases from breast cancer. Radiology 192:201-204, 1994.
63. Plotkin D, Lechner JJ, Jung WE, et al: Tamoxifen flare in
advanced breast cancer. JAMA 240:2644-2646, 1978.
64. Falkson G, Gelman RS, Pandya KJ, et al: Eastern Cooperative
Oncology Group randomized trials of observation vs maintenance
therapy for patients with metastatic breast cancer in complete
remission following induction treatment. J Clin Oncol 16:1669-1676, 1998.
65. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer:
Correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science 235:177-182, 1987.
66. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of
the efficacy and safety of humanized anti-HER2 monoclonal antibody in
women who have HER2-overexpressing metastatic breast cancer that has
progressed after chemotherapy for metastatic disease. J Clin Oncol
67. Slamon D: Biologic approach to managing advanced breast cancer.
Cancer Control 6 (suppl 5):7-10, 1999.
68. Norton L, Slamon D, Leyland-Jones B, et al: Overall survival (OS)
advantage to simultaneous chemotherapy plus the humanized anti-HER2
monoclonal antibody Herceptin in HER2-overexpressing metastatic
breast cancer (abstract). Proc Am Soc Clin Oncol 18:127a, 1999.
69. Brem S: Angiogenesis and cancer control: From concept to
therapeutic trial. Cancer Control 6:436-458, 1999.
70. Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with
epoetin alfa on clinical outcomes in patients with nonmyeloid
malignancies during cancer chemotherapy in community oncology
practice. J Clin Oncol 15:1218-1234, 1997.
71. Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in
chemotherapy patients treated with epoetin alfa is independent of
disease response or tumor type: Results from a prospective community
oncology study. J Clin Oncol 16:3412-3425, 1998.
72. Perez E: Management of bone metastases in advanced breast cancer.
Cancer Control 6:28-30, 1999.
73. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term
prevention of skeletal complications of metastatic breast cancer with
pamidronate. J Clin Oncol 16:2038-2044, 1998.
74. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces
skeletal morbidity in women with advanced breast cancer and lytic
bone lesions: A randomized, placebo-controlled trial. J Clin Oncol