Zusammenfassung
Die endokrine Therapie ist eine vergleichbar nebenwirkungsarme und gleichwohl effektive Modalität der systemischen Behandlung des metastasierten Mammakarzinoms. Analysen des Genprofils von Mammakarzinomen weisen darauf hin, dass hormonrezeptorpositive und negative Tumore unterschiedlichen Erkrankungsentitäten zugeordnet werden können, die sich in Tumorbiologie und Tumorgenese voneinander abgrenzen lassen. Während Tamoxifen am Östrogenrezeptor je nach Zelltyp überwiegend antagonistische oder agonistische Wirkungen entfaltet, so gehört Fulvestrant einer neuen Klasse steroidaler Substanzen an, die als reine Antiöstrogene wirken und daher auch nach Entwicklung einer Tamoxifenresistenz noch wirksam sein können. Die Aromatasehemmer der dritten Generation unterscheiden sich hinsichtlich ihrer Pharmakologie und Pharmakodynamik, trotzdem zeigen sie bei postmenopausalen Patientinnen eine vergleichbare klinische Effektivität, die in der endokrinen Erstlinientherapie einer Tamoxifenbehandlung und in der Zweitlinientherapie einer Behandlung mit Megestrolacetat mindestens ebenbürtig, in einigen Studien auch überlegen war. Die prädiktive Bedeutung der HER-2/neu-Überexpression für den Behandlungserfolg endokriner Therapieansätze muss aufgrund der kontroversen Datenlage als weitgehend unklar bezeichnet werden.
Summary
Endocrine therapy is a comparably well tolerated but nevertheless effective modality for systemic treatment of metastatic breast cancer. Analyses of genetic profiles suggest that hormone receptor positive and negative tumors can be attributed to different disease entities defined by specific characteristics of tumor biology and tumorgenesis. While tamoxifen may induce predominantly antagonistic or agonistic effects at the estrogen receptor according to cell type, fulvestrant belongs to a new class of steroidal agents which act as pure antiestrogens and therefore maintain antitumor activity even after failure of tamoxifen. Third generation aromatase inhibitors like anastrozole, letrozole or exemestane show major differences in pharmacology and pharmacodynamics. Clinical efficacy in postmenopausal women is, however, comparable. Various randomised trials demonstrated that first-line use of aromatase inhibitors was at least as effective as tamoxifen, while in second-line treatment antitumor efficacy proved to be equal or superior to megestrol acetate. In view of controversial trial results, the predictive value of HER-2/neu overexpression for the therapeutic efficacy of endocrine treatment remains to be clarified.
Key Words
breast cancer - endocrine therapy - tamoxifen - fulvestrant - aromatase inhibitors
Literatur
-
1
Bonneterre J, Robertson J, Thurlimann B. et al. .
Anastrozole versus Tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the (TARGET) tamoxifen or arimidex randomised group efficacy and tolerability study.
J Clin Oncol.
2000;
18
3748-3757
-
2
Bonneterre J, Buzdar A, Robertson J. et al. .
Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma.
Cancer.
2001;
92
2247-2258
-
3
Buzdar A, Jones S, Vogel C. et al. .
Phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma.
Cancer.
1997;
79
730-739
-
4
Buzdar A, Jonat W, Howell A. et al. .
Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of survival update based on a combined analysis of data from two mature phase III trials.
Cancer.
1998;
83
1142-1152
-
5
Buzdar A, Douma J, Davidson N. et al. .
Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate.
J Clin Oncol.
2001;
19
3357-3366
-
6
Buzdar AU.
Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors.
Clin Cancer Res.
2003;
9
468-472
-
7
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.
1998;
16
453-461
-
8
Early Breast Cancer Trialists' Collaborative Group. .
Tamoxifen for early breast cancer - an overview of the randomised trials.
Lancet.
1998;
351
1451-1467
-
9
Ellis MJ, Coop A, Singh B. et al. .
Etrozole 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.
2001;
19
3808-3816
-
10
Geisler J, Haynes B, Anker G. et al. .
Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized cross-over study.
J Clin Oncol.
2002;
20
751-757
-
11
Gruvberger S, Ringnér M, Chen Y. et al. .
Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns.
Cancer Res.
2001;
5979-5984
-
12
Howell A, Robertson JF, Quaresma AJ. et al. .
Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.
J Clin Oncol.
2002;
20
3396-3403
-
13
Jonat W, Howell A, Blomquist C. et al. .
A randomized trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer.
Eur J Cancer.
1996;
404-412
-
14
Kaufmann M, Bajetta E, Dirix LY. et al. .
Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial.
The Exemestane Study Group. J Clin Oncol.
2000;
18
1399-1411
-
15
Klijn JG, Blamey RW, Boccardo F. et al. .
Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials.
J Clin Oncol.
2001;
19
343-353
-
16
Li CI, Daling JR, Malone KE.
Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998.
J Clin Oncol.
2003;
28-34
-
17
Lipton A, Ali SM, Leitzel K. et al. .
Elevated serum HER-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer.
J Clin Oncol.
2002;
20
1467-1472
-
18
Lonning PE, Bajetta E, Murray R. et al. .
Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.
J Clin Oncol.
2000;
18
2234-2244
-
19
Milla-Santos A, Milla L, Raool L. et al. .
Phase III trial of anastrozole vs. tamoxifen in postmenopausal patients with hormone-dependent advanced breast cancer (abstract).
Eur J Cancer.
2001;
4
-
20
Milla-Santos A, Milla L, Portella J. et al. .
A randomized trial of groserelin (ZoladexTM) + tamoxifen versus goserelin + anastozole (ArimidexTM) in pre/perimenopausal patients with hormone dependent advanced breast cancer.
Breast Canc Res Treat 2002; abstract.
289;
-
21
Mouridsen H, Gershanovich M, Sun Y. et al. .
Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.
J Clin Oncol.
2001;
19
2596-2606
-
22
Nabholtz J, Buzdar A, Pollak M. et al. .
Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women : results of a North American multicenter randomized trial.
J Clin Oncol.
2000;
18
3758-3767
-
23
Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG. et al. .
Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer.
J Natl Cancer Inst.
1995;
87
746-750
-
24
Osborne CK, Pippen J, Jones SE. et al. .
Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial.
J Clin Oncol.
2002;
20
3386-3395
-
25
Osborne CK, Bardou V-J, Hilsenbeck SG. et al. .
The estrogen coactivator AIB1 (SRC3) in combination with HER-2 is a prognostic and predictive marker in patients with breast cancer.
Proc Am Soc Clin Oncol.
2002;
21
-
26
Parker LM, Webster A.
Greater duration of response in patients receiving fulvestratnt (Faslodex) compared with those receiving anastrozole (Arimidex).
Proc Am Soc Clin Oncol.
2002;
21
-
27
Pritchard KI.
Endocrine therapy of advanced disease: analysis and implications of existing data.
Clin Cancer Res.
2003;
9
460-467
-
28
Pyrhonen S, Ellmen J, Vuorinen J. et al. .
Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer.
Breast Cancer Res Treat.
1999;
56
133-143
-
29
Rose C, Vtoraya OAP, Neave F. et al. .
Letrozole (Femara) vs. Anastrozole (Arimidex): second-line treatment in postmenopausal women with advanced breast cancer.
Proc Am Soc Clin Oncol.
2002;
21
-
30
Taylor CW, Green S, Dalton WS. et al. .
Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study.
J Clin Oncol.
1998;
16
994-999
-
31
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.
2002;
347
1999-2009
1 Arimidex or Tamoxifen alone or in combination
Anschrift des Verfassers
PD Dr. Volker Heinemann
Klinikum Großhadern Ludwig-Maximilians-Universität München
Medizinische Klinik und Poliklinik III
Marchioninistr. 15
81377 München
