Individualisierte Therapie
des Mammakarzinoms

J Eucker; K Possinger

doi:10.1055/s-0031-1274532

DMW - Deutsche Medizinische Wochenschrift, Table of Contents

Dtsch Med Wochenschr 2011; 136(10): 486-491
DOI: 10.1055/s-0031-1274532

Übersicht | Review article

Onkologie, Gynäkologie
© Georg Thieme Verlag KG Stuttgart · New York

Individualisierte Therapie des Mammakarzinoms

Individualized treatment of breast cancerJ. Eucker¹ , K. Possinger¹

¹Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie, Charité – Universitätsmedizin Berlin, Campus Charité Mitte

Abstract

Zusammenfassung

Das Mammakarzinom ist die häufigste Tumorentität bei Frauen. Die klinische Forschung hat in den letzten Jahren zu einer immer differenzierteren Therapie sowohl in der adjuvanten als auch in der palliativen Situation beigetragen. Die medikamentöse Therapie des Mammakarzinoms wurde in den letzen Jahren durch Substanzen mit neuen Wirkprinzipien ergänzt, deren Einsatz und Wirksamkeit von den biologischen Eigenschaften des Tumors abhängt. Da sie auf die individuellen Tumorcharakteristika zugeschnitten sind, werden sie als „targeted agents” oder „targeted therapy” bezeichnet. Als Ziele gelten häufig Rezeptoren des Mammakarzinoms, Schlüsselproteine intrazellulärer Signaltransduktionswege, Tyrosinkinasen oder Zytokine. Auch bei der endokrinen Therapie haben sich praxisrelevante Änderungen ergeben. Mit Schwerpunkt auf der Therapie des metastasierten Mammakarzinoms wird eine Übersicht über die wichtigsten zielgerichteten Therapien gegeben, die sich in der klinischen Prüfung befinden oder bereits zugelassen wurden.

Abstract

Breast cancer is the most frequent tumor in women. Clinical research over the last few years has resulted in an increasing differentiation of treatment strategies in the adjuvant setting as well as in metastatic breast cancer. In recent years, the medical treatment of breast cancer was complemented by agents with new mechanisms of action that depend on biological properties of the tumor. As these agents target tumor specific characteristics they are called targeted agents or targeted therapy. Most frequently, different receptors, key proteins of intracellular pathways, thyrosinkinases, or cytokines serve as tumor targets. Even in endocrine treatment relevant changes of practical guidelines emerged. The most important targeted therapies are reviewed with special regard to metastatic breast cancer.

Schlüsselwörter

Mammakarzinom - zielgerichtete Therapie - endokrine Therapie - Chemotherapie - small molecules - monoklonale Antikörper

Keywords

breast cancer - targeted therapy - endocrine therapy - chemotherapy - small molecules - monoclonal antibodies

Full Text

References

Literatur

1 Baselga J, Gelmon K A, Verma S. et al . Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010; 28 1138-1144
2 Baselga J, Roché H, Costa F. Grupo Español de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Sólidos .SOLTI-0701: A multinational double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC). Abstract Nr. 45, 32th Annual SABCS. , 2009
3 Baselga J, Semiglazov V, van Dam P. et al . Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009; 27 2630-2637
4 Bergh J, Greil R, Voytko N. et al . Sunitinib (SU) in combination with docetaxel (D) versus D alone for the first-line treatment of advanced breast cancer (ABC). J Clin Oncol. 2010; 28 (Suppl.) 18 s (Abstract LBA1010)
5 Bianchi G, Loibl S, Zamagni C. et al . Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anti-Cancer Drugs. 2009; 20 616-624
6 Burris H A, Rugo H S, Vukelja S J. et al . Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2) -positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2010; 29 1-9
7 Burstein H J, Prestrud A A, Seidenfeld J. et al . American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer. J Clin Oncol. 2009; 28 3784-3796
8 Burstein H J, Sun Y, Dirix L Y. et al . Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010; 28 1301-1307
9 Burstein H J, Elias A D, Rugo H S. et al . Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and taxane. J Clin Oncol. 2008; 26 1810-1816
10 Bertz J, Giersiepen K, Haberland J. et al .Krebs in Deutschland: Häufigkeiten und Trends. 5. Aufl. Gesellschaft der epidemiologischen Krebsregister in Deutschland e. V. in Zusammenarbeit mit dem Robert Koch Institut (Hrsg), Saarbrücken; 2006
11 Bonneterre J, Buzdar A, Nabholtz J MA. et al . Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer. 2001; 98 2247-2258
12 Bueno-de-Mesquita J M, Linn S C, Keijzer R. et al . Validation of 70-gene prognosis signature in node-negative breast cancer. Breast cancer Res Treat. 2009; 117 483-495
13 Cameron D, Casey M, Press M. et al . A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab. Breast Cancer Res Treat. 2008; 112 533-543
14 Cancello G, Maisonneuve P, Rotmensz N. et al . Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer. Ann Oncol. 2010; 21 1974-1981
15 Chia S K, Speers C H, D’yachkova Y. et al . The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2001; 110 973-979
16 Choueiri T K. Axitinib, a novel anti-angiogenic drug with promising activity in various solid tumors. Curr Opin Investig Drugs. 2008; 9 658-671
17 Chow L SY, Jassem J, Baselga J. et al . Phase III study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res Treat. 2006; 97 (Suppl.) Abstr. 6091
18 Cobleigh M A, Langmuir V K, Sledge G W. et al . A phase I/II dose escalation trial of bevacizumab in previously treated metastastic breast cancer. Semin Oncol. 2003; 30 (Suppl 16) 117-124
19 Cristofanilli M, Valero V, Mangalik A. et al . Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2010; 16 1904-1914
20 Crown J, Dieras V. et al . Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC). J Clin Oncol. 2010; 28 (Suppl) 18 s (Abstract LBA1011)
21 Dalenc F, Campone M, Hupperet P. et al . Everolimus in combination with weekly paclitaxel and trastuzumab in HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial. J Clin Oncol. 2010; 28 (Suppl.) 15 s (Abstract 1013)
22 Dickler M N, Cobleigh M A, Miller K D. et al . Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat. 2009; 115 115-121
23 Di Leo A, Jerusalem G, Petruzelka L. et al . Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010; 28 4595-4600
24 Folkman J. What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Inst. 1990; 82 4-6
25 Gianni L, Pienkowski T, Im Y H. et al .Neoadjuvant pertuzumab (P) and trastuzumab (H): antitumor and safety analysis of a randomized phase II study (‘NeoSphere’). Abstract Nr. S3 – 2, 33th Annual SABCS 2010
26 Gradishar W J, Kaklamani V, Prasad S ahoo T. et al .A double-blind, randomized, placebo-controlled, phase 2b study evaluating the efficacy and safety of sorafenib (SOR) in combination with paclitaxel (PAC) as a first-line therapy in patients (pts) with locally recurrent or metastatic breast cancer (BC). Abstract Nr. 44, 32th Annual SABCS. , 2009
27 Hicklin D J, Ellis L M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005; 23 1011-1027
28 Howell A, Pippen J, Elledge R M. et al . Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma. Cancer. 2005; 104 236-239
29 Johnston S, Pippen Jr J. et al . Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009; 27 5538-5546
30 Karaman M W, Herrgard S, Treiber D K. et al . A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008; 28 127-132
31 Kaufman B, Mackey J R. et al . Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009; 27 5529-5537
32 Kaur H, Silverman P, Singh D. et al . Toxicity and outcome data in a phase II study of weekly docetaxel in combination with erlotinib in recurrent and/or metastatic breast cancer. J Clin Oncol. 2006; 24 Suppl. Abstract 10623
33 Kennecke H, Yerushalmi R, Woods R. et al . Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010; 28 3271-3277
34 Konecny G E, Meng Y G, Untch M. et al . Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res. 2004; 10 1706-1716
35 Krop I E, Beeram M, Modi S. et al . Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2010; 28 2698-2704
36 Mayer E L, Dhakil S, Patel T. et al . SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer. Ann Oncol. 2010; 21 2370-2376
37 Meric-Bernstam F, Gonzalez-Angulo A M. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009; 27 2278-2287
38 Miles D W, Chan A, Dirix L Y. et al . Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol. 2010; 28 3239-3247
39 Miller K, Wang M. et al . Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357 2666-2676
40 Miller K D, Chap L I, Holmes F A. et al . Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005; 23 792-799
41 Moreno-Aspitia A, Morton R F, Hillman D W. et al . Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to nthracyclines or taxanes. J Clin Oncol. 2009; 27 11-15
42 Mouridsen H, Gershanovich M. et al . Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the international letrozole breast cancer group. J Clin Oncol. 2003; 21 2101-2107
43 Osborne K, Neven P, Dirix L. et al .Randomized Phase II study of gefitinib (IRESSA) or placebo in combination with tamoxifen in patients with hormone receptor positive metastatic breast cancer. Abstract Nr. 2067, präsentiert auf dem 30th Annual SABCS. Dec 13 – 16, 2007
44 O’Shaughnessy J, Osborne C, Pippen J. et al .Final results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a poly (ADP-Ribose) polymerase (PARP) inhibitor, in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC). Abstract Nr. 3122, präsentiert auf dem 32th Annual SABCS Dec 8 – 13, 2009
45 Papaldo P, Fabi A, Ferretti G. et al . A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol. 2006; 17 630-636
46 Perez E A, Dirix L, Kocsis J. et al . Efficacy and safety of trastuzumab-DM1 versus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease. Ann Oncol. 2010; 21 (Suppl. 8) 1-12
47 Relf M, LeJeune S. et al . Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placental growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997; 57 963-969
48 Robert N J, Dieras V, Glaspy J. et al . RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer. J Clin Oncol. 2009; 27 15 s (Abstr. 1005)
49 Robert-Koch-Institut .Verbreitung von Krebserkrankungen in Deutschland. Entwicklung der Prävalenzen zwischen 1990 und 2010. http://www.rki.de
50 Robertson J FR, Llombart-Cussac A. et al . Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-Line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009; 27 4530-4535
51 Romond E H, Perez E A. et al . Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Eng J Med. 2005; 353 1673-84
52 Rugo H S, Stopeck A, Joy A A. et al . A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor Axitinib in combination with docetaxel compared to docetaxel plus placebo in metastatic breast cancer. J Clin Oncol. 2007; 25 (Suppl.) 18 s Abstract 1003
53 Slamon D J, Leyland-Jones B, Shak S. et al . Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med. 2001; 344 783-792
54 Smith I, Procter M, Gelber R D. et al . 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. Lancet. 2007; 369 29-36
55 Sverrisdottir A, Johansson H. et al .Interaction between goserelin and tamoxifen in a controlled clinical trial of adjuvant endocrine therapy in premenopausal breast cancer. Abstract S1 – 5, 33th Annual SABCS 2010
56 Schreiber V, Dantzer F, Amé J C, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 2006; 7 517-528
57 Tutt A, Robson M, Garber J E. et al . Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2009; 376 235-244
58 Twelves C, Trigo J M, Jones R. et al . Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: A dose escalation study. Eur J Cancer. 2008; 44 419-426
59 Von Minckwitz G, du Bois A, Schmidt M. et al . Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03 – 05 study. J Clin Oncol. 2009; 27 1999-2006
60 Wildiers H, Fontaine C. et al . Multicenter phase II randomized trial evaluating antiangiogenic therapy with sunitinib as consolidation after objective response to taxane chemotherapy in women with HER2-negative metastatic breast cancer. Breast Cancer Res Treat. 2010; 123 463-469

Dr. Jan Eucker

Medizinische Klinik mit Schwerpunkt Onkologie und Hämatologie
Charité – Universitätsmedizin Berlin

Charitéplatz 1

10117 Berlin

Phone: 030/450-613409

Fax: 030/450-513952

Email: jan.eucker@charite.de