Individualisierte Therapie des Mammakarzinoms

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

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