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Deutsche Zeitschrift für Onkologie 2015; 47(2): 57-65
DOI: 10.1055/s-0035-1547554
Forschung
© Karl F. Haug Verlag in MVS Medizinverlage Stuttgart GmbH & Co. KG

Individuelle Tumortherapie beim Mammakarzinom – Möglichkeiten der Vermeidung von Über- und Untertherapie unter besonderer Berücksichtigung zielgerichteter Therapien

Tom Degenhardt
,
Nadia Harbeck
,
Rachel Würstlein
Further Information

Publication History

Publication Date:
07 July 2015 (online)

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Zusammenfassung

Die individualisierte Medizin ist bereits ein integraler Bestandteil der Therapie des frühen sowie des metastasierten Mammakarzinoms. Hierfür ist neben individuellen Faktoren der Patientinnen das Wissen über die Tumorbiologie, Prognosefaktoren und prädiktive Marker die Grundvoraussetzung. Die molekularen Subtypen (Luminal A, Luminal B, HER2-positiv, TNBC) haben klinische Relevanz und sind beim frühen Mammakarzinom für die Therapieentscheidung bezüglich einer (neo-)adjuvanten Therapie und auch in der Therapie des metastasierten Karzinoms nicht mehr wegzudenken. Für die Vermeidung von Über- und Untertherapie des frühen Mammakarzinoms liefern gut validierte Biomarker wie uPA/PAI-1 oder die Genexpressionsanalysen zusätzliche therapierelevante Informationen über die Tumorbiologie und Aggressivität. Hinzu kommen neue zielgerichtete Substanzen, die eine effektive Therapie in Ergänzung zur konventionellen endokrinen Therapie, HER2-gerichteten Therapie und Chemotherapie ermöglichen. Moderne Operations- und Bestrahlungsverfahren bilden zudem die Basis für einen individualisierten Ansatz in der Lokaltherapie des primären und metastasierten Mammakarzinoms. Außerdem fordern neue Subgruppen wie das BRCA-positive Mammakarzinom noch mehr Interdisziplinarität und vorausschauende Therapieplanung. Insgesamt steigen somit die Komplexität der Therapiekonzepte und damit der Anspruch an die Therapeuten und die beteiligten Disziplinen. Die beste Möglichkeit, Patientinnen eine moderne und individualisierte Therapie anbieten zu können, stellen klinische Studien dar. Daher sollten Studienoptionen für die einzelne Patientin bereits in den präoperativen interdisziplinären Tumorkonferenzen geprüft werden. Um den Studieneinschluss für viele Patientinnen zu ermöglichen, sind der weitere Ausbau von zentrumsübergreifenden Netzwerken und die Intensivierung der interdisziplinären Zusammenarbeit nötig.

Summary

Individualized medicine plays an important role in the treatment of primary and metastatic breast cancer. The fundamental principles of individualized medicine consist of individual characteristics of the patient as well as the knowledge about tumor biology, prognostic and predictive factors. In early breast cancer the molecular subtypes (Luminal A, Luminal B, Her2-positive, TNBC) are clinically relevant and important for (neo-)adjuvant treatment decisions and treatment decisions in the metastatic setting. To avoid over treatment or under treatment good validated and modern biomarkers such as uPA/PAI-1 and the multi gene assays provide further treatment related information about tumor biology and aggressiveness of early stage breast cancer. New targeted substances offer opportunities for an effective therapy in addition to conventional endocrine treatment, anti-Her2 treatment and chemotherapy. Furthermore, modern surgical techniques and radiation therapy concepts allow an individualized approach for the local treatment of primary and metastatic breast cancer. New subgroups, like the BRCA-positive breast cancer, require multidisciplinarity and a foresightful planning of the treatment. The increasing complexity of breast cancer treatment has been challenging for physicians of all involved disciplines. The best opportunities for patients to receive a modern and individualized therapy are clinical studies. Hence clinical study options should already be checked during the preoperative tumor boards. To make the inclusion into a clinical study possible for many patients it is required to improve the network between centers and to intensify the cooperation between the involved disciplines.

Schlüsselwörter

Mammakarzinom - prognostische Marker - prädiktive Marker - individualisierte Therapie - zielgerichtete Therapie - interdisziplinäre Netzwerke

Keywords

breast cancer - prognostic markers - predictive markers - individualized therapy - targeted therapy - interdisciplinary network
 

  • Literatur

  • 1 Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72(5): 1117-30
    CrossrefPubMedGoogle Scholar
  • 2 Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366(6): 520-529
    CrossrefPubMedGoogle Scholar
  • 3 Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P, Gianni L. 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(7): 1138-44
    CrossrefPubMedGoogle Scholar
  • 4 Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, De Mattos-Arruda L, Ignatiadis M, Lebofsky R, van Laere SJ, Meier-Stiegen F. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014; 15(4): 406-14
    CrossrefPubMedGoogle Scholar
  • 5 Bossung V, Harbeck N. Angiogenesis inhibitors in the management of breast cancer. Curr Opin Obstet Gynecol 2010; 22: 79-86
    CrossrefPubMedGoogle Scholar
  • 6 Byrski T, Gronwald J, Huzarski T et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010. 28. 375-9
    Google Scholar
  • 7 de Bono JS, Ashworth A. Translating cancer research into targeted therapeutics. Nature 2010; 467(7315): 543-9
    CrossrefPubMedGoogle Scholar
  • 8 Dowsett M, Nielsen TO, A’Hern R et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 2011; 103: 1656-64
    CrossrefPubMedGoogle Scholar
  • 9 Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16 (1): 25-35
    CrossrefPubMedGoogle Scholar
  • 10 Geyer CE, Forster J, Lindquist D et al. Lapatinib plus Capecitabine for her2-positive advanced breast cancer. N Engl J Med 2006; 26: 2733-2743
    PubMedGoogle Scholar
  • 11 Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13(1): 25-32
    CrossrefPubMedGoogle Scholar
  • 12 Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, McCall LM, Morrow M. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011. 305(6). 569-75
    Google Scholar
  • 13 Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ und members Panel. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. 2011; Ann Oncol 2011; 22(8): 1736-1747
    CrossrefPubMedGoogle Scholar
  • 14 Graeff H, Harbeck N, Prechtl A, Schmitt M, Jänicke F, Lisboa B, Thomssen C, Hepp H, Hasmüller S et al. Ten-year analysis of the prospective multicentre Chemo-N0 trial validates ASCO-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients. Eur J Cancer. 2013. 49 (8). 1825-35
    Google Scholar
  • 15 Harbeck N, Salem M, Nitz U et al. Personalized treatment of early-stage breast cancer: present concepts and future directions. Cancer Treat Rev 2010; 36: 584-594
    CrossrefPubMedGoogle Scholar
  • 16 Iglehart JD, Silver DP. Synthetic lethality - a new direction in cancer-drug development. N Engl J Med 2009; 361(2): 189-91
    CrossrefPubMedGoogle Scholar
  • 17 Johnston SR, Leary A. Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc) 2006; 42(7): 441-53
    CrossrefPubMedGoogle Scholar
  • 18 Johnston SR, Pippen J, jr Pivot X. et al. lapatinib combined with letrozole versus letrozole and placebo as first line therapy for postmenopausal hormonreceptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538-5546
    CrossrefPubMedGoogle Scholar
  • 19 Kuehn T, Bauerfeind I, Fehm T et al. Sentinel-lymphnode biopsy with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective multi-center cohort study. Lancet Oncol 2013; 14: 609-18
    CrossrefPubMedGoogle Scholar
  • 20 Moy B, Goss PE. Estrogen receptor pathway: resistance to endocrine therapy and new therapeutic approaches. Clin Cancer Res 2006; 12: 4790-4793
    CrossrefPubMedGoogle Scholar
  • 21 Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T et al A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 2010; 16(21): 5222-5232
    CrossrefPubMedGoogle Scholar
  • 22 Nitz U, Gluz O, Kates RE et al. Prognostic impact of discordance between different risk assessment tools in early breast cancer (recurrence score, central garde, ki67): early outcome analysis from the prospective phase III WSG-Plan B trial. 2014: P4–11–01. San Antonio Breast Cancer Symposium 2014; P4: 11-01
    PubMedGoogle Scholar
  • 23 O’Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol 2014; 32(34): 3840-7
    CrossrefPubMedGoogle Scholar
  • 24 Perou CMl, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000; 17 406(6797): 747-52
    CrossrefPubMedGoogle Scholar
  • 25 Pópulo H, Lopes JM, Soares P. he mTOR signalling pathway in human cancer. Int J Mol Sci 2012; 13: 1186-1198
    CrossrefPubMedGoogle Scholar
  • 26 Sendur MA, Zengin N, Aksoy S, Altundag K. Everolimus: a new hope for patients with breast cancer. Curr Med Res Opin 2014; 30(1): 75-87
    CrossrefPubMedGoogle Scholar
  • 27 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11): 783-92
    CrossrefPubMedGoogle Scholar
  • 28 Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J und Group CLEOPATRA Study. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372(8): 724-34
    CrossrefPubMedGoogle Scholar
  • 29 Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh D-Y, Diéras V, Guardino E, Fang L, Lu M, Olsen S, and Blackwell K. for the EMILIA Study Group. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N Engl J Med 2012; 367: 1783-1791
    CrossrefPubMedGoogle Scholar
  • 30 von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30(15): 1796-804
    CrossrefPubMedGoogle Scholar
  • 31 von Minckwitz G, Hahnen E, Fasching PA, Hauke J, Schneeweiss A, Salat C, Rezai M, Blohmer JU, Zahm DM, Jackisch C, Gerber B, Klare P, Kummel S, Eidtmann H, Paepke S, Nekljudova V, Loibl S, Untch M, Schmutzler R. BG and AGO-B Study Groups: Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (gBRCA) mutation and triple-negative breast cancer (TNBC): Results from GeparSixto. J Clin Oncol 32: 5s 2014; (suppl; abstr 1005), ASCO
    PubMedGoogle Scholar
  • 32 Voss MH, Molina AM, Motzer RJ. mTOR inhibitors in advanced renal cell carcinoma. Hematol Oncol Clin North Am 2011; 25(4): 835-852
    CrossrefPubMedGoogle Scholar
  • 33 www.ago-online.de
    PubMed
  • 34 www.success-studie.de
    PubMed
  • 35 www.wsg-online.com
    PubMed