TumorDiagnostik & Therapie 2018; 39(10): 657-664
DOI: 10.1055/a-0787-7840
Thieme Onkologie aktuell
© Georg Thieme Verlag KG Stuttgart · New York

Zirkulierende Tumorzellen, zirkulierende Tumor-DNA und zirkulierende microRNA beim metastasierten Mammakarzinom – oder: Welche Rolle spielt die Liquid Biopsy beim Brustkrebs?

Circulating tumour cells, circulating tumour DNA and circulating MicroRNA in metastatic breast carcinoma – what is the role of liquid biopsy in breast cancer?
Arkadius Polasik
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Marie Tzschaschel
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Fabienne Schochter
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Ameli de Gregorio
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Thomas W. P. Friedl
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Brigitte Rack
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Andreas Hartkopf
2   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Tübingen, Tübingen
,
Peter A. Fasching
3   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Erlangen, Erlangen
,
Andreas Schneeweiss
4   Nationales Centrum für Tumorerkrankungen, Universitätsklinikum Heidelberg, Heidelberg
,
Volkmar Müller
5   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Hamburg-Eppendorf, Hamburg
,
Jens Huober
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Wolfgang Janni
1   Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm
,
Tanja Fehm
6   Klinik für Gynäkologie und Geburtshilfe, Heinrich-Heine-Universität Düsseldorf, Düsseldorf
› Author Affiliations
Further Information

Publication History

Publication Date:
04 December 2018 (online)

Zusammenfassung

Die Streuung von Tumorzellen und Entstehung solider Metastasen findet sowohl über das Lymph- als auch das Blutsystem statt. Der Nachweis zirkulierender Tumorzellen (CTCs) und der zirkulierenden Tumor-DNA (ctDNA) im venösen Blut ist sowohl beim frühen als auch beim metastasierten Mammakarzinom möglich. Ihre prognostische Relevanz wurde bereits mehrfach bewiesen. Dabei ist die repetitive Untersuchung der CTCs bzw. ctDNA im Sinne einer regelmäßigen „liquid biopsy“ jederzeit und problemlos möglich. Durch die zusätzlichen molekularen Analysen ist es möglich, Tumorcharakteristika und ihre Heterogenität, die mit möglichen Resistenzen einhergehen, zu definieren. Dies ermöglicht den Einsatz einer personalisierten und zielgerichteten Therapie, um neben einem verlängerten Gesamtüberleben auch die Verbesserung der Lebensqualität zu erreichen.

Abstract

Dissemination of tumour cells and the development of solid metastases occurs via blood vessels and lymphatics. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) can be detected in venous blood in patients with early and metastatic breast cancer, and their prognostic relevance has been demonstrated on numerous occasions. Repeated testing for CTCs and ctDNA, or regular so-called “liquid biopsy”, can be performed easily at any stage during the course of disease. Additional molecular analysis allows definition of tumour characteristics and heterogeneity that may be associated with treatment resistance. This in turn makes personalised, targeted treatments possible that may achieve both improved overall survival and quality of life.

 
  • Literatur

  • 1 Aktuelle Empfehlungen zur Diagnostik und Therapie primärer und metastasierter Mammakarzinome der Kommission MAMMA in der AGO e. V. 2017. Online: http://www.ago-online.de ; Stand: 09/2017
  • 2 Gerlinger M, Rowan AJ, Horswell S. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883-892
  • 3 Paget S. The distribution of secondary growth in cancer of the breast. Lancet 1889; 133: 571-573
  • 4 Braun S, Vogl FD, Naume B. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353: 793-802
  • 5 Janni W, Vogl FD, Wiedswang G. et al. Persistence of disseminated tumor cells in the bonemarrow of breast cancer patients predicts increased risk for relapse – a European pooled analysis. Clin Cancer Res 2011; 17: 2967-2976
  • 6 Fehm T, Muller V, Aktas B. et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 2010; 124: 403-412
  • 7 Bidard FC, Peeters DJ, Fehm T. et al. Clinical validity of circulating tumor cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2015; 15: 406-415
  • 8 Müller V, Riethdorf S, Rack B. et al. Prognostic impact of circulating tumor cells assessed with the CellSearch System™ and AdnaTest Breast™ in metastatic breast cancer patients: the DETECT study. Breast Cancer Res 2012; 14: R118
  • 9 Bidard FC, Peeters DJ, Fehm T. et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014; 15: 406-414
  • 10 Rack B, Schindlbeck C, Jückstock J. et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 2014; 106: pii: dju066 . doi:10.1093/jnci/dju066
  • 11 Janni W, Rack B, Terstappen LW. et al. Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin Cancer Res 2016; 22: 2583-2593
  • 12 Yang YF, Liao YY, Yang M. et al. Discordances in ER, PR and HER2 receptors between primary and recurrent/metastatic lesions and their impact on survival in breast. Med Oncol 2014; 31: 214
  • 13 Heitz F, Barinoff J, du Bois O. et al. Differences in the receptor status between primary and recurrent breast cancer – the frequency of and the reasons for discordance. Oncology 2013; 84: 319-325
  • 14 Somlo G, Lau SK, Frankel P. et al. Multiple biomarker expression on circulating tumor cells in comparison to tumor tissues from primary and metastatic sites in patients with locally advanced/inflammatory, and stage IV breast cancer, using a novel detection technology. Breast Cancer Res Treat 2011; 128: 155-163
  • 15 Munzone E, Nolé F, Goldhirsch A. et al. Changes of HER2 status in circulating tumor cells compared with the primary tumor during treatment for advanced breast cancer. Clin Breast Cancer 2010; 10: 392-397
  • 16 Jäger BA, Finkenzeller C, Bock C. et al. Estrogen receptor and HER2 status on disseminated tumor cells and primary tumor in patients with early breast cancer. Transl Oncol 2015; 8: 509-516
  • 17 Santinelli A, Pisa E, Stramazzotti D. et al. HER-2 status discrepancy between primary breast cancer and metastatic sites. Impact on target therapy. Int J Cancer 2008; 122: 999-1004
  • 18 Schramm A, Friedl TWP, Schochter F. et al. Association between HER2-phenotype on circulation tumor cells and primary tumor characteristics in women with metastatic breast cancer. AscoAnnuMeet 2015; 51: 266
  • 19 Hanf V, Schütz F, Liedtke C. et al. AGO recommendations for the diagnosis and treatment of patients with advanced and metastatic breast cancer: Update. Breast Care (Basel) 2014; 9: 202-209
  • 20 Paoletti C. Abstract OT1-3-01: Characterization of circulating tumor cells from subjects with metastatic breast cancer using the CTC-endocrine therapy index: the COMETI‑P2-2012.0 trial. Cancer Res 2013; 73 (Suppl. 24) OT1-3-01
  • 21 Online: www.clinicaltrials.gov/ct2/show/NCT01349842 ; Stand: 09/2017
  • 22 Smerage JB, Barlow WE, Hortobagyi GN. et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 2014; 32: 3483-3489
  • 23 Online: www.clinicaltrials.gov/ct2/show/NCT01710605 ; Stand: 09/2017
  • 24 Kataoka Y, Mukohara T, Shimada H. et al. Association between gain-offunction mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 2010; 21: 255-262
  • 25 Eichhorn PJA, Gili M, Scaltriti M. et al. Phosphatidyinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008; 68: 9221-9230
  • 26 Dupont Jensen J, Laenkholm AV, Knoop A. et al. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 2011; 17: 667-677
  • 27 Mandel PM. Les acides nucleiques du plasma sanguin chez lʼhomme. CR Acad Sci Paris 1940; 142: 241-253
  • 28 Casciano I, Vinci AD, Banelli B. et al. Circulating tumor nucleic acids: perspective in breast cancer. Breast Care (Basel) 2010; 5: 75-80
  • 29 Lo YM, Rainer TH, Chan LY. et al. Plasma DNA as a prognostic marker in trauma patients. Clin Chem 2000; 46: 319-323
  • 30 Sozzi G, Conte D, Leon M. et al. Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 2003; 21: 3902-3908
  • 31 Leon SA, Shapiro B, Sklaroff DM. et al. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 1977; 37: 646-650
  • 32 Bettegowda C, Sausen M, Leary RJ. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6: 22ra224
  • 33 Dawson SJ, Rosenfeld N, Caldas C. Circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013; 369: 93-94
  • 34 Heidary M, Auer M, Ulz P. et al. The dynamic range of circulating tumor DNA in metastatic breast cancer. Breast Cancer Res 2014; 16: 421
  • 35 Madic J, Kiialainen A, Bidard FC. et al. Circulating tumor DNA and circulating tumor cells inmetastatic triple negative breast cancer patients. Int J Cancer 2015; 136: 2158-2165
  • 36 Board RE, Wardley AM, Dixon JM. et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat 2010; 120: 461-467
  • 37 Baselga J, Im SA, Iwata H. et al. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2–advanced breast cancer (BC): first results from the randomized, phase III BELLE‑2 trial. San Antonio Breast Cancer Symposium. San Antonio, TX, USA: Abstract S6-01 2015
  • 38 Di Leo A, Ciruelos E, Janni W. et al. BELLE‑3: A phase III study of the panphosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib (BKM120) with fulvestrant in postmenopausal women with HR+/HER2- locally advanced/metastatic breast cancer (BC) pretreated with aromatase inhibitors (AIs) and refractory to mTOR inhibitor (mTORi)-based treatment. ASCO Annual Meeting. Chicago, Il: Abstract TPS626 2015
  • 39 Di Leo A, Seok Lee K, Ciruelos E. BELLE‑3: a phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment. San Antonio Breast Cancer Symposium 2016. San Antonio, TX, USA: Abstract S4-07
  • 40 Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006; 354: 270-282
  • 41 Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A. et al. D538 G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 2013; 73: 6856-6864
  • 42 Toy W, Shen Y, Won H. et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 2013; 45: 1439-1445
  • 43 Wang P, Bahreini A, Gyanchandani R. et al. Sensitive detection of monoand polyclonal ESR1 mutations in primary tumors, metastatic lesions and cell free DNA of breast cancer patients. Clin Cancer Res 2016; 22: 1130-1137
  • 44 Chandarlapaty S, Chen D, He W. et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO‑2 clinical trial. JAMA Oncol 2016; 2: 1310-1315
  • 45 Ma F, Zhu W, Guan Y. et al. ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy. Oncotarget 2016; 7: 66020-66031
  • 46 Fasching PA, Brucker SY, Fehm TN. et al. Biomarkers in patients with metastatic breast cancer and the PRAEGNANT study network. Geburtsh Frauenheilk 2015; 75: 41-50
  • 47 Lee RC, FeinbaumRL RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-854
  • 48 Roth C, Rack B, Muller V. et al. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res 2010; 12: R90
  • 49 Madhavan D, Peng C, Wallwiener M. et al. Circulating miRNAs with prognostic value inmetastatic breast cancer and for early detection of metastasis. Carcinogenesis 2016; 37: 461-470