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Molekulare Pathologie beim Mammakarzinom

Wertigkeit der Genexpressionsprofile

Molecular pathology for breast cancer

Importance of the gene expression profile

  • Schwerpunkt: Molekularpathologie
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Zusammenfassung

Therapeutische Entscheidungen beim Mammakarzinom werden zunehmend über Genexpressionstests gesteuert. Die Indikation für einen Genexpressionstest besteht v. a. dann, wenn bei einem HR-positiven, HER2-negativen Tumor entschieden werden soll, ob eine alleinige endokrine Therapie ausreichend ist oder ob eine zusätzliche Chemotherapie gegeben werden sollte. In dieser Situation sind die konventionellen klinisch-pathologischen Parameter oft nicht geeignet, um die Patientinnen zu selektieren, die von einer ausschließlich endokrinen Therapie profitieren. Genexpressionstests können hier zusätzliche Informationen liefern, den Entscheidungsprozess unterstützen und eine Übertherapie vermeiden. Die verschiedenen vorhandenen Testsysteme stellen Kliniker und Pathologen vor die Frage, welcher Test für welche Patientin ausgewählt werden sollte und wie die Testverfahren im direkten Vergleich zu bewerten sind. Der vorliegende Beitrag stellt 3 gängige Testsysteme vor (OncotypeDx®, Endopredict®, PAM50/Prosigna®), erläutert ihre Gemeinsamkeiten und Unterschiede und diskutiert deren Auswirkungen auf Therapieentscheidungen. In den letzten Jahren sind zunehmend Studien publiziert worden, in denen die verschiedenen Genexpressionstests an identischen Kohorten aus klinischen Studien evaluiert wurden, sodass ein Vergleich der Tests möglich ist. Diese Untersuchungen ermöglichen eine erste vergleichende Bewertung der verschiedenen Assays beim Mammakarzinom.

Abstract

Gene expression arrays are currently used to guide therapy decisions in breast cancer. The indications for gene expression tests are especially important in the group of hormone receptor negative, HER2 positive tumors to decide whether endocrine therapy alone is sufficient or additional chemotherapy is necessary. In this group of luminal tumors conventional clinicopathological parameters are often not suitable to select patients who would benefit from an endocrine therapy alone. Gene expression tests can provide additional information and, therefore, support decision-making and avoid unnecessary chemotherapy. There are a variety of test systems available which poses the questions of which tests should be selected for which patients and how the test results should be evaluated in a direct comparison. This report provides information about three currently available gene expression tests (i.e. OncotypeDx®, Endopredict® and PAM50/Prosigna®), comments on similarities and differences and discusses the impact on therapy decisions. The focus of this article is on a discussion of clinical studies that have compared the different molecular tests in the same clinical study cohort. These investigations allow a first comparative evaluation of the various assays for breast cancer.

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Literatur

  1. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795

    Article  PubMed Central  PubMed  Google Scholar 

  2. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) American society of clinical oncology; college of american pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013

    Article  PubMed  Google Scholar 

  3. van de Vijver MJ (2014) Molecular tests as prognostic factors in breast cancer. Virchows Arch 464(3):283–291

    Article  PubMed  Google Scholar 

  4. Sinn P, Aulmann S, Wirtz R, Schott S, Marmé F, Varga Z, Lebeau A, Kreipe H, Schneeweiss A (2013) Multigene assays for classification, prognosis, and prediction in breast cancer: a critical review on the background and clinical utility. Geburtshilfe Frauenheilkd 73(9):932–940

    Article  PubMed Central  PubMed  Google Scholar 

  5. Paik S, Shak S, Tang G, et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Article  CAS  PubMed  Google Scholar 

  6. Onkotype-DX-Brustkrebstest (2015). http://breast-cancer.oncotypedx.com/de-DE/Professional-Invasive/Resources/FAQs.aspx. Zugegriffen: 17.03.2015 aspx

  7. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE Jr, Wickerham DL, Wolmark N (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24(23):3726–3734

    Article  CAS  PubMed  Google Scholar 

  8. Tang G, Shak S, Paik S, Anderson SJ, Costantino JP, Geyer CE Jr, Mamounas EP, Wickerham DL, Wolmark N (2011) Comparison of the prognostic and predictive utilities of the 21-gene Recurrence Score assay and Adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Breast Cancer Res Treat 127(1):133–142

    Article  PubMed Central  PubMed  Google Scholar 

  9. Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, Quinn E, Dunbier A, Baum M, Buzdar A, Howell A, Bugarini R, Baehner FL, Shak S (2010) Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol 28(11):1829–1834

    Article  PubMed  Google Scholar 

  10. Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, Ravdin P, Bugarini R, Baehner FL, Davidson NE, Sledge GW, Winer EP, Hudis C, Ingle JN, Perez EA, Pritchard KI, Shepherd L, Gralow JR, Yoshizawa C, Allred DC, Osborne CK, Hayes DF; Breast Cancer Intergroup of North America (2010) Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 11(1):55–65. doi:10.1016/S1470-2045(09)70314-6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Tang G, Cuzick J, Costantino JP, Dowsett M, Forbes JF, Crager M, Mamounas EP, Shak S, Wolmark N (2011) Risk of recurrence and chemotherapy benefit for patients with node negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors. J Clin Oncol 29(33):4365–4372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Goldstein LJ, Gray R, Badve S, Childs BH, Yoshizawa C, Rowley S, Shak S, Baehner FL, Ravdin PM, Dvidson NE, Sledge GW Jr, Perez EA, Shulman LN, Martino S, Sparano JA (2008) Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol 26(25):4063–4071

    Article  PubMed Central  PubMed  Google Scholar 

  13. Zujewski JA, Kamin L (2008) Trial assessing individualized options for treatment for breast cancer: the TAILORx trial. Future Oncol 4(5):603–610

    Article  CAS  PubMed  Google Scholar 

  14. Sparano JA (2006) TAILORx: trial assigning individualized options for treatment (Rx). Clin Breast Cancer 7(4):347–350

    Article  PubMed  Google Scholar 

  15. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, Freibauer C, Müller V, Jänicke F, Schmidt M, Kölbl H, Rody A, Kaufmann M, Schroth W, Brauch H, Schwab M, Fritz P, Weber KE, Feder IS, Hennig G, Kronenwett R, Gehrmann M, Gnant M; EP Investigators (2011) A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 17(18):6012–6020

    Article  CAS  PubMed  Google Scholar 

  16. Martin M, Brase JC, Calvo L, Krappmann K, Ruiz-Borrego M, Fisch K, Ruiz A, Weber KE, Munarriz B, Petry C, Rodriguez CA, Kronenwett R, Crespo C, Alba E, Carrasco E, Casas M, Caballero R, Rodriguez-Lescure A (2014) Clinical validation of the Endopredict test in node-positive, chemotherapy-treated ER+/HER2- breast cancer patients: results from the GEICAM 9906 trial. Breast Cancer Res 16(2):R38

    Article  PubMed Central  PubMed  Google Scholar 

  17. Denkert C, Kronenwett R, Schlake W, Bohmann K, Penzel R, Weber KE, Höfler H, Lehmann U, Schirmacher P, Specht K, Rudas M, Kreipe HH, Schraml P, Schlake G, Bago-Horvath Z, Tiecke F, Varga Z, Moch H, Schmidt M, Prinzler J, Kerjaschki D, Sinn BV, Müller BM, Filipits M, Petry C, Dietel M (2012) Decentral gene expression analysis for ER+/Her2- breast cancer: results of a proficiency testing program for the Endopredict assay. Virchows Arch 460(3):251–259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Kronenwett R, Bohmann K, Prinzler J, Sinn BV, Haufe F, Roth C, Averdick M, Ropers T, Windbergs C, Brase JC, Weber KE, Fisch K, Müller BM, Schmidt M, Filipits M, Dubsky P, Petry C, Dietel M, Denkert C (2012) Decentral gene expression analysis: analytical validation of the Endopredict genomic multianalyte breast cancer prognosis test. BMC Cancer 12:456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Poremba C, Uhlendorff J, Pfitzner BM, Hennig G, Bohmann K, Bojar H, Krenn V, Brase JC, Haufe F, Averdick M, Dietel M, Kronenwett R, Denkert C (2014) Preanalytical variables and performance of diagnostic RNA-based gene expression analysis in breast cancer. Virchows Arch 465(4):409–417

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167

    Article  PubMed Central  PubMed  Google Scholar 

  21. Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, Davies SR, Snider J, Stijleman IJ, Reed J, Cheang MC, Mardis ER, Perou CM, Bernard PS, Ellis MJ (2010) A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 16(21):5222–5232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Gnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, Mlineritsch B, Kwasny W, Knauer M, Singer C, Jakesz R, Dubsky P, Fitzal F, Bartsch R, Steger G, Balic M, Ressler S, Cowens JW, Storhoff J, Ferree S, Schaper C, Liu S, Fesl C, Nielsen TO; Austrian Breast and Colorectal Cancer Study Group (2014) Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol 25(2):339–345

    Article  CAS  PubMed  Google Scholar 

  23. Overmoyer B (2015) Treatment with adjuvant endocrine therapy for early-stage breast cancer: is it forever? J Clin Oncol

  24. Nanostring technologies—EU Version—Package Insert Prosigna™ Breast Cancer Prognostic Gene Signature Assay CE Version 06, created 2013–8

  25. Nanostring technologies—US Version - Package Insert Prosigna™ Breast Cancer Prognostic Gene Signature Assay CE Version 03, created 2013–11

  26. Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, Cowens JW, Ferree S, Schaper C, Fesl C, Gnant M (2014) Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol

  27. Nielsen T, Wallden B, Schaper C, Ferree S, Liu S, Gao D, Barry G, Dowidar N, Maysuria M, Storhoff J (2014) Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens. BMC Cancer 14:177

    Article  PubMed Central  PubMed  Google Scholar 

  28. Varga Z, Sinn P, Fritzsche F, von Hochstetter A, Noske A, Schraml P, Tausch C, Trojan A, Moch H (2013) Comparison of Endopredict and OncotypeDx test results in hormone receptor positive invasive breast cancer. PLoS One 8(3):e58483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Martin M, Brase JC, Perou CM, Ruiz A, Prat A, Weber KE, Calvo L, Petry C, Bernard PS, Ruiz-Borrego M, Kronenwett R, Rodriguez CA, Alvarez IM, Segui MA, Casas M, Carrasco E, Caballero R, Rodriguez-Lescure A (2013) Comparison of PAM50 risk of recurrence (ROR) scores with EndoPredict for predicting risk of distant metastasis in ER+/HER2-, early node-positive breast cancer patients treated with adjuvant chemotherapy—a GEICAM/ 9906 sub-study. Poster—San Antonio Breast Cancer Symposium—Cancer Therapy and Research Center at UT Health Science Center—December 10–14

  30. Dowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, Ferree S, Storhoff J, Schaper C, Cuzick J (2013) Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 31(22):2783–2790

    Article  PubMed  Google Scholar 

  31. Cardoso F, Van’t Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ (2008) Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 26:729–735

    Article  PubMed  Google Scholar 

  32. Harbeck N, Schmitt M, Meisner C, Friedel C, Untch M, Schmidt M, Sweep CG, Lisboa BW, Lux MP, Beck T, Hasmüller S, Kiechle M, Jänicke F, Thomssen C; Chemo-N 0 Study Group (2013) Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients. Eur J Cancer 49:1825–1835

  33. Dubsky P, Brase JC, Jakesz R, Rudas M, Singer CF, Greil R, Dietze O, Luisser I, Klug E, Sedivy R, Bachner M, Mayr D, Schmidt M, Gehrmann MC, Petry C, Weber KE, Fisch K, Kronenwett R, Gnant M, Filipits M; Austrian Breast and Colorectal Cancer Study Group (ABCSG) (2013) The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer 109(12):2959–2964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Filipits M, Nielsen TO, Rudas M, Greil R, Stöger H, Jakesz R, Bago-Horvath Z, Dietze O, Regitnig P, Gruber-Rossipal C, Müller-Holzner E, Singer CF, Mlineritsch B, Dubsky P, Bauernhofer T, Hubalek M, Knauer M, Trapl H, Fesl C, Schaper C, Ferree S, Liu S, Cowens JW, Gnant M; Austrian Breast and Colorectal Cancer Study Group (2014) The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer. Clin Cancer Res 20(5):1298–1305

    Article  CAS  PubMed  Google Scholar 

  35. Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, Erlander MG, Dunbier A, Sidhu K, Lopez-Knowles E, Goss PE, Dowsett M (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14(11):1067–1076

    Article  PubMed Central  PubMed  Google Scholar 

  36. Dubsky P, Filipits M, Jakesz R, Rudas M, Singer CF, Greil R, Dietze O, Luisser I, Klug E, Sedivy R, Bachner M, Mayr D, Schmidt M, Gehrmann MC, Petry C, Weber KE, Kronenwett R, Brase JC, Gnant M; Austrian Breast and Colorectal Cancer Study Group (ABCSG) (2013) EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer. Ann Oncol 24(3):640–647

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E, Zabaglo L, Mallon E, Green AR, Ellis IO, Howell A, Buzdar AU, Forbes JF (2011) Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 29(32):4273–4278

    Article  PubMed  Google Scholar 

  38. Schmidt M, Untch M (2014) Prediction of benefit from chemotherapy in ER-positive/HER2-negative breast cancer–a problem still to be solved. Ann Oncol 25(3):754

    Article  CAS  PubMed  Google Scholar 

  39. Lo SS, Mumby PB, Norton J, Rychlik K, Smerage J, Kash J, Chew HK, Gaynor ER, Hayes DF, Epstein A, Albain KS (2010) Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol 28(10):1671–1676

    Article  PubMed  Google Scholar 

  40. Müller BM, Keil E, Lehmann A, Winzer KJ, Richter-Ehrenstein C, Prinzler J, Bangemann N, Reles A, Stadie S, Schoenegg W, Eucker J, Schmidt M, Lippek F, Jöhrens K, Pahl S, Sinn BV, Budczies J, Dietel M, Denkert C (2013) The endopredict gene-expression assay in clinical practice—performance and impact on clinical decisions. PLoS One 8(6):e68252

    Article  PubMed Central  PubMed  Google Scholar 

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  1. Institut für Pathologie, Charité Universitätsmedizin Berlin, Campus Mitte,Charitéplatz 1, 10117, Berlin, Deutschland

    C. Denkert, B.M. Pfitzner, B.I. Heppner & M. Dietel

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C. Denkert und M. Dietel weisen auf folgende Beziehung hin: sie sind Mitgründer von Sividon Diagnostics. B.M. Pfitzner und B.I. Heppner geben an, dass kein Interessenkonflikt besteht.

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C. Röcken, Kiel

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Denkert, C., Pfitzner, B., Heppner, B. et al. Molekulare Pathologie beim Mammakarzinom. Pathologe 36, 145–153 (2015). https://doi.org/10.1007/s00292-015-0009-z

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