8]. International initiatives have established the combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard [9, 10]. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue [11-span class="a-plus-plus citation-ref citationid-c-r13_3200">13]. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models [14]. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER [15]. A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in [15]). In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial [5]. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR [11]. The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective." />
HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer
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  • 作者：Carsten Denkert (1)
    Jens Huober (2) (3)
    Sibylle Loibl (4)
    Judith Prinzler (1)
    Ralf Kronenwett (5) (6) (7)
    Silvia Darb-Esfahani (1)
    Jan C Brase (6)
    Christine Solbach (8)
    Keyur Mehta (4)
    Peter A Fasching (9)
    Bruno V Sinn (1)
    Knut Engels (10)
    Mattea Reinisch (4)
    Martin-Leo Hansmann (10)
    Hans Tesch (11)
    Gunter von Minckwitz (4)
    Michael Untch (12)
  • 刊名：Breast Cancer Research
  • 出版年：2013
  • 出版时间：February 2013
  • 年：2013
  • 卷：15
  • 期：1
  • 全文大小：458 KB
  • 参考文献：1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Herceptin Adjuvant (HERA) Trial Study Team: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. / N Engl J Med 2005, 353:1659-672. CrossRef
    2. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J, Breast Cancer International Research Group: Adjuvant trastuzumab in HER2-positive breast cancer. / N Engl J Med 2011, 365:1273-283. CrossRef
    3. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. / N Engl J Med 2005, 353:1673-684. CrossRef
    4. Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkki? S, M?ykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL: Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel orvinorelbine with or without trastuzumab as adjuvant treatments of breast cancer: final results of the FinHer Trial. / J Clin Oncol 2009, 27:5685-692. CrossRef
    5. Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kühn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, von Minckwitz G: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. / J Clin Oncol 2010, 28:2024-031. CrossRef
    6. Untch M, Fasching PA, Konecny GE, Hasmüller S, Lebeau A, Kreienberg R, Camara O, Müller V, du Bois A, Kühn T, Stickeler E, Harbeck N, H?ss C, Kahlert S, Beck T, Fett W, Mehta KM, von Minckwitz G, Loibl S: Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. / J Clin Oncol 2011, 29:3351-357. CrossRef
    7. 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, 13:25-2. CrossRef
    8. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M, NeoALTTO Study Team: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO):a randomised open-label, multicentre, phase 3 trial. / Lancet 2012, 379:633-40. CrossRef
    9. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF, American Society of Clinical Oncology/College of American Pathologists: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. / Arch Pathol Lab Med 2007, 131:18-3.
    10. Hammond ME, Hayes DF, Wolff AC: Clinical Notice for American Society of Clinical Oncology-College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. / J Clin Oncol 2011, 29:e458. CrossRef
    11. Müller BM, Kronenwett R, Hennig G, Euting H, Weber K, Bohmann K, Weichert W, Altmann G, Roth C, Winzer KJ, Kristiansen G, Petry C, Dietel M, Denkert C: Quantitative determination of estrogen receptor progesterone receptor and HER2 mRNA in formalin-fixed paraffin-embedded tissue-a new option for predictive biomarker assessment in breast cancer. / Diagn Mol Pathol 2011, 20:1-0. CrossRef
    12. Noske A, Loibl S, Darb-Esfahani S, Roller M, Kronenwett R, Müller BM, Steffen J, von Toerne C, Wirtz R, Baumann I, Hoffmann G, Heinrich G, Grasshoff ST, Ulmer HU, Denkert C, von Minckwitz G: Comparison of different approaches for assessmentof HER2 expression on protein and mRNA level: prediction of chemotherapy response in the neoadjuvant GeparTrio trial (NCT00544765). / Breast Cancer Res Treat 2011, 126:109-17. CrossRef
    13. Baehner FL, Achacoso N, Maddala T, Shak S, Quesenberry CP Jr, Goldstein LC, Gown AM, Habel LA: Human epidermal growth factor receptor 2 assessment in a case-control study: comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories. / J Clin Oncol 2010, 28:4300-306. CrossRef
    14. Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H, Slamon DJ: Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. / J Natl Cancer Inst 2003, 95:142-53. CrossRef
    15. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ, Panel members: 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, 22:1736-747. CrossRef
    16. von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kühn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M: Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. / J Clin Oncol 2010, 28:2015-023. CrossRef
    17. von Minckwitz G, Darb-Esfahani S, Loibl S, Huober J, Tesch H, Solbach C, Holms F, Eidtmann H, Dietrich K, Just M, Clemens MR, Hanusch C, Schrader I, Henschen S, Hoffmann G, Tiemann K, Diebold K, Untch M, Denkert C: Responsiveness of adjacent ductal carcinoma in situ and changes in HER2 status after neoadjuvant chemotherapy/trastuzumab treatment in early breast cancer-results from the GeparQuattro study (GBG 40). / Breast Cancer Res Treat 2012, 132:863-70. CrossRef
    18. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics: Reporting recommendations for tumor marker prognostic studies. / J Clin Oncol 2005, 23:9067-072. CrossRef
    19. Altman DG, McShane LM, Sauerbrei W, Taube SE: Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration. / PLoS Med 2012, 9:e1001216. CrossRef
    20. Bohmann K, Hennig G, Rogel U, Poremba C, Mueller BM, Fritz P, Stoerkel S, Schaefer KL: RNA extraction from archival formalin-fixed paraffin-embedded tissue: a comparison of manual semiautomated, and fully automated purification methods. / Clin Chem 2009, 55:1719-727. CrossRef
    21. Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von T?rne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G: Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. / J Clin Oncol 2010, 28:1146-452. CrossRef
    22. Hennig G, Gehrmann M, Stropp U, Brauch H, Fritz P, Eichelbaum M, Schwab M, Schroth W: Automated extraction of DNA and RNA from a single formalin-fixed paraffin-embedded tissue section for analysis of both single-nucleotide polymorphisms and mRNA expression. / Clin Chem 2010, 56:1845-853. CrossRef
    23. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, Freibauer C, Müller V, J?nicke F, Schmidt M, K?lbl 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: 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 2011, 17:6012-020. CrossRef
    24. Pentheroudakis G, Kalogeras KT, Wirtz RM, Grimani I, Zografos G, Gogas H, Stropp U, Pectasides D, Skarlos D, Hennig G, Samantas E, Bafaloukos D, Papakostas P, Kalofonos HP, Pavlidis N, Fountzilas G: Gene expression of estrogen receptor progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial. / Breast Cancer Res Treat 2009, 116:131-43. CrossRef
    25. Lazar AA, Cole BF, Bonetti M, Gelber RD: Evaluation of treatment-effect heterogeneity using biomarkers measured on a continuous scale: subpopulation treatment effect pattern plot. / J Clin Oncol 2010, 28:4539-544. CrossRef
    26. Bonetti M, Gelber RD: Patterns of treatment effects in subsets of patients in clinical trials. / Biostatistics 2004, 5:465-81. CrossRef
    27. Dowsett M, Procter M, McCaskill-Stevens W, de Azambuja E, Dafni U, Rueschoff J, Jordan B, Dolci S, Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart M, Leyland-Jones B: Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. / J Clin Oncol 2009, 27:2962-069. CrossRef
    28. Zhao W, Zhang Q, Kang X, Jin S, Lou C: AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells. / Biochem Biophys Res Commun 2009, 380:699-04. CrossRef
    29. Osborne CK, Shou J, Massarweh S, Schiff R: Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. / Clin Cancer Res 2005, 11:865s-870s.
    30. Lahusen T, Fereshteh M, Oh A, Wellstein A, Riegel AT: Epidermal growth factor receptor tyrosine phosphorylation and signaling controlled by a nuclear receptor coactivator amplified in breast cancer 1. / Cancer Res 2007, 67:7256-265. CrossRef
    31. Fereshteh MP, Tilli MT, Kim SE, Xu J, O'Malley BW, Wellstein A, Furth PA, Riegel AT: The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice. / Cancer Res 2008, 68:3697-706. CrossRef
    32. Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS: Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. / Nature 2008, 456:663-66. CrossRef
    33. Chang JCN, Mayer IA, Forero-Torres A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Rimawi MF and on behalf of the Translational Breast Cancer Research Consortium: TBCRC 006 A multicenter phase II study of neoadjuvant lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer. / J Clin Oncol Volume 29 2011 ASCO Annual Meeting Proceedings June 3-, 2011, Chicago 2011, (Suppl):505.
    34. Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, Cameron D, Bari M, Smith I, Leyland-Jones B, de Azambuja E, Wermuth P, Khasanov R, Feng-Yi F, Constantin C, Mayordomo JI, Su CH, Yu SY, Lluch A, Senkus-Konefka E, Price C, Haslbauer F, Suarez Sahui T, Srimuninnimit V, Colleoni M, Coates AS, Piccart-Gebhart MJ, Goldhirsch A, HERA Study Team: Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. / Ann Oncol 2008, 19:1090-096. CrossRef
    35. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. / J Clin Oncol 2009, 27:5538-546. CrossRef
    36. Paik S, Bryant J, Tan-Chiu E, Romond E, Hiller W, Park K, Brown A, Yothers G, Anderson S, Smith R, Wickerham DL, Wolmark N: Real-world performance of HER2 testing-National Surgical Adjuvant Breast and Bowel Project experience. / J Natl Cancer Inst 2002, 94:852-54. CrossRef
    37. Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, Addo FK, Murphy B, Ingle JN, Perez EA: Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. / J Natl Cancer Inst 2002, 94:855-57. CrossRef
    38. Perez EA, Suman VJ, Davidson NE, Martino S, Kaufman PA, Lingle WL, Flynn PJ, Ingle JN, Visscher D, Jenkins RB: HER2 testing by local central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. / J Clin Oncol 2006, 24:3032-038. CrossRef
    39. Dowsett M, Hanna WM, Kockx M, Penault-Llorca F, Rüschoff J, Gutjahr T, Habben K, van de Vijver MJ: Standardization of HER2 testing: results of an international proficiency-testing ring study. / Mod Pathol 2007, 20:584-91. CrossRef
    40. Pinhel I, Hills M, Drury S, Salter J, Sumo G, A'hern R, Bliss JM, Sestak I, Cuzick J, Barrett-Lee P, Harris A, Dowsett M, the NCRI Adjuvant Breast Cancer Trial Management Group: ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer. / Breast Cancer Res 2012, 14:R46. CrossRef
    41. Paik S, Kim C, Wolmark N: HER2 status and benefit from adjuvant trastuzumab in breast cancer. / N Engl J Med 2008, 358:1409-411. CrossRef
    42. ClinicalTrials.gov, identifier NCT01275677 [http://clinicaltrials.gov/ct2/show/NCT01275677?term=NCT01275677&rank=1]
    43. Dabbs DJ, Klein ME, Mohsin SK, Tubbs RR, Shuai Y, Bhargava R: High false-negative rate of HER2 quantitative reverse transcription polymerase chain reaction of the Oncotype DX test: an independent quality assurance study. / J Clin Oncol 2011, 29:4279-285. CrossRef
    44. 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, 30:1796-804. CrossRef
    45. Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G, German Breast Group (GBG); Arbeitsgemeinschaft Gyn?kologische Onkologie-Breast (AGO-B) Study Group: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. / Lancet Oncol 2012, 13:135-44. CrossRef
    46. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M, NeoALTTO Study Team: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised open-label, multicentre, phase 3 trial. / Lancet 2012, 379:633-40. CrossRef
    47. 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, 13:25-2. CrossRef
    48. Robidoux Andre, Tang Gong, Rastogi Priya, Geyer CharlesE, Azar CatherineA, Atkins James Norman, Fehrenbacher Louis, Bear Harry Douglas, Baez-Diaz J Luis, Kuebler Phillip, Margolese RichardG, Farrar William Blair, Brufsky Adam, Shibata HenryR, Bandos Hanna, Paik Soonmyung, Costantino JosephP, Swain SandraM, Mamounas EleftheriosP, Norman Wolmark: Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41. / J Clin Oncol 2012.,30(suppl): abstr LBA506
  • 作者单位：Carsten Denkert (1)
    Jens Huober (2) (3)
    Sibylle Loibl (4)
    Judith Prinzler (1)
    Ralf Kronenwett (5) (6) (7)
    Silvia Darb-Esfahani (1)
    Jan C Brase (6)
    Christine Solbach (8)
    Keyur Mehta (4)
    Peter A Fasching (9)
    Bruno V Sinn (1)
    Knut Engels (10)
    Mattea Reinisch (4)
    Martin-Leo Hansmann (10)
    Hans Tesch (11)
    Gunter von Minckwitz (4)
    Michael Untch (12)

    1. Institute of Pathology, Charité-Universit?tsmedizin Berlin, Charitéplatz 1, D-10117, Berlin, Germany
    2. Breast Cancer Center, Heinrich-Heine-University of Düsseldorf, Universit?tsstr.1, Düsseldorf, Germany
    3. Breast Center, Kantonsspital St. Gallen, Rorschacher Strasse 95, CH-9007, Kragujevac, Switzerland
    4. German Breast Group, Martin-Behaim-Str. 12, D-63263, Neu-Isenburg, Germany
    5. Department of Internal Medicine, Heinrich-Heine-University of Düsseldorf, Universit?tsstr.1, Düsseldorf, Germany
    6. Sividon Diagnostics, Nattermannallee 1, D-50829, Cologne, Germany
    7. Siemens Healthcare Diagnostics, Cologne, Nattermannallee 1, D-50829, Kragujevac, Germany
    8. Frauenklinik, Johann-Wolfgang-Goethe-Universit?t, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany
    9. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Universit?tssstr. 21, D-91054, Erlangen, Germany
    10. Senckenbergisches Institut für Pathologie, Johann-Wolfgang-Goethe-Universit?t, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany
    11. Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Im Prüfling 17-19, D-60389, Frankfurt am Main, Germany
    12. Helios Klinikum Berlin-Buch, Schwanebecker Chaussee 50, D-13125, Berlin, Germany
  • ISSN：1465-5411
文摘
Introduction Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group. Introduction The human epidermal growth factor receptor 2 (HER2) is the prototype of a predictive biomarker for targeted treatment [1-span class="a-plus-plus citation-ref citationid-c-r8_3200">8]. International initiatives have established the combination of immunohistochemistry (IHC) and in situ hybridization as the current gold standard [9, 10]. As an additional approach determination of HER2 mRNA expression is technically feasible in formalin-fixed paraffin-embedded (FFPE) tissue [11-span class="a-plus-plus citation-ref citationid-c-r13_3200">13]. Crosstalk between the estrogen receptor (ER) and the HER2 pathway has been suggested based on cell culture and animal models [14]. Consequently, the 2011 St Gallen panel has pointed out that HER2-positive tumors should be divided into two groups based on expression of the ER [15]. A retrospective analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 study has suggested that mRNA levels of HER2 and ESR1 might be relevant for the degree of benefit from adjuvant trastuzumab. By subpopulation treatment effect pattern plot (STEPP) analysis in ER-positive tumors, benefit from trastuzumab was shown to be restricted to those with higher levels of HER2 mRNA (S Paik, personal communication, results summarized in [15]). In our study we evaluated this hypothesis in the neoadjuvant setting in a cohort of 217 patients from the neoadjuvant GeparQuattro trial [5]. All patients had been HER2- positive by local pathology assessment and had received 24 to 36 weeks of neoadjuvant trastuzumab plus an anthracycline/taxane-based chemotherapy. For central evaluation we used three different methods, HER2 IHC, and HER2 silver in situ hybridization (SISH), as well as measurement of HER2 mRNA by quantitative real-time (qRT)-PCR [11]. The primary objective of this analysis was to investigate if pathological complete response (pCR) rate in HER2-positive breast cancer would depend on the level of HER2 mRNA expression, with a separate analysis for HR-positive and -negative tumors. Central evaluation of the HER2 status showed that 27% of the tumors with HER2 overexpression by local pathology were HER2-negative. This enabled us to compare response rates in patients with HER2-positive and -negative tumors as a secondary objective.

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