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Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

Silvia Darb-Esfahani _, Carsten Denkert, Albrecht Stenzinger, Christoph Salat, Bruno Sinn, Christian Schem, Volker Endris, Peter Klare, Wolfgang Schmitt, Jens-Uwe Blohmer, Wilko Weichert, Markus Möbs, Hans Tesch, Sherko Kümmel, Peter Sinn, Christian Jackisch, Manfred Dietel, Toralf Reimer, Sherene Loi, Michael Untch, Gunter von Minckwitz, Valentina Nekljudova, Sibylle Loibl

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Oncotarget. 2016; 7:67686-67698. https://doi.org/10.18632/oncotarget.11891

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Abstract

Silvia Darb-Esfahani1, Carsten Denkert1,2, Albrecht Stenzinger3,4, Christoph Salat5, Bruno Sinn1, Christian Schem6, Volker Endris3, Peter Klare7, Wolfgang Schmitt1, Jens-Uwe Blohmer8, Wilko Weichert2,9, Markus Möbs1, Hans Tesch10, Sherko Kümmel11, Peter Sinn3, Christian Jackisch12, Manfred Dietel1, Toralf Reimer13, Sherene Loi14, Michael Untch15, Gunter von Minckwitz16, Valentina Nekljudova16 and Sibylle Loibl16

1 Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany

2 German Cancer Consortium, (DKTK), Berlin, Germany

3 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

4 Department of Pathology, Center for Integrated Diagnostics (CID), Massachusetts General Hospital, Boston, MA, USA

5 Hämatoonkologische Schwerpunktpraxis, Munich, Germany

6 Department of Gynecology and Obstetrics, University Hospital Schleswig-Hostein, Kiel, Germany

7 Praxisklinik Krebsheilkunde für Frauen/Brustzentrum, Berlin, Germany

8 Department of Gynecology and Obstetrics, Charité Universitätsmedizin Berlin, Berlin, Germany

9 Institute of Pathology, Technical University Munich, Munich, Germany

10 Center for Hematology and Oncology Bethanien, Frankfurt/Main, Germany

11 Breast Unit, Kliniken Essen Mitte, Essen, Germany

12 Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany

13 Department of Gynecology, Klinikum Südstadt Rostock, Rostock, Germany

14 Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

15 Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany

16 German Breast Group c/o (GBG Forschungs GmbH), Neu-Isenburg, Germany

Correspondence to:

Silvia Darb-Esfahani, email:

Keywords: TP53, mutation, triple negative breast cancer, HER2, pathological complete response

Received: May 03, 2016 Accepted: August 24, 2016 Published: September 07, 2016

Abstract

Background: TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.

Methods: 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.

Results: Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019).

Conclusions: Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.


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