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

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

doi:10.18632/oncotarget.11891

Abstract

BackgroundTP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.Methods450 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.ResultsOf 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).ConclusionsOur 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.

Highlights

RESULTSTP53 is the prototype of a tumor-suppressor gene and TP53 mutations emerged as a core component of cancer development since its discovery in 1979 [1]
We studied whether there was a link between TP53 status and the expression of various immune-related genes assessed in a previous project [10], and the only significant positive association was seen for missense mutations as compared to other mutations and CD8A gene expression in triple negative breast cancer (TNBC) (p = 0.020; not shown)
We studied the link between TP53 status and pathological complete response (pCR) in TNBC and HER2 cancers stratified for the type of chemotherapy as well as clinico-pathological factors, PIK3CA mutations, and Lymphocyte-predominant breast cancer (LPBC) subtype

Summary

Introduction

TP53 is the prototype of a tumor-suppressor gene and TP53 mutations emerged as a core component of cancer development since its discovery in 1979 [1]. It is by far the most frequently mutated gene in human cancer with varying mutation rates across entities and in entity subtypes [2, 3]. TP53 mutations in TNBC and HER2-positive cancers arise in a frequency that suggests that there could be an relevant connection between TP53 status and therapy response. TP53 mutations are frequent in breast cancer, their clinical relevance in terms of response to chemotherapy is controversial

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