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. 2016 Oct 18;7(42):67686-67698.
doi: 10.18632/oncotarget.11891.

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

Silvia Darb-Esfahani  1 , Carsten Denkert  1   2 , Albrecht Stenzinger  3   4 , Christoph Salat  5 , Bruno Sinn  1 , Christian Schem  6 , Volker Endris  3 , Peter Klare  7 , Wolfgang Schmitt  1 , Jens-Uwe Blohmer  8 , Wilko Weichert  2   9 , Markus Möbs  1 , Hans Tesch  10 , Sherko Kümmel  11 , Peter Sinn  3 , Christian Jackisch  12 , Manfred Dietel  1 , Toralf Reimer  13 , Sherene Loi  14 , Michael Untch  15 , Gunter von Minckwitz  16 , Valentina Nekljudova  16 , Sibylle Loibl  16
Affiliations

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

Silvia Darb-Esfahani et al. Oncotarget. .

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.

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

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Figures

Figure 1
Figure 1. Consort diagram
Figure 2
Figure 2
A. Distribution of mutations among exons. B. Distribution of mutation effects
Figure 3
Figure 3
A. Associations of mutations with molecular tumor type. p value: chi square B. Association with pCR in the total study group. C. Association with pCR in the HER2-positive group. D. Association with pCR in the TNBC group. B-D) p values: univariate logistic regression
Figure 4
Figure 4
A. Distribution of mutations among exons. B. Distribution of mutation effects.
See this image and copyright information in PMC

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