Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy.
TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.



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.



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).



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.
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Silvia
S
Darb-Esfahani
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.|German Cancer Consortium, (DKTK), Berlin, Germany.
Carsten
C
Denkert
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Department of Pathology, Center for Integrated Diagnostics (CID), Massachusetts General Hospital, Boston, MA, USA.
Albrecht
A
Stenzinger
Hämatoonkologische Schwerpunktpraxis, Munich, Germany.
Christoph
C
Salat
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Bruno
B
Sinn
Department of Gynecology and Obstetrics, University Hospital Schleswig-Hostein, Kiel, Germany.
Christian
C
Schem
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Volker
V
Endris
Praxisklinik Krebsheilkunde für Frauen/Brustzentrum, Berlin, Germany.
Peter
P
Klare
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Wolfgang
W
Schmitt
Department of Gynecology and Obstetrics, Charité Universitätsmedizin Berlin, Berlin, Germany.
Jens-Uwe
JU
Blohmer
German Cancer Consortium, (DKTK), Berlin, Germany.|Institute of Pathology, Technical University Munich, Munich, Germany.
Wilko
W
Weichert
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Markus
M
Möbs
Center for Hematology and Oncology Bethanien, Frankfurt/Main, Germany.
Hans
H
Tesch
Breast Unit, Kliniken Essen Mitte, Essen, Germany.
Sherko
S
Kümmel
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Peter
P
Sinn
Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany.
Christian
C
Jackisch
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Manfred
M
Dietel
Department of Gynecology, Klinikum Südstadt Rostock, Rostock, Germany.
Toralf
T
Reimer
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Sherene
S
Loi
Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany.
Michael
M
Untch
German Breast Group c/o (GBG Forschungs GmbH), Neu-Isenburg, Germany.
Gunter
G
von Minckwitz
German Breast Group c/o (GBG Forschungs GmbH), Neu-Isenburg, Germany.
Valentina
V
Nekljudova
German Breast Group c/o (GBG Forschungs GmbH), Neu-Isenburg, Germany.
Sibylle
S
Loibl
D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D018943:Anthracyclines; D000068258:Bevacizumab; D001952:Bridged-Ring Compounds; D016190:Carboplatin; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53; C080625:taxane
HER2; TP53; mutation; pathological complete response; triple negative breast cancer