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

• Published in: Oncotarget Vol. 7; no. 42; pp. 67686 - 67698
• Main Authors: Darb-Esfahani, Silvia, Denkert, Carsten, Stenzinger, Albrecht, Salat, Christoph, Sinn, Bruno, Schem, Christian, Endris, Volker, Klare, Peter, Schmitt, Wolfgang, Blohmer, Jens-Uwe, Weichert, Wilko, Möbs, Markus, Tesch, Hans, Kümmel, Sherko, Sinn, Peter, Jackisch, Christian, Dietel, Manfred, Reimer, Toralf, Loi, Sherene, Untch, Michael, von Minckwitz, Gunter, Nekljudova, Valentina, Loibl, Sibylle
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 18.10.2016
• Subjects: Anthracyclines - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab - administration & dosage; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Bridged-Ring Compounds - administration & dosage; Carboplatin - administration & dosage; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Middle Aged; Mutation; Neoadjuvant Therapy; Priority Research Paper; Quinazolines - administration & dosage; Receptor, ErbB-2 - metabolism; Taxoids - administration & dosage; Trastuzumab - administration & dosage; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; mutation; pathological complete response; triple negative breast cancer; HER2; TP53
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11891

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.