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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 42 Pg. 67686-67698 (10 18 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27611952 (Publication Type: Journal Article)

Chemical References

• Anthracyclines
• Bridged-Ring Compounds
• Quinazolines
• Taxoids
• Tumor Suppressor Protein p53
• Lapatinib
• taxane
• Bevacizumab
• Carboplatin
• Receptor, ErbB-2
• Trastuzumab

Topics

• Anthracyclines (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (administration & dosage)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Bridged-Ring Compounds (administration & dosage)
• Carboplatin (administration & dosage)
• Chemotherapy, Adjuvant
• Disease-Free Survival
• Female
• Humans
• Lapatinib
• Middle Aged
• Mutation
• Neoadjuvant Therapy
• Quinazolines (administration & dosage)
• Receptor, ErbB-2 (metabolism)
• Taxoids (administration & dosage)
• Trastuzumab (administration & dosage)
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)
• Tumor Suppressor Protein p53 (genetics, metabolism)