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

ABSTRACT: 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.

SUBMITTER: Darb-Esfahani S

PROVIDER: S-EPMC5356512 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Darb-Esfahani Silvia S Denkert Carsten C Stenzinger Albrecht A Salat Christoph C Sinn Bruno B Schem Christian C Endris Volker V Klare Peter P Schmitt Wolfgang W Blohmer Jens-Uwe JU Weichert Wilko W Möbs Markus M Tesch Hans H Kümmel Sherko S Sinn Peter P Jackisch Christian C Dietel Manfred M Reimer Toralf T Loi Sherene S Untch Michael M von Minckwitz Gunter G Nekljudova Valentina V Loibl Sibylle S

Oncotarget 20161001 42

<h4>Background</h4>TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.<h4>Methods</h4>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 ...[more]

PMID: 27611952

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Project description:Objective:This study aims to identify effective gene networks and biomarkers to predict response and prognosis for HER2-negative breast cancer patients who received sequential taxane-anthracycline neoadjuvant chemotherapy. Materials and Methods:Transcriptome data of training dataset including 310 HER2-negative breast cancer who received taxane-anthracycline treatment and an independent validation set with 198 samples were analyzed by weighted gene co-expression network analysis (WGCNA) approach in R language. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were performed for the selected genes. Module-clinical trait relationships were analyzed to explore the genes and pathways that associated with clinicopathological parameters. Log-rank tests and COX regression were used to identify the prognosis-related genes. Results:We found a significant correlation of an expression module with distant relapse-free survival (HR = 0.213, 95% CI [0.131-0.347], P = 4.80E-9). This blue module contained genes enriched in biological process of hormone levels regulation, reproductive system, response to estradiol, cell growth and mammary gland development as well as pathways including estrogen, apelin, cAMP, the PPAR signaling pathway and fatty acid metabolism. From this module, we further screened and validated six hub genes (CA12, FOXA1, MLPH, XBP1, GATA3 and MAGED2), the expression of which were significantly associated with both better chemotherapeutic response and favorable survival for BC patients. Conclusion:We used WGCNA approach to reveal a gene network that regulate HER2-negative breast cancer treatment with taxane-anthracycline neoadjuvant chemotherapy, which enriched in pathways of estrogen signaling, apelin signaling, cAMP signaling, the PPAR signaling pathway and fatty acid metabolism. In addition, genes of CA12, FOXA1, MLPH, XBP1, GATA3 and MAGED2 might serve as novel biomarkers predicting chemotherapeutic response and prognosis for HER2-negative breast cancer.

Project description:BACKGROUND:Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. METHODS:Patients with primary triple negative breast cancer ?2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. RESULTS:In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2-5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of ?-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. CONCLUSIONS:Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of ?-catenin pathway core proteins, supposedly outside the domain of epithelial-mesenchymal transition, claims for further investigation. TRIAL REGISTRATION:EU Clinical Trial Register, EudraCT number 2012-004956-12.

Dataset Information

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

Publications

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

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