Dataset Information

TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting.

ABSTRACT:

Background

We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era.

Results

TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009).

Materials and methods

TP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off).

Conclusions

TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.

SUBMITTER: Fountzilas G

PROVIDER: S-EPMC5078047 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting.

Fountzilas George G Giannoulatou Eleni E Alexopoulou Zoi Z Zagouri Flora F Timotheadou Eleni E Papadopoulou Kyriaki K Lakis Sotiris S Bobos Mattheos M Poulios Christos C Sotiropoulou Maria M Lyberopoulou Aggeliki A Gogas Helen H Pentheroudakis George G Pectasides Dimitrios D Koutras Angelos A Christodoulou Christos C Papandreou Christos C Samantas Epaminontas E Papakostas Pavlos P Kosmidis Paris P Bafaloukos Dimitrios D Karanikiotis Charisios C Dimopoulos Meletios-Athanassios MA Kotoula Vassiliki V

Oncotarget 20160501 22

<h4>Background</h4>We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era.<h4>Results</h4>TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein p ...[more]

PMID: 27129168

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Project description:BackgroundTP53 is the most commonly mutated gene across all cancer types. R175H mutation was considered structural mutation where the mutation causes misfolding of the protein and leads to a significant conformational alterations within p53's DNA binding domain. The aim of this study was to explain the reason why R175H worse the response to immunotherapy by analyzing tumor immune microenvironment through the expression of immune cells and PD-1.Materials and methodsPatients diagnosed with metastatic carcinoma, including colorectal cancer (CRC), breast cancer (BRCA), gastric cancer (GC), non-small cell lung cancer (NSCLC), and 20 other cancer types, treated in a palliative setting at Samsung Medical Center between October 2019 and April 2021, were enrolled. Of these patients, those who underwent TDS analysis (TruSight™ Oncology 500 assay [TSO 500]) were finally analyzed.ResultsOf 1770 patients, 1012 (57.2%) harbored genetic alterations in TP53. All mutations were single nucleotide variants (SNVs), and the most frequent SNV was R175H (n = 84, 7.5%) which was known as one of the most common hotspot TP53 mutation. The overall survival of patients with TP53 R175H mutations was significantly worse following chemotherapy (606 vs. 456 days, p < 0.001) or immunotherapy (822 vs. 350 days, p < 0.001) compared to those with TP53 mutation in other loci. RNA sequencing indicated that the immune response-related pathways were downregulated in tumors harboring TP53 R175H mutation. Moreover, the expression of CD8(+) T cells PD-1 were lowered in R175H mutation tumors. In the analysis of TP53 structural domain, compared to those having TP53 mutation in other domain, patients with mutations occurring in the nuclear exporter signal (NES) and E4F1-binding domains had significantly worse overall survival following chemotherapy (NES: 606 vs. 451 days, p = 0.043; E4F1: 606 vs. 469 days, p = 0.046) and immunotherapy (NES: 822 vs. 403 days, p < 0.001; E4F1: 822 vs. 413 days, p < 0.001). In addition, tumors with TP53 mutation and co-existing copy number amplification of CCND1, FGF4, and FGF19 in chromosome 11 conferred worse prognosis than those with only TP53 mutation (p < 0.050).DiscussionEach TP53 mutations indicated differential treatment outcomes following chemotherapy or immunotherapy in patients with metastatic cancer. Functional analysis including RNASeq suggested that TP53 mutation downregulated immune response.ConclusionOverall, we found each TP53 mutation to indicate different prognoses in patients with metastatic tumors undergoing chemotherapy and ICI treatment. Further validations, including a prospective cohort study or a functional study, would be particularly valuable in advancing the knowledge on this aspect and developing improved prognostic parameters.

Dataset Information

TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting.

Background

Results

Materials and methods

Conclusions

Publications

TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting.

Similar Datasets

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