TP53 Mutational Analysis Enhances the Prognostic Accuracy of IHC4 and PAM50 Assays.

Ching-Hung Lin,Chung-Chieh Wang,Wen-Hung Kuo,Chiun-Sheng Huang,Dwan-Ying Chang,Yen-Shen Lu,Ming-Yang Wang,Chin-Hao Chang,Wei-Wu Chen,Ann-Lii Cheng,Kuan-Ting Kuo,Fu-Chang Hu,I-Chiun Chen,Pei-Fang Wu

doi:10.1038/srep17879

Ching-Hung Lin, Chung-Chieh Wang + Show 12 more

Open Access

https://doi.org/10.1038/srep17879

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Abstract

IHC4 and PAM50 assays have been shown to provide additional prognostic information for patients with early breast cancer. We evaluated whether incorporating TP53 mutation analysis can further enhance their prognostic accuracy. We examined TP53 mutation and the IHC4 score in tumors of 605 patients diagnosed with stage I–III breast cancer at National Taiwan University Hospital (the NTUH cohort). We obtained information regarding TP53 mutation and PAM50 subtypes in 699 tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. We found that TP53 mutation was significantly associated with high-risk IHC4 group and with luminal B, HER2-enriched, and basal-like subtypes. Despite the strong associations, TP53 mutation independently predicted shorter relapse-free survival (hazard ratio [HR] = 1.63, P = 0.007) in the NTUH cohort and shorter breast cancer-specific survival (HR = 2.35, P = <0.001) in the METABRIC cohort. TP53 mutational analysis added significant prognostic information in addition to the IHC4 score (∆ LR-χ2 = 8.61, P = 0.002) in the NTUH cohort and the PAM50 subtypes (∆ LR-χ2 = 18.9, P = <0.001) in the METABRIC cohort. We conclude that incorporating TP53 mutation analysis can enhance the prognostic accuracy of the IHC4 and PAM50 assays.

Highlights

Prognostic value[7,8]
We evaluated the prognostic effect of TP53 mutation in one retrospective cohort by using IHC4 scores and in one public data set by using PAM50 scores
This study shows that TP53 mutation is an independent prognostic factor beyond the IHC4 and PAM50 assays

Summary

Introduction

Prognostic value[7,8]. The PIK3CA and TP53 somatic mutations are the 2 most frequently mutated genes in breast cancer, and their frequencies are much higher than other somatic mutations[10,11]. In contrast to the conflicting findings about prognostic value of PIK3CA mutation[12,13,14,15], TP53 mutation has been consistently shown to predict poor outcomes in 2 meta-analyses (hazard ratio [HR] = 2.0 and 2.27)[16,17]. TP53 mutation in breast cancer is associated with high-grade tumor behavior, and is molecularly distinct from wild type tumor[18,19]. We determined whether incorporating TP53 mutation can enhance the prognostic accuracy of the IHC4 and PAM50 assays

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Results

Conclusion