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Updated: Feb 26, 2026

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Clonal Dynamics and Molecular Heterogeneity of Metaplastic Breast Cancer: Focus on TP53 and PIK3CA Truncal Mutations

Rupei Ye1,2, Xinzhi Dai3, Zihan Yang1,2

  • 1Department of Pathology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China.

Breast Cancer (Dove Medical Press)
|February 25, 2026
PubMed
Abstract

Insights

Metaplastic breast carcinoma (MBC) has key genetic drivers like TP53 and PIK3CA, with evolving MCL1 amplification. Targeting the PI3K-Akt pathway offers a new therapeutic strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Biology

Background:

  • Metaplastic breast carcinoma (MBC) is a rare, aggressive triple-negative breast cancer subtype.
  • Its distinct molecular features are not fully understood, limiting effective treatment development.

Purpose of the Study:

  • To characterize the genomic landscape and clonal evolution of MBC.
  • To identify potential therapeutic vulnerabilities in MBC.

Main Methods:

  • Integrated clinicopathological data with next-generation sequencing (NGS) of 437 cancer genes.
  • Analyzed 25 tumor samples from 17 MBC patients, including primary and metastatic sites.
  • Performed functional enrichment analysis to identify key signaling pathways.

Main Results:

  • Identified recurrent alterations in TP53 (87.5%), PIK3CA (56.2%), and MCL1 (62.5% amplified).
  • TP53 and PIK3CA mutations showed consistent patterns between primary and metastatic tumors.
  • MCL1 amplification displayed dynamic evolution, with loss in some primary tumors and acquisition in metastases.
  • The PI3K-Akt signaling pathway was the most significantly altered pathway.

Conclusions:

  • MBC is characterized by truncal TP53/PIK3CA mutations and dynamic MCL1 amplification.
  • Persistent PI3K-Akt pathway activation represents a key therapeutic vulnerability.
  • PI3K-Akt inhibition and metastasis-specific targeting strategies show promise for MBC treatment.
Keywords:
PIK3CATP53clinicopathological characteristicsfunctional enrichment analysismetaplastic breast carcinomamolecular characteristicsnext-generation sequencing

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