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Updated: Aug 9, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
PTEN in triple-negative breast carcinoma: protein expression and genomic alteration in pretreatment and posttreatment
Hui Chen1, Qingqing Ding1, Laila Khazai1
1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Background:
Recent advances have been made in targeting the phosphoinositide 3-kinase pathway in breast cancer. Phosphatase and tensin homolog (PTEN) is a key component of that pathway.
Objective:
To understand the changes in PTEN expression over the course of the disease in patients with triple-negative breast cancer (TNBC) and whether PTEN copy number variation (CNV) by next-generation sequencing (NGS) can serve as an alternative to immunohistochemistry (IHC) to identify PTEN loss.
Methods:
We compared PTEN expression by IHC between pretreatment tumors and residual tumors in the breast and lymph nodes after neoadjuvant chemotherapy in 96 patients enrolled in a TNBC clinical trial. A correlative analysis between PTEN protein expression and PTEN CNV by NGS was also performed.
Results:
With a stringent cutoff for PTEN IHC scoring, PTEN expression was discordant between pretreatment and posttreatment primary tumors in 5% of patients (n = 96) and between posttreatment primary tumors and lymph node metastases in 9% (n = 33). A less stringent cutoff yielded similar discordance rates. Intratumoral heterogeneity for PTEN loss was observed in 7% of the patients. Among pretreatment tumors, PTEN copy numbers by whole exome sequencing (n = 72) were significantly higher in the PTEN-positive tumors by IHC compared with the IHC PTEN-loss tumors (p < 0.0001). However, PTEN-positive and PTEN-loss tumors by IHC overlapped in copy numbers: 14 of 60 PTEN-positive samples showed decreased copy numbers in the range of those of the PTEN-loss tumors.
Conclusion:
Testing various specimens by IHC may generate different PTEN results in a small proportion of patients with TNBC; therefore, the decision of testing one versus multiple specimens in a clinical trial should be defined in the patient inclusion criteria. Although a distinct cutoff by which CNV differentiated PTEN-positive tumors from those with PTEN loss was not identified, higher copy number of PTEN may confer positive PTEN, whereas lower copy number of PTEN would necessitate additional testing by IHC to assess PTEN loss.
Trial Registration:
NCT02276443.
Insights
PTEN expression can vary in triple-negative breast cancer (TNBC) tumors over time and between tumor sites. Copy number variation (CNV) by next-generation sequencing (NGS) may complement immunohistochemistry (IHC) for assessing PTEN loss.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is a key target in breast cancer treatment.
- Phosphatase and tensin homolog (PTEN) is a critical regulator within the PI3K pathway.
Purpose of the Study:
- To investigate changes in PTEN expression during triple-negative breast cancer (TNBC) progression.
- To evaluate if PTEN copy number variation (CNV) detected by next-generation sequencing (NGS) can substitute for immunohistochemistry (IHC) in identifying PTEN loss.
Main Methods:
- PTEN expression was assessed using IHC in pretreatment and posttreatment tumors from 96 TNBC patients.
- PTEN CNV was analyzed using whole exome sequencing (WES) in a subset of patients.
- Correlative analysis was performed between PTEN protein levels (IHC) and PTEN CNV (WES).
Main Results:
- Discordance in PTEN expression was observed between pretreatment and posttreatment tumors (5%) and between primary tumors and lymph node metastases (9%).
- Intratumoral heterogeneity for PTEN loss was noted in 7% of patients.
- While PTEN-positive tumors generally showed higher PTEN CNV than PTEN-loss tumors, overlap in copy numbers was significant, indicating limitations for CNV alone.
Conclusions:
- PTEN expression can be dynamic in TNBC, necessitating clear criteria for specimen selection in clinical trials.
- NGS-based PTEN CNV analysis shows potential but does not fully replace IHC for definitive PTEN loss assessment due to overlapping copy numbers.
- Lower PTEN CNV may warrant further IHC testing to confirm PTEN loss in TNBC.
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