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Immunohistochemistry for PTEN testing in HR +/HER2- metastatic breast cancer
Nicola Fusco1,2, Elena Guerini-Rocco3,4, Isabella Castellano5
1Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy. nicola.fusco@ieo.it.
Abstract:
The PTEN tumor suppressor regulates the PIK3CA/AKT1 pathway, and its inactivation significantly contributes to tumorigenesis and progression in hormone receptor-positive/HER2-negative (HR + /HER2 -) metastatic breast cancer (MBC). In ~ 5% of these patients, PTEN loss, primarily due to gene deletions, leads to aberrant PI3K signaling and enhanced oncogenic potential. Findings from the CAPItello-291 study further establish PTEN together with PIK3CA and AKT1 as a predictive biomarker for Capivasertib, a pan-AKT inhibitor, in these patients. Despite next-generation sequencing (NGS) being the most precise method for detecting gene losses, immunohistochemistry (IHC) offers some advantages, including accessibility, cost-effectiveness, and applicability when archival tissue is inadequate for NGS or when pre-analytical failure occurs. Notably, recent evidence supports a pragmatic IHC positivity criterion, defining PTEN deficiency as staining in less than 10% of tumor cells, regardless of intensity. In this manuscript, we provide a comprehensive overview of the clinical scenarios associated with PTEN IHC testing in HR + /HER2 - MBC, outline best practices to minimize the impact of pre-analytical and analytical variability, and propose a structured pathology report to standardize PTEN IHC evaluation in this context.
Insights
PTEN loss is common in hormone receptor-positive metastatic breast cancer and impacts treatment. Immunohistochemistry (IHC) is a practical method for detecting PTEN deficiency, guiding therapy decisions.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- PTEN tumor suppressor inactivation drives tumorigenesis in HR+/HER2- metastatic breast cancer (MBC).
- PTEN loss, often via gene deletion, activates PI3K signaling, promoting cancer progression in ~5% of HR+/HER2- MBC patients.
- PTEN, PIK3CA, and AKT1 are predictive biomarkers for the pan-AKT inhibitor Capivasertib, as shown in the CAPItello-291 study.
Purpose of the Study:
- To provide an overview of PTEN immunohistochemistry (IHC) testing in HR+/HER2- MBC.
- To outline best practices for minimizing variability in PTEN IHC testing.
- To propose a standardized pathology report for PTEN IHC evaluation.
Main Methods:
- Review of clinical scenarios for PTEN IHC testing in HR+/HER2- MBC.
- Discussion of best practices for pre-analytical and analytical variability in IHC.
- Proposal of a structured pathology report format.
Main Results:
- Immunohistochemistry (IHC) offers advantages over next-generation sequencing (NGS) for PTEN loss detection, including cost-effectiveness and accessibility.
- A pragmatic IHC criterion defines PTEN deficiency as staining in <10% of tumor cells.
- Standardized PTEN IHC evaluation is crucial for clinical decision-making.
Conclusions:
- PTEN IHC testing is valuable in HR+/HER2- MBC for identifying patients who may benefit from specific therapies.
- Standardized protocols and reporting for PTEN IHC are essential to ensure reliable results.
- Optimizing PTEN IHC testing improves patient stratification and treatment selection.
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