Immunohistochemistry for PTEN testing in HR +/HER2˗ metastatic breast cancer

TL;DR

This paper discusses the use of immunohistochemistry to test for PTEN in hormone receptor-positive/HER2-negative metastatic breast cancer and its role in predicting treatment response.

Contribution

The paper introduces best practices and a standardized pathology report for PTEN IHC testing in HR+/HER2− metastatic breast cancer.

Findings

PTEN loss is associated with aberrant PI3K signaling and oncogenic potential in HR+/HER2− metastatic breast cancer.

IHC with a positivity criterion of less than 10% staining is a practical alternative to NGS for PTEN evaluation.

A structured pathology report is proposed to standardize PTEN IHC evaluation in clinical settings.

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.

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