Abstract
BackgroundPhosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer.MethodsA cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher’s exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method.ResultsAlteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002).ConclusionsThe combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer.
Highlights
Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer
Decreased PTEN protein expression is more frequent than gene alterations in breast cancer Taken together, 46.1% (n = 280/608) cases showed a decreased or null expression of the PTEN protein by IHC, as depicted in Fig. 1, and were classified as PTEN-L
PTEN-L PTEN low, PTEN-WT PTEN wild-type, hormone receptor (HR) Hormone receptors, OR Odds ratio, confidence interval (CI) Confidence interval. None of these conditions were related to a worse prognosis when the expression of PTEN was retained (p = 0.73 and p = 0.52, respectively). These findings suggest that patients with HR- and/or HER2+ breast cancer have an unfavorable prognosis in terms of overall survival (OS) in the presence of low or null expression of PTEN but not if PTEN expression is retained
Summary
Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. Loss of PTEN activity has been reported across a variety of primary and metastatic malignancies, including breast cancer, and is related to tumorigenesis, tumor progression, and therapy resistance [3,4,5]. The clinical actionability of PTEN status has been studied in both prognostic and predictive settings [6, 7]. Analysis of PTEN expression has been proposed as a complementary biomarker for mismatch repair status assessment in breast cancer, potentially contributing to the selection of patients, including those with a hormone receptor (HR) + tumor, eligible to immune-checkpoint blockade [4, 9]. The consistency of PTEN testing in clinical practice for patients with breast cancer remains unclear [14]
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