Abstract P4-10-23: Combined analysis of PTEN and routinely assessed biomarkers reveals new high-risk subgroups of HR- or HER2+ breast cancers
Authors: Fusco Nicola , Sajjadi Elham , Venetis Konstantinos , Invernizzi Marco , Gambini Donatella , Runza Letterio , Ferrero Stefano , Guerini-Rocco Elena 
Published: March 2022

Abstract
Background: The activity impairment of Phosphatase and tensin homolog (PTEN), a tumor suppressor and negative regulator of the PI3K/Akt pathway, 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 for the identification of high-risk breast cancer is improved by the analysis of PTEN status.Methods: The study group consisted of 608 breast cancers (group A) extracted from our tissue microarray biobank and a total of 4,265 patients (group B) from the METABRIC and MSK studies available at cBioPortal. Cases from the group A were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT) according to the PTEN expression levels by immunohistochemistry (IHC) and scored based on the ratio between normal and tumor tissue. Clinical and genomic data from group B were also analyzed, and, together with those from group A, relationships between PTEN and the clinicopathologic and molecular features were assessed using Fisher’s exact test, Chi-squared test, or Shapiro-Wilk test for continuous variables. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated for each variable. To identify factors associated with PTEN expression, multinomial logistic regression models were defined considering a stepwise selection procedure. Survival curves were built according to the Kaplan-Meier method and compared using the log-rank test.Results: Alteration 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 group A, while genetic aberrations in only 315/4,265 (7.4%) cases of group B. 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 but not disease-free survival in PTEN-L but not in PTEN-WT breast cancers (p&lt;.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).Discussion: We confirm that in breast cancer a wide spectrum PTEN expression patterns can be observed, emphasizes the need for the implementation of well-defined IHC guidelines. Furthermore, our data suggest that the different frequency of PTEN protein and gene alterations can be due to the several regulatory layers that mediate PTEN function, including transcriptional (e.g. epigenetic mechanisms and transcription factors), post-transcriptional (e.g. miRNAs, PTEN pseudogene), and post-translational mechanisms (e.g. phosphorylation, acetylation, ubiquitination, etc.). Despite their well-defined predictive role for endocrine therapy, HR are weak prognostic biomarkers in breast cancer. We show that loss of HR expression and HER2 overexpression/amplification is an independent poor prognostic factor in PTEN-L breast cancers. Conclusions: In conclusion, decreased expression of PTEN at the protein level is seen in almost half of breast cancer patients. We found a positive correlation between PTEN protein expression with HR and HER2 status and by the decreased relative expression of PTEN, both HR- and HER2 overexpression/amplification were significantly related to worse OS compared to the HR+/HER2- status. Moreover, this HER2 positivity either alone or concomitantly with HR positivity was associated with poorer survival compared to the HR+/HER2- status. Hence, the combined analysis of PTEN, HR, and HER2 may provide additional data to perform a tailored risk assessment while evaluating patients with breast cancers.
Citation Format: Nicola Fusco, Elham Sajjadi, Konstantinos Venetis, Marco Invernizzi, Donatella Gambini, Letterio Runza, Stefano Ferrero, Elena Guerini-Rocco. Combined analysis of PTEN and routinely assessed biomarkers reveals new high-risk subgroups of HR- or HER2+ breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-23.