PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

Abstract

Mismatch repair (MMR) analysis in breast cancer may help to inform immunotherapy decisions but it lacks breast-specific guidelines. Unlike in other neoplasms, MMR protein loss shows intra-tumor heterogeneity and it is not mirrored by microsatellite instability in the breast. Additional biomarkers can improve MMR clinical testing. Phosphatase and tensin homolog (PTEN) inactivation is an early oncogenic event that is associated with MMR deficiency (dMMR) in several tumors. Here, we sought to characterize the diagnostic utility of PTEN expression analysis for MMR status assessment in breast cancer. A total of 608 breast cancers were profiled for their MMR and PTEN status. Proteins expression and distribution were analyzed by immunohistochemistry (IHC) on tissue microarrays and confirmed on full sections; PTEN copy number alterations were detected using a real-time PCR assay. Overall, 78 (12.8%) cases were MMR-heterogeneous (hMMR), while all patterns of PTEN expression showed no intra-tumor heterogeneity. Wild-type PTEN expression was observed in 15 (18.5%) dMMR tumors (p < 0.0001). Survival analyses revealed significant correlations between MMR-proficient (pMMR), PTEN expression, and a better outcome. The positive predictive value of PTEN-retained status for pMMR ranged from 94.6% in estrogen receptor (ER)+/HER2- tumors to 100% in HER2-amplified and ER-/HER2- cases. We propose a novel diagnostic algorithm where PTEN expression analysis can be employed to identify pMMR breast cancers.

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

“…In an elegant study, Djordjevic and collaborators observed that in non-endometrioid endometrial carcinomas, a PTEN-retained and/or wild-type status significantly co-occur with a retained positive expression of the MMR proteins [46]. Similarly, significant correlations between MMR proficiency, PTEN wild-type expression, and a better outcome have been recently reported in breast cancers [47]. These observations can be of clinical value not only for Lynch syndrome screening (e.g., endometrial cancer, colorectal cancer) but also for prognostication and immunotherapy prediction (e.g., breast cancer).…”

“…Genomic scars in the MMR system are relatively rare in breast cancer, being reported in~2% of cases [49]. However, this subject is controversial in literature given the lack of companion diagnostics and/or tumor-specific guidelines for MMR analysis [47,[49][50][51][52][53][54]. Unlike in endometrial and colorectal cancers, MSI is restricted to a minority of breast cancers showing MMR protein loss [54].…”

“…PTEN altered function occurs in approximately 13.5% of human cancers through inframe, missense, and truncating mutations, gene fusions, amplifications, deletions, epigenetic silencing, and transcriptional modifications ( In particular, PTEN gene alterations are more frequent in endometrial cancer (35%), glial tumors (32%), prostate cancer (17%), melanoma (13%), non-small small-cell lung cancer (NSCLC) (12%), and breast cancer (9%) [63][64][65][66][67][68]. Of note, PTEN protein loss is a more frequent event in cancer, compared to PTEN genetic alterations, particularly in lung cancer and breast cancer [42,47,69]. Hence, only 9% of lung squamous cell carcinoma harbor PTEN somatic mutations, while up to 44% showed decreased protein levels [69].…”

Present and Future of Anti-Glioblastoma Therapies: A Deep Look into Molecular Dependencies/Features

“…The tumor suppressor PTEN has an important role as a lipid and protein phosphatase, regulating cell proliferation, adhesion, and invasion, and DNA damage repair [ 67 ]. PTEN dephosphorylates the PIP3 to create PIP2, and thereby inhibits the PI3K/AKT pathway [ 68 , 69 ]. The PI3K/AKT pathway is dysregulated in GBM and supports cell proliferation by promoting the presence of anti-apoptotic signals in the cell [ 70 ].…”

Mismatch Repair System Genomic Scars in Gastroesophageal Cancers: Biology and Clinical Testing

“…However, many Centers have recently adopted panels consisting of mononucleotide markers due to their higher sensitivity and specificity compared to dinucleotide markers [47]. Unlike in other types of tumors (e.g., breast cancer), there is a general agreement on the high correlation between MSI testing and MMR immunohistochemistry in GEC [48][49][50][51][52][53]. Epigenetic silencing of MLH1 by promoter hypermethylation is a crucial event that leads to dMMR both in the sporadic setting (more than 50% of MSI GCs) and in familial MSI GEC cases [43,54].…”