Comparison of the PI3KCA pathway in circulating tumor cells and corresponding tumor tissue of patients with metastatic breast cancer

Abstract

The aim of the present study was to compare the phosphatidylinositol 3-kinase (PI3KCA)-AKT serine/threonine kinase (AKT) pathway in circulating tumor cells (CTCs) and corresponding cancerous tissues. Stemness-like circulating tumor cells (slCTCs) and CTCs in epithelial-mesenchymal transition (EMT) have been implicated as the active source of metastatic spread in breast cancer (BC). In this regard, the PI3KCA-AKT signaling pathway was demonstrated to be implicated in and to be frequently mutated in BC. The present study compared this pathway in slCTCs/CTCs in EMT and the corresponding tumor tissues of 90 metastatic BC patients (pts). slCTCs and CTCs in EMT were isolated using the AdnaTest EMT-1/StemCell for the detection of aldehyde dehydrogenase 1 family member A1 (ALDH1) (singleplex PCR) and PI3KCA, AKT2 and twist family bHLH transcription factor 1 (multiplex PCR). Tumor tissue was investigated for PI3KCA hotspot mutations using Sanger sequencing of genomic DNA from micro-dissected formalin-fixed paraffin-embedded tissue, and for the expression of ALDH1 and phosphorylated AKT (pAKT), and phosphatase and tensin homolog (PTEN) loss, by immunohistochemistry. slCTCs were identified in 23% of pts (21/90 pts) and CTCs in EMT in 56% (50/90 pts) of pts. pAKT and ALDH1 positivity in tumor tissue was identified in 47 and 9% of cases, respectively, and a PTEN loss was observed in 18% of pts. A significant association was detected between pAKT expression in cancerous tissue and AKT2 expression in CTCs (P=0.037). PI3KCA mutations were detected in 32% of pts, most frequently on exons 21 (55%) and 10 (45%). Pts with PI3KCA mutations in tumor tissue had a significantly longer overall survival than pts with wild-type PI3KCA expression (P=0.007). Similar results were obtained for pts with aberrant PI3KCA signaling in CTCs and/or aberrant signaling in cancerous tissue (P=0.009). Therapy-resistant CTCs, potentially derived from the primary tumor or metastatic tissue, may be eliminated with specific PI3K pathway inhibitors, alone or in combination, to improve the prognosis of metastatic BC pts.

Targeted deep sequencing revealed variants in cell-free DNA of hormone receptor-positive metastatic breast cancer patients

“…The study was carried out at the Department of Gynecology and Obstetrics, in collaboration with the Department of Medical Oncology (for specimen recruitment), both at the University Hospital Essen, Germany and in collaboration with QIAGEN GmbH, Hilden, Germany (for library preparation and sequencing analysis). The eligibility criteria have been previously published [15]. Written informed consent was obtained from all participants at enrollment and specimens were collected using protocols approved by the institutional review board (12-5265-BO).…”

Circulating tumor cells and breast cancer‑specific mutations in primary breast cancer

“…While there are some studies that investigate the correlations between mutations in specific genes in CTCs and corresponding tumor tissue, trials addressing the association between mutational status of the primary tumor and the presence of CTCs are currently lacking. For example, in a study by Bredemeier et al, no correlation was observed between PI3KCA mutations in cancerous tissue and the presence of CTCs in peripheral blood (19). In another study, there was a high match rate between specific mutations in CTCs and corresponding tumor tissue, but no data regarding the association between a specific mutation and the number of CTCs were reported (18).…”

“…In a study including 216 patients, 12 genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB and CDKN2A) were established as significantly mutated in metastatic breast cancer (mBC), while 8 genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1 and AGRN) were more frequently mutated in mBC as compared to early breast cancer (17). Several published studies have investigated the mutational status of CTCs (18)(19)(20)(21); however, data on the association between gene mutations in primary tumor tissue and the presence of CTCs in the peripheral blood are lacking.…”

New insights into the genomic landscape of meningiomas identified FGFR3 in a subset of patients with favorable prognoses

“…PI3KCA was the most mutated gene in non- NF2 tumors. Mutations in these survival genes are typically associated with therapeutic resistance and chemotherapy-induced mutagenesis [37–40]. This highlights the importance of genetic assessment following surgical resection; if PI3KCA - and AKT1 -mutated tumors recur and undergo malignant progression to a higher histological grade, postoperative adjuvant treatment using known and well-characterized inhibitors should be employed, as opposed to radiotherapy or chemotherapy interventions.…”