PI3K pathway protein analyses in metastatic breast cancer patients receiving standard everolimus and exemestane

Abstract

Purpose Everolimus plus exemestane (EVE/EXE) is a registered treatment option for ER-positive, HER2-negative (ER +/HER2-) metastatic breast cancer (MBC), but resistance mechanisms limit efficacy. We aimed to find markers that might help select patients with a higher chance on benefit from EVE/EXE. Methods Immunohistochemistry (IHC) of PTEN, p-AKT(Thr308), p-AKT(Ser473), p-4EBP1, p-p70S6K, p-S6RP(Ser240/244), p-ERK1/2 and p-S6RP (Ser235/236) was performed on primary tumour tissue and on biopsies immediately taken from ER +/HER2- MBC patients before the start of standard EVE/EXE (Eudract 2013-004120-11). Unsupervised hierarchical clustering was executed to create heatmaps to distinguish subgroups of preferentially activated and less-activated PI3K/MAPK proteins. Uni- and multivariate Cox models were used for associations with PFS. Results Primary tumour tissue from 145 patients was retrieved. Median PFS was 5.4 months. Patients without (neo)adjuvant therapy (p = 0.03) or bone only disease (p = 0.04) had longer PFS on EVE/EXE. In primary tumours, neither single proteins nor PI3K/MAPK-associated heatmap subgroups were significantly associated with PFS. In 21 patients a non-osseous biopsy obtained before dosing was useful for continuous scoring, which demonstrated upregulation of several proteins as compared to readings in corresponding primary tumour tissues. These comparisons revealed that increased expression of p-4EBP1 was significantly associated with worse PFS (multivariate HR 3.69, p = 0.05). Conclusions IHC of single proteins or heatmap subgroups of the differentially activated PI3K/MAPK pathways was not able to discriminate patients on EVE/EXE with poor or better PFS. Upregulation of p-4EBP1 in pre-treatment biopsies as compared to levels in primary tumours pointed towards shorter PFS.

A Systematic Review of Artificial Intelligence Techniques in Cancer Prediction and Diagnosis

“… Radiation treatment : Radiation therapy kills the cancerous cells or slows down the growth of cancerous cells by damaging their DNA. Medical experts often recommend this treatment to shrink tumors or minimize cancer symptoms before surgery [ 89 ]. Stem cell transplant : Stem cell transplant is helpful for cancer that is related to blood, such as leukemia or lymphoma.…”

“…Radiation treatment : Radiation therapy kills the cancerous cells or slows down the growth of cancerous cells by damaging their DNA. Medical experts often recommend this treatment to shrink tumors or minimize cancer symptoms before surgery [ 89 ].…”

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

“…IHC of MYC in ER+/HER2− breast cancer samples FFPE blocks from primary tumor of the patients participating in the everolimus biomarker study (EudraCT number 2013-004120-11) were collected as previously described (Kruger et al, 2020). The study was approved by the Independent Ethics Committee of Amsterdam University Medical Centers and Institutional Review Board at each participating site and was performed in compliance with Good Clinical Practices, the Declaration of Helsinki, and carried out in keeping with applicable local law(s) and regulation(s).…”

Biomarkers of everolimus efficacy in breast cancer therapy

“…33 In a series of 145 ER positive, HER2 negative metastatic breast cancer who participated in a study of exemestane with everolimus therapy, expression of phosphorylated forms of five proteins (2 phosphorylated forms of AKT at positions T308 and S473, 4EBP1, p70S6 K, and S6RP) of the PI3 K/ AKT/ mTOR pathway by immunohistochemistry of primary tumor samples did not correlate with treatment benefit either individually or when examined together grouped in an activated pathway group and a normal group. 34 In contrast, in a sub-group of 21 patients participating in the study who had material from a biopsy of a metastatic site done just before the start of the exemestane/ everolimus therapy, patients with high phosphorylated 4EBP1 (p4EBP1) expression had worse PFS compared with patients with low p4EBP1. Since all patients in this study received exemestane with everolimus, it is not possible to deduce from the data whether p4EBP1 expression is a predictive biomarker of therapy efficacy or a prognostic biomarker.…”