Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus

Abstract

Background Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. Patients and Methods Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. Results The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. AKT1E17K was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (AKT1E17K, PI3KCAE545K, and KITG565R,S709F). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. Conclusions The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study.

<p>Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an <em>omic</em> approach to identify novel druggable targets</p>

“…Mutational analysis did not reveal additional KIT mutations in BYL719-resistant cell lines by Sanger sequencing or SNV calling. With regard to PI3KCA , we Sanger sequenced exons 9 and 20, both codifying for the catalytic p110a subunit and associated with drug resistance 23–26. All samples were wild type.…”

Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

“…Breast cancer (BC) is the malignant neoplasm with the highest prevalence in women (Omarini et al, 2018 ). An extremely high frequency of AKT1(E17K) mutations has been reported in benign papillary tumors of the mammary gland [up to 20–62% (Dunlap et al, 2010 ; Troxell et al, 2010 ; Alves et al, 2018 ; Mishima et al, 2018 )] and is mainly found in BCs with positive estrogen receptor (ER) expression (Stemke-Hale et al, 2008 ; Lauring et al, 2010 ).…”

“…However, it is also noteworthy that AKT1(E17K) mutant oncoproteins can also selectively destroy rare, quiescent, chemotherapy-resistant, and tumor-promoting AKT1 low quiescent cancer cells (QCC) (Yeh and Ramaswamy, 2015 ; Alves et al, 2018 ). Multiple studies have reported significantly longer survival time after treatment in patients carrying the E17K mutation (Alves et al, 2018 ), suggesting that AKT1(E17K) expression plays a crucial role in its oncogenic/anti-tumor mechanism (Omarini et al, 2018 ).…”

The importance of androgen receptors in breast cancer

“…Subsequently, PTEN restrains PI3K action, which in turn weakens AR activity. In AR+ TNBC, the presence of PIK3CA mutation was higher than the AR negative, therefore dual targeting the AR and PI3K way leads to a synergistic anti-tumor effect [49][50][51][52][53].…”