GAITHERSBURG, Maryland, July 18, 2017 /PRNewswire/ —
Two thirds of all breast cancer (BC) tumors are estrogen receptor positive (ER)+
ER+ BC patients have mixed responses to endocrine therapy
Research demonstrates mTOR pathway activation status prospectively predicts endocrine therapy treatment response
Avant Diagnostics, Inc. (“Avant”) (OTC: AVDX), an oncology-focused healthcare technology company commercializing the proprietary Theralink® phospho-protein biomarker platform across multiple cancers, today highlighted independent published literature that provides critical validation for the clinical utility of the Company’s proprietary Theralink® mTOR phosphoprotein assay in segmenting the estrogen receptor positive (ER+) breast cancer (BC) population by mTOR activation status. The data, published in multiple journals by leading independent research groups, demonstrates that ER+ BC patients whose tumors had highly activated mTOR pathway who were treated with anti-endocrine therapy such as Tamoxifen® are likely to exhibit treatment resistance, whereas patients whose tumors had low levels of mTOR pathway activation are likely to respond to treatment. Taken together, the data provides a compelling case for physicians treating ER+ BC patients to seek-out mTOR pathway activation status prior to initiating ER hormone therapy.
“The body of evidence regarding endocrine therapy treatment outcomes for ER+ breast cancer patients based upon mTOR pathway activation status as measured by activation of specific mTOR kinase substrates is compelling,” said Emanuel Petricoin, PhD, Co-Director of the Center for Applied Proteomics and Molecular Medicine (CAPMM) at George Mason University. “The data provides a strong rationale for physicians to seek-out mTOR pathway activation status as measured by protein phosphorylation of specific mTOR kinase substrates as part of the standard biomarker profiling paradigm in this patient population. The mTOR pathway activation assay licensed to Avant by George Mason University is patent protected and provides a significant barrier to entry so that Avant can commercialize this technology with the appropriate strategic plan under newly-appointed President & CEO Dr. Philippe Goix’s leadership.”
Avant has developed an analytically and clinically validated mTOR-pathway activation-focused assay that measures the activation state of specific mTOR protein kinases such as p70S6 and 4EBP1 that indicate mTOR pathway activation and endocrine resistance in the ER+ BC patient population. The Company’s mTOR pathway activation assay is protected by the issued US patent #8,628,931 that describes predicting a response to chemotherapy based upon the assay. The Company is evaluating strategic options for commercially launching the assay.
“This data provides further evidence that we, as a medical community, can push precision medicine to higher levels,” said Brian Harvey, Former Director of the Division of Gastroenterology Products at the Center for Drug Evaluation Research at the FDA. “Testing that optimizes treatment for each individual patient is the ultimate clinical goal.”
mTOR prognostic data for Tamoxifen response in ER+ Breast Cancer from five publications
Karlsson et al. Breast Cancer Research 2013, 15:R96
The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomized Stockholm tamoxifen trials
Elin Karlsson1*, Gizeh Pérez-Tenorio1, Risul Amin1, Josefine Bostner1, Lambert Skoog2, Tommy Fornander3, Dennis C Sgroi4, Bo Nordenskjöld1, Anna-Lotta Hallbeck1 and Olle Stål1
Introduction: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with estrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.
Methods: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomized Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.
Results: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signaling may be involved and the results further support a combination of ER and mTOR signaling targeted therapies.
Conclusion: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signaling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.
2.Beelen et al. Breast Cancer Research 2014, 16:R6
Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment
Karin Beelen1, Mark Opdam1, Tesa M Severson1, Rutger HT Koornstra1, Andrew D Vincent2, Jelle Wesseling3, Jettie J Muris3, Els MJJ Berns4, Jan B Vermorken5, Paul J van Diest6 and Sabine C Linn1,6,7*
Introduction: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycin (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients.
Methods: We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1-3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy.
Results: Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P
GAITHERSBURG, Maryland, July 18, 2017 /PRNewswire/ —
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