1167P - Functional characterization of variants of unknown significance (VUS) in patients and their responsiveness to targeted therapy drugs (TTD)

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Presenter Gabi Tarcic
Citation Annals of Oncology (2016) 27 (6): 401-406. 10.1093/annonc/mdw380
Authors G. Tarcic1, C.M. Walko2, H.L. McLeod2, J.K. Hicks2, Z. Barbash1, O. Edelheit1, B. Miron3, M. Vidne1, E. Padron2
  • 1R&d, NovellusDx, 91120 - Jerusalem/IL
  • 2Malignant Hematology, H. Lee Moffitt Cancer Center University of South Florida, Tampa/US
  • 3Medical Affairs, NovellusDx, Jerusalem/IL

Abstract

Background

Molecular diagnostics revolutionized cancer care, allowing precision medicine to identify actionable mutations in patients' tumors. However, VUS are frequently found in potentially actionable genes and lack information for inclusion in treatment strategy. Uncovering the clinical relevance of these variants and their response to TTDs, is a crucial step in the development of precision medicine. To address this, we utilized NovellusDx's Functional Annotation for Cancer Treatment (FACT) platform, which monitors the activity of signaling pathways by means of a transfected cell-based personalized assay. As a functional platform, FACT reveals activated pathways regardless of the type of mutation, and measures their activity in the presence of TTDs

Methods

We analyzed advanced stage patients, some after multiple lines of treatment, in which a VUS was identified in potentially actionable genes. The patients' variants were synthesized from the clinically derived NGS data and analyzed with the FACT platform. We compared the activity level induced by the patient's variants compared to corresponding known hotspots, as well as their response to relevant TTDs

Results

Two Non-small cell lung cancer and one salivary gland patients are presented. VUS mutations were present in the key oncogenes KRAS, BRAF and EGFR. One patient's VUS (BRAF N581Y) was functionally inactive by the FACT system compared to the known hot spot mutations, therefore the use of the relevant TTD was predicted to be ineffective. On the other hand, two additional patients' VUS (KRAS G13P, EGFR S720Y) were found to be active. When measuring the potential benefit of TTDs (Erlotinib, Gefitinib or Trametinib), these active VUS were responsive to off-label TTDs at levels comparable to the known hotspot mutations providing sound evidence for off-label drug use

Conclusions

The diversity of VUS identified in cancer patients requires a functional assay to segregate clinically relevant variants which may predict response to TTD from those that are clinically inconsequential. The FACT platform can successfully provide sound rationale for considering novel oncogenic mutations as therapeutic, providing new treatment opportunities for these patients

Clinical trial identification

Legal entity responsible for the study

NovellusDx

Funding

NovellusDx

Disclosure

G. Tarcic: A full time employee of NovellusDx. Z. Barbash, O. Edelheit, B. Miron, M. Vidne: A full time employee of NovellusDx. All other authors have declared no conflicts of interest.