64P - Identification of the functional significance of mutations using the novel Precision Cancer Analysis System

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Nir Peled
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors N. Peled1, G. Tarcic2, Z. Barbash2, E. Besser2, M. Vidne2, M. Adamek3, Y. Fellig4, Y. Altschuler2
  • 1Davidoff Cancer Center, Rabin Medical Center Davidoff Cancer Centre, Beilinson Campus, 49100 - Petach Tikva/IL
  • 2R&d, NovellusDx, 91120 - Jerusalem/IL
  • 3Thoratic Surgery, Medical University of Silesia, Katowice/PL
  • 4Pathology, Hadassah Ein Kerem, Jerusalem/IL

Abstract

Background

Mounting evidence indicates that growth of pathologically identical lung cancers in each patient is fueled by different sets of mutations. The need to identify these drivers stems from the necessity for tailoring therapy and scheduling surveillance. This personalized medical approach has provided better treatment outcomes. We present a novel Precision Cancer Analysis system (PCAS) capable of identifying activated signaling pathways by means of a cell-based assay yielding a quantitative output of pathway activation. Being a functional platform PCAS reveals activated pathways regardless of the mutation type behind it, even if a variant of unknown significance (VUS) mutation.

Methods

In 10 patients with lung cancer next generation sequencing (NGS) was employed to sequence a set of 37 relevant genes, with 90–100% coverage. According to the prevalence of mutations in the analyzed cohort 3 major genes were selected: EGFR, PIK3CA and KRAS. These genes were then mapped to their major signaling pathways and the reporters that best account for their activation were selected (MAPK, STAT, NFkB and AKT).

Results

14 mutations were found, among them 3 in the tested genes: 2 in KRAS and 1 complex mutation in EGFR. In KRAS 1 was a known mutation and 1 was VUS. The former caused activation via MAPK but not the AKT pathway. The latter, never so far reported in cancer, significantly activated both pathways. Interestingly the VUS KRAS mutation was identified in carcinoid, whereas 2 carcinoid samples from other individuals displayed no mutations in the 37-gene panel. Additionally, 1 VUS in RB1 and 2 mutations in STK11 were found to be associated with cancer cells aggressiveness evidenced by vessel and nerve tissue invasion.

Conclusions

Measuring the functional mechanism behind known mutations and VUS provides critical information to the physician. The study produced a comprehensive delineation of the oncogenic activity of each patients' mutations demonstrating the ability of the PCAS to accurately deliver comparable actionable information as found by NGS; Functionally characterize mutations annotated as VUS; Monitor oncogenic activity of signaling pathways induced by different mutations and mutation-combinations enabling informed treatment decisions.

Clinical trial identification

Legal entity responsible for the study

NovellusDx

Funding

NovellusDx

Disclosure

N. Peled: Member of the Medical Advisory Board of NovellusDx. G. Tarcic, Z. Barbash, E. Besser, M. Vidne, Y. Altschuler: Employee of NovellusDx. All other authors have declared no conflicts of interest.