Analysis Reveals Potentially Targetable Fusion Genes in Various Cancer Types

CHICAGO —An RNA assay for common gene fusions is now validated and available to guide patients with cancer to clinical trials and through drug treatment options, a fusion analysis of solid tumors presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting has shown.¹

“Fusions of genes are common events in epithelial cancers, with recurrent fusions arising as a result of genomic rearrangements or abnormal processing of mRNA,” explained lead investigator Igor A. Astsaturov, MD, PhD, medical oncologist at Fox Chase Cancer Center in Philadelphia, Pennsylvania. “Proteins translated from gene fusions are potential drug targets.”

Researchers retrospectively analyzed 1915 solid tumor specimens via fusion analysis using the ArcherDx FusionPlex Assay with or without next-generation sequencing. Commonly-profiled cancer specimens included colorectal adenocarcinoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, and glioblastoma multiforme. A confirmatory assay with validated gene fusions was used in 140 total samples.

One hundred and ninety-seven fusions were detected in 9.5% of the 1915 specimens. Kinase fusion genes that can be targeted with FDA-approved therapy or in the clinical trial setting included: ALK, BRAF, BRD3, BRD4, EGFR, FGFR1, FGFR2, FGFR3, MET, NTRK1, NTRK2, NTRK3, PKN1, PRKCA, PRKCB, RAF1, RET, and ROS1. One ligand fusion gene identified (NRG1) can also be targeted.

NTRK1/2/3 were identified in 4 cases of glioblastoma multiforme, 1 case of renal cell carcinoma, 1 case of gastrointestinal stromal tumor, 1 case of non-small cell lung cancer, and 1 case of soft tissue sarcoma, suggesting their clinical importance.

A subgroup analysis of 194 cases of breast adenocarcinomas detected a total of 21 unique fusions in 16 cases, including ESR1, RAF1, FGFR2, PPARG, RET, EGFR, FGFR3, MAST2, PRKCA, PRKCB, ERG, and ETV6.

Multiple types of ESR1 transcription factor fusions were identified, including ESR1-ATP2B2, ESR1-MKL1, ESR1-TNRC6B, ESR1-ARNT2, and ESR1-C6ORF211.

“ESR1 fusions are associated with anti-androgen resistance,” Dr Astsaturov explained. “Multiple ESR1 fusions should be prospectively evaluated for anti-estrogen resistance.”                          

Reference

1. Astsaturov IA, Ellis P, Swensen J, Arguello, D, Reddy, SK, Gatalica, Z, et al. Fusion analysis of solid tumors to reveal novel rearrangements in breast carcinomas. J Clin Oncol. 2016; 34 (suppl; abstr 11504).