Discovery of novel rearrangements and fusions supports role for NGS in treatment of cancer

Feb 13 2012

Foundation Medicine, Inc., a molecular information company that brings comprehensive cancer gene analysis to routine clinical care, and Dana-Farber Cancer Institute today announced the Nature Medicine publication of results from their collaborative next-generation sequencing (NGS) study to assay cancer-relevant genes in 24 non-small cell lung cancer (NSCLC) and 40 colorectal cancer (CRC) cases. In this study, 59% of the samples were found to have genomic alterations directly associated with a clinically-available targeted therapeutic or a relevant clinical trial of a targeted therapy. Two novel gene fusions, KIF5B-RET in NSCLC and C2orf44-ALK in CRC, were discovered among the potentially druggable alterations identified in the study. Both of these findings may expand therapeutic options for a subset of cancer patients. This publication demonstrates that using targeted NGS to profile patient tumors for molecular alterations associated with therapeutic responses may have an important clinical impact in cancer treatment.

“This joint research with Dana-Farber translates genomic research to the clinic and we expect that it may quickly have a positive impact for patients.”

"In this collaboration, we detected clinically-relevant genomic alterations in more than half of the samples profiled, and, because Foundation Medicine's NGS assay detects all classes of alterations with clinical-grade sensitivity, this research was able to identify both expected as well as completely novel alterations," said Maureen Cronin, Ph.D., senior vice president, research & product development of Foundation Medicine and co-author of the study. "The discovery of novel rearrangements and fusions, such as KIF5B-RET and C2orf44-ALK, supports an important role for NGS in the clinical understanding and treatment of cancer."

"In a common indication like NSCLC, identifying even a small subpopulation of individuals with gene fusions who may be responsive to a targeted therapy has the potential for major therapeutic impact," said Phil Stephens, Ph.D., executive director, cancer genomics of Foundation Medicine and co-author of the study. "This joint research with Dana-Farber translates genomic research to the clinic and we expect that it may quickly have a positive impact for patients."

Clinically-relevant alterations, which are defined here as being associated with an available clinical treatment option or ongoing clinical trial investigating a new targeted therapy, were identified in 72% of NSCLC tumor samples and 52.5% of CRC tumor samples.

The novel, recurrent KIF5B-RET fusion was identified by the NGS assay in one patient with NSCLC. In subsequent screening, 11 additional RET fusions were identified in 561 lung adenocarcinoma samples from a cohort of never or limited former smokers with NSCLC. In common with known oncogenic alterations in EGFR and EML4-ALK, the KIF5B-RET gene fusion was found more than twice as often in NSCLC samples from individuals of Asian descent (0.8% (1/212) of the Caucasian samples and 2% (9/405) of the Asian patient samples). Additionally, none of the fusion-positive tumors contained alterations in any of the other known oncogenes that drive lung cancer (EGFR, ERBB2, BRAF or KRAS or rearrangements of EML4-ALK or ROS1).Tumors with this fusion were specifically sensitive to targeted drugs that inhibit RET, suggesting that prospective clinical trials of RET-targeted therapeutics may benefit individuals with NSCLC with KIF5B-RET rearrangements.

The second novel finding in the study was a potentially clinically-relevant gene fusion between C2orf44 and ALK identified in one CRC patient. Additional assays suggest this fusion gene yields 90-fold overexpression of anaplastic lymphoma kinase (ALK), the target of crizotinib, a U.S. FDA approved therapy for NSCLC. Given the structure of the rearrangement that generated the C2orf44-ALK fusion, it is unlikely that current clinical detection methods would have detected this alteration. This research thus suggests that a previously unrecognized subset of individuals with CRC may harbor genetic alterations that may make them responsive to ALK-inhibitor treatment.

The assay used for the testing described in this Nature Medicine paper is analytically validated to have a false discovery rate of less than 1% with at least 99% sensitivity for base substitutions occurring with at least 10% frequency.

The paper, "Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies" by Lipson, D. et al. is now available online.

Source Foundation Medicine