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Dec 8, 2017

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ALK, RET, ROS1, MET Gene Fusion and MET Exon Skipping Detection by NGS

ALK, RET, ROS1, MET Gene Fusion and MET Exon Skipping Detection by NGS (LTFP) Molecular Diagnostics Lab Test

Name: ALK, RET, ROS1, MET Gene fusion by NGS

Test Name: ALK, RET, ROS1, MET Gene Fusion and MET Exon Skipping Detection by NGS

Health Link Test Code: LTFP

LIS Test Code: LTFP

CPT Code(s): 81479 (ALK), 81405 (RET), 81479 (ROS1), 81479 (MET)

Test Component:

Among a wide array of genomic alterations, the translocation (rearrangement) and subsequent fusion of normally non-contiguous chromosomal gene sequences or the loss of a coding segment within a gene can be an oncogenic driver in human cancers, usually through expression of chimeric or unique proteins with altered or unique functional properties.

 

Using targeted next generation sequencing, the Fusion Plex® CTL panel (Archer DX, Inc., Boulder, CO) allows for the concurrent screening of specific exons within the 18 genes listed in the table below, thereby enabling the detection of fusions or rearrangements that have been associated with a variety of human malignancies. These targeted genetic alterations can be important diagnostic and prognostic biologic biomarkers in cancer by providing important individualized information regarding tumor development and progression, along with predicting the response to various therapies.

 

Gene Targets within Archer DX Fusion Plex® CTL panel 

AKT1 ALK AXL BRAF CCND1 FGFR1 FGFR2 FGFR3 MET
NRG1 NTRK1 NTRK2 NTRK3 PPARG RAF1 RET ROS1 THADA

As a part of the Fusion Plex® CTL panel (Archer DX, Inc., Boulder, CO), this test is validated to qualitatively detect fusions involving the ALK, RET, ROS1 and MET genes most commonly found in lung adenocarcinoma or non-small cell lung carcinoma. ALK (exons 2, 4, 6, 10 and 16-23), RET (exons 2, 4, 6 and 8-14), ROS1 (exons 2, 4, 7, and 31-37) and MET (exons 2, 4, 5, 6, 13, 14, 16, 17 and 21) are not sequenced in their entirety and only rearrangements within these aforementioned targeted exons will be detected. This technology permits identification of theoretically any possible fusion partners involving these targeted exons of ALK, RET, ROS1 and MET, along with the clinically significant skipping of exon 14 in MET. Identification of fusions involving ALK, RET, ROS1 and MET, along with exon 14 skipping in MET, will be detected most common as a mutually exclusive oncogenic driver and will provide important clinical information with regarding to treatment selection among various tyrosine kinase inhibitors in the setting of lung adenocarcinoma and non-small cell lung carcinoma. While the intended use of this test is for screening gene rearrangements within ALK, RET, ROS1 and MET and MET exon 14 skipping, fusions involving other genes within the Fusion Plex® CTL panel may be detected in the setting of lung cancer and will be reported as additional findings.

Methodology: Next Generation Sequencing

Days Performed: Once a week.

In-Lab Turnaround Time: 2 weeks.

Specimen: Formalin fixed, paraffin embedded tissue (FFPE), Fine needle aspirate (FNA) or corresponding cell blocks from these specimens

Collection Instructions:

Batched runs begin on Monday or first working day of each week.

 

Provider must contact patient’s insurance about coverage for this molecular test and then counsel the patient on out-of-pocket costs.

 

For Unity and WI-MA patients, documented prior authorization will need to be present in Health Link or sent to laboratory before test will be collected and/or performed.

 

For all other managed care plans, referral must be placed in Health Link in order for testing on tissue specimens to be performed at UW Health; and patients should be referred to their primary care physician for collection of blood specimens.

 

For any other insurers, providers must check with insurer before ordering testing.

Stability Ambient:

Indefinitely.

Stability Refridgerated:

Indefinitely.

Stability Frozen:

Not acceptable.

Sample Analyzed: Tissue

Specimen Processing:

Five slides each containing 5 microns (uM) of FFPE tissue should be sent. Third slide should be H&E stained with the tumor circled. Please indicate percent tumor on Intra-Lab Send-Out Form.

In order to ensure that molecular testing is conducted on a representative sample and a direct correlation of molecular results with morphologic findings is possible, a pathologist selects the specimen(s) and, whenever possible, identifies the suspicious or neoplastic cells submitted for molecular testing.

Outreach Specimen Processing:

Transport with a cold pack. Avoid excessive heat.

Specimen Transport:

Transport at room temperature.

Interpretation:

A written interpretive report is provided by the laboratory detailing all genetic fusions detected. The significance of genetic fusions to pathogenicity and therapeutic response will be indicated whenever possible.

Test Limitations:

This assay will not be applied to the detection of single nucleotide variants, large insertions, deletions, duplications in or copy number variants of these genes. This test cannot differentiate between somatic (acquired) or germline (inherited) genetic variants. Additional testing may be necessary to clarify the significance of these results if there is potential for hereditary risk. While at present, gene rearrangements have not been implicated in hereditary cancer, however, this risk cannot be entirely excluded as certain other genetic variants in RET and MET have been associated with the predisposition to cancer. Consequently, where appropriate, it is recommended that patients receive genetic consultation to explain the implications of these test result(s), including probabilistic risk of disease and uncertainties, and the reproductive or medical options it may raise. Test results should be interpreted in the context of clinical findings, tumor sampling, histopathology and all other laboratory data. The presence or absence of a genetic variant(s) may not be predictive of a response to therapy in all patients.

 

While not possible to evaluate all types of fusions or possible fusion partners, based on validation studies relative to other forms of testing such as immunohistochemistry, fluorescence in situ hybridization and independent next generation sequencing, this assay has an estimated sensitivity of >95% and a specificity of >98% in the detection of gene fusions involving the ALK, RET, ROS1 and MET genes. This method cannot reliably detect fusions below the analytical sensitivity of 10% and without meeting the established quality thresholds. A negative result does not rule out the presence of gene rearrangements of ALK, RET, ROS1 and MET outside the targeted regions of Fusion Plex® CTL gene specific primers, or in the case of sequence polymorphisms not accommodated by these gene specific primers or below the sensitivity of the assay (~10%).

Additional Information:

A "Detected" results indicates the presence of a fusion. Inadequate specimen collection, processing and storage may invalidate test results. This test should not be used as the only criterion to form a clinical conclusion, instead, results should be correlated with other test results, patient symptoms and clinical presentation.

 

The performance characteristics of this test were validated by UWHC Clinical Laboratories. The U.S. Food and Drug Administration (FDA) has not approved or cleared this test; however, FDA approval or clearance is currently not required for clinical use of this test. The UWHC Clinical Laboratories is authorized under Clinical Laboratory Improvement Amendments (CLIA) to perform high-complexity testing.

 

A professional fee is associated with this test (CPT Code G0452).