Researchers Unveil Method to Identify Patients With CRC and NTRK Gene Fusions

Researchers have unveiled an effective method for identifying the majority of patients with colorectal cancer (CRC) who have NTRK gene fusions (Mod Pathol. 2019 Dec 2. Epub ahead of print).

“NTRK gene rearrangements are important to identify as predictors of response to targeted therapy in many malignancies. Only 0.16-0.3% of colorectal carcinomas…harbor these fusions making universal screening difficult,” according to Angela Chou, PhD, FRCPA, Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Australia, and colleagues.

Because of this, Dr Chou and co-investigators conducted a study to determine whether pan-Trk immunohistochemistry (IHC), mismatch repair deficiency (MMRd), and BRAFV600E mutation status could be used to triage molecular testing in patients with CRC.

A total of 4569 unselected patients with CRC underwent IHC in TMA format using 2 different anti-pan-Trk rabbit monoclonal antibodies. The investigators identified positive cases before performing RNA sequencing.

There were 9 (0.2%) cases in which pan-Trk IHC was positive, and both antibodies yielded similar staining characteristics with diffuse positive staining across all neoplastic cells.

Notably, 8 (89%) of these patients were MMRd (all showing MLH1/PMS2 loss) and lacking in the BRAFV600E mutation.

“That is, IHC was positive in 5.3% (8/152) MLH1/PMS2/BRAFV600E triple negative CRCs, but only 0.02% (1/4417) not showing this phenotype,” Dr Chou explained.

Gene rearrangements, including LMNA-NTRK1 in 5 CRCs, TPR-NTRK1, STRM-NTRK1, MUC2-NTRK2, and NTRK1 were observed in all 9 IHC-positive CRCs. According to Dr Chou et al, this suggests an approximate 100% specificity for IHC in this subgroup.

In addition, NTRK fusions were tied to larger (P = .029), right-sided (P = .02) tumors with infiltrative growth (P = .021).

The researchers state that testing of all CRCs for MMRd is routine at many institutions, as per universal Lynch syndrome screening, as well as testing of MLH1/PMS2-negative CRCs for BRAFV600E mutation.

“We conclude that performing pan-Trk IHC on this preselected subgroup of MLH1/PMS2/BRAFV600E triple negative CRCs (only 3.3% of all CRC patients) is a resource effective approach to identify the overwhelming majority of CRC patients with NTRK gene fusions,” Dr Chou and colleagues concluded.—Hina Porcelli