I'm Dr. Vivek Subbiah from the University of Texas
MD Anderson Cancer Center, Houston, Texas.
We’re talking about testing for NTRK fusions.
They are rare in common tumors like lung cancer or breast cancer
and common in rare tumors.
Like the MASC, which is the mammary analogue secretory carcinoma,
or secretory breast cancer, and in pediatric patients,
it is common in the rare tumors, like congenital mesoblastic nephroma,
infantile fibrosarcoma, and secretory breast cancer.
There are four different methodologies that we can detect NTRK gene fusions.
FISH, which is the fluorescent in situ hybridization,
RT-PCR, which is a reverse transcriptase polymerase chain reaction,
immunohistochemistry, which is IHC.
And next generation sequencing, or NGS panel.
So let's talk about the difference between the DNA based
next generation sequencing and RNA based next generation sequencing.
With DNA based NGS, there is potential for detection of multiple different targets.
It detects fusions that may or may not be expressed.
It requires tiling through intronic regions,
which is difficult in genes with large introns,
for example the NTRK3.
The fusion positions here are inferred based on reads through genomic DNA.
Let's talk about RNA based NGS.
There is potential for detection of multiple different fusions and splice variants.
There is detection of express transcripts.
It reads directly through express transcripts, so no issues with introns,
just as we have with DNA based NGS.
The fusion positions with RNA based NGS are directly detected.
This is a 46-year old man who was diagnosed with stage IV
non-small-cell lung cancer.
After diagnosis, the patient received 1st line platinum-based chemotherapy.
Unfortunately progressed after nine months of therapy,
and then was a PD-1 inhibitor.
In this case, the immune checkpoint therapy with dostarlimab,
unfortunately progressed after two months of therapy.
At this time, a comprehensive next generation sequencing panel
was done, which revealed a TPM3-NTRK1 fusion.
Based on the fact that this patient's lung cancer harbored the NTRK1 fusion,
the patient was enrolled on an NTRK inhibitor trial–
in this case, Larotrectinib.
Partial response was achieved after 1.8 months.
Disease was controlled for 39 months. Unfortunately,
the treatment was discontinued due to progressive disease after 39 months.
The detection of NTRK1 fusion by comprehensive NGS testing,
conferred the gift of time to this patient.
Let's talk about the key takeaways.
Testing options include immunohistochemistry, FISH, and RT-PCR.
IHC is easily accessible, but lacks sensitivity
and specificity for routine clinical use.
FISH is highly sensitive, but requires technical expertise.
The RT-PCR is able to identify fusion partners, but unfortunately,
cannot detect unknown fusion partners
and poor preservation of tumor samples reduces sensitivity to RT-PCR.
Next generation sequencing allows testing for multiple alterations simultaneously.
RNA-based NGS is preferred for fusion detection,
can detect additional gene fusions relative to DNA-based NGS.
DNA NGS is, of course, an option, but some NTRK1 and NTRK3 fusions
may not be detected.
Thank you.