Thread by @AshleySumrallMD

🚨Tweetorial: NTRK 101 🚨Given the data discussed at @asco #ASCO2019 & @sno #SNO2019 on #NTRK fusions in primary brain tumors & brain mets, I thought we could review the background of these fusions, how to find them, and then look at potential options for tx. #btsm

<Disclaimer: I’m a speaker for Bayer (larotrectinib) and a subI for the STARTRK trial using entrectinib. I also have ongoing research work w @carisls > I’m keeping this as bias-free as possible though. Ok, next...

With the increase in tumor profiling & expanded options using #RNAseq, it seems like it is getting easier to find an #NTRK fusion. It can easily feel like Christmas when you do! 🎄 Just remember that an #NTRK MUTATION is not 🚫 fusion. They aren’t = & treatments aren’t the same.

What is an #NTRK anyway? Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC). These serve as tumor drivers.

Image from above is in this great piece. nature.com/articles/s4157…

Who gets these fusions? Kids & adults. I commonly reference 2 papers: TCGA & the @carisls experience. Still, numbers are small. I think we will see growing incidence as NGS, WES, & RNAseq become more mainstream #NTRK

This graphic is from Bayer who makes #larotrectinib, but I like the simple design. Most common tumors w/ #NTRK fusions.

1) From TCGA: ncbi.nlm.nih.gov/pmc/articles/P…

2) From the team from @carisls: nature.com/articles/s4137…

But what do we really know about #brainmets? There are very few instances of pre & post brain met tumor assessment (i.e. matched pairs) so we can’t truly determine if/ how/when #NTRK fusions show up. Acquired after RT, chemo, or targeted tx? Who knows? 🤷🏻‍♀️

And what about gliomas? 🤷🏻‍♀️ These are questions that we should all try to figure out over the next few years! #NTRK #SNO2019 #btsm

From a #braintumor stance, the incidence is debated as ~1-5%. In comparison to the low incidence of some molecular findings in lung cancer that are routinely screened, IMO we should be screening ALL primary brain tumors for #NTRK. I would also like to see it on #NCCN guidelines!

#NTRK fusions: how do you find them? Your choice of company matters!!! Look at this analysis from @sloan_kettering on tumors profiled @sloan_kettering 😳 ncbi.nlm.nih.gov/pubmed/3137576…

Did you catch that? #NTRK fusions were missed!! At an awesome cancer center w/ awesome teams. IHC & NGS w DNA 👏🏻are 👏🏻 not 👏🏻 enough!!

From the paper published by @carisls notice the discordance b/w IHC vs. ArcherDX RNA based fusion testing! #NTRK

The gold standard if you are looking for #NTRK fusion analysis should be RNA seq.

Even @myESMO issued a statement. #NTRK #RNAseq ncbi.nlm.nih.gov/pubmed/3126812…

To summarize, depending on how you look for #NTRK fusions, you may MISS some. Does your pathologist or profiling company offer IHC vs. NGS vs. RNAseq? 🤷🏻‍♀️ My best advice: ASK your service provider. I’m going to work through 3 examples. #rnaseq

Example 1: @carisls offers whole transcriptome sequencing. RNA-based testing is comprehensive

Example 2: @foundationone offers several options for profiling tumors. #Foundationheme will give you the best chance of detecting #NTRK fusions b/c #RNASEQ is used. I repeat... #FOUNDATIONHEME not #FoundationCDX (wish they would rename it, honestly, b/c it‘s for solids & sarcoma)

The popular #FoundationCDX only uses DNAseq. Be sure you know what to order! assets.ctfassets.net/vhribv12lmne/6…

Example 3: @NeoGenomics also offers #RNAseq analysis 👍🏻 neogenomics.com/test-menu/ntrk…

In the future when WES (exome) may be offered readily, we may see incidence of these #NTRK fusions and more related molecular findings increase

So, if you find an #NTRK fusion, what to do? That’s our next topic. But, first, questions? Comments?

@threadreaderapp plz unroll

Adding this tidbit after looking for an answer to @adamhayden ‘s question. ❤️ this article on the hx of fusions! #BCRABL #NTRK