I need help, does anyone understand these results. I am currently on the Bruin 321 clinical trial and am on 3rd cycle of Pirtobrutinib. So far things are going good. I saw my doctor and she explained it somewhat but maybe someone on here can explain it to me in layman's terms.
Sequence Variants Detected:
BTK c.1442G>C p.Cys481Ser 5%
TP53 c.707A>G p.Tyr236Cys 51%
PLCG2 c.2120C>T p.Ser707Phe 31%
Copy Number Variants Detected: Loss 17p13 (TP53) seq[GRCh37] 17p13.3p11.2(65606_22072005)x1.14
These are mutations detected that they checked for in your blood or bone marrow.
I think they collect mutations in DNA floating around in your blood. Sometimes mutations might not have anything to do with CLL and are in fact germline mutations. The ones they listed here I suspect are related to CLL if they bothered to tell you.
The BTK mutation suggests there is probably some resistance to older generation BTK drugs like ibrutinib. But, I do not know the percent cut off to know if it matters. Some labs require certain percentages for it to be clinically meaningful. For example, 10% or something. It might even vary a little from lab to lab. If the percent is low it is used for future comparison to see if it increases over time.
TP53 mutation is at a high percent so you definitely have it. Not ideal but if you have had prior treatments not too surprising. We unfortunately keep meaner CLL cells the more treatment we do.
I assume PLCG2 is what we hear doctors talk about PLCgamma2. A mutation you have but I do not recall the relevance. I suspect they keep track of it for drug resistance like the BTK mutation.
You can go into a blackhole of mutations if you start googling them. They keep track of these sort of mutations for research.
If pirto is working that is all that matters!
My trial doctor is very good at explaining but sometimes during the visit lots of things are mentioned and after when I get home I sometimes forget what she explained to me. Yes these results are just for trial info but I guess they could come in handy further down the road.
I stay away from Google but I also like to be informed about these things. So far I am doing well on Pirtobrutinib after 3 cycles, actually haven't felt this good in a long time and hoping it stays this way for awhile.
On the Bruin 321 trial I was randomized to the Idelalisib + 6 months of Rituximab arm. This only lasted 9 months before complications from the Idelalisib ended me up in hospital for 10 days and then it took another 3 months to straighten me out before they could start me on the Pirto.
But as you said if the Pirto is working that's all that matters right now.
Wonderful that the pirtobrutinib is working and that you are feeling better than you've felt in a long time! As you said, so far so good. 😊
I know that you said that you wanted an explanation of your results in layman's terms, so I've given it a try:
BTK c.1442G>C p.Cys481Ser 5%
Short story: This mutation causes resistance to covalent BTK inhibitors ibrutinib, acalabrutinib & zanubrutinib, but does not affect noncovalent BTK inhibitors like pirtobrutinib, as DriedSeaweed mentioned.
Detail:
A mutation was detected at position 1442 of the BTK gene in 5% of your CLL cells. In these mutant cells the nucleotide guanosine/G was replaced by cytosine/C resulting in the amino acid serine replacing the amino acid cysteine in position 481 of the resulting BTK protein. The covalent BTK inhibitors such as ibrutinib, acalabrutinib and zanubrutinib inactivate BTK by binding covalently to cysteine at position 481, so any BTKs with that mutation would not be inhibited by covalent BTK inhibitors.
You are on pirtobrutinib, a noncovalent BTK inhibitor that does not require cysteine at position 481 to inactivate BTK. It binds BTK and inhibits it by another mechanism.
TP53 c.707A>G p.Tyr236Cys 51%
Short story:
This mutation in the TP53 gene causes the resulting p53 protein to be inactive in 53% of your CLL cells. That along with the del17p in your report may make it more likely that resistant mutations may show up over time.
Detail:
At position 707 of your TP53 gene adenosine (A) has been replaced by guanosine (G) causing the resulting protein to have a Cysteine (Cys) at position 236 of the protein instead of a Tyrosine (Tyr), resulting in a defective p53 protein.
onlinelibrary.wiley.com/doi...
PLCG2 c.2120C>T p.Ser707Phe 31%
Short story:
This mutation allows the B-cell–receptor signaling pathway to be operative even in the presence of BTK inhibitors. The mutation was found in a subclone representing 31% of your CLL cells. It is a subclone likely to increase in frequency over time because the mutation allows the CLL cells to evade pirtobrutinib inhibition leading eventually to pirtobrutinib resistance.
Detail:
PLCG2 is a gene that codes for the PLCγ2 protein which is downstream of BTK in the B-cell–receptor signaling pathway. The Ser707Phe mutant means that phenylalanine has replaced serine in the protein causing the enzyme to be constitutively active, meaning that inhibiting the upstream BTK with a BTK inhibitor would not block the pathway. This mutation is one of the common mutations leading to resistance to BTK inhibitors, covalent or noncovalent.
nejm.org/doi/full/10.1056/N...
Copy Number Variants Detected: Loss 17p13 (TP53) seq[GRCh37] 17p13.3p11.2(65606_22072005)x1.14
Short story:
It looks like your CLL clone is 100% del17p in one copy of the two #17 chromosomes. The .0.14 may be a subclone with a homozygous 17p deletion, meaning a small portion of your CLL cells may not have any TP53 gene. As others have said del17p is a very common mutation in CLL.
Detail:
The DNA between 17p13.3 and 17p11.2 has been deleted in one copy of chromosome 17. Specifically, nucleotides between 65606_22072005 are missing. The gene, TP53 which codes for the tumor suppressor p53 is located between base pairs 7,565,097-7,590,856 (17p13.1), and therefore is missing from one of your copies of chromosome 17 and possibly from a the second copy of chromosome 17 in a few cells (x1.14) The seq[GRCh37] refers to the Genome Reference Consortium human 37 genome that was used as a reference genome.
I thought that I'd make an attempt to help you understand your report by breaking down the mutation reporting language, after all you did say that you "like to be informed" For reporting gene mutations this is the language:
-The name of the gene
-The position of the mutation in the gene (c.###)
-The nature of the mutation (X>Y)
-The location and nature of the resulting mutation in the protein (p. xxx>yyy)
-The % occurrence in your CLL cells.
Please continue to report on your experience in the Bruin 321.
Whew, thanks for the explanations, I think....Lol. It will take some time to digest it all, if I can and if I can't well that's what my doctor is for and right now I am doing good and taking it 1 month at a time.
Thanks again,
Jack
Well Jack, the most relevant information for any of us is what effect any specific mutations have on our treatment plan, and our doctors can tell us that.
When a doctor receives a mutation report they can look up the specific mutation to see what the likely effect is. Many mutations don't affect treatment choices because they are neutral, that is they don't affect protein function.
I find that it is psychologically helpful for me to understand the meaning of reports that I get, i.e., what does "c." mean or "p." or "A>G" etc. Don't worry about any of this, I just did it for fun!
Nice Work gardening-girl! I felt like I understood for a minute.
JM
Only for a minute JM? What questions do you have? Maybe I can do a better job of explaining.
Just having fun with you. You did great job of making the difficult look easy "Sprezzatura".
Sprezzatura's a new word for me. I just looked it up. We never stop learning do we? 🤗
To treat or not to treat, that is the question..
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