Genomic testing for stage IV
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Thank you Moth for starting this thread. I got approval to get a tissue biopsy of my largest lung nodule in 2 weeks. I haven't had a tissue biopsy for 3 years and have faced progression many times. My liquid biopsy was from Guardant360 a year ago, and I didn't show any actionable mutations or amplifications likely due to a low tumor burden. My Onc ordered a new Guardant360 liquid biopsy last week. For the tissue biopsy, I wanted to know if I was still ER+ or possibly HER2low. I guess I should be asking my Onc for a Foundation One or Caris test from my tissue sample to learn more than just the basics? ~Kar
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received results of my testing - ERBB2 amplification ( I take it is a different name to Her2- then it is not a new info); CDK6 amplification and Tp53 213 .
TNB 9.
Shall talk to oncologist in 2 weeks
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I have shocking results from my lung biopsy. I have liver mets that are estrogen positive, and for the past 3 years my liver has remained tumor free. For the first time, my lung nodules were large enough to biopsy last week. Over the past 3 years they have slowly grown with my largest nodule going from 4mm to 17mm. The smaller nodules from 2-3mm to 10mm. A few days ago, I received my results from my liquid blood biopsy and I had the Pi3k mutation. Today I received my lung biopsy results and I am triple negative!!! OMG, I've only researched estrogen positive over the years. I am at a complete loss.
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KarPC, ugh, kick in the teeth for sure. Marker loss is pretty common (marker gain happens too but it is rarer). I would ask to have a PD-L1 assay run on that lung sample to see if you're a candidate for immunotherapy.
Will be interesting to see what your team recommends. You might want to re-biopsy the liver mets. Or just treat based on clinical presentation. I've had 2 lung biopsies but no liver biopsies - it sort of depends how things are presenting. Pi3k does open a treatment option too now.
Is it still Grade 3? Because such slow growing tnbc would be unusual that it took 3 yrs for them to get large enough, kwim? Gr 3 TN tends to just sort of explode like a pinata & go big & fast.
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Hi Moth, Thanks for the info! Yes, it is grade 3, so I guess that means it probably lost the estrogen receptor recently. My liver is tumor free right now so there is nothing to biopsy. Pi3k can be used for triple negative (since I have that mutation)? I just sent my onc a request to have the PD-L1 assay run on my lung sample - (thanks for that info). Are you both triple negative and estrogen positive?
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Hi all. Are there opinions on which genomic test is the best? I've had a Foundation One liquid. I'm thinking of ordering Caris on a tissue biopsy I should be getting done soon on my lung. Caris does whole exome and also RNA as well as DNA which seems the best - but wondering if people have thoughts.
In other gene news, has anyone had private genetic testing done (i.e. on germline, not somatic, mutations)? I'm in the UK and the NHS only tests for mutations if they think your family history points to them and even then it's a small number they do. I was advised by an oncologist to look into Ambry Genetics and their 70-gene hereditary cancer assay. Does anyone have experience with this?
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phet, how much would ambry cost?
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Moth - I think it is roughly $3000 USD, but I have written to them to ask exactly and waiting for a response.
I consulted with a friend of a friend who is an oncologist with a lung specialism but came highly recommended for general oncology so I had a chat. He was the one who recommended Ambry - he said with the behaviour of my tumor and the somatic mutation profile he would want to investigate all germline possibilities. It's like getting blood from a stone to get testing on the NHS (a whole other issue I could write a book on) so I just want to organise it myself. My oncologist will be on board I'm sure. I had recent progression to my brain and feel like I need to leave no stone unturned now.
Incidentally, I have tp53 and RB1 somatic mutations (among a number of others) and this oncologist told me that in lung and prostate that combination means a cancer begins to act *like* a high grade neuroendocrine tumor and also tends to switch from a less to a more aggressive subtype of cancer. I've since read a bit more about this in prostate and it's a recognised phenomenon and strongly linked to subtype 'switchers' (I switched from strongly ER+ at primary to TNBC at secondary only a year later). Obviously breast cancer is not prostate or lung but it's interesting that this combo causes both those cancers to morph into a much more aggressive iteration of prostate or lung cancer. Would be good to see some research in this in breast too. It does tend to make cancers more responsive to immuno though (like many other markers of aggression, plasticity and mutancy) so again, would be good to see research on this in breast.
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that's super interesting phet!
One of the reasons I asked is that my germline testing (negative for known muts) was paid for by my provincial cancer agency but they outsourced it to Color Genomics and their test is cheap. Like it's always way cheaper than anything else people mention and I'm always wondering whether I should redo it with another company. Otoh, the provincial cancer agencies here seem to be fairly strictly evidence based so it can't have been totally bogus but it's just ... weird...
My maternal aunt died in her early 60s of an occult cancer they were never able to identify. She had elevated serum tumor markers for ovarian and breast but not primary was ever found. We actually managed to get permission to access her medical records to review them because my genetics counsellor thought I was just being a ditz & didn't know her medical history properly... but that was her situation after all. Given her case & my triple neg, I was really thinking a gene would pop up. I have a daughter so if there IS a gene that is acting up, I really want to know for her sake.
I too read a bit about the switchers and gain and loss of certain characteristics. It's an interesting research topic but I now stop reading if I can't think of a direct clinical application for me, kwim? If it's not a targetable mutation and since I clearly can't control my mutations I'm just skipping all that bench research now. I was getting so anxious for a while (...who am I kidding, I'm still anxious lol)
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phet, I hope you find some answers, please keep us posted. Progression to the brain is a new challenge for sure, but I hope you will be able to stabilize that for the time being. I have also have a Tp53 mutation, although I don't know much that's useful about it (except that it is a feature that tends to make cancers very aggressive). All the same I will let you know if I come across anything that could be helpful regarding the Tp53 mutation.
I've been ER/PR+ but I'm starting to have progression in some places and not others. I am wondering if I have also switched to being TN in those places. Last I asked my MO did not want to attempt a new biopsy (for a combination of reasons) but maybe things will have changed.
Best wishes to everyone.
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I have TP53 too. I can't remember if it was in this thread or somewhere else that I mentioned that almost all my tumor mutations are on a handful of chromosomes. TP53 is on chr 19. I have two more known muts on chr 19 and a whole bunch of VUS. Apparently I really messed up my 19th chr. I have a bunch in other places too but it was weird to see how many were in 19.
just a weird and useless aside. (Unless CRISPR gets itself together and figures out for real to replace chunks of broken cancer DNA instead of making glow in the dark animals)
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I initially tested for BRCA in 2008 at 44 years old with my stage 1 dx but it was negative. I saw a genetics person again in 2018 (1 year prior to my stage IV dx) and they found I have an ATM mutation (germline). My 2 sisters and mother were recommended to test with Color.com and all of them also have the ATM mutation. www.color.com was pretty fast, we are in the US and they mailed a tube that you spit in and mailed back. So far I am the only one with cancer, my younger sister had a large (15cm) pancreatic mucinous cystic neoplasm removed in 2013, non malignant but is now considered to be ATM related. I also have variances in PHOX2B and probable copy loss of TP53 and a portion of chromosome 19 . Not sure what any of this means! So far, the genetic testing is considered "non actionable". I have responded well to Fulvestrant/Ibrance. I started pancreatic screening in 2018 due to this but they refused to do any pet scans for breast cancer as I was considered to be such low risk for recurrence (node neg stage 1 completed chemo/rads and 6 years of femara). If i could add an emoji it would be an eye roll! My maternal grandfather died before I was born from "stomach cancer" in 1961 - most likely pancreatic from ATM mutation. Other than him, we have very little cancer in our family.
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I was tested through color too. Good to hear your family got good results from that test, aprilgirl
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I posted this on the Liver Met Thread and cross posting here as suggested by another member....
Got my Tempus report today.
Ok, I do not understand most of this Tempus report. But looks like only actionable mutation is the BRCA2, which also showed up in the 2017 original liver tumor biopsy report (Foundation One that time). TMB is 5.3 (whatever that means) and Microsatellite instability is "stable". Biologically Relevant is CDKN1B and MAP3K1 (whatever that means). FDA approved Therapies are PARP inhibitors.
This is the DNA portion of the test, awaiting the RNA portion.
Thoughts.....
A couple of people commented in the Liver Met Thread so I have a discussion going there too. Any other suggestions???
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I'm going to copy & paste my response here too for continuity
TMB (tumor mutational burden) has to be over or equal to 10 to be "high" & qualify for pembrolizumab
Definitely PARP inhibitor is on the table with the BRCA mutation.
The other identified things are names of genes. CDKN1B is cykline dependent kinase inhibitor 1B. It's one of the genes that puts the brakes on cells replicating. If yours is low, that could be one of the drivers of your cancer. (it's on chromosome 12)
if you think about the category of cancer drugs CDK4/6 inhibitors, like Ibrance, they are trying to target that same pathway & make up for the faulty genes not working to stop cells from replicating.
MAP3K1 is another protein kinase gene (chromosome 5). It's implicated in breast cancer but I'm not sure its role is well understood.
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Cross- posting my response for continuity too.....
Moth- I cross posted to the genomic Thread, but since we have a discussion going here I wanted to expound on your comments here.
My CDKN1B was 37.8%--- low or not?? And since I am on a CDK inhibitor now (Ibrance) then would we continue it?
This is waaay over my head.
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candy, I'm just having a look at a sample Tempus report and the percentage they report for a gene is likely a "variant allele fraction" - it can be used to determine if a mutation is somatic or germline. I'm reading that a germline mutation would give a 50-100% result. I don't think this percentage issue is relevant for you. It still means you have a mutation in that gene.
I think given you have this mutation it's reasonable to discuss with your MO whether cdk 4/6 should remain part of your treatment. If you're progressing on one, you might want a trial with another. There are 3 approved in US: verzenio, ibrance, kisqali. This is where your MO should be providing guidance though.
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Another cross post from the Ibrance Thread----
I am wondering about my ER flipping from strongly positive to now 0, negative. My PR is still positive. No ESR mutations mentioned. So will hormone therapy still work?? And nothing mentioned about PIK3CA, so no Piqray??
Sounds like maybe a PARP, but nothing else suggested on this report. So where does that leave me????? Does that mean I don't have many options????
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Moth- I know my MO is the doctor and she will suggest my next treatment plan. Just wanted to pick the brains on here to help me understand.
Yes the % is listed under :Variant Allele Fraction". I have no idea what that means. And "germline", what does that mean? My percentages were all under 50%-- 46.5 for the BRCA, 37.8 for the CDKN1B, and 13.1 for MAP3K1.
I mentioned to my MO before about changing from Ibrance to Verzenio and she said the insurance would say NO since documentation would show progression on a CDK so we could not go to another CDK. But I say we try and see what insurance says.
Edited--- I Googled Germline vs Somatic. Germline is hereditary. So with my percentages it may mean that they are somatic?? Anyway, just wanted to say I googled the terms.
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germline mutations are ones you inherit from your parents
somatic mutations are ones that spontaneously develop
If you don't have P13K mutation then piqray is not going to help.
Your most actionable mutation from what I see is BRCA2 because PARP inhibitors do work well.
Not sure about the hormone profile & whether hormone therapy is still indicated when you have 0 ER but still have PR. I think that's still under debate - like so much in breast cancer.
You do have lots of chemo options in addition to the PARP.
At this point in the state of cancer treatment, there are really only a few targettable mutations that these tests can identify. I got nothing useful out of mine really
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Since a BRCA2 mutation was found in the tumor, there are two possibilities: The mutation could be only in the rogue cells that are cancer, meaning in the tumor only -- somatic. Or the mutation could be in all your cells (including the tumor cells) as an inherited mutation -- germline. So that is why I asked on the liver mets thread if you had done a good, thorough BRCA germline test. (Not a cheap one that only checks a few BRCA mutations.)
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ShetlandPony- Back then we did the genetic testing from the company Myriad and the genomic testing from Foundation One. I don't know if Myriad is considered the "cheap" one. Just did what my MO at the time suggested.
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Ok, one other thing. I am not a doctor and this is waaay above my head. But when I compare my testing from 2017 Foundation One to the Tempus testing now I found the BRCA, CDKN1B, and MAP3K1 are all on the original testing from 2017. Low TMB then and now. Microsatellite Instability stable now and then.
So the only change I see, and I am not a doctor, is the ER flipped from positive to negative. No new findings, that I see.
So progression? And why?
I will ask my MO, but nothing jumping out to me that BAM you have developed these mutations and that is why you are progressing.
Confusing.....
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I think Myriad is good. You could ask if they have added new BRCA mutations to their test, especially if there are other BRCA-related cancers in the family. But this could simply be a somatic mutation. In either case the PARP inhibitor could be used.
As far as the same mutations appearing in the past and now, based on my experience, it could just be a matter of what was the driver of the cancer back then and what is the driver of the cancer now. Perhaps in the past the ER pathway was driving it, and now the BRCA pathway is. You inhibited the ER pathway so it turned to the BRCA pathway. (Sneaky you-know-what that cancer is.) After Ibrance + letrozole failed me, and so did Faslodex + afinitor, we realized the cancer was no longer affected by hormonal treatment, even though it still tested ER+. The ERBB2 (Her2) mutation showed up on my tumor genomics test at that point. Maybe that was now the driver. We considered neratinib for the ERBB2 mutation, but chose to go with a general chemo, Xeloda, and it worked for two years. Then when it failed, and Halaven and Doxil had no effect, we decided to address the ERBB2 mutation still showing up on my test, with neratinib, and Bingo! It did the trick.
(By the way, my combo also includes Faslodex so that when we inhibit the ERBB2 pathway, the cancer cannot revert to the ER pathway.)
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Candy. Was tempus a blood test or a tissue biopsy? I just got a blood biopsy from Guardant and it showed I qualify for piqray. Then a few days later, I got my lung tissue biopsy results and the report showed I am now triple negative. I've only been treated for ER+. We think my liver is still ER+ since it remains tumor free. What a mess. I want a do-over of my lung tissue biopsy!
My favorite treatment to date was Xeloda which I believe would be a good option for you. I had no hair loss and the other side effects were mild for me. I liked it much better than Ibrance. You still have so many options available. ~kar
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Xeloda was my favorite, too.
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KarPC-- Tempus was tissue. We did Guardant first--blood. But it didn't show ANYTHING. So we did tissue with Tempus.
This is so confusing. I have telephone visit with my MO tomorrow (Thursday) so I will hear her plan. Just wanted to post here to try to understand so I can participate in the doc discussion. And know the basics of my test results.
Just frustrating I cannot use Piqray and probably not immunotherapy. CDK's probably off the table now with progression while on a CDK. Feels like I am limited.
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Candy. It is confusing - ugh! Hopefully your onc has some good ideas.
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I think one thing we need to talk about more is that for most of us, these tests do not yield actionable information. I think it's just too early in the technology, too early in our understanding of specific cancer drivers and we simply do not have enough pharmaceuticals to address whatever drivers we find. It's often recommended and if insurance pays and esp if you're getting a biopsy anyway, I think it obviously can be very useful for some, but for most of us it's just data we can't use.
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I also liked Xeloda. I was on it for six months after my local recurrences. Tried it again in the metastatic setting briefly but it didn't work that time around for me.
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