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Genomic testing for stage IV

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moth
moth Member Posts: 3,293

This is a thread for discussing next generation sequencing and molecular profiling of metastatic tumors through tests such as Foundation One, Caris etc.

We can talk about the tests themselves as well as what the results mean and how they might affect treatment options.

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  • phet7178
    phet7178 Member Posts: 57
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    Thanks for starting this moth! When I got my Foundation One results back a month or so ago I searched a lot on here for people with similar mutations to me - it would be good to have a record of what mutations people have, the information they glean from their oncologists about that and treatment or trial options moving forward.

    I will start - I have TNBC mets to lung and mediastinal nodes which appeared less than 2 years after I was treated for a node-negative, strongly hormone-positive primary. This suggests something kind of mutant to begin with, which is why my oncologist immediately ordered a Foundation One.

    It came back that I have:

    EGFR amplification, FGFR1 amplification, AURKA amplification (equivocal), MYCN amplification, ESR1 amplification, NSD3 amplification

    CASP8 E293* and S355C, ETV6 deletion exons 3-5, RB1 Y446*; SPEN rearrangement exon 11, TP53 P77fs*46

    I have a TMB of 8 and MSI could not be determined.

    I also have about 25 VUS, including a few that could indicate 'BRCA-ness' (though they are just VUS).

    None of this screams a particular treatment path, although the TMB is high by breast cancer standards (though not 'high' overall) which can signal immunotherapy benefit. There are clinical trials attempting to inhibit EGFR and FGFR1 in breast cancer but not much success yet. From my reading an Aurora Kinase Inhibitor could also help with these amplifications.

    Curious to know if others share these amplifications/mutations

  • moth
    moth Member Posts: 3,293
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    phet, wow, you got a lot on yours!

    I'm a wiffly waffley triple neg. Original IHC in 2017 was 10%ER+, then Oncotype said triple negative & they treated me with chemo as if it were triple neg. IHC was redone over & over again & they decided I really was essentially triple neg & recommended against tamoxifen.

    Recurrence to lung & liver 26 months later. Went on clinical trial immunotherapy+ chemo for mTNBC. A subsequent biopsy of a lung tumor in Dec shows again a bit of ER activity so we've added letrozole in case there is some estrogen driving the train.

    Foundation One Dec 2020

    BRD4 - amplification equivocal

    PTEN - loss

    NOTCH3 - amplification equivocal

    TP53 - Y205N

    SMARCA4 - S1640*

    CREBBP - Q2263*

    TMB: 6.3; MSI: stable


    I don't see anything actionable on mine except the PTEN - the original trial I was in was for immunotherapy + chemo + Ipatasertib/placebo. Ipatasertib is not approved in Canada, I had been in the placebo arm, and then the trial was shut down....but ipatasertib is *thought* to have some benefit for PTEN loss pts. So my MO is asking the manufacturer if there's any way they can get it for me given these Foundation One results - but the general feeling is that it's probably not going to happen.

    Cure-ious posted in another thread that PTEN can also be potentiall targetted with statins.


    I have questions for anyone who's done the research:

    1) is this type of testing something you should repeat at some interval? If so, what interval?

    2) is one type of test better than another?

    3) do we want TMB to be high and MSI to be unstable or not? I don't know what is a 'good' result with those terms?

  • BevJen
    BevJen Member Posts: 2,341
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    I'll come back on to post my results in a couple of days, but thought I'd pass along this article about genomic testing. In it, there is a list of all of the different types and what they show. It's pretty comprehensive.

    https://www.hematologyandoncology.net/files/2019/0...

    So I am quite interesting in this, and thought I'd take a crack at Moth's questions:


    1) is this type of testing something you should repeat at some interval? If so, what interval?

    From the research that I have done, and several seminars that I've attended, most doctors who are using this testing say that you should get another test done when you have "progression." Preferably, you will have a new lesion biopsied and checked -- what they are looking for is tumor characteristic changes.

    2) is one type of test better than another?

    I think that MOs have preferences, but that linked article explains what the various tests go through. I'm sure that is changing all the time.

    3) do we want TMB to be high and MSI to be unstable or not? I don't know what is a 'good' result with those terms?

    I don't know much about MSI stability but my understanding is that high TMB is not that usual with breast cancer. I've read that several times. My understanding of this is that as the BC becomes resistant to different treatments, it will morph/mutate to try to find a different path. Having said that, my first F1 tests was a tissue sample in May 2019. For the preceding 13 years, I had only been on letrozole. But my F1 report indicated over 25 mutations! That is especially unusual in BC, and that's a high TMB. So my situation is truly weird.

    I think that high mutation burden is seen as a biomarker for success with immunotherapy. That is the reason for wanting it to be high, from my perspective. Also, if you have more mutations, I guess it's more likely that you will come up with something that's potentially actionable by a targeted therapy -- e.g., piqray with the PIK3CA mutation.

  • cure-ious
    cure-ious Member Posts: 2,758
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    Moth, Thanks for starting this thread!

    These tests are here to stay and probably will be routinely used at progression to check for a newly-acquired ESR1 mutation, for example, or for other mutants associated with progression. It's helpful to know what the tests do and do not look for, Foundation One is looking at mutants, not at loss or gain of protein expression. I spoke with my MO today, who said the Foundation One test does not routinely detect PI3KCA mutations (why not?) and those usually need tissue biopsy.

    I'm not sure if any particular result is "good" or "bad" so much as having the information helps us better understand know what we are dealing with. The issue of TMB and MSI, for example. TMB greater than ten is a ticket to immunotherapy, so that's great, but if you don't have that then you can try to work around it by adding in a DNA damage drug. Another issue is the tumor microenvironment (immunological phenotype) and there again, either you have high infiltrating T cells or you don't. If you do, that's great, but if you don't you can try to fix that- for example, this paper shows that Aurora Kinase A inhibitors can increase the infiltrating T cell numbers, and so one might need to take that drug if the tumor is "cold"

    https://advances.sciencemag.org/content/7/4/eabd78...

    In pre-clinical work, inhibitors of CDK12 were also really good at increasing tumor-infiltrating T cells. Apparently the requirement for IO response is that the tumor has to have high mutations and the environment needs to allow access to T cells.

  • moth
    moth Member Posts: 3,293
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    Just a note that there are two Foundation One tests - one is a tissue biopsy and one is a 'liquid biopsy' aka blood test. I had the tissue one from a lung tumor.

  • Hopfull2
    Hopfull2 Member Posts: 287
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    imageHi. Interesting topic. I had just asked for a copy of my foundation one results. I took it back in 8/2020. It says specimen type FFPE-block-bone. But I do remember them also taking blood. Here is what it said. It's 26 pages long but I think this is the sum of it all.

    I don’t know what any of this means. I need to ask onc next time I see him.

  • figtree
    figtree Member Posts: 34
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    my tissue biopsy from April 2019 showed AKT1 amp, CDK12 loss of function, and tp53 loss of function. Gardant360 liquid biopsy in December 2020 only showed CDK12 mutation.

    Cure-ious, are you aware of any studies that point to breast cancer cells with CDK12 loss of function are sensitive to immunotherapy? I’ve read some studies on immunotherapy for CDK12 mutantprostate cancer.

  • maaaki
    maaaki Member Posts: 105
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    Hi I has DMTN1 mutation in liquid biopsy, I have read Cure-ious that you had it as well. Do you think it is something affected the blood cells by CDK4-6? I mean may be this mutation is in neutrophils not in cfDNA from tumor?. It is written there that it has something with blood cancers or aging. I am 46, so not that old

  • phet7178
    phet7178 Member Posts: 57
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    Thank you everyone for posting your results - it's so interesting to see what everyone has! I wonder if people have repeated these tests on progression and if they've changed? I have heard of people doing them multiple times but I don't know how useful that is. As they focus on genetic mutations and amplifications, I wonder if there are other tests that do check for protein amplifications of mRNA (for some amplifications, I've read that the latter is more important than genetic amplification, if I've understood that right...)


  • cure-ious
    cure-ious Member Posts: 2,758
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    Phet,

    I think these genetics tests are so new, we will be a kind of trial group that finds out if they are consistent from time to time. I do wonder if I had another tesr right now, would these same mutations show up, or another four "maybe something" mutations would be there. I think the CHEK2 mutation might recurr because it is a moderate-risk factor for getting breast cancer, and mine showed up at 48 and had clearly been growing there for quite awhile. Your question about mRNA amplification, by that you mean protein expression levels as opposed to DNA amplifications?

  • cure-ious
    cure-ious Member Posts: 2,758
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    Maaki- That is a great question, I'm going to go look that up! It's funny, I was wondering if some of these mutations might be in the blood cells rather than the cancer, like how do they know they are in breast cancer cells per se? Did you have a high or low tumor mutation burden?

  • cure-ious
    cure-ious Member Posts: 2,758
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    Figtree, Well, that's weird and wonderful to lose two more aggressive cancer mutations in the more recent blood test, but then also calls to question how reliable are these tests anyway?! But still new, so definitely the newer test is better.

    And like you say, most important that both of them picked up loss of CDK12- at least it is consistent! I will be back shortly with a link to the trial, anyone with a CDK12 mutation is eligible for immunotherapy, it causes a huge increase in T cells infiltrating the tumor. The studies started out with pre-clinical trial data on prostate cancer, and then they looked and saw the small number of prostate cancer patients who did respond to immunotherapy were ones that had CDK12 mutation. That started a clinical trial for anyone with any solid tumor having a CDK12 mutation, and I wonder if there are now updates. Whether the mutation is by itself sufficient to confer response or you still want a combo trial is also a relevant question- back shortly..

  • cure-ious
    cure-ious Member Posts: 2,758
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    Figtree, As you know, loss of CDK12 makes the tumor aggressive, genomically unstable, creating and expressing all kinds of "neoantigens", new weird proteins and protein fusions. While aggressive, this also really attracts the immune system to kill these cells, and makes them more sensItitive to immunotherapy.

    https://ascopubs.org/doi/10.1200/JCO.2019.37.15_su...

    The IMPACT trial is testing immunotherapy on CDK12 mutant cancers

    https://clinicaltrials.gov/ct2/show/NCT03570619

    It is an interesting trial because it was originally just at Univ of Michigan, where the team that discovered the role of CDK12 in immunotherapy are located, but now has expanded a bit and you could access it at UCSF, UCSD, Memorial Sloan Kettering, and a few other places but its not widespread. It combines Nivo and Ipi. However, if these aren't convenient, maybe you could get into some more generic immunotherapy trial, like the one combining Nivo and EP4.

    In cell lines, CDK12 is needed for BRCA1 expression and so these cells are also sensitive to PARP inhibitors- they are way more screwed up than BRCA1 mutant, so they might be super-sensitive to PARP and immunotherapy, or chemo and immunotherapy, etc. The lesson is, like with HER2, these cancers can be more aggressive than the standard MBC but if you find the right treatment then they can be the more responsive and controlled. The cancer is definitely attracting immune cells, the separate issue is to get a trial that gets rid of the T-regs that may be masking the cancer, and so if you try standard Immuno and its not sufficient to take these out, then look for a trial that would also add in a drug to make the T-regs get out of the way. Your cancer is basically at least already part way primed to respond really well to immunotherapy

  • nkb
    nkb Member Posts: 1,561
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    I had a STRATA test on a bone biopsy. It showed an amplification of CCND1- UCSF says no known treatment for this. I am MS Stable, TB low and PD-L1 low with a score of 18. The Strata immune signature is low. I do not have ESR1 or PIK3CA. there were some additional mutations - the only only being studied per UCSF right now is my ARID1A and it is not being studied in breast cancer. I have 2 MAPs and NF1 (which I think is in all lobular cancers). There were a few that couldn't be assessed due to "quality control parameters"

    The CCND1 is present in 13% of cancers- along with breast it is Esophageal and prostate.

    I am also Her 2 low from my original breast biopsy 2+ with negative FISH which makes Enhertu a possibility at some point.

  • figtree
    figtree Member Posts: 34
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    Cure-ious, thanks so much for the article and trial info. The IMPACT trial is interesting, but its research sites are too far for me to travel to. Here is one that is similar, combining nivo + ipi + AR inhibitor for any HER2 negative MBC. Not too crazy about mixing in an ARi though. What do you think? ClinicalTrials.gov Identifier: NCT03650894

    Guardant360 also suggested PARPi, but it looks like I have to be on a clinical trial to access it. Sigh. What I really would like to try is a PARP + immunotherapy trial. None is available in my area (Oregon). Double sigh.

    As far as liquid biopsy potentially shows less mutations, my MO says it's common unless there is a good amount of cfDNA in the sample it's not going to be as accurate as tissue biopsy. My Guardant360 has this “fine print": cdk12 mutations detected in this test is germline, somatic mutations are out of range of this test. What?? Basically no tumor mutations showed up in my test. I have AKT1 amp in my prior tissue biopsy and this alteration is known to be “stable", meaning it doesn't tend to go away over time.

  • figtree
    figtree Member Posts: 34
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    does anyone one knowwhy i can’t post links ??

  • figtree
    figtree Member Posts: 34
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    Maaaki, I see you have AKT3 mutation, have you considered a trial with Capivasertib? AKT1,2,3 are known oncogenes that drive cancer growth. Capivasertib is a strong pan-AKT inhibitor. I have looked at CAPItello-291 trial for myself, but it’s not convenient for me to travel to.

  • figtree
    figtree Member Posts: 34
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    I found this is a very helpful site to search clinical trials based on any bio markers.

    Mycancergenome.org

  • maaaki
    maaaki Member Posts: 105
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    Cure-ious I have 3 mutations, so not a high mutation burden, in previous tissue biopsy three imageyear ago, I had 1.

    Figthree I dont have AKT1 mutation, or did not have previously.

    In the recent blood biopsy I had only DMTN1 and SUFU (it was in 50% so I think it is germline). And I also had 6 VUS variants including BRCA2 and Msh6.

    In my tissue biopsy three year ago, I had mutations in the picture.

  • phet7178
    phet7178 Member Posts: 57
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    Wondering if anyone out there has the combination of ESR1 amplification, NSD3 amplification and FGFR1 amplification? I've been doing some reading around and apparently ESR1 and NSD3 are almost always amplified together (as they are in me), meanwhile NSD3 and FGFR1 come from the same part of the chromosome and are thus also related. Also this amplification signature is seen mostly (almost always?) in highly ER+ cancers that are nonetheless endocrine resistant. These three all came up in my liquid biopsy and I'm curious as, at least according to biopsy of my mediastinal nodes, my mets are TNBC (but I was originally highly ER+). As it was a liquid biopsy this might suggest there's an ER+ tumour in there shedding dead cancer cells? Those cells couldn't from my primary could they (removed in August 2019)?

    I know there's a far bit of research on ESR1 mutations but much less on ESR1 amplification, which despite seeming like it would make cancer extra responsive to estrogen suppression apparently does the opposite and helps make the tumours grow independently of estrogen itself.

    Also wondering - how might I find out how many copy numbers are involved in my amplifications? Would I contact Foundation One? I have a lot of amplifications and wondering if some are more amplified than others (to help work out what might be driving things)

  • cure-ious
    cure-ious Member Posts: 2,758
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    Phet, Interesting questions, hope you can find others here who have your subtype. Perhaps the high levels of estrogen receptor (ESR1) that occur upon gene amplification are sufficient to allow the receptor to accumulate into the nucleus and turn on genes without estrogen? Normally moving to the nucleus requires the receptor first bind to estrogen, but at high levels of ER this restraint may be overcome and ould explain why the cancer is no longer dependent on estrogen. The cancer would nevertheless remain dependent on the estrogen receptor and respond to SERDs or Faslodex. But with FGFR1 amplification also in the mix, would it still depend on ER?

  • cure-ious
    cure-ious Member Posts: 2,758
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    Here is a Nature paper from 2019: https://www.nature.com/articles/s41586-019-1007-8showing that just four of the 11 IntClust breast cancer subtypes are most likely to lead to a late (greater than five years) recurrences for ER-positive tumors. So perhaps most of us will sort in one of these four categories:

    "Among ER-positive patients, those with IntClust3, IntClust7, IntClust8 and IntClust4ER+ subtypes exhibited a better prognosis, whereas patients with IntClust1, IntClust2, IntClust6 and IntClust9 subtypes exhibited late-recurring cancer with distant relapse up to 20 years after diagnosis. The IntClus1,2,6, and 9 subtypes together account for around one quarter of all ER-positive tumours and the vast majority of late recurrences. Importantly, the four 'high risk of relapse' subgroups were enriched in characteristic genomic-copy-number alterations, which represent the likely drivers of each subgroup."

    IntClust2 tumours (4.5% of ER-positive cases) are defined by amplification and concomitant overexpression of multiple oncogenes on chromosome 11q13, including CCND1, FGF3, EMSY, PAK1 and RSF1. Approximately 96% of IntClust2 have the RSF1 amplification, compared with 0–22% in other subgroups.

    IntClust6 (5.5% of ER-positive tumours) is characterized by focal amplification of ZNF703 and FGFR1 on chromosome 8p12 (100% of IntClust6 cases, versus 2–21% of others).

    IntClust1 (8% of ER-positive tumours) exhibited amplification of chromosome 17q23 in a region spanning the mTOR effector RPS6KB1 (also known as S6K1), which was gained or amplified in 96% and 70% of cases, respectively (versus amplification in 0–25% of other subtypes).

    IntClust9 (8% of ER-positive cases) was characterized by amplification of the MYC oncogene at chromosome 8q24, with amplification in 89% of these tumours (versus 3–42% of other groups).

    "Thus the late-recurring ER-positive subgroups are defined by genomic drivers, several of which are viable therapeutic targets."

  • buttonsmachine
    buttonsmachine Member Posts: 339
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    Cure-ious, thanks for posting that article - it's very valuable information for many of us.

    I recently found out that my cancer belongs to IntClust6 while being assessed for a clinical trial. Knowing this made me feel oddly more at peace with things, actually. I think it helped me to know that there's a scientific or logical explanation for my cancer behaving so badly. Having more information helps me, and this particular research was a big "Aha!" moment for me.

  • phet7178
    phet7178 Member Posts: 57
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    Thank you Cure-ious! That's really useful. Yes I also wonder whether, with FGFR1 in the mix, it would be dependent on ER at all (I've also switched in at least some of my tumor to TNBC, despite this continuance of ER+ gene mutations).

    I've tried before to work out what IntClust I am, but as I only had genomic testing on the metastasis and not the primary, and was ER+ at primary and TNBC at spread, I can't get my head around it. If you switch ER+ to TNBC do you also switch clusters? I have a hunch my primary might have been IntClust 6, assuming the NSD3 and FGFR1 were there in the primary (the 8p11.23 amplicon). That would explain relapse, though mine was rapid not late stage :( I had no lymph spread and no LVI at primary, so I clearly have a very biologically aggressive tumor to have spread anyway. I've also read that IntClust 6 is highly genomically unstable which would make sense given I switched types and also have quite a lot of mutations/amplifications.

    Buttonsmachine - very interesting you were able to find out your IntClust. Did they give you any more info about 6? I think you have FGFR1 too, is that right? Are there other mutations you have that characterise this cluster?

  • buttonsmachine
    buttonsmachine Member Posts: 339
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    Phet, they did give some information about IntClust6 - mostly that it is a highly aggressive variety of ER+ breast cancer. (Which for me, certainly fits.) So while IntClust6 is ER+, it has some other features that drive the cancer growth besides just the estrogen, which might be part of the reason we don't respond especially well to hormonal therapy. (Which again, for me, fits.) There are a number of early trials assessing drugs that block the FGFR pathways, but nothing that is about to come out on the market to my knowledge.

    My FoundationOne Results (from an early metastatic recurrence solid tumor specimen) found the following:

    FGFR1 amplification; FGFR4 amplification; EPHA3 amplification - equivocal; NSD3 (WHSC1L1) amplification; TP53 P278H; ZNF703 amplification

    Also, these variants of unknown significance: FGFR1 rearrangement; FGFR3 S236N; IRS2 G879S and G882A; SPEN D2266N; WT1 amplification

    Obviously I don't know what some of that even is, but my cancer does seem to be FGFR-heavy with FGFR 1, FGFR4, FGFR 3, and an FGFR "rearrangement."

    Despite all that my cancer is MSI stable and the TMB is zero.

  • snooky1954
    snooky1954 Member Posts: 850
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    Oh, you guys. I'm sitting ere crying because I don't understand any of this. I doubt my ONC goes either. He's just a cancer doctor not a breast cancer doctor.

    Is this how the normal visits occur for you? (He's always an hour late even though I've called him on it) When he enters the room, he as no idea what current bloodwork is, what latest scans reports or anything. He spends half my visit reading to catch up.

    Last time I was in there h e was telling my son my history and said cancer had mildly proceeded on my breast. I said, mildly? I told my son to leave the room so I could undress and show him the cancer was all over the top of my breast, underneath to my ribs and there were two holes boring thru my breast, not to mention my right side.

    He seemed mortified. "why did I not know about this? He started rustling papers. BUT, hr did know, last visit I had showed him and said this was moving fast. He left me with no hope that day. He said the only chemo I can offer you is Haveline, then there's nothing. Th other chemos are too harsh for you.

    So, I feel abandoned

  • moth
    moth Member Posts: 3,293
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    snooky, can you not switch oncologists? My MO is actually not a breast cancer specialist either - in our provincial system, all the clinical oncologists are sort of generalists and take all sorts of cancer pts. BUT my MOs (I've had a locum while mine went on mat leave) are always up to date on my lab results, are knowledgeable about goals of care and what therapies we're considering. I also have a physical exam at almost every appt so they know what is happening to my body.

    When is the last time you've had a scan? I'd question specifically why certain chemos are off the table for you - there might be something in your blood work or personal health history that make some chemos unacceptable but you should know exactly why.

    None of what you're describing sounds right


    (ps - I don't think this is the right thread for this. I suggest you start a new topic in the Stage 4 forum https://community.breastcancer.org/forum/8

    . This thread is about genomic tests such as Foundation, Caris, Tempus etc. & what the results of the panels mean)

  • buttonsmachine
    buttonsmachine Member Posts: 339
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    Snooky, is your cancer breaking through your skin? That often does not show up on imaging like PET/CTs, which is probably why your MO was surprised by it - not that I am defending him - he should have seen it before now. Doesn't he examine you regularly? Did he forget what he saw?

    I have some lesions under my skin that I think will break through one of these days. They seem to grow despite chemo. I think the chemo just doesn't reach them. :-(

    I haven't been on Haveline so I cannot say how that is, but maybe it is worth a try for you? I'm so sorry you are going through this. This disease can be so discouraging to say the least.

  • moth
    moth Member Posts: 3,293
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    just a picture of the list of genes Foundation One tests for.

    Nicole you'll see NOTCH1 2 3 for ex all listed here but there's no AAMDC on the list so it's not a gene they test for right now


    image

  • moth
    moth Member Posts: 3,293
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    This is all in light of a study in Nature saying the oncogene AAMDC, when over expressed or amplified was associated with hormone therapy resistance in ER+ breast ca.

    "High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens." https://www.nature.com/articles/s41467-021-22101-7

    I don't see AAMDC listed as a gene tested on Foundation, Caris or Tempus right now.