Are you currently (or have you been) in a Clinical Trial?
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NinaCA, the same thing happened to my tumor markers… they rose by 30 points a month after my first vaccine. I think there are so many unknowns around this vaccine, I did see an article alerting radiologists about false positive mammograms after the Pfizer vaccine, so surely tumor markers could also be affected? I will go find that article and share if you want.
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i was in an earlier ipatasertib trial (ipatunity) & eventually found out I'd been randomized to the placebo but I can tell you they expected a lot of diarrhea because they gave me insane amounts of loperamide.... so be prepared for that
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Thank you for the information Cure-ious. I am afraid I would be excluded from many trials due to the many lines I have been on. I just recently found out I had this mutation after a second liquid biopsy. The first one showed nothing a year ago.
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Cure-ious,
I couldn't see anything on the link about PMS2 and endocrine resistance. I have the PMS2 somatic mutation. What does this mean for me? Anything actionable?
Also, looks like the Phase 3 ARTEST trial (https://clinicaltrials.gov/ct2/show/NCT04869943) for Enobosarm will be starting this Fall. There will be 47 locations so I'm hoping many of us can join. The UCSF trial will be run by Hope Rugo. Looking at the exclusions/inclusions it looks like I will be able to join despite being heavily pre-treated. Saw her this morning but we had so much to discuss that I didn't ask about this trial.
Hugs, Susan
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Susan, Thanks for bringing up the Enobosarm trial!! They are moving that fast- phase 3 already!! Of course, they already know Enobosarm is safe, and how much to use, etc. Still, 200 or so is not huge for a phase 3 trial, so I wonder if they are planning other trials that use it in combination with other drugs. And no sites yet at MD Anderson, Sloan-Kettering, Sarah Cannon, etc. Also they must be planning, or already have, trials for early breast cancer, since their goal is to replace AIs up-front.
However, regarding restrictions, they do exclude people who have had more than one chemo in the metastatic setting. Also, the control group is on exemestane-everolimus, so that would indicate they are aiming for second- or thirdline treatments in this trial. So, you might not end up in this trial, but either way they are moving fast so even if not, it may end up FDA-approve and in the clinic sooner than later, then you could take it when and how you want to...
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PS The PSM2 mutation means you should be planning to try Enhertu or other ADCs directed at Her2, but I think you already had that? OTOH, new anti-HER2 therapies are everywhere, and they are making a CAR-T against Her2, so I think having the PSM2 mutation means you might be a HER2-low status and should keep an eye on all the HER2-directed therapies that come out
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Cure-ious,
Shucks. Missed that exclusion of > 1 systemic chemo therapy in the metastatic setting. I have been on Xeloda, Abraxane and now Gem+Carbo so I'm way past that. I will hope for fast-track status since, as you said, they already know it is safe. Just need to prove efficacy in Phase III. Also, I can always take it myself. Thanks to tips fromHusband11, I was able to buy it on a research site. We already know the dosage, 9mgs.
Thanks for the info on the PSM2 mutation. I am HER2 equivocal/2+/90% and even have one early test saying I am HER2+. I do have Enhertu on my list but unsure it if will work for me since I progressed on Trodelvy after a year. Similar toxic payload, right? I also have lots of lung tumors and other lung issues and I think that Enhertu can be hard on the lungs. Keeping an eye out for any new HER2-low trials.
Hugs, Susan
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Hi Curious,
Does foundation one testing show AR staining ?
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werone, mine didn't.
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Werone,
Caris gave me my AR info. Positive, 2+, 90%. Method: IHC. Analyte: Protein.
If you haven't done Foundation One yet, maybe ask for Caris?
Hugs, Susan
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werone, maybe ask on the genomic test thread.
https://community.breastcancer.org/forum/8/topics/...
I had my foundation one done through a clinical trial and I'm not entirely convinced that it's the same one that people get when they access it normally
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Thank you Moth & Susan
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WeR1: My understanding is that Foundation One tests only for specific gene mutations, does not test the levels of receptors or other proteins...
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weare1
My foundation tested for AR. I was negative in DNA but positive in RNA. Don’t know what that means.
Dee
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Susan, have you had germline testing for that PMS2? I have read a bit about it since I have a germline MSH6 mutation, and these are both Lynch genes. Cure-ious, I am confused about why you say Enhertu because of PMS2.
Edit: Oh, I read further back to where you said, "paper in Nature Comm looks at ER-positive cancers that acquire expression of HER2, and because of that become resistant to endocrine therapy. What happens in these cells is that when they are exposed to endocrine therapy, they lose expression of two mismatch DNA repair genes, MLH1 and PMS2 (also called MutL), which activates HER2 and that then gives rise to endocrine resistance. Treating these cells with HER2 inhibitors restores sensitivity to anti-estrogen therapy." Is there anything about the mismatch repair gene MSH6?
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Susan, a page back you said, "In my Caris report, it does mention that a PARP inhibitor may work since I have a high LOH. I asked Hope about it and she said PARP inhibitors were unlikely to work for me." What does LOH mean and why is a PARP inhibitor unlikely to work for you?
Nina, I had the same question about whether the covid vaccine could make TMs rise, because my CA 27.29 and CA 19.9 have been rising, but my scans are clear. My onc did not think the vaccine would cause it. More likely an early sign of progression. Darn.
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I know what LOH is in genetics- loss of heterozygosity
don't know how it relates to parp inhibitors....
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Shetland & Susan, The Nat Comm paper reported that cancers that had lost expression of PSM2 and MLH1 during treatment with AIs, and were now endocrine-resistant, were responsive to any of the several anti-Her2 treatments they tried, including Herceptin. This was due to an increase in Her2 expression, which created the Her2-low cancer subtype. In cancers that had lost either of these proteins at baseline before AI treatment they could detect some small amount of Her2, but subsequent exposure to AI further increased the Her2 levels to the point where they could be successfully treated with anti-Her2 therapy.
These two proteins, PSM2 and MLH1 form a complex called MutL. They found 2/3 of MBCs with a deficiency in either of these proteins responded to anti-Her2 treatment compared to less than 1/10 of those that have the normal proteins. Presumably now our genetic tests will start looking at the levels of these proteins as the most sensitive way to know if Her2 therapy might work- they currently look for low levels of Her2 but this gives another, more sensitive, biomarker to look at. So Susan, there are lots of Her2 therapies other than Enhertu (like Neratinib etc), and more coming including ADCs different from Enhertu that target Her2-expressing cancers, as well as CAR-T. They say the anti-Her2 agent needs to be combined with an AI because the cancers will revert to estrogen-dependence once the Her2 pathway is blocked.
Shetland, the MutL complex works with other proteins that are mutated in Lynch Syndrome and the authors say this needs to be looked at more closely. However, they did not find Her2 levels going up in MSH2 mutant cancers, and did not test MSH6 specifically. Nevertheless they cited one report of a response of a Lynch syndrome colon cancer to a pan-Her inhibitor drug. The Lynch Syndrome MBCs are so rare that there aren't good data, most of the papers recommend trying checkpoint inhibitors- but at least you can ask for the Her2 assay which may pick up if the cancer is Her2-low.
Here is a link to the paper: https://www.nature.com/articles/s41467-021-23271-0...
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Cure-ious,
I am positive MLH1 (2, 90%) and PMS2 (2, 10%) so doesn't that mean that I won't respond to HER2+ treatments even though I am HER2 equivocal? I think these positive results occurred in those with a loss of these two proteins.
ShetlandPony,
High Loss of Heterozygosity means that "If there is one normal and one abnormal allele at a particular locus, as might be seen in an inherited autosomal dominant cancer susceptibility disorder, loss of the normal allele produces a locus with no normal function. When the loss of heterozygosity involves the normal allele, it creates a cell that is more likely to show malignant growth if the altered gene is a tumor suppressor gene."
My Caris report said that "Pathogenic or likely pathogenic alterations in genes FDA-approved for PARP inhibitors were not detected in this sample, however, not all of these alterations are detectable with standard NGS methodology (i.g., promoter methylation. The high level of LOH in this sample could be a result of alterations in these genes. High LOH has been associated with response to PARP-inhibitors in some studies."
Hugs, Susan
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Susan, I don't know your test and the significance of the readouts, but if it means you are positive for MLH1 and PSM2 mutation, then the cancer has probably lost expression of these proteins because they are unstable when mutated, and so their expression goes down.
So, it sounds like you need to find out the significance of the MLH1 and PSM2 on your report- if it is mutated, then the paper is saying that you probably have Her2-low, especially if you were previously treated with an AI. The paper is arguing to have genetic tests look directly at the expression levels of the MLH1 and PSM2 proteins (they currently do not do that) and say that this is a more reliable way of knowing who is Her2-low than even doing the Her2 staining (since it is low)...
So I would show the paper to Hope and ask her if those genes on your report mean they are mutated, and if so request to look at that more carefully, ie expression of the proteins, maybe re-check Her2-low staining, in case you are eligible for the anti-Her2 meds...
PS Over half of all MBCs are Her2-low, and its more like 65%+ of the ER-positive MBCs are Her2-low, so its well worth looking at carefully to be sure of your cancer subtype. Here is a review of some of the newer anti-Her2 agents- it says Herceptin is not strong enough on its own to treat the Her2-low cancers, but they were targeted by Enhertu, and there are newer ADCs in clinical trials will be tested for Her2-low, plus plans to combine the ADCs with CDK4,6i etc for these cancers. Lot of excitement in Her2-low
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC79577...
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Here's something for TNBC or flippers like me. I've been on Piqray for 3 months and my 3 month scans today were good. Everything is stable and 2 of my small lung mets got smaller. My Guardant360 report showed I had the PIK3CA mutation at the same time my tumor biopsy had me switching to tnbc. I had SBRT to the tumor I had biopsied because it was the only one not responding to treatment. My doctor and I think that I probably still have some er receptor is some of my other tumors. But we don't know.
Piqray has been approved for ER positive but not TNBC so this was a risky treatment for me to start. But there are some trials out there for PIK3ca mutations and tnbc.
Another study I found, "In metastatic TNBC, ... findings suggest that there is an opportunity to develop PI3K inhibitors, especially in patients whose primary tumours express HR." Link
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KarPC- Congratulations!!! The ER(+) to ER(-) converters are a rare group, so we don't know too much about the molecular makeup of this MBC subtype. Good to know that Piqray may be a good option. They generally respond better to checkpoint inhibitors as well.
I was just reading a paper indicating that cancers that contain a mutation or loss of expression of the NF1 gene, in addition to Pi3KCA, are hypersensitive to Piqray and a woman with this cancer type has been on Piqray + Fulvestrant for six years now- the NF1 mutation (or loss) is more commonly seen in lobular and Her2-positive cancers, but who knows about the "flipper" cancers!
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Cure-ious,
Thanks for your response.
According to the Caris report, the PMS2 is a pathogenic variant, DNA tumor. However, both PMS2 and MLH1 show up in the category "Immunohistochemistry Results" along with ER, AR, PTEN, ERBB2, etc. So I guess this means that I have the PMS2 mutation but MLH1 expression?
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Susan, Because these related proteins bind to specific partners in their complex, some mutations affect the stability of other proteins and some do not. Here is a review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24381...
Mutation of MLH1 or MSH2 Will Result in Concurrent Loss of MLH1/PMS2 or MSH2/MSH6, Respectively, by IHC, Whereas Mutation of PSM2 or MSH6 Will Result in Isolated Loss of PMS2 or MSH6 Only
When mutation occurs in MSH6 and PMS2, there may not be concurrent loss of the obligatory proteins, MSH2 and MLH1. Mutations of MLH1 or MSH2 often cause concurrent loss of MLH1/PMS2 or MSH2/MSH6, respectively, by IHC, whereas mutations of PSM2 or MSH6 often cause isolated loss of PMS2 or MSH6 only.
Anyway, the Nat Comm paper says a mutation in either PSM2 or MLH1 is sufficient to render the cancer sensitive to anti-Her2 drugs- if the mutation causes loss of function then it doesn't matter whether or not the mutant is stable or degraded because its not working, and Her2 levels should go up
I don't know what Her2-equivocal means?
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Cure-ious,
This is, I think, very hopeful information about PMS2. Her2 equivocal means that I'm right at the edge, 2+ between Her2- and Her2+. I can't qualify for Her2+ trials. But with the advent of Her2-low trials, I perhaps have a better chance of them working.
I think your explanation matches with what I see in the report. I have a PMS2 mutation and test positive for MLH1, MSH2, MSH6, and PMS2 expression.
Also, according to the report, I have a
RAD51D mutation that could be targeted by cell cycle inhibitors or Chk1/Chk2 inhibitors.
ERBB3 mutation that could be targeted by HER3 or Pan-HER inhibitors.
PMS2 mutation that could be targeted by Immunomodulatory agents or PARP inhibitors
PIK3CA mutation that could be targeted by PI3K/Akt/mTor inhibitors.
Seems like a lot of possibilities but Hope didn't think any of them were actionable.
Hugs, Susan
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Well Hope has the experience, but I'd ask about the Her2 expression you already know about, and the PMS2 mutation, essentially backing that up.As you say, Enhertu is not an option because you were on Trodelvy, but maybe some of the other ADCs: https://www.healio.com/news/hematology-oncology/20...
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Susan - thank you for the post on Enobosarm. I have a initial consult in a week , maybe telemed, as it turns out with one of the DRs involved with the trial. I will ask about it. But I would not want to be randomized into one of the arms for drugs I'm already taking (Exemestane/everolimus).
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Susan, it does sound like you need Hope to explain her thinking more. When my F1 report recommended neratinib (among others) for my ERBB2 mutation, my onc said the particular mutation found was not an activating one, so neratinib would not help. So I called F1 and asked what they thought, and didn't their recommendation indicate that the mutation was indeed actionable? They said that it was actionable. (Apparently, as my research showed, it was not a typical one on the standard list my onc had in her head.) Next time I saw my onc I told her I had called F1, and she said they had called her! After that she was on board with neratinib and eventually we employed it. I have been NED on it for a year and a half. (But markers are starting to rise now.)
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ShetlandPony,
Hope spends a lot of time with me despite her busy schedule. I could ask her to explain every one of her thoughts but I try to focus on actionable treatments. If I look through my list, I have to agree that none of them are actionable. I also have to consider my lung issues and years of oral mucositis when making treatment decisions.
You have had incredible responses to treatments. NEAD on Taxol, Xeloda and Fas/Herceptin/Neratinib. I'm glad you followed up on Neratinib and were able to participate in the SUMMIT trial since you have had such wonderful results. I hope that those of us who are HER2 low will be able to access some of these treatments.
Hugs, Susan
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Cure-ious,
Thanks for your ideas. I understand that Herceptin doesn't work for HER2 low, so wouldn't an ADC using Herceptin as the antibody not work for us as well? I'm sure I look at things from a simplified perspective.
Hugs, Susan
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