Are you currently (or have you been) in a Clinical Trial?
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A new paper published in Nature Comm reveals that one way MBC endocrine-resistance can develop is due to loss or mutation of specific mismatch repair proteins, called MLH1/2/3 and PSM1/2, which form the MutL complex. Loss of either of these MutL complex mismatch repair proteins occurs in response to treatment with endocrine therapy and so would usually not be picked up in the primary tumor- these mutations are responsible for about 15-17% of endocrine resistance. What happens in these cells is that the HER2 protein at the surface is not degraded the way it normally would be and therefore the cancer gains increased HER2 activity and resists endocrine therapy.
In these resistant cancers, the loss of MutL prevents CHK2 from inhibiting CDK4, which is a step that is needed for AIs to work. However, CDK4,6 inhibitors still work in these cells and they remain sensitive to Ibrance. I think they are still working out how this change eventually leads to an increase in HER2 protein.
The paper shows that HER2 is driving the growth of these resistant cells, and that they are very sensitive to anti-HER2 agents in combination with anti-estrogens. They say these proteins are routinely assayed for colon cancer in the lab and so could be easily included in breast cancer biopsies, and would provide a clear biomarker for those who would benefit by adding anti-HER2 drug to restore sensitivity to anti-estrogens.
This is not the entire subgroup of ER+Her2-low cells, so other causes of increased Her2 expression exist and have yet to be described. Also these proteins are affected in those with Lynch syndrome, so this approach would work there, too- also note that other mismatch repair proteins like MSH2 do not cause this kind of resistance.
https://www.nature.com/articles/s41467-021-23271-0...
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Curious..thanks for that info.. I don't believe I can get neratinib or Enhertu covered (actually I definitely cant, since even JFL had LOW HER2+ and had to fight to get Enhertu) she paid out of pocket for it... So that link is that what you were talking about earlier that you were just reading about it?
So basically the Affintor and Faslodex is going to do nothing for me... I had a feeling it isn't working and wouldn't anyway...but yea....
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Nicole, I think these are only available to us in clinical trials..
TRINITI-1 Clinical trial of everolimus with exemestane and CDK4,6 inhibitor (ribociclib) showed 41% clinical benefit rate (stable disease at 6 mos), that's pretty good, similar to the results on the SERDs, and all done on cancers that progressed on I-F. If it seems like its working can you add Verzenio?
https://pubmed.ncbi.nlm.nih.gov/33722897/
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For oligo mets, a recent survey of 73 patients with less than five lesions in no more than two sites, none over 5 cm, about half were treated with both radiation and drugs (curative intent), they found overall survival rates were 28.3% and 18.9% at 20 and 25 years, respectively, and relapse-free rates (presumed cures) were 26.7%. As you might think, those with only one metastatic site and fewer lesions had the best chance of cures; cures plateau out around 20 years. And this is the old data, nowadays must be even higher chance for success.
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My doc is currently trying to get neratinib for me but it's a battle. I have ERBB2 mutations, and on first appeal, she was shot down. Now they are launching a second appeal. But for now, that drug seems embargoed for use as a trial drug within the SUMMIT basket trial. This is one of the drugs that Shetland pony is using in the SUMMIT trial and it's been quite effective for her. The initial denial indicated that for me, it would be off label use.
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BevGen
How are you recovering?
Can you invoke right to try for neratinib? it just stinks that you have to fight to get a drug that seems to have potential.Hope you get access and it works.
De
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Bev, I emailed my NP who got neratinib approved for me before I decided to go with the trial, and asked if she has any advice or tips for you to win your appeal.
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Regarding the oligo article, those are impressive statistics. Here is what I wonder: If one does not start out oligo -- too many liver mets, too big -- but then achieves NED on systemic therapy, is that a re-set? Is there now a chance to be in that group by using rads on anything that pops back up?
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Hi all, I have not been on these sites for a long time. Happy to see all know names from the smart and helpful posts.
Shetland, I think it is possible to get treated only couple of mets by SBRT or radiofrequence ablation in case of oligoprogression, even your starting point was many mets. At least it is done in my country, but f.e. For SBRT (liver, bone, lung, brain) it can not be more than 3 or 4.
I asked about the enobosarm in the veru company and they wrote me that in 2021 they will start trials in Europe, may be Czech rep. which I have close to travel for. My original met from liver in 2017 was Er+Pr- and had 99% of androgen receptors.
In the meantime I am stable after small progression in October on vertebra after SBRT I have changed treatment from kisqali faslodex to verzenios and letrozole and I am doing fine...so yes the change from one cdk4-6 to another can work for some.
Greeting to all. Maki
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Dee,
I'm recovering - slowly. I am walking some with a walker. When walking, I don't really have pain. It's after I get back to my room and get settled that I start to ache despite taking tramadol, Tylenol, and Celebrex. My doc has me on an around the clock schedule for pain meds so that I can better manage it, and I can also get a "rescue" dose of Tylenol or tramadol on those days when I feel I need it. I am scheduled to go home this coming Wednesday, so I'm loaded up with a hip kit, a walker, a rented hospital bed, a raised toilet seat, arms for the toilet seat, a shower chair, and grab bars in my downstairs shower. Hopefully my improvement will speed up.
SP, thanks for any info you can get. I think my MO is trusting the department pharmacy to figure this out, and they are appealing on two grounds -- that I need the drug bc of my condition and it's proved worth so far for that, and also on the financial front, so perhaps I can get it at a reduced price or for free. So far, nothing is working. So any ideas are welcome. When I get out of here, I will call the person in charge of the trial up at Delaware and get some more info from her to see how much I could possibly do at Hopkins versus the Delaware hospital.
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Cure...Are you saying if the Affinitor/Faslodex (i don't take EXE) is working to add Verzenio? I don't think you can take Affinitor/Faslodex and Verzenio? That would be a LOT on a person with regards to side effects?
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Hi Nicole, The TRINITI-1 trial combines Affinitor/AI (same as your Affinitor/Faslodex) with Ribociclib (CDK4,6 inhibitor) and so far they are seeing that almost half of patients make it out to six months, and 33% are stable at a year. They aren't seeing SEs beyond those known for each of the drugs individually. So I was thinking if it works you could boost that with Verzenio, an even stronger CDK4,6 inhibitor. But of course its unlikely your MO could do that, since this particular combo is not yet FDA-approved and insurance would not go for it-not clear how much the CDK4,6i is helping, since this is phase 1/2 trial and they do not have an arm without Ribociclib, but so far this trial is saying that this combo works well for those with progression.
PS However, I was just reading that if the cancer has FGFR1 amplification/mutations, it may be resistant to CDK4,6 inhibitors. For those cancers they are testing dovitinib (not sure how good that is) but also those cancers can have high levels of AURKA kinase, which is very responsive to Alisertib with Fulvestrant (NCT02860000).
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Thanks Cureious.... I do have FGFR1...Looks like that trial with Aliserib is suspended... I just looked it up. Shame to bc it was at Georgtown in DC not far for me. So I guess I am really wasting my time with Affinitor being that I have FGFR1....
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I think one of the interesting features of Triniti-1 is that they are using lower doses of ribociclib and everolimus than when used individually, with the thought that lower, doses of both can minimize side effects while gaining benefit.
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Spouse...I agree about the less side effects...I am on a lower dose of Afinitor..I started at 2.5mg...then after 2 weeks up to 5mg...then after 4 weeks now 7.5mg and we are stopping at that we will not do the full 10mg.
I just looked at that TRINITI trial its over and to me...the results were not good?...Am I correct?
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Nicole, The Alisertib trial is just temporarily closed because they have reached the limit of patient accrual, if some drop out it will open up again. The trial supposed to end this Dec and assuming they have good news there will be follow up trials, perhaps even phase 3. Numbers out of phase 1 (monotherapy) were great, PFS of 12.4 mos and CBR of 78%, one person still on the drug at 32 months out.
Also, you are wrong about the Everolimus, FGFR1 cancers are resistant to CDK4,6 inhibitors but not to mTORi
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC68255...
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Cure... thats right mTOR....my bad... I seriously think chemo brain is a real thing..my husband says I am forgetting everything...
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Nicole...I wouldn't say the results are not good. They aren't world-changing, but it definitely met the primary endpoint:
"Continuous RIB + EVE + EXE demonstrated clinical benefit at week 24 in 39 patients (41.1%), exceeding the predefined primary end point threshold (> 10%)."
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maki- stable is great! There is more and more coming out about switching CDK 4/6 and getting good results.
BevGen- hoping your homecoming goes well. You have had a rough go. Will “right to try” be something your doctor could help you with on neratinib? It is supposedly a national law but insurance does not have to pay so “expanded access” route may be better.
Cure-ious- I have the AURKA overexpression. I will ask about Alisertib as something to put in my bucket.
Dee
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Dee, Also if I recall, SusaninSF was in that trial with Alisertib, probably in the phase 1 as monotherapy. To me that drug looks more promising than the various FGFR inhibitors I've read about so far, in terms of side effects and efficacy..
Nicole, It's all is overwhelming for sure, I just didn't want you to despair about the drug you are taking- especially since it could be just fine!!!!
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Hi Cure-ious, I'm new to the forum. I joined because at some point I'll need to make a decision for my next move and I noticed a lot of knowledgable people here, but for now I'm stable on Ibrance/Faslodex. 🙏🏽
My friend, on the other hand, has FGFR1, PTEN and ATM. She's been progressing every 3-6 months on all the ER+, CDK 4/6, Xeloda, Afinitor. Her MO put her on Taxol and she's been in the hospital for a week. Taxol knocked her out... that was a bad move for her. She'll need more options once discharged. These posts are very helpful!! I'm sending her all the tips I pick up here. Futibatinib and mTORs seem to be good options for FGFR. I also found a clinical trial for ATM. NCT02693535. I tried to post a link, but it said I’m not allowed at this time. Too new maybe 🤔
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Early results out of the GELATO trial suggest that Triple-Negative Lobular cancers are responding to immunotherapy-chemo (Atezo-Carboplatin)
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Was just reading that one way by which ER-positive cancers "convert" to ER-negative is through up-regulation of the Aurora-A kinase (AURKA)- this activates SMAD5 signaling in the nucleus and down-regulates ER expression. AURKA activity is associated with chemoresistance and shorter overall survival in TNBC (but not in other MBC subtypes). Like the FGFR1-amplified cancers, these subtype "converters" may benefit from Alisertib.
PS Grace- All the promising therapies for aggressive cancers like your friend has are in clinical trials, has she tried a consult at a major NCI cancer center?
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Cureious...I do not believe when I had Foundation 1 that AURKA was tested how do they check for that in a biopsy or F1, Tempus?
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FYI-Update on trial drug SERCA that shows some hope for ESR1 mutation (cross post on that thread
ASCO abstract on trial H3B-6545 http://clinicaltrials.gov/show/NCT03250676
Clinical activity was observed in pts with ESR1mutations.
https://meetinglibrary.asco.org/record/195753/abstractFYI-My trial MO is the first name under authors
Dee
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hi all - just jumping on the AURKA conversation here. My Foundation One showed I had AURKA amplification (it said ‘equivocal’ after that which I assume means right on the border for amplification?) I was ER+ at primary and TNBC mets. I just found out first line chemotherapy didn’t work (and I’ve been diagnosed with a bunch of brain mets) so I guess I’m another data point for AURKA amplification and chemo resistance?
I got a new biopsy done at this progression that I hope is going to reveal some pathway forward. I’m also going to get new genomic testing on it - I had Foundation One last time and I fancy Caris this time for the whole exome sequencing and RNA as well. Does RNA add much to DNA sequencing? I had the blood biopsy for Foundation One in December and will get tissue biopsy this time. Will this be more or less reliable? One issue with my earlier liquid biopsy is that I showed continued gene alterations characteristic of hormone positive BC and others characteristic of TNBC. Which suggests heterogenous mets. At least if this one is tissue we might get a sense of what ONE of the cancers is doing.
Deep down I hope this biopsy shows I’ve miraculously become HER2 positive but as I’ve never shown any evidence or HER2 I doubt it.
My fear is that it will come back strongly ER again but I have an RB1 mutation and AURKA amplification which suggests cdk4/6 inhibition won’t work and to be honest I don’t know what the next step would be. My recent brain mets likely rule me out of any trial in the future
sigh
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phet, sorry this stupid disease is unwinding in a messy way for you.
I hope Caris comes through with something super useful. I hate that thing about the brain mets being excluded from trials. I know there are a couple pt advocacy groups really pushing this issue to get brain mets pts included in more trials.
If you have time after you get your Caris maybe you could pop into the genomic testing for stage 4 thread and tell us about it whether the RNA & full exome reveals different/new things. It's something I've been wondering about in terms of Caris v Foundation etc. https://community.breastcancer.org/forum/8/topics/...
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Phet maybe you are HER2+ now...I mean they usually get the brain mets....
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Phet, Usually brain mets are allowed in clinical trials once they have been treated. Immunotherapy can work quite well on conversion cancers, (ER+ to ER-) and the AURKA inhibitor Alisertib not only inhibits cancer cell growth for triple negative cases, but also has beneficial effects on the immune microenvironment to make cold tumors more responsive. So a combination trial would be good, if available..
https://pubmed.ncbi.nlm.nih.gov/33523948/
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Phet, my MO said that the tissue biopsy for FoundationOne will provide more information than the liquid biopsy can, so maybe something will pan out this time. I've had the same thought as you - a change to Her2+ would open up new drug options - who knows, we can hope, right? I hope you get some actionable results. Please keep us posted.
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