Are you currently (or have you been) in a Clinical Trial?
Comments
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@believe60 Dang. I’m sorry to hear this disappointing news. I hope you can recover fully soon. The downside of phase 1 trials is that the scientists make the calls on dosage and there is no leeway. I was fortunate that when I reported severe SE on my first trial (but not severe enough to be hospitalized), the scientists reduced my dose in half. if they had gone from 800 mg to 600 mg (as my doctor had feared) instead of 400 mg, I would not have been able to tolerate the drug.
@vlnrph Another disappointing outcome for sure. I hope you bounce back quickly.
Thank you both for advancing science to help find a cure. Even when a drug doesn’t work for us, it still moves science forward. Hugs to you both. ❤️1 -
cure-ious,
I hope you see this message. I may private message you. I'm now off Xeloda due to progression in the liver and saw my MO today. Three treatment options were presented to me. One option is to target my Her2 low status with Enhertu. Or two options to target my ESR1 mutation with 1.) Elacestrant or 2.) Study NCT04174352 - "A Pilot Study of FES imagining to Optimize Tamoxifen Dose of Metastatic Breast Cancer Patients with ESR1 mutation". My MO said the study is now testing the 80mg dose. I'd appreciate your comments on the study NCT04174352. The study lead researcher wants me to responds by Wed of this week. Thank you.
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WeninWI- OK, in general I would favor getting the ESR1 mutation taken care of, because it will drive the cancer without estrogen, and it means that the cancer is still endocrine sensitive. It would be so helpful to get a FES-PET. I think there should be better options for SERD trials than the tamoxifen one, at least trials that have had more interim readouts about how they are doing. Where is the nearest clinical trial center for you? Its hard for us that there are so many different options (a good thing generally) but little info about how to sequence them, ie what is the preferred order.
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Oh, well, look at that!! Your trial is specifically about getting a FES-PET to follow the estrogen-dependent cancer!! Good call, I like it a lot!!
However, does tamoxifen really get rid of ESR1 mutations? Will look into that. Lasofoxifene is a tamoxifen derivative and boy they have great data on getting rid of ESR1… So I would take that trial, at least you can jump in and get the scan, see how much of the cancer is still endocrine-dependent, if tam is not strong enough you have time to find a different SERD trial to join, at least you would know from the FES-PET that it should work! And in the meantime, consider applying to the NIH TILs trial, they have moved up eligibility and only need a good juicy liver met (excuse my indiscretion) to isolate and grow up the TILs…
Here is a link to your trial:
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PS Normally, you have to go off of Fulvestrant for a full freaking six months in order to washout the estrogen inhibition enough in order to get a FES-PET. But in your case you've been on Xeloda, so no washout needed. Its kinda perfect…
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And the thing is, you can drop out of a clinical trial at any time, so you get the FES-PET, and then if tam doesn't look good enough, you have time to find a good SERD trial to try for something stronger. Maybe tamoxifen will be fine, too, and in the meantime you have a bit of time to recover from chemo!!!
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WeninWI, You are right, just take elascestrant and forgo the FES-PET if its only available in trial, because if Elascestrant works then who cares about the scan. Also I have been corrected for saying that the new SERDs eliminate ESR1 mutants, they degrade the ESR1 mutant protein (and the normal estrogen receptor) but the ESR1 gene remains, and in principle the ESR1 mutant protein could re-emerge, as could the normal estrogen receptor. However, what usually happens is the ESR1 mutant cells do not grow back up to high levels because they are not being selected for (as they are under AI treatment) and instead some other type of resistant cells may emerge, so new testing is required to see what could be driving the cancer at that point. Perhaps it would be the usual suspects, things like PI3KCA or Her2low- or other mutant growth factors, etc
MOs generally advocate to go through the endocrine therapies before moving to chemo, and once in chemo then try moving back, basically to "delay the time to IV chemo", I'm not sure why but perhaps the mechanisms of resistance to chemo tend more to be in the growth factor rather than estrogen pathways. Nevertheless the new antibody directed chemos can have good activity in later stages of cancer, so there are increasingly good options once endocrine treatments stop working. The question is when will immunotherapies come up as viable options for us, and where would they be sequenced, relative to ET and chemo?
If you want to add on something to hit other pathways and help Elascestrant, you could consider statins (they inhibit AKT, which is the main kinase in the PI3KCA pathway), or Celecoxib (it can inhibit CDK2,4 but not obviously as strong as CDK4,6i and also of course also hits the COX2 pathway which is turned on by mutant PI3KCA), or the i3c broccoli supplement, which stabilizes PTEN, which is the suppressor of the PI3KCA pathway. These would not be sufficient on their own, but they could complement the anti-estrogen activity of Elascestrant, and by following TMs you could assess if they are helping
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I recently read somewhere that ESR1m upregulates CDK7, so a CDK7i trial (with elecestrant?) might be worth looking for.
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An interesting interview w/Hope Rugo (UCSF) about treating PI3KCA and ESR1 mutations:
https://www.obroncology.com/podcast/dont-just-throw-drugs-together-how-to-best-approach-esr1-mutations-in-breast-cancer
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great article!
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Believe60, vlnrph, nikkiqh, Any updates? Concerned about you guys…
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Hi cure-ious, thank you for asking. I’m finally off insulin and my pancreas seems to be back online! They were worried that I might shoot too low as my body kicked back in and that’s what happened. I had taken insulin that day and so kept dropping to 65 or so. But better than the 695 blood sugar I had when admitted to icu! I knew nothing about ketoacidosis before this. Now I test everyday to make sure. It’s the extensive systemic edema that’s really challenging me. And at 63 I am not recovering from my icu stay very rapidly. Still using the wheelchair to get around. I see my cardiologist tomorrow to see if I can drop the metoprolol. Home health nurse felt 100 mg too much as tachycardia has stopped. I am running into many differences of opinion among the docs.
So the million dollar question is do I go back on the trial drug. The sponsor has offered for me to restart at 600 mg. I was taking 1000 mg before this happened. I had good results in that all liver spots were shrinking. Same for bone. You can only be off the trial drug for 28 days. Then you are out. I have to decide. We know what to watch for now. I just don’t know.1 -
Oh, wow!!! What a story, what a scary result, and now a real dilemma, what to do?! Is the drug a pill or tablet, is it taken a couple times a day? Is it possible to build back up to the 600mg, at least over a couple of days, or you have to just down the pills and push forward? What are the other side effects, beyond the sugar issue? What do these guys think, that we are all going to be fine with taking a GRAM of some drug every day?! Do they ever consider getting real? It seems to me that most people on this site who entered a trial ended up being given way too much drug, is it just us or is this the way they always do things?!
Do you do nighttime fasting?! It has a dramatic effect on blood sugar levels if you just take water after early dinner, and get a good 14 hr fast at night. After about an hour you are burning fat (before that, sugar) and someone I know who works in this area says its as good as drugs for a quick A1C drop. Basically burn down the sugar you ate that day.
How much longer do you have to decide? For sure at least you'd need to see that sugar come down and be well-behaved. At least they are offering a significant drop in drugs, and with good results in scans its surely tempting, but geez, not like we don't have things hard enough as it is than to have to make decisions like that. Can you talk to someone else who has tried the lower dose? And was anyone else given the 1000mg dose they gave you?
PS I hear that 63 is the new 43…
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Another important advance in immunotherapy!
A recent paper in Nature examined why the bacteria in the gut play such a big role in determining whether cancer patients will or will not respond to checkpoint inhibitors. Checkpoint inhibitors are monoclonal antibodies that block the binding of PD1 protein (on the surface of T cells) to PDL1 and PDL2 (proteins on the surface of tumors), which frees up the T cell to attack the tumor. The authors identify a gut bacteria that reduces the level of PDL2 protein as well as a new target for PDL2, called RGMb, which was not previously known to exist. Blocking this new pathway connection, which links PDL2 to RGMb (using an antibody or removing RGMb genetically) was sufficient to switch non-responder mice to responders to checkpoint inhibitors and was sufficient to explain how the gut bacteria can affect the response to checkpoint inhibitors. Great progress!!!
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Sure wish the Immune Checkpoint Inhibitor (KEYTRUDA) trial I was on would have worked but alas. Fortunately, my liver enzymes are now within normal limits so my oncologist did a 20% dose reduction on the paclitaxel which I’m tolerating much better compared to the 1st time I took it 3 weeks ago. With gemcitabine, it’s sort of an “old school” treatment.
I’m thinking the revised format of these boards have caused people to avoid posting or there are not many of us on traditional chemotherapy anymore. Or perhaps it’s a case of so many cutting edge advancements available that little interest exists for the meds which came before. Either way, I may start a new topic about options common in the past.
The high dose steroids I was given in an effort to control my unusual response regarding the study drug have caused both eyes to rapidly develop cataracts. My vision is blurry & I will need surgery prior to getting the lenses in my glasses replaced. Without being able to read the music or move my bow arm due to the cracked collarbone, violin playing this fall isn’t likely…
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vlnrph I'm sorry to hear about your eyes and playing the violin. I agree with you there isn't much activity in the older treatment forums for whatever reason. I am on weekly paclitaxel for 12 weeks and have done 3 of the 12. I started it shortly after I started Piqray. Not sure if one or both together was the key but my breathing with the lymphangitic spread is back to normal and I've been off oxygen for weeks. I'm very anxious to see what my scans say at the end of the month. I think sometimes there is benefit in the older "known" drugs despite all the exciting advances.
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vlnrph,
Hope you do start a new thread regarding "old school" chemo options that may still be used. So happy to hear that you're tolerating the lower dose chemo combo. But sorry to hear about the rapid development of cataracts. I didn't know this risk was associated with steroids. At least cataract surgery is common and highly effective. Hope you continue to stabilize and improve, including your violin arm.
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Interesting report that subsequent biopsies show that eventually all Her2-negative will move into the low Her2 category… Her2 is a potent way to drive gene expression in HR-positive MBC, so it makes sense that if one is not blocking that pathway, at least some subset of the cancer would eventually move in that direction. In the case of Enhertu, the stronger the Her2 levels, the stronger the response to the drug, although even some Her2-negative cancers do also respond
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Another analysis has popped up comparing tumor mutations before and after Ibrance-Femara/Faslodex, I'm posting both studies below. The first one looked at a sample of patients that had mostly been on AI-Ibrance, whereas the second was from a Faslodex-Ibrance group. These seem fairly compatible with respect to ESR1m, whereas more PI3KCA mutations popped up in the Faslodex group. The first paper discusses an increase in genomic stress in the cancers that might make them more sensitive to a PARP inhibitor, or PARP inhibitor with immunotherapy- they are trying to get a trial going to follow CDK4,6i -Endocrine Therapy with Talazoparib +/- immunotherapy. It is similar to the recent report on the PACE trial, which found that immunotherapy was able to boost endocrine therapy after progression on a firstline I-F regimen.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10360358/
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From the above article, dated 2018, posted by cure-ious: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10360358/:
"Significance: Acquired mutations from fulvestrant are a major driver of resistance to fulvestrant and palbociclib combination therapy. ESR1 Y537S mutation promotes resistance to fulvestrant."
Based on my solid tumor biopsy genomic testing, done Aug 2022, I had ESR1 Y537S and yet my next treatment was Afinitor and fulvestrant. I was on this treatment for 3 months and had progression. I don't understand why this treatment decision was made given it was known back in 2018 that ESR1 Y537S was a driver of resistance to fulvestrant. It's water under the bridge; just thinking out loud. Maybe the rationale for the decision was more complicated and justified, but it doesn't instill much confidence.
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There is a great deal of information in the scientific literature that takes years to permeate the medical community, especially groups that do not go to all the recent conferences or are involved in clinical trials. Even something as fundamental as the fact that Fulvestrant does not inhibit ESR1 Y537S mutation, probably there are many MOs today who are unaware of that fact. I was surprised to see that the list of possible clinical trials from the Guardant 360 test does not include any of the mutation-specific PI3KCA inhibitors, so even those "recommended clinical trials" are also way out of date, or maybe they only update them every five years or so.
Even today, the majority of the clinical trials for second or thirdline still use Fulvestrant as the endocrine therapy. Everyone here should be aware that Fulvestrant has very little activity after progression on a Fulvestrant-CDK4,6i combination. The pending new drug, Capivasertib (Akt inhibitor) was in phase 3 with Fulvestrant. They got about a 5 month PFS, and the scientists on that study reported that the drug is better than that, its very strong, but the problem is that Fulvestrant itself was a weak partner to pair it with, because most people in the trial had prior Fulvestrant with CDK4,6i. They pointed out Fulvestrant as a monotherapy was good for a 4-5month PFS for people who had not seen it before, whereas it was only good for about 1.5-1.7 months PFS after a round of Fulvestrant-CDK4,6i.
Bottom line is that after progression on Fulvestrant+CDK4,6i, people should be looking for an oral SERD, alone or in combination with other targeted therapies.
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Cure - Im looking at Affinitor/Fulvestrant if next scan in 8 weeks shows Xeloda definitely isnt working. I haven't have Fulvestrant yet, so Im wondering at this combo as a next line. Still super ER/HR positive though it does seem like Im starting to mirror WenninWi a bit. Affinitor/Fulvestrant doesnt seem very common, though, any papers on that? (Edit: I do not have any other actionable mutations than my BRCA1, GATA3, and P53 mutations at this time)
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Sondra, I think Fulvestrant is a really great drug, look at how long and hard they have tried to make an oral SERD to replace it! Clearly it does more than degrade and inactivate the estrogen receptor, now there are reports it also slows its movements through the nucleus. Its been hard to replace, so a good choice that still leaves oral SERDs and PROTACs as options for treatments after that.
It's a reasonable question as to how effective is Affinitor/Everolimus? Those trials were done before CDK4,6i. Does your cancer have a PI3KCA mutation? Capivasertib in combination with Fulvestrant is expected to be an approved regimen later this year, so could be an alternative. It is a potent inhibitor of Akt, which is turned on by PI3KCA as well as other cancer drivers. However, there is an open question as to whether Capi works on p53 mutant cancers, and some say it might depend on the particular p53 mutation.
BRCA1 is of course sensitive to PARP inhibitors, and talazoparib is about 100x stronger than the others in that class, and combinations with immunotherapy have also been impressive.
https://www.nejm.org/doi/full/10.1056/nejmoa1802905
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@cure-ious Can you comment on treatments for paraneo plastic syndrome? A spinal tap will be scheduled shortly but the MO strongly suspects I have this rare autoimmune disorder.
Thanks,
Irishlove aka Laurel
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Hi IrishLove- I never heard of it, but asked my BIL ( a physician) for comments, and will post what he sends. I see this also can arise when taking checkpoint inhibitor immunotherapy, so we all should be aware of it. Here's some info from PubMed:
Paraneoplastic antibody syndromes result from the anti-tumor antibody response against normal antigens ectopically expressed by tumor cells. Although this antibody response plays an important role in helping clear a nascent or established tumor, the engagement of antigens expressed in healthy tissues can lead to complex clinical syndromes with challenging diagnosis and management. The majority of known paraneoplastic antibody syndromes have been found to affect the central and peripheral nervous system. The first and most important goal of treating PNSs is identifying and treating the underlying malignancy. In addition to treating the primary malignancy, early and aggressive immunomodulatory and immunosuppressive treatment with corticosteroids and IVIG provide the best chance of neurologic recovery…
Paraneoplastic neurologic syndromes (PNS) are a group of neurological disorders that are possibly caused by immunological mechanisms triggered by an underlying tumor that involves every part of the nervous system. Autoantibodies were categorized according to the risk of cancer association. Antibodies against intracellular proteins
are excellent markers for tumor detection, however, without functional roles in neuronal loss, the direct effector of neuronal damage is thought to be cytotoxic T cells. The frequently associated symptoms include limbic encephalitis, cerebellar ataxia and sensory neuronopathy. The associated tumors are mainly small-cell lung cancer, breast/ovarian/uterine cancers, and thymoma. Timely diagnosis, prompt immunotherapy, and treatment of the underlying tumor are essential for managing PNS. However, we need to be cautious about the high frequency of false-positive/negative results of antibodies using commercial antibody tests. This highlight the importance of the careful evaluation of clinical features. Recently, PNS emerged after immune check point inhibitor administration, and this became a subject of attention exploring its pathogenesis. Basic studies to understand the immunological background of PNS are progressing.Intriguingly, patients with PNSs may have a better prognosis compared with patients with identical tumors but without PNSs… So I wonder if they respond better because the immune system is attacking them more? They do go on to say the tumors are often loaded with infiltrating T cells.
Anyway, I guess the short answer is that the tumors have stuck some normal proteins onto their surface, and the immune system is making a bunch of antibodies to go attack those normal proteins (basically autoimmune antibodies, but arising from the tumor), which causes the problem. So as treatment, they both want to reduce the numbers of tumors and also dampen down the immune system. Hopefully you will get a definitive answer soon, and a good course of treatment if that is the problem!
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@cure-ious Thank you so much for your time and information. I had read a Pub Med article listing check point inhibitor treatment as potentially triggering PNS, as you pointed out. It appears that people with this syndrome are oftentimes misdiagnosed or underdiagnosed. We will see what the spinal tap shows, but I'm hoping to ward off permanent neurological damage. I did receive 4 rounds of solumedrol since July, so hopefully that has helped buy me more time. That was administered because I have MS for 22 years and assumed it was an MS attack. The MRI with contrast showed zero enhancing MS lesions, so we can rule that out.
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from my BIL:
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Cure- I already failed Lynparza and no other actionable mutations. Capivasertib will be coming into clinic here by end of year apparently (as per my MO) but with no good mutations, to Fulvestrant it will be. However, there is still a question mark over X, I just dont expect it to resolve favorably.
Talazoparib is currently under cost effectiveness review and not available here yet.
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Well Capi is a strong drug: The phase II FAKTION trial found that the combination of capivasertib with fulvestrant in ER-positive/Her2-negative MBC doubles PFS (10.3 v 4.8 months), with a strong trend towards improved OS. Even tho people who progressed on I-F got a shorter PFS, its still true half go longer than 6 months plus if you have had a break since taking I-F it might be stronger.
Capi is given 4 days on, 3 off due to extensive diarrhea and other side effects, so hopefully they have made it tolerable. For right now Fulvestrant combos are the vast majority of what we have available, so hopefully more drugs will show up soon, oral SERDs, PROTACs, enobosarm, etc, there are a lot of irons in the fire
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Sometimes research just flips dogma upside-down, like it did a couple of years ago when it was realized that androgen receptors actually inhibit estrogen activity in ER-positive breast cancer cells, rather than stimulate the ER, so you want to treat ER+ cancers with androgen boosters (agonists) rather than inhibitors.
A similar story has now emerged in a recent Nature paper. It was well-known that inducing chromosome instability (CIN) and genome/DNA damage in normal cells turns on the STING immune pathway and arrests cell growth or leads to immune clearance of those cells. Scientists reasoned that STING activators (agonists) would do the same for cancer, however in clinical trials they didn't work. Further study showed that genome damage and CIN can lead to metastasis and immune evasion, because the cells quickly adapt to chronic STING activity by re-wiring the pathway so that they can use STING to survive and help evade the immune system. So, opposite to what was previously believed, they now find in mouse models that it's important to inhibit the STING pathway, rather than activate it, in order to get rid of the immune suppressive cells that are protecting the tumor. Fortunately STING inhibitor drugs are already in development, so this finding may point a new way to disrupt the protective immune microenvironment and help immunotherapy to work on MBC…
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