Are you currently (or have you been) in a Clinical Trial?
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Hi all,
I may not have a slot for TTX-MC138, so they're floating the BG-68501/ETX-197 (CDK2i) again. According to the SABCS abstract:
These data suggest that ETX-197 has the potential to be a best-in class CDK2 inhibitor for the treatment of cancer with CCNE amplification or RB1 deficiency, including breast cancer that has progressed on treatment with a CDK4/6 inhibitor because of these genomic alterations.
So I don't think I have a CCNE amplification—according to the Caris test, my Gene Expression is 38. But my RB1 is 6. I wonder if that would be considered a deficiency? Am I looking at the right thing? Neither is listed in the DNA Sequencing or Relevant Biomarkers section.
I know cure-ious has mentioned that the CDK2 treatment doesn't do much without a CDK4 at the same time, (though I will be on Fulvestrant as well) but I'm probably going to end up on this one. Am I wasting my time?
Thank you for any input as I am completely over my head. :)
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Happy belated New Year everyone. I don't check this thread as much as I used to, but it's always inspiring to see the level of commitment to research (although of course I wish that the current conventional drugs worked better and longer, but I digress).
I am still stumbling along on Enhertu (since May), which is a pleasant surprise as it is my 15th time up at bat:). I find I'm very tired. I'm already down to the 60% dose.
WeinWI - I'm sorry you are now at the stage that you have to worry about previous systemic chemotherapies. It's very frustrating when there's a good class of drugs coming up but you can't get in (the newer SERDs have been like that for me). Earlier you wrote your two chemos were Afinitor and Enhertu. Did you mean capecitabine and Enhertu? Of the three conventional therapies your oncologist has suggested, eribulin was easier for me in terms of side effects but paclitaxel did knock back a pretty serious progression I had to the pericardium. I've had some luck "layering" chemos with clinical trials. Good luck with your choices.
cblaurenceauthor - the drugs you are looking at are so interesting, but beyond what I've been able to keep up with. Good luck with getting into the trial of your first choice.
tougholdcrow - at times, finding clinical trials have been having a job! I agree we need all the help we can get. For the U.S. there's now the https://metastatictrialtalk.org/Over the years, I've tried to listen in to research webinars when I can (the LBBC conference is coming up), track the big breast cancer conferences, and read!
Cure-ious - as always thank you for sharing your knowledge and helping us all on our searches.
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A quick follow up - while I was posting, new posts came in.
Luce - thank you for that chart! It so clearly summarizes about the ESR mutations. And here I am with Y537S (2017 & 2022) and I've gone back to the fulvestrant well 3 times! (2012, 2018 and 2023) . Last two times were in combination, so I guess we know what was actually doing the work.
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newgardener : I too find the chart useful but sure wish there was newer data. There may well be but I haven’t found it.
regarding ESr1 mutations, lasofoxifene might be an interesting drug for a small subset if it gets approved at some point . It was fast -tracked in 2019 (!) and started with phase 2 trials as safety had already been proven years earlier, when it was approved as an osteoporosis drug in Portugal and Latvia (since discontinued in that indication). It’ll prob only work for a few people in advanced setting but its mechanism is interesting to me: instead of degrading the mutated ER, it changes it back to its original, deactivated form (at least according to the claims on its manufacturer’s website). I’m livid they don’t have an expanded-access or compassionate-use program. (This is probably a very cheap and safe drug.) I like that unlike the SERDs, lasofoxifene, as a SERM, doesn’t act as an antiestrogen in some off-target tissues, so has a very tolerable side-effect profile.0 -
It's just in small print in my signature, but in 2015 I did a trial of palbo with bazedoxifene - another SERM that was approved as an osteoporosis drug. I wonder how much it has in common with lasofoxifene.
I did well on that trial, but bazedoxifene didn't go anywhere after that as a breast cancer drug. Unfortunately bazedoxifene is only available in combination with estrogen now it seems (Duavive).
When/if my time on Enhertu comes to an end, I had been wondering about revisiting tamoxifen at a high dose (I haven't had it in 15 years). But the chart seems to suggest the cancer might also be "very strong"-ly resistant to it too. Darn.
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New Gardner- Happy New Year!!! So great to hear from you!!! Have you had any recent genomic testing? there are a lot of new trials floating around..
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CBL, Do they have any trials that include the new Pfizer CDK4 inhibitor (PF-07220060) because they are reporting responses even for cancers that were resistant to CDK4,6i, given how strong it is…
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@cure-ious Doesn't look like it unfortunately. I looked at all the PF-07220060 trials on clinicaltrials.gov, and none are in Dallas. A few in San Antonio, but I'd rather not travel.
I have an appointment at UT Southwestern on Friday, so I'll have to make a decision then. We'll see what the new oncologist has to say—he's a MBC specialist and involved in trials as well—and go from there.
Thanks for the input!
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@newgardener Thank you so much for these resources. I will dive in when I can.
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newgardener,
You mentioned high dose tamoxifen. There's a clinical study of this drug at the facility where I go (Carbone Cancer Center Madison, WI). Unfortunately, I don't know the study number. The study was presented to me a couple of years ago and they're still running it. The drug can cause uterine cancer and this concerns me as I still have my uterus. It can also cause deep vein thrombosis. So I've never been too interested, but I'll ask again if I would qualify.
Cure-ious, Do you having thoughts about this treatment?
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WeninWI, I'm not familiar but I bet Luce is, she has seen success using high dose estrogen (estradiol).., and I think there is a way to prevent uterine cancers too
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polemonium: Dana Farber has the Elaine 3 trial, abemaciclib plus lasofoxifene. Half the patients are randomized to abemaciclib with fulvestrant, your oncologist’s SOC recommendation, so you’d be good in either arm.
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I think they found that high-dose tamoxifen still works in some esr 1 mutations. Okay to try as salvage therapy but wouldn’t be my first choice. What we really want is lasofoxifene, which is a third-generation SERM that doesn’t cause endometrial overgrowth and works on esr1 m. But still in phase 3 trial (Elaine).
(I have used high-dose estradiol (look up Polly and Esther and Phoebe trials at Dartmouth) but got uterine bleeding five or six weeks in. I suppose one could get an IUD. Celebrex helps a little to slow down endometrial overgrowth too.)
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NewGardner, Combinations can make everything different, for example, mutant-specific PI3KCA drugs are offered with faslodex, but it seems that the PI3KCA drug leads to a drop in both PI3KCA and ESR1 mutations in subsequent Guardant testing, no idea why- the PI3KCA kinase going down is no doubt because it was inhibited, cells often have pathways that degrade and clear out inactive proteins- so in a case like that the faslodex can work…
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CBLAuthor- So CDK2 inhibitors on their own would work, its just that from first principles they should work better with CDK4 inhibitors. You could make the reverse argument, that CDK4 inhibitors should not work if you don't also add a CDK2 inhibitor, and of course they do, its just that upon resistance the cancer often upregulates or otherwise activates the CDK2 kinase. For those cells, the CDK2 inhibitor should help a lot, however resistance could be due to flipping back on the CDK4. In future they will block both, but if you can get in a trial with CDK2i I think its a very good treatment to get back to the point of endocrine sensitivity, and then maybe get a trial that includes the new CDK4i or the new CDK2+4i…
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So, for PI3KCA inhibition, there are now clinical trials for two drugs that hit all mutations (RLY-2608 and STX-478), and one trial for a drug that can only hit one specific mutation (OKI-219), and yet another drug (TOS-358) that hits all mutations and also binds to PI3KCA covalently (ie, not in a reversible way like the others do)- so TOS-358 might be the strongest, and it is in pre-clinical trials, however it might also come with some stronger or newer side effects. All of these drugs have the advantage that they do not cause the high blood sugar and rashes that is seen with the drugs that inhibit the PI3KCA pathway in all cells (Piqray, Trucap, Inavolisib), rather than only in the cancer cell (where the mutants are found). This are is getting very hot, with Eli Lily just buying STX-478 for 2.5 billion, and RLY-2608 (furthest ahead in clinical testing) running to start their phase 3 trial this year… If these drugs sail through testing there are going to be multiple options, and possibly they will be used in combination with oral SERDs in a manner similar to how the various CDK inhibitors are used.. So its key to keep doing the genomic testing because the ESR1 and PI3KCA mutations often pop up as cancer cells become resistant, are are not seen in early tests…
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CBLA- Did you see their poster?
https://www.beigenemedical.com/CongressDocuments/Barve_BG-68501-101_SABCS_Poster_2024.pdf
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PS Also, they have been trying to get a CDK2i drug that we can tolerate for quite awhile, so asking for CDK2 plus CDK4 is quite a lot, and for all we know that is just not going to be feasible. In my case the cancer has mutations that up-regulate CDK2, and I would definitely try this trial. Basically, I'm changing my mind about the comments I've read of how you would want both, we don't know its even possible and that hitting one at a time, ping-pong, isn't potentially even a better way to go. It's still early days
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Okay, that makes me feel a whole lot better accepting this trial! Thank you. I really want the TTX, but this isn't a bad second choice. The study page mentions an arm with an included CDK4, but that's not what was offered me, at least not the first time. Maybe this time they will—maybe not ideal but I'll take either one.
Thanks for the needed boost of confidence!
CBL
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cure-ious,
You wrote "So its key to keep doing the genomic testing because the ESR1 and PI3KCA mutations often pop up as cancer cells become resistant, are are not seen in early tests…"
I've asked my MO for a blood biopsy and she responded back asking what the benefit would be. I explained my understanding that new mutations can occur after progression and I've had four progressions since my Strata liver biopsy analysis in 2022.
Strata identified a ESR1 mutation which was treated with Orserdu. PI3KCA was not seen. My MO responded back again saying she would order the test if I wanted, but she doubted any new "actionable" mutation would show up. And she didn't know if my insurance would cover.
Question: Do you think a blood biopsy would be worthwhile for me at this point in time?
More Questions: UW Madison has a Tamoxifen study: ClinicalTrials.gov: NCT04174352. My MO is the investigator. She mentioned this study to me a few years ago and I declined. I have a vague memory that asked you about the study back then. When I saw her Jan 7 and she mentioned it again. My response was concern about uterine cancer and DVT. I see her again Jan 21 and will ask more questions. What do you think of this study? What questions should I ask about this study?
This study uses FES to Optimize the Tamoxifen dose. It's a small study that dates back to 2019, but apparently is still recruiting. Neuropathy greater than grade 1 is a disqualifier. I have neruopathy, but no pain. Her2 Negative is a qualifier, but there is no mention if Her2Low is a disqualifier.
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Luce- thank you for that screenshot. I do have all the 537s listed above on my Guardant report, but all under 1%. I would prefer the IBrance instead of Verzenio, but guess I will go with what the Doctor ordered. I expect the 150 mg will drop quickly. Nervous about this change after 8 years of fairly stable mets. Thanks for your comments also, cure-ious. The potential for participating in trials for new SERDs was mentioned by my oncologist, Dr. Nancy Lin from Dana Farber, who I very much trust and respect. I see her about once a year since there are no mbc specialists within 3 hours here in upstate NY. P.S.- if anyone knows of one, please let me know!
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I'm in the TTX-MC138 trial! Yay!
The nurse just called and said they secured a spot in the 3.2mg cohort. I'll do screening on Thu 23 and start Tue 4. I'm so relieved. The CDK2 is a great back up if I progress on this one (seems like they have frequent spots available) but hopefully, I won't need it for a long time.
I'll keep you posted.
Thanks for all the support,
CBL
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Very excited for you!
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@luce Thank you! I'm really hoping the 3.2 will be a therapeutic dose because they haven't seen results yet, but they were only giving .4 and .8. Fingers and toes and eyes crossed!
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Whoo-Hoo, CBL, I am so happy for you!!! And dang, it will be something the cancer has not seen in any form before, which is always exciting. Did they give any indications of how you will be monitored? Like do scans in 2 months, or I guess if they haven't seen responses then they don't know what the normal time to response would be. GOOD LUCK!!! I guess it will be such a relief to be moving on, so just post us often, did they say if people have had any side effects? Another huge unknown for this drug, but a targeted miRNA antagomir ought to be pretty dang specific…
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Thank you!! I'm excited and will absolutely keep everyone updated. Should learn a lot more at the screening next week. I don't know the scan cycle yet, but I believe the drug is given every 28 days, so two months makes sense. So far no toxicities have been reported, but they've been given tiny doses, so there absolutely could be with this dose increase.
Yes, it is a huge relief to have a path forward, especially this path since I've been watching it for months. I will definitely be keeping the thread updated, you'll be sick of me, haha.
I knew inhibitor wasn't the right word! Thanks for the "antagomir"- I'll have to look it up. I have an appointment at UT Southwestern today with a new doctor so I want to sound somewhat educated. :)
CBL
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WeninWI: Oh, I see what your MO is saying- she already has genomic data for existing liver mets- if subsequent biopsy showed a Pi3KCA mutation, it would presumably be sub-clonal and not in the original liver mets. But still, that could be useful information as those mets with PI3KCA mutation could be treated, but in combination with endocrine therapy or some other drug that should hit all mets. I do think I would ask for a new liver biopsy after several progressions, what if some new tumors are very different, its hard to imagine the harm in getting more data. With respect to a new blood biopsy, again that is done all the time now at progression it seems, but it won't necessarily instruct you much about the liver, my MO says liver mets are fairly well esconced in the liver and don't shed a lot of cells into the bloodstream, so a biopsy of liver is the only way to know what is happening there.
As for the trial, I will look tomorrow as I'm not familiar with it-
LUCE, do you know anything about this trial?
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cure-ious,
Thanks for the info. I don't want another liver biopsy. I hadn't heard of liver lesions being esconced and not shedding cells into blood stream. Yesterday my Mayo second opinion MO messaged me that she would recommend doing a blood biopsy.
If I start chemo I would probably choose Eribulin, but I'm concered about worsening neuropathy. Some women on the Eribulin FB page talk about "legs like jello" - can't stand up - falls - all apparently related to worsening neuropathy.
If I'm eligible for the tamoxifen study I might do it inspite of the uterine cancer and DVT risks. Luce referred to high dose tamoxifen as "salvage therapy". Not a term I'd heard of and not very encouraging, but I've salvaged items as a hobby (old trunk, spinning wheel, old photos) and enjoyed breathing new life into the items. Liver pain (pressure) has started, but I'm still active around the house, walking outside, etc. If nothing looks even a little promising, I'll start Hospice.
I await your opinions on the trial. Please let me know what quesions I should ask. Seems to me a study, even a small study, that's been running since 2019 should have some data.
Wendy
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Hi WeninWI,
Are you sure this is right trial? Its an imaging technique to see where the ER-positive cells are and to better decide how much tamoxifen to use- probably I didn't read it carefully enough to understand it, so can you say how its supposed to work in terms of treatment? You would go just on tamoxifen or its some kind of combination therapy?
PS FES-PET scans are used to confirm that the cancer remains endocrine-sensitive, and also you would need to have been off of all endocrine therapy for at least 6 months, which I think is fine in your case.
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cure-ious,
I sent the trial number and study title to my MO and she said, yes, this was the study. I see my MO on Tues Jan 21 and will ask more questions.
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