ESR1 mutation treatment options and new SERD/SERM research
![[Deleted User]](https://us.v-cdn.net/6037276/uploads/defaultavatar/nF0ALO3I3QJM7.jpg)
Hello everyone,
I was asked to start a thread about the ESR1 mutation that many ER+ survivors find in their genomic testing. I have the specific mutation of ESR1-Y537S. Which can make me not respond as well to AIs and even Faslodex shots according to my reading.
This resistance to estrogen blocking therapies is something I am interested in finding out more how to overcome. In my specific case I have progressed on all 4 lines of therapy- 2 with faslodex.
So I thought we could start a thread that highlights research articles, patient stories, clinical trials for the new SERDs that may overcome resistance and general support.
I will gather some of my info and post again soon. In the mean time please post your experienceshere for us to share.
My youngest daughter is studying to become a counselor and told me today, “We learn better in Community where we can share, care and grow!"
Comments
-
Your daughter is right, Dee! Let's Crowdsource to the Cure!!
Here is a link showing a Liquid Biopsy developed by Stand Up for the Cure and AstraZeneca can be used to identify ESR1 mutations. These mutations often arise following treatment with aromatase inhibitors (30-40%), usually they are not present in the primary (5%). The mutations cause the estrogen receptor to become active even without estrogen around, so aromatase inhibitors have no effect and they aren't much sensitive to Faslodex either.
0 -
A SERM (Lasofoxifene) is being tested as a selective inhibitor of ESR1 mutant MBC
Clinical trials
Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation – NCT03781063
Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation (ELAINEII) – NCT044324540 -
The PADA-1 trial reported that patients who started out with an ESR1 mutation got a median PFS of about 11 months (on AI + Ibrance) compared to those with no estrogen receptor mutation, who got 26 months.
Serial testing of these patients showed that 69% of these patients shed the ESR1 mutation within the first month of starting treatment - the subgroup that eliminated the mutation (and did not have it return at later times) ended up with a PFS of 24 months, compared to the cohort who never lost the ESR1 mutation, who got a PFS of only 7 months. These data show the mutation is associated to early resistance to I-F, but also that sensitivity to the drug combo can be reversed if the mutant ESR1 protein goes away.
Apparently the ESR1 mutation can come and go in serial biopsies, in this study a majority of ESR1 mutations were cleared after the first month of treatment, but then in about half of those cases it returned later. Hence the interest in using SERDs and SERMs to better take out the ESR1 mutation
https://ascopost.com/issues/july-25-2020/pada-1-tr...
0 -
Dee, I'm so glad you started this thread.
As you know, I have ESR1. Two different liver BX, two years apart, showed the same pathology. I've had two different Genomic testings done, one from F1 and a different one, showed the same results.
I guess I'm one of the lucky ones because my tumors are responding to Faslodex. I've been on it for ten months. Four other TX, including IF and AA failed.
I've also had two sets of y90's so I'm not sure if my stubborn liver mets are responding to Faslodex but my lung and chest mets are.
I'll have more scans in October, hoping for continued shrinkage of lesions.💞
0 -
Thanks Cure-ious
So many ER+ survivors are failing on hormonal therapy. Learning about the ESR1 mutation is a great milestone. The Lasofoxifene trial is important because the FDA is trying to help fast track this drug, if I understand correctly.
The thing I want everyone to know is that these SERD and SERM trials are limiting prior regimens. SOME TRIALS ONLY ALLOW 1 CHEMO. That means our oncologists need to know our genomic profile early in the metastatic setting and realize these trials are available and timing is crucial!
I tried to get into the Lasofoxifene trial BUT I already had 2 chemos. Dr. Hamilton at Sarah Cannon Tennessee Oncology is now trying to get me in this class of trial because I am ER+100% And progressed on every systemic drug including Faslodex and a CDK 4/6. I will know next week which one.
Clinical trials are no longer the last hope with no other options available. Many trials are available if we are refractory (which means not responding to current therapy/stubborn) We can choose to participate earlier in our journey because we have testing for mutations and amplifications that can benefit from promising targeted therapies.
Knowledge is power I just want oncologists to be on top of these trials so we would not miss the opportunity to at least consider the best fit before we are disqualified.
Dee
0 -
Grannax2
So glad you are responding to Faslodex. Scientists are still learning why some people respond and others don’t. It’s mostly statistical research that ESR1 is more resistant to hormone therapy. It could have to do with the specific Mutation. Do you know which ESR1 mutation you have?
There is some data that the one I have ESR1-Y537S is more resistant to Faslodex.There is a trial for this specific mutation in one of the arms of
Trial of H3B-6545, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer
https://clinicaltrials.gov/ct2/show/NCT03250676
Dee
0 -
Dee,
Thanks for starting this thread. I don't have this mutation yet but I am trying to learn as much as I can. I have learned so much from you and Cure-ious and appreciate you both sharing your knowledge.
It is very helpful to have all this info when talking to my MO about future treatments.
0 -
Dee, That is such a great point- given that ESR1 mutations can be readily identified with a liquid biopsy, its something everyone should check for once I/F fails, or if it never worked. However, as you say, the trial only allows 0-1 chemo in the metastatic setting. The drug is a SERM, like tamoxifen, and apparently few side effects.
the FDA put lasofoxifene on the fast-track last spring
https://www.onclive.com/view/fda-grants-lasofoxife...
0 -
Here is an interesting discussion- for one, they expect to be able to show that lasofoxifene doubles the average PFS compared to fulvestrant for ESR1 mutant cancers, that would be huge! And they discuss that this drug inhibits ESR1, working differently to the SERDs that degrade it, so that both approaches could be used in these cancers (if the ESR1 mutation even persists after the treatment). It's been tested already in many patients in early trials for a variety of reasons and has a great tolerability and safety profile.
https://www.onclive.com/view/expanding-the-treatme...
"We see that the proportion of patients with ER-positive, HER2-negative metastatic breast cancer who develop this [mutation] ranges from 20% to 30% or maybe even higher. [ESR1] an incredibly common resistance mutation as we have a huge number of patients with this disease. Therefore, developing optimal and new ways to target this particular set of mutations is going to be critical as we continue to move the field forward."
0 -
this study allows a few more treatment regimens
In preclinical studies ARV-471 has shown promising activity as an ER degrader, demonstrating superior tumor growth inhibition compared to fulvestrant. ARV-471 has demonstrated potency as both a single agent and as a combination therapy with CDK4/6 inhibitors.
https://clinicaltrials.gov/ct2/show/NCT04072952
Arvinas is a biopharmaceutical company developing therapies that degrade disease-causing proteins. It developed a platform called PROTAC, which can target any protein for degradation by the body's natural mechanisms. ARV-471 is an oral investigational therapy that uses PROTAC technology to target the ER for degradation. "ARV-471 is a potent ER degrader that has demonstrated significant anti-tumor activity in preclinical models...
Let’s hope this drug gets some traction. Plus it is oral and not a shot like Faslodex!
Dee
0 -
Dee, I'll have to dig through my papers to check on which ESR1 I have.
I know I wouldn't qualify for Elaine trial but after lasofoxafiine is FDA approved my MO could try it on me if I fail Faslodex, right?
That's why I'm so interested in this thread. I have no idea what's next for me if my scans show progression in October. So, maybe I can learn something here to suggest if/when that happens. Always good to have new info in my pocket for future use.
Also, I don't think a third y90 is an option for me. I know there's a lifetime limit for how much yittrium my liver can take. My IR has indicated I've had close to the maximum. 💞
0 -
Just realized the Elaine trial is listed as terminating this month (altho it also says still recruiting so they might have been delayed by covid)- which could mean a phase 3 trial may be starting relatively soon? might allow two prior chemos? and include an arm for a CDK4,6 inhibitor. In the case of Ibrance, once phase 3 was fully enrolled the FDA approved the drug so everyone could have access and not have to wait five years for the data to roll in; if the numbers in phase 2 look really good perhaps they would do the same? Altho the Elaine trial is only 100 patients, surely that would not be enough for FDA approval?
0 -
my new doctor is a principal investigator at SC for the Elaine trial. I will ask her if she knows anything when I see her in a couple weeks. 😉
Dee
0 -
https://clinicaltrials.gov/ct2/show/NCT04505826
I will be starting this CERAN trial for my ESR1 mutated cancer.
A Dose Escalation/Expansion Study of Oral OP-1250 in Subjects With Advanced and/or Metastatic HR+,
HER2- Breast Cancer
here are some articles about this new drughttps://cancerres.aacrjournals.org/content/80/16_Supplement/4376
Good news it should work better than Faslodex and it is a pill!
Dee0 -
Good news for you that you get to be in this trial. I know it will be very time consuming and a lot of travel. I hope all of that won't be too hard on you.. You are paving the way for the rest of us. Of course I'm most hopeful that it will help you.💞
0 -
The SERD that is furthest along in development, called Elacestrant, announced that they have completed accrual for phase 3 testing. A committee reviewed the data thus far and recommended they keep going without modification, so presumably they are seeing some positive activity. The SERD is being tested here as monotherapy.
About elacestrant (RAD1901) and EMERALD Phase 3 Study
Elacestrant is a selective estrogen receptor degrader (SERD), out-licensed to Menarini Group, which is being evaluated for potential use as a once daily oral treatment in patients with ER+/ HER2- advanced breast cancer. Studies completed to date indicate that the compound has the potential for use as a single agent or in combination with other therapies for the treatment of breast cancer. The EMERALD Phase 3 trial is a randomized, open label, active-controlled study evaluating elacestrant as second- or third-line monotherapy in ER+/HER2- advanced/metastatic breast cancer patients. The study has enrolled 466 patients who have received prior treatment with one or two lines of endocrine therapy, including a cyclin-dependent kinase (CDK) 4/6 inhibitor. Patients in the study were randomized to receive either elacestrant or the investigator's choice of an approved hormonal agent. The primary endpoint of the study is progression-free survival (PFS) in the overall patient population and in patients with estrogen receptor 1 gene (ESR1) mutations. Secondary endpoints include evaluation of overall survival (OS), objective response rate (ORR), and duration of response (DOR).
https://www.streetinsider.com/Globe+Newswire/Radiu...
Below is a link to the EMERALD trial, and it is still recruiting. The primary completion date is AUG 2021, and patients will be followed a year beyond that. Criteria are that patients progressed on prior treatment with a CDK4/6 inhibitor with either fulvestrant or an AI, no more than two endocrine therapies, cancer has to remain endocrine sensitive, no more than one chemo in the metastatic setting, and no prior SERDs. Phase 3, 200 sites, lots in US, and global sites include Argentina, Australia, Europe, Canada, Israel, Korea...
https://clinicaltrials.gov/ct2/show/NCT03778931
They also developed a liquid biopsy to test for ESR1 mutations:
0 -
After reading your post I don't think I would qualify for that study. Thanks for all the info, Cure-ious.,💞
0 -
If its better than fulvestrant alone, it may be useful for ESR1 mutations in combination with everolimus, for example. Earlier studies of this drug gave just a 19.4% ORR and a PFS of 4.5 months, but this is on patients who had seen extensive endocrine therapy already- not sure what fulvestrant alone would have done for that group. This is just the first SERD, will see if it can withstand challenges from some of the newer SERDs that are coming up.
0 -
Cure-ious. Yes, after its approved it might be an option to consider. Thanks for being so diligent in your research, especially for people like me who are not as good at researching.💞
0 -
0 -
Just talked to Dr Hamilton at SCRI about lasofoxafiine. She said the phase 3 trial is only 25% accrued and it will be a loooong time before it can reach FDA approval. She wouldn't give years but seems like I won't be waiting around for lasofoxafiine for my esr1 mutation.
I signed papers for the CDK2/4/6 trial Single agent.
FYI- the arm with letrazole/Faslodex is about to open in the next few weeks. If anyone progressed on a cdk 4/6 with letrazole you may be able to qualify for the Faslodex cohort of cdk 2/4/6
Cross posting this on the clinical trials page.
Dee
0 -
Dee- very interested in how you are doing in the CDK2/4/6 trial. where will you be posting your experience and results?
thank you- I appreciate your posts!
0 -
nkb- I will post updates over at the clinical trials thread
https://community.breastcancer.org/forum/8/topics/868597
Dee0 -
So the ESR1 mutant estrogen receptor has been shown to be phosphorylated by CDK2 at a spot that is required for its activity. The upshot is that cancers with ESR1 mutations should be effectively blocked by a CDK2 inhibitor.
https://pubmed.ncbi.nlm.nih.gov/29137354/
PS Dee, you and your docs must have known about this, but somehow I missed the connection! - Great promise for your upcoming trial!!
0 -
thanks cure-ious. I had not seen that article. It is reassuring!
Dee
0 -
I came across an interesting clinical trial for a New scan to show show ERa expression in ESR1 mutated cancer to know how much tamoxifen to prescribe.
https://clinicaltrials.gov/ct2/show/NCT04306900
18F]-fluoroestradiol Positron Emission Tomography/Computed tomography (FES-PET/CT) imaging is a novel functional imaging technique that can non-invasively measure ERα expression and inhibition in metastatic ERα+ breast cancer. The proposed a pilot study uses FES-PET/CT imaging to measure ERα blockade to determine the optimal dose of tamoxifen in patients with ESR1 mutations.
Dee
0 -
Dee, the CDK2 inhibitor's main job is to inhibit Cyclin E:CDK2 kinase complexes, which can go up in CDK4,6i-resistant cancers. what this new study means is that the CDK2 can do a second thing, which is to inhibit the activity of ESR1 directly- so, if you respond, it could be for either/or both reasons. Although you and perhaps your doctors weren't aware of this second route to response, for sure the trial team knows it and it may have figured in them accepting you and putting you in the monotherapy arm of the trial. Surely they are keeping track of how the ESR1 population is responding to the drug. Is there any point at which you could add in tamoxifen or faslodex?
Frisky had problems with side effects and left this trial, and the company shortly after announced a big dose reduction. Hopefully they now have it right but don't hesitate to speak up if not (!!), we all want to take this and not get hit with fatigue or really unpleasant side effects, its a very powerful formulation so one should not have to take a ton of it..
0 -
cure-ious
I will bring up this article when I see them next week. Very interesting but a bit above my head too! 😉
Glad to have you here pointing the way.
Dee
0 -
Way above my head.💞
0 -
Reposting from Breaking news thread care of MOTH. Thanks for posting.
ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trialshttps://clincancerres.aacrjournals.org/content/26/...
& plain language summary: "Patients with metastatic breast cancer carrying a particular mutation fare better on one form of hormone therapy than another and can be identified using a blood test, according to a new study.
In a combined analysis of two major Phase III clinical trials, called SoFEA and EFECT, researchers were able to show that patients with advanced hormone-receptor positive breast cancer, which has developed a mutation in its androgen receptors called ESR1, fared better on a hormone therapy drug called fulvestrant, compared with another called exemestane." https://www.icr.ac.uk/news-archive/new-study-sheds...
ESR1 can be identified through liquid biopsy
0
