Are you currently (or have you been) in a Clinical Trial?
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Curious: From what you've seen, how long after beginning Faslodex does it usually take to be effective if it's going to work? I have been on it for almost two month now and will go in for lab(tumor marker) and CT scan next week. I was switched to it from Letrozole with progression. Is it really that different than Letrozole?
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Elenas, I don't know (have not taken Faslodex yet), but I'm sure you will get lots of help shortly. I read it can take a couple of months because you are needing to degrade all of the estrogen receptor, and there was one MO suggesting people stay on the Femara until the Faslodex has time to fully kick in (given that, despite progression, many of the mets are still responsive to it)
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Elenas, I don't know exactly but hormone therapy can take some time to start working. Although you may already have some results, I would say you need to give it a full 3 months before assessing if it is working. As you know, Faslodex is a monthly injection but in the first month, you have 2, two-week doses, which are loading doses to get the medicine up to full therapeutic levels. It does work very differently than AIs. Many people who develop resistance to AIs have success with Faslodex. I hope it will work for you. I just started Faslodex again three weeks ago along with Piqray. I took Faslodex 5-6 years ago as my first line treatment along with aromasin and Ibrance. I haven't taken Faslodex alone but hope that will work for you.
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JFL, I think I remember you have the FGFR1 amp mutation. So we can still get the faslodex injections with that mutation? That info would make my day. Faslodex and Verzenio were to be my next line, until this mutation happened. Probably what kicked me off Letrozole and Ibrance.
Is it all a guessing game what we can and cannot try with these type of mutations?
I read and read, but none of the literature sound 100% certain about where to go next unless you have the ESRI ir PK3 mutations..which I do not have.
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Here you can see how drug resistance sorts into four categories- the largest of which is "unknown" We hear a lot about ESR1 and MAPK/PI3KCA mutations, but not as much about Myc. It can be targeted with CDK7 inhibitors
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Thanks Cure-ious
You are so good at providing the research. Sarah Cannon is looking at SERDs as well as CDK 2/4/6 for me since I am ESR1. I will know Friday which trial they suggest.
CERAN NCT04505826
ARV-471 NCT04072952
Plus a couple others that she did not elaborate. They want to make sure the hypogammaglobulenemia is not an issue and number of chemo allowed. They are contacting the pharm companies to be sure.
Dee
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Dee, its great to have good options!! And I did wonder if the SERDs might not be a better place to start- you want to get the endocrine backbone right and then figure out about the CDK4,6 inhibitor. You could still be sensitive to Ibrance at this point, right?..
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By looking in detail at DNA and RNA levels in patients before and after a combo immunotherapy treatment, UCLA researchers found that they could predict "responders" by those who turned on interferon-gamma signaling in the T cells. So this is a biomarker of response, they can now presumably test drug combos more rapidly for what enables this signal to happen
https://medicalxpress.com/news/2020-09-interferon-...
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I was struck by a report that BMS is paying Dragonfly $475 million for an (IL-12 based) immunotherapy booster. That's a serious chunk of change, no? Of note, Dragonfly is a startup founded in 2015 by Tyler Jacks, a superstar in the cancer research field.
The idea is that the Dragonfly IL-12 fusion protein (DF6002, engineered to have a longer half-life than the natural IL-12 cytokine) can activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities, creating an inflamed tumor microenvironment that is needed to synergize with (boost) the action of checkpoint inhibitor drugs.
https://www.dragonflytx.com/copy-of-about-us
A phase 1/2 clinical trial just dosed its first patient last month, following FDA approval this May, and will be testing DF6002, alone and in combination with Keytruda, in various solid tumors, including triple negative breast cancer. An unrelated earlier trial using a strategy to manipulate IL-12 levels in glioma brain cancers extended overall survival by a year. They have to be careful about SEs because high IL-12 levels can cause cytokine storms.
"Dragonfly's pre-clinical data package on IL12 is extraordinary, and we are eager to demonstrate its effects in cancer patients"," said said Dr. Tyler Jacks, Director of the Koch Institute at MIT and Chairman of the Company's Scientific Advisory Board."
https://clinicaltrials.gov/ct2/show/NCT04423029
Right now it is just at Brown University in Rhode Island but plans are to expand this trial quickly
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Dragonfly also has one other clinical trial, started in fall 2019, a NK and T cell immunotherapy for HER2-expressing cancers of any origin, alone and with Keytruda, offered at Brown, RI and MD Anderson
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cure-ious
My first line was verzenio and Faslodex for 3 months. One of my 2 liver tumors had some necrosis the other did not and both were larger in the scans.
So to answer your question- am I still sensitive to a cdk 4/6? We just don’t know if it was the verzenio or Faslodex allowed progression
I read that my ESR1-Y537S can also beresistant to Faslodex. So getting the estrogen blocker right would be a good plan.
I find out tomorrow what Sarah Cannon suggests.
Dee
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Dee- We don't have a thread on ESR1- maybe you would like to start one? It's such a common mode of resistance, and seems there should be some discussion- also no thread for SERDs and the newer anti-estrogens, so that could become a busy one.. There have been many SERDs in trials, but it seems they keep dropping off the radar before they get to the FDA approval stage. Perhaps as newer-gen versions come along during the long trial testing periods, they figure their drugs won't be competitive for long. One or two SERDs currently in phase 3 have now started new phase one trials to test their activity with and without Ibrance (Could they not have designed the trial that way from the start?!!- at this rate, it will take forever!)
On the other hand, you are in the position to give them some good data to hang their hat on for the more-promising next-gen drugs. The SERDs you are considering have been shown to do better than Faslodex in pre-clinical trials (and are presumably WAY better than faslodex for an ESR1 mutation), either alone or in combination with Ibrance.. And we do not really have any trial we can access that tests a SERD with a CDK4,6 inhibitor, because the few that exist exclude prior use of Ibrance. Will be interesting to see what they recommend..
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Sandibeach, I know generally FGFR1 tend to be hormone resistant. However I have had success on hormone therapy and you have had great success. I haven’t heard a distinction between AIs and Faslodex as far as FGFR1 is concerned. I do also have PI3K mutation and the ESR1 Y537S which I developed after my first line. I think the “takeaways” about which mutations are resistant to certain treatments identify trends but do not mean that a given treatment won’t work. More likely, FGFR1 mutations statistically become resistant faster on average than persons without the mutation. How big that difference is, who knows.
For example, I have always heard that someone who starts out ER+/PR+ and subsequently develops PR- tend to have a worse prognosis. That scared me until I found the fine print in one research paper identifying the difference in outcomes being only a few percentage points different for 5-yr survival. I assumed it was a much, much bigger difference in prognosis - like 30-40%.
Cure-ious, thanks for the resistance map and other info. I have the MYC alteration and understand a good portion of BC patients have it. It is surprising more focus has not been put on it until recently. I think for many, researchers will need to find a good cocktail that addresses all or most of those key pathways simultaneously like the HIV cocktails that became game changers.
I do worry that there is no new research in chemos, which have become pretty targeted and effective with minimal side effects, and all focus is in targeted therapies. Targeted therapy is a misnomer as many result in a high degree of collateral damage/side effects to healthy cells and most are not very effective. I have found all of the chemos I have taken for stage 4 (and there is a long list) both more tolerable and more effective than the targeted therapies I tried after my first line, Ibrance. Ibrance is the only targeted therapy that gave me a good run and was tolerable. Not sure how much of a part Ibrance played versus the hormone therapy. Ibrance was added to my first line after it became approved with Fasloddx, after I already had 7 months of success on hormone therapy alone (Faslodex/Aromasin). I am on Piqray now since 3 weeks ago. Boy, do I miss Gemzar. So much more tolerable and it worked for a long time until it didn’t. Praying for a miracle Piqray actually works.
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JFL
I understand your thoughts but I have had the opposite experience. Targeted therapIes of verzenio and Afinitor have been relatively easy to tolerate but chemo Xeloda and doxil were horrible for me. I heard Pikray can be a bugger. Hoping it really knocks down the progression! 🙏🏻
Cure-ious
I will start an ESR1 Mutation thread but please hop over and Post your research. Even if it just a cut and paste of what you have posted on other threads. 😉
SC put me off until early next week for trial answers. I am stopping the Afinitor to flush in preparation for which ever trial I am assigned. Some are 2 weeks flush and some are 4 weeks.
Dee
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Dee, yes you have had the opposite experience! Thanks for your post. Great idea to start an ESR1 thread. I will save it to my favorites
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JFL...I started as Stage 0 ER+ PR+ and when I was re-diagnosed Stage 4 I became ER+ PR-.... I didn't know that, that means I have worse prognosis...but I guess explains why nothing is working for me.... I figure I am technically at 2 years out...l officially I am 1 and half years from diagnosis...so I don't think I even have a year left..and I guess the PR- would explain it....
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Some exciting news!!
Approximately 9% of all primary breast cancers have a gene amplification of chromosome 17q23, which leads to high levels of genome instability and overexpression of a protein called TRIM37 (also called MUL). A new paper in Nature shows that these cancers are unable to use a backup program for centrosome (cell division) activity that exists in normal cells and therefore this subgroup of breast cancer cells can be killed by inhibitors of the PLK4 kinase. PLK4 inhibitors do not affect cancer cells that do not have the amplification or overexpression of TRIM37 (because only very high levels of this protein switches off the backup program), and also normal cells are not sensitive to the PLK4 inhibitors, because they also can use the backup program. So here is a new drug for nearly 10% of breast cancers, which is reportedly well tolerated with few side effects. The investigators say they are interested in developing an inhibitor that lasts longer in the body than the current one, so apparently the existing drug can be improved further..
There is a small phase two clinical trial in Canada for triple negative TNBC testing a PLK4 inhibitor (CFI-400945) with immunotherapy- this new Nature paper suggest a specific biomarker that can be used to predict who might respond best to that drug combo.
https://clinicaltrials.gov/ct2/show/NCT04176848
https://www.fiercebiotech.com/research/blocking-tu...
https://www.nature.com/articles/s41586-020-2690-1
Here is a 2014 Nature paper identifying TRIM37 as an important driver of breast cancer cell growth, and says that it modifies histones as part of a repressor complex, which would be how it shuts down the backup cell duplication program.
They say this amplification happens in 40% of all breast cancers, so obviously that would be a much larger group than the above paper mentions. Need to look more at this and see if TRIM37 overexpression is associated with different MBC subgroups
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"The 17q23 amplification also represents the defining feature of IntClust1 tumours, a subset of primarily oestrogen-receptor (ER)-positive, luminal B-type breast cancers that was detected following the genomic and transcriptomic profiling of more than 2,000 primary breast tumours by the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) project"
Here is a link to a paper that defines the ten clusters (subgroups) of MBC. In addition to the 17q23 amplification, IntClust1 also has high levels of GATA3 and PPM1D mutations, among others..
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC35909...
And this paper gives additional information about the ten different clusters:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC58412...
So hopefully a trial pops up with a test for the amplification and makes this drug available everybody with the responsive ER-positive luminal B cancers!
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I'm 15 years out with stage 3 BC 22/22 nodes. WE never know how long we have so please don't get your head in the rut that I have only X amt of time here on this earth !
My first suggestion is reach out to another medical center ..a BIG one associated with a teaching center. DO not stay in a small town for your treatment. Get a 2nd or 3rd consult and see what they say .....I have ?had 2 stage 4 friends . One is at 20 years ! Yes, I said 20 !! the other past away after 4 .....we just never know. PLease keep your chin up and know we are here to support you..all the way !
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Texgirl, this is a stage 4 thread only
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Cure-ious- interesting article. I hope that they have some new strategies since I think with my CCND1 mutation I would be in cluster 2 (I also have pleomorphic ILC) so poor prognosis according to this article.
At least the drug companies think that breast cancer treatment is a profitable research area
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Nkb- Oh, they do! Did you hear Gilead announced today they bought Immunomedics to get Trodelvy, the new TNBC ADC drug - paid 21B!! It was just approved by FDA this spring- they figure by 2024 or so the drug will have paid for itself, and everything after that is gravy. Not to be outdone completely, Merck announced a 1.6B deal with Seattle Genetics for the antibody drug-conjugate they are developing for TNBC, will be a direct competitor, of course they already have Keytruda to go with it.
check out IMMU stock today, shooting up like a rocket
Wish they would throw a bit more of that cash to smarter clinical trial combos for us..
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Nicole, I was ER/PR+ at Stage 2, was ER+/PR- at Stage 4 diagnosis and then two years into diagnosis, was ER+/PR+. Not really sure what the deal is.
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ICRF in London is the best at designing cancer drugs- they are moving forward after a successful phase 1 trial that combined PARP and AKT inhibitors, good response in hormone-responsive cancers (breast/ovarian/prostate)
https://www.sciencedaily.com/releases/2020/09/2009...
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Cure-ious I saw that news about Gilead-Immunomedics, I had wanted to share the article but wasn't sure where to put it. They paid twice the share price to acquire the company! I hope this bodes well for our TNBC sisters and anyone else who might benefit from Trodelvy.
Also, here's an excerpt from the WSJ article, indeed BC drugs are a very lucrative market.
“Breast-cancer treatment is one of the most lucrative segments of the world-wide cancer-drugs market, which EvaluatePharma pegs at $157 billion this year.
The market has become among the most precious in pharmaceuticals, because advances in understanding the disease have opened up new opportunities for drugmakers to find treatments that can help patients, and the therapies can command high prices.“
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JFL..I am the same.
ER+, PR+ at DCIS (both times), ER+ (65%), PR- at Stage IV 2016, then back to ER+(90%), PR+ (<10%) at progression 2020. My MO said sometimes it is the biopsy specimen location and what the stains are picking up in that specimen.
What does it mean? Got me. I just figured I was ER+ and left it at that.
I am pretty sure my first liver bx was IHC 1+ for HER2 and the latest liver bx was HER2 -. I will confirm that..need to find my original 2016 report.
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cure-ious
I just looked at the 10 cluster article. Very interesting.
I of course fall into worst prognosis cluster 2 with my breast cancer having 3 amplifications in the cytoband 11q13.3. CCND1, FGF19, FGF3
I am probably Luminal B, I have genetic Tp53 VUSI have known from other readings that these were worse prognosis. BUT there is always something new being developed out there to treat breast cancer. So even though I have that label, I hope to be out of the norm and get longer survival since I aggressively pursue my next options.
It’s interesting that none of my MOs have ever discussed these labels. Not my luminal status or cluster number or even my prognosis. The only thing my MDACC MO said was “you probably know the statistics from your reading.” “2-5 years” I said. And she quietly nodded her head.
Dee0 -
Olma, Thanks for sharing that- Indeed, we are "precious", I love that!! Precious and Powerful. Sure doesn't feel like that from where we sit, though. Somehow we need to tap into that power and get many more immunotherapy and CAR-T trials and whatever other high risk, high reward approach might work.
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Dee,
You are so right, I used to dread reading "poor prognosis", as I was trying to understand my diagnosis, until I realized half the time they were referring to whether or not the cancer would metastasize (well it already did that) and that, yeah, Her2 used to be the scary one until they found the right treatment, and now its the one most likely to be cured first. So a poor prognosis only means a cancer in need of a more specific inhibitor, or maybe none of these distinctions will matter at all once they find a way to expose solid tumors so they can get killed by the immune system
I am surprised about this ten categories of cancer given how long this has been out there and quite a few researchers use it, but I'd never heard of it before. I would think all the genomics analyses would use this as a better starting place than just ER/PR/HER2 status. I don't have any genomics data so don't know where I fit, but my ER+PR-HER2 would suggest a luminal B of some kind, those are spread around in categories 1,6 and 9. On the other hand, apparently bone biopsies are prone to giving a PR-negative reading that isn't real and reverses once more biopsy material is available..
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I am being considered for, OP-1250 a CERAN. Open slots to be confirmed with Pharm on September 25. I will continue my washout for this trial since it requires 4 weeks.
They are looking at 4 other trials for me to see if I qualify and should know by this Wednesday if any of these would work
2 trials for the drug H3B-6545 SERCAs
-NCT03250676 single agent targets my exact ESR1 mutation-Y5376 (At Tennessee Oncology)
-NCT04288089 in combo with Ibrance
2 trials for the SERD ZN-C5
-NCT04176757 single agent
-NCT03560531 ZN-C5 with IbrancePlus, I still have a spot in the CDK 2/4/6 until I get the final recommendation of which way to go.
It's exciting to qualify for this new drug. It is very new and I will probably be among the first patients 😳
CERAN/SERD OP-1250. OP-1250 completely blocks both AF2 and AF1 activity as seen in cell culture and the ovex mouse uterine weight gain assay. Unlike SERM/SERDs, OP-1250 is a potent inhibitor of CAMA1 and HCC-1500 breast cancer cell proliferation. OP-1250 also is a SERD in a large variety of cell lines including those in which some SERM/SERDs have little activity. OP-1250 achieves high and stable drug exposure in multiple animal species unlike fulvestrant and many SERMs. As might be expected for a compound with this spectrum of activities, OP-1250 shrinks tumors in xenograft models in which fulvestrant (because of limited drug exposure) and SERM/SERDs (because of residual estrogen-like action) fail to shrink the tumors. These models include HCC-1500 xenografts with a wild type ER and HCI-013 patient-derived xenografts with ESR1Y537S. These results suggest that OP-1250 has potential to be a superior compound to treat ER+ MBC, especially in patients whose tumors allow high activity of AF1 and including those with activating mutations ins ESR1.
https://cancerres.aacrjournals.org/content/80/4_Supplement/P5-05-02
Shrinkage and an oral pill!! Just waiting now.FYI- My MDACC doc called me yesterday to find out which trial I qualified for and to make sure my labs were still good. She said she would run it by the phase 1 department. So blessed!
My new local MO had his PA call me today to confirm he got my portal message and would review the trial to give his opinion. I'm so glad I switched!Dee
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