Are you currently (or have you been) in a Clinical Trial?
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KarPC that is great news. Hopefully you will maintain and not progress without the SE of envirolimus. Getting more time from the serd is awesome. 2mm is smal
My trial doc said that if I progress on my trial serd, she would try another serd trial since I had some stable disease response to this estrogen downgrader. Her goal is to keep finding targeted therapies and hold off more chemo.Dee
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Thanks Dee. I like your trial doctor's plan!
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Yes, and to help us keep chemo at bay, a new drug is in development that boosts the activity of Ibrance in mouse models and may be able to overcome resistance. It also reverses the ability of Ibrance to lower neutrophil levels. The drug (SDX-7320) inhibits MetAP2, which is overexpressed in many types of cancer. Drugs in this class have been shown to reduce weight and help with diabetes.
https://www.onclive.com/view/addition-of-sdx-7320-...
From the company website:
SynDevRx is developing SDX-7320 initially for the treatment of postmenopausal women with HR+,Her2-, metastatic breast cancer with the PIK3CA mutation who have progressed following initial aromatase therapy with or without CKD4/6 inhibitor treatment. In a recently completed Phase 1 study in late-stage solid tumor cancer patients, SDX-7320 showed significant reductions in fasting insulin and leptin, for cancer patients that had baseline elevated levels (resistance), plus significant increases in the hormone adiponectin. They say further trials are in the works.
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Fantastic news! ARV-471 is working for me! Stable disease again. Tiny shrinkage in liver mets and no new tumors. 8 more weeks until the next scan. 🙌🏻💃🏻
Dr. Hamilton explained that the PROTAC delivery of my downgrader is like a cousin to the other SERDs. Maybe that vehicle is why I am responding. She had a great illustration but my brain was too happy to catch all the medical terms. 😉
A few labs are slightly low but liver enzymes are good. Getting a mag infusion. Hubby and I are going to the beach to celebrate 🏝
Cross posted from liver mets thread
Dee
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Whoo-Hoo, Dee!! Now you're dancing!! Clearly, this drug is for-real, and already tops my "what's next" list!! This pharma also has protacs that degrade other "undrugabble" proteins that drive aggressive cancer, including MYC and KRAS...
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Dee, do you have the FGFR1 amp mutation?
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Dee - Very, very happy for you!!! It's breathtaking that this new drug appears to work in patients with an ESR1 mutation!!! We desperately need drugs that can get around the ESR1 mutations that so frequently cause resistance to hormonal therapy. Thanks for sharing your fantastic news!!! I hope that ARV-471 will effective for you for a long time!
Celebrating with you!!! Theresa
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Dee- I am so happy for you and super excited about this drug!!
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Thanks all! I’m still on cloud 9 since this is the first systemic drug to hold back the cancer. I am hopeful for ARV471 because SCRI has a few patients going on a year as a single agent.
SandiBeach- no to FGFR1 butI do have the ESR1, CCND1, FGF19 and FGF3 plus some others on the TEMPUS.
My RNA sequence showed EGFR, CCND1, AR and ERBB4 among a few others
Dee0 -
Thanks Dee and happy for the success of that oral SERD. I am monitoring this.
Enjoy the well deserved beach trip.
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Did anyone talk about this yet???
If so, do we know what drugs block this gene they found and do tests like Tempus and F1 tell us if our tumors have this gene?
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Hi Nicole, I think that article you linked is talking about this study in Nature
https://www.nature.com/articles/s41467-021-22101-7
I just looked at my Foundation One report & it doesn't look like it tests for AAMDC
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Congrats Dee, enjoy your day at the beach!
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Moth...I am hearing on FB that the AAMDC is part of PIK3?
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I don't think so?
AAMDC is on chromosome 11 https://www.genecards.org/cgi-bin/carddisp.pl?gene...
p13kca (which codes for p13k) is on chromosome 3 https://www.genecards.org/cgi-bin/carddisp.pl?gene... (they list the location under the genomics tab)
but p13k is an enzyme which affects tons of different processes & I *think* what they're saying is that this gene affect p13k pathways
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Moth...HRMMMMM oh ok....
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Hey Nicole, we discussed AADMC a couple pages back- this is the IntClust2 subtype, an aggressive ER-positive cancer that has turned on PI3K and mTOR (notably without mutating PI3K), and they show it is sensitive to a drug called dactosilib and suggest you would want to inhibit PI3K and Myc. Now that they identified the problem they will look for more selective inhibitors. It is an amplification of chr. 11, so won't show up in Foundation One testing that only looks for gene mutations. Means more people might benefit from a drug like Piqray than just those with PI3K mutant cancers, but they need screens to define which cancers have turned on the PI3K pathway...
Add to this the paper last fall showing that a different subgroup, called IntClust1, is driven by amplification of the TRIM37 gene and uniquely responds to inhibitors of PLK4 kinase. Wish this system of classifying MBC was more broadly used so we could know which of the ten IntClust groups our cancer is part of, and how those cancer subtypes might be better treated
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With respect to PLK4 kinase inhibitors, the Canadian Stand Up 2 Cancer Dream Team is sponsoring their own Phase 2 clinical trial of this kinase inhibitor, with three arms: 1) TNBC; 2) ER-positive cancers that lack the PTEN tumor suppressor; and 3) ER-positive cancers that have normal PTEN activity. So if anyone knew they were in IntClust1, or knew that they lacked PTEN activity (a common thing in MBC) then this trial could be good- the drug supposedly has modest SEs, mostly neutropenia. Trial is available only in Canada at the moment.
https://clinicaltrials.gov/ct2/show/NCT03624543
Their description: CFI-400945 is a new type of drug for breast cancer. Laboratory tests show that it works by blocking a specific protein called Polo-like Kinase 4 (PLK4) that is involved in cancer cell growth. CFI-400945 may slow down the growth of cancer cells or may cause cancer cells to die. This drug has been shown to shrink tumours in animals and has been studied in some patients and appears well tolerated with little side effects.
Patients must have had at least 1 prior line of cytotoxic chemotherapy for breast cancer, in any setting, which must have included an anthracycline and a taxane. There is no limit to the number of prior chemotherapy regimens
The listed trial ending is this fall, so maybe there will be some data coming out of this trial by year end...
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I'm lost Cure-ious. I don't understand why AAMDC wouldn't show up on Foundation One etc for any reason other than that they just don't test for it yet, It's a gene on chromosome 11 & its over expression & amplification are the mechanism here. That should be testable just like all the gene muts they do, shouldn't it? The Nature article doesn't just say a normal AADMC drives some p13kca processes; it requires an amplification or overexpression mutation.
I have NOTCH3 amplification on my results & it's just a gene on chromosome 19. I also have over amplification of BRD4 which also happens to be on chr 19. Apparently I really botched my 19th chromosome in addition to messing several other ones as well....
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Moth which testing did you have done to find all that out.??? When I see my F1 (even though I did it 2 years ago) I don't see anything like the things you describe??? I see things like CCND1..... FGFR etc..... I didn't see NOTCH (which I know can be a pathway needed to be blocked)..... did you have a different test than F1?
Moth and Cure. is there any kind of testing we can ask for to see if we have the the genes..or chrom. that these drugs might work on? What kind of test do we ask for?
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Nicole, I'm going to put up pix of pages from my foundation on the genomic testing thread as I don't think it belongs here. https://community.breastcancer.org/forum/8/topics/...
As far as your 2nd q - I don't think we're there yet? I saw a company trying to launch a product which would test genes and suggest drugs but I think that's still in development?
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Moth, I could be wrong about the testing, I'm basing it on comments I read here that Foundation One lists only gene mutations, not amplifications or gene over-expression (e.g., it would list specific Her2 mutants, but not Her2 gene amplification).. Others here know more about what these tests check for. I wish they would include gene expression data, because with bone-only progression you do not have anything else to tell whether the cancer even remains ER-positive, for example. because they do not go back to the bone for new biopsy
PS The Foundation One list you posted includes the genes they check for mutations and genes tested for rearrangements- it seems to me that they would pick up point mutations and individual gene translocations, but not larger chromosomal amplifications (they must address this somewhere in their literature)
PPS Oh, wait, it does say "copy number alterations"-, which would indicate it does see gene expression, at least for the indicated genes- so does it report ER-, PR-status? I only got a summary of the result from my MO, so I never saw the original paperwork
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Foundation One tests amplification because I have 5 of those. (3 are VUS). Amplification is afaik the same a copy number alteration. Over expression is trickier - it's how much protein it codes which could be related to amplification but can also occur with a mutation of the gene. If a known mut cause over expression, then again that mutation will show up on a panel that is set up to test for it.
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Moth, got it! so what region of chr 19 might be amplified? BRD4 high would mean you want a BET inhibitor, right?
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Yes, I BET inhibitor is the thing for BRD4. See stuff about them in heme cancers but less in solid tumors. But something I'll keep eye on.
What I'm wondering about now is if I have my Foundation One, shouldn't I be able to work out which of the 10 clusters I'm in? I don't even know if i want to know but I'm sort of surprised that the genomic report doesn't even give that answer. Is the cluster classification not considered clinically useful?
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Some clinical trials are using this classification, but obviously medicine moves slowly. Studies show IntClust2 cancers have poor survival because they are almost completely resistant to chemo, it would be good to know this kind of thing.
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IntClust1: ER-positive, many are luminal B cancers. Chr 17 (q23 locus) is amplified and TRIM37 is a driver, should respond to PLK4 inhibitors. High levels of GATA3.
IntClust2: ER-positive, includes some luminal A and B subtypes. Amplified for chr 11 and AAMDC is a driver. Turns on PI3K and mTOR pathways, should respond to dactolisib or (presumably) Piqray. These cancers tend to be resistant to chemos; they may also be relative endocrine-resistant or even grow more under conditions of low estrogen.
IntClust3: ER-positive, mostly luminal A, enriched also for lobular. But highest frequency of PI3KCA mutations are found in this subgroup.
IntClust4: Some ER-positive, some ER-negative, and about 1/3 of TNBC. Many tumors in this subgroup show high infiltration of T cells and may respond to immunotherapy. A subset of lobular cancers is in this category.
IntClust5: Her2-positive subtype, amplified region of chr 17 (q12 locus), can be ER-negative or -positive. Used to be most aggressive, now most easily treated- IntClust2 is second most aggressive.
IntClust6: ER-positive, some luminal A and B cases. Amplified for chr 8 (p12 locus). High genome instability but low PI3KCA mutation.
IntClust7: ER-positive, mostly luminal A. Highest frequency of MAP3K1 mutations.
IntClust8: ER-positive, mostly luminal A. Translocation of chr 1q gain:chr 16q loss.
IntClust9: ER-positive, enriched in luminal B (as are clusters 1 and 6; all tend to lack PPP2R2A tumor suppressor and may be sensitive to PARP, ATR, or CHK1 inhibitors).
IntClust10: Mostly TNBC in this group. Highest rates of p53 mutation- prognosis for this cancer is relatively good if mets have not formed after five years.
IntClust1, 2, 6 and 9 tend to be late-recurring subgroups and account for 26% of all ER+ Her2- cases, these are at particularly high risk of late relapse after surgery; so if your mets showed up after 10-20 years, the cancer was probably one of these types. https://www.nature.com/articles/s41586-019-1007-8
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New study in high-profile journal CELL shows bone environment causes mets to revert to a more cancer stem cell like phenotype, and that chromatin remodeling by EZH2 is part of this process- they conclude EZH2 inhibitors may be very important drugs for reversing endocrine resistance.
https://pubmed.ncbi.nlm.nih.gov/33878291/
https://www.genengnews.com/news/breast-cancer-meta...
*EZH2 inhibitors don't work on solid tumors as monotherapy, but do synergize with immunotherapy (sometimes also chemo), previously noted to be esp useful for treating luminal B cancers
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Wonderful news Dee! Everyday should be a beach day.
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What exactly is EZH2 is it a drug ? Im sorry don't want to sound stupid here but I feel like you are speaking in a different language..I feel so dumb..
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