Will 30% of Early Stage (1-IIIA) go on to metastasize??
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I'm hoping someone like BarredOwl will talk me off the walls after i read this article. It appears 2/3rds of us have this variation. ugh.
Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells
"The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer."
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The science nerd in me is intrigued. Hoping they find a simple way to test for this so they know who should start with an AI and skip Tamoxifen. Having failed on Tamoxifen rather quickly, I found this interesting.
I did not catch the 2/3 number in the article, but I did not red every word of it; I skimmed a few parts that were a bit over my head.
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I used this to get the 2/3rds... The antibody was used to examine the expression of ERα36 in 1 677 human breast cancer samples from five independent cohorts. In the first cohort (Cohort Chongqing) of 1 068 cases, 734 (68.7%) breast cancer specimens were ERα66+ and 493 (46.2%) were ERα36+ Among 734 ERα66+ samples, 329 (44.8%) co-expressed ERα36. ERα36 was also detected in 164 of 334 (49.1%) ERα66− tumor specimens
1677 total and 1068 of those were ER+ cases:46.2 were ER36+ from the study (493)..
among the 734 that were ER66+, 44.8% co expressed ER36+.(329)
among the ER-, there were half that expressed ER36+ as well: (164)..
so of the 1677 cases 964 were ER36+... = 57% or close to the 2/3rds I estimated.0 -
I would say it’s related Lisey. And it seems that Tamoxifen “activates” the ERa36? They better start testing for it. Yes, we need BarredOwl for this
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It does seem like higher expression is the biggest problem. Hopefully it'll eventually be like HER2; they can measure if it's over expressed, and have a drug to target it. Hoping it comes in our lifetimes!
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Solfeo, when I read what your oncologist says, 'big girl meds', what a frickin asshole! Is this a joke to him? Are the side effects and the real concerns you have something for him to give pet names to? Oh my god, your big girl foot should kick him in his big boy ass!
I tell myself I am 'lucky' that tamoxifen offers me some hope. Because as much as I didn't want to do chemo, scared to death, I also felt that it was at least some sort of hunting party to actively KILL the dirty cancer. But no. No chemo for me. Chemo won't do me a lick of good. Take your tamoxifen and don't give it a second thought.
Well I do give it a second thought. The more I read the more I realize that tamoxifen has some pretty big holes in its protective shield. Right off the start some of us will never metabolize it. Then those of us who do metabolize it initially may, over time, develop a resistance to it. Oh joy.
The more I read this the more vulnerable and exposed I feel. Some days it's a battle to not feel like a sitting duck with a target on my back. I cannot say for sure but I don't think the Oncotype test looks into these genes. Maybe this test that we all placed our hopes in, holding onto those scores like lifelines, is going to go up in flames as not adequately covering the bases?
This calls for alcohol. Lots and lots of alcohol.
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Hi:
Hartmaier et al (2018), described in Marijen's feature, and Wang et al (2018), linked by Lisey, are different studies from different groups, and relate to different potential mechanisms of resistance to endocrine therapy. The full-length articles are available for free at the links.
======> Such studies about potential mechanism(s) of drug resistance may provide possible explanations for observed treatment failures. Such treatment failures are already baked into the statistics we have regarding distant recurrence rates in those who receive(d) the drug. Thus, such studies do not undermine the results of clinical trials that have established the therapeutic efficacy (benefit) of Tamoxifen or AIs in reducing distant recurrence, or the observed distant recurrence rates in patients receiving such treatments.
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Hartmaier (2018), entitled "Recurrent hyperactive ESR1 fusion proteins in endocrine therapy resistant breast cancer" is about ESR1 fusion proteins.
"Fusion proteins" are encoded by "mutant fusion genes", resulting from "genetic rearrangements" that break DNA and re-seal the break incorrectly, fusing a segment from one gene to a segment of a different gene.
They looked for and found various gene rearrangements in tumor samples, in which part of the estrogen receptor gene (ESR1) was fused at the DNA level to part of a gene encoding something else (a "partner gene"). This created a "fusion gene" which is part estrogen receptor and part partner gene, and it encodes a sort of "hybrid" fusion protein.
Interestingly, the fusion junctions occurred in the same area of the ESR1 gene in various fusions, resulting in removal of the estrogen-binding domain of ESR1. The estrogen-binding domain of ESR1 also happens to contain the site of action of Tamoxifen.
You might think removal of this domain would inactivate the estrogen receptor (with no place for estrogen to bind and activate it). But some fusions were "hyperactive" (more active than normal), despite the missing estrogen-binding domain, and this "hyperactivity" was dependent upon the nature of the partner gene portion in the fusion. Thus, some ESR1 fusion proteins display "constitutive, ligand-independent activity" (always "on" even without estrogen).
The activity of this type of ESR1 fusion protein would be resistant to inhibition by Tamoxifen (nowhere to bind), as well as to Aromatase Inhibitors (always "on" even with effective inhibition of estrogen synthesis by an AI).
Two Key quotes:
-- "Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers . . ."
-- "Our data establish ESR1 fusion proteins as recurrent, albeit rare, events, enriched in metastatic ER-positive breast cancer and likely contribute to endocrine therapy resistance."
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Wang (2018), entitled "Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells," is rather long and complicated.
I haven't studied it in detail. However, it does not relate to ESR1 fusion proteins.
Per Wong, "The 66 kDa estrogen receptor alpha [protein] (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment."
So, what is "ERα36"?
ERα36 is 36 kDa and is a shortened "splice variant" of ERα66.
-- Per Thiebaut (2017), ERα36 mRNAs have been found in normal ovary, uterus, breast and testis tissues as well as endothelial and vascular smooth muscle cells, kidney, cartilage, bone, lung and heart . . "
-- Per Soltysik (2015), ERα36 was found in most cells of animals at various ages.
-- Per Yan (2017), "ERα36 is a naturally occurring, membrane-associated, isoform of estrogen receptor α. The expression of ERα36 is due to alternative splicing and different promoter usage."
-- Per Omarjee (2017), "Several ERα variants, derived from the alternative mRNA splicing of ESR1 gene, have been reported, [3] including ERα-36. [4] The transcription of ERα-36 is initiated by a previously unidentified promoter located in the first intron of the ESR1 gene."
It appears that ERα36 can be found in normal cells, although levels may be aberrantly increased in some breast cancers.
The Wang study adds to the slowly growing body of work on this splice variant, and observed "agonist" effect of Tamoxifen on ERα36. Much remains to be done.
These types of pre-clinical, mechanistic studies should not deter patients from proven therapies.
BarredOwl
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Thanks BarredOwl. There are issues here for men, too, since tamoxifen is the post-treatment gold standard for us guys who are 90% ER+/HR+ HER2-.
I have a male friend who started on Femara nd went metastatic four years later, so the dilemma of changing from tamoxifen to an AI is not necessarily a sure bet.That said, my friend has been going well on all the mets treatments for nearly four years now and his onc is holding back a few treatments should the current ones fail to work.
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Thanks BarredOwl, I was hoping you'd show up. The fact is Tamoxifen doesn't work for some women and men... I'm an ultra rapid processor, so the other side of Solfeo on that, but like her, I'd like to know if I have the ER36+ or if it's the normal ER66+. This will change my course of which hormonal I'll continue with. I don't think there's any way to test for this after the fact, or is it a simple blood test?
I will admit this study had me more upset than the one I just read saying that Asparagus leads to breast cancer. ugh. Everything leads to cancer.0 -
these investigations are a window into the future of genomics.....and how it will and already does influence screening, therapeutics and the mechanics of how cancer works.....
For those of you who are interested in these topics, but are intimidated by the studies and find them over your heads, try reading Eric Topol, M.D's The Creative Destruction of Medicine.
I wish to add, on a more sobering note, is that when The Genome Project announced back in 2000 that all of the genes were “identified"...there was great hope that disease would shortly be understood and eliminated. Back then, “junk DNA" was just that, junk! But, today, scientists appear more humbled. it seems the more they learn, the less they know and “junk DNA" has proven not to be junk after all. With all of that said, another provocative book, written by Columbia University Professor, Stuart Firestein, Ignorance, How it Drives Science, gives everyone hope. What Firestein discovered, is, when you put a group of scientists in a room and ask them what they are doing, they don't tell you what they know, they tell you what they are working on and hoping to learn and discover....
Studies like these show us the discovery process that will one day, which I hope will be soon, will lead to better screening, diagnostics, treatments and hopefully a cure...
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Hi Lisey:
Re: "I'd like to know if I have the ER36+ or if it's the normal ER66+."
This is a candidate biomarker. Additional clinical research is required to establish its clinical validity and utility as a prognostic marker and/or in the selection of particular endocrine therapies.
Also, it does not appear to be an "either or" situation. Both forms (ERα36 and ERα66) appear to be found in normal cells.
In primary breast tumors, they detected expression of ERα36 in primary breast cancer tissues either with or without ERα66 expression (ERα66+, ERα36+ tumors; and ERα66-, ERα36+ tumors).
In addition, the level of ERα36 may also be important.
BarredOwl
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barred owl have you read anything about how the broccoli family sprouts specifically and mushrooms might therapeutically work to prevent mestasis? I k n ow john Hopkins was interested. One tumor was er+ one(I take tamoxifen for) was not. I worry that of the one kind doesn't get me the other will.
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Hi exercise_guru:
No, I haven't researched that, although I feel virtuous when consuming crucifers or cooked exotic mushrooms, as I ponder all the potentially healthful effects of cruciferous beta-carotene, lutein, zeaxanthin, indoles (e.g., indole-3-carbinol), and isothiocyanates (e.g., sulforaphane) or strange mushroom triterpenes and polysaccharides.
BarredOwl
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Thanks Barred. If they have to test the original tumor, I think I'm out of luck. Hopefully they figure all this out quickly so even if we do go to Stage 4, it becomes a livable disease.
Also, Here is fun read about how Aspargus, Legumes, Nuts and other healthy food can cause cancer... maybe. UGH! https://www.sciencealert.com/a-new-study-is-linking-asparagus-to-the-spread-of-cancer-and-the-internet-is-freaking-out?perpetual=yes&limitstart=1
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Stephaniebc, I read your posts with interest about meditating on death. Delighted to see it. I am a long time meditator and enjoy many Indo-Tibetan meditations on death. I read a great article about an app that reminds you of death daily which I gather will be a bit much for many folks, but I thought the concept was interesting. Here is favorite quote of mine:
BarredOwl, I always delight in your thoughtful posts and I wondered if you had seen much of Ruth Patterson's work at UCSD. I am posting a link here to an interview with her. A 40% reduction with few side effects is rather wowing! I am practicing Time Restricted Feeding and enjoying it tremendously as I can't take AI's. I see an oncologist at UCSD as a second opinion on everything and even they have never suggested her work to me when I have asked for any info on supporting myself naturally on this path. Dr. Rhonda Patrick's videos on broccoli sprouting are terrific as she gets down to the nuts and bolts and even amounts needed to get benefits.
My best to everyone. May we all be well.
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BarredOwl, why are you removing so many of your posts?
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not sure where to post .... just got denied my annual MRI by insurance. This ever happen to anyone?
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May I ask why you were getting annual MRIs?
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My MO told me without any treatment my recurrence rate would be between 20 to 30%. Interestingly, both my MO and surgeon told me those statistics don't classify local vs metastasized recurrence. In other words, all recurrence is lumped together. Treatment makes a difference. No one knows what the future holds. Why not pursue the best treatment possible and then choose optimism?
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unless they is something that may be suspicious there are no annual mri's. If you have symptoms that makes sense to scan then that's when it's done. Mri is pricey so unless there is a good reason, it won't be covered. But if your doc is good with coding, maybe with the right code it may work. My checks on my bilat mx with implants is my docs feeling around for lumps. So unless I have a symptom, no scans.
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I have dense breasts as well as implants. Well now one dense breast and one full implant. Mammography never picked up the IDC that I had which was Grade 3 and a node positive. It was the MRI that found it. Guess that may be the reason for annual MRI. Don't the Mamo reports now say that if you have dense breasts your doctor may want to have MRI done??
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I also have one dense breast and one implant. I get an annual mammogram but also get an MRI every 3 years. And since I have a breast exam by my BS, MO and GYN, I spread them out over the year so I get a physical breast exam every 4 months. My BS orders the mammograms and MRI. He says the MRI is to catch anything the mammogram doesn't as well as to check the implant to make sure it's holding up and hasn't sprung a leak.
My insurance only pays if I've hit my deductible but my BS makes the hospital give me a steep discount. 0 -
If one still has a breast MRI might be useful but I would be surprised if they covered it every year unless there is a specific reason. ThinkingPositive, your signature reads you have implants on both sides so I got confused.
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I still get the mri every year and it is covered by my BCBS.
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muska... I had a Mastectomy on left side so that's s full implant. The right side they did lift and reduction so I have s very small implant on that side so both look alike.
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So my BS’s PA called me today to let me know she was able to get it approved. Thank you all for your responses. Nice to know there is somewhere to go and talk to those who understand!!
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I just got the results of my ANA (antinuclear antibody) blood test, and I'm very concerned. Shortly before I was diagnosed in 2016 with a small, grade 3, estrogen-receptive tumor, my ANA titer was 1:160, which is slightly worrisome. It was 1:320 last year, and now it's 1:640, and that's frightening to me - because of the role inflammation plays in metastasis. Since surgery and radiation, I've been taking Arimidex. I eat very well, try to stick to an anti-inflammatory diet, and take a turkey tail capsule each day. According to several clinical studies I've read, an abnormal ANA is associated with a poor BC prognosis. So far my medical oncologist has refused to discuss this with me. Anyone have advice or a similar experience? I know that many people are unaware of the ANA test. My primary care doctor starting including it in my blood-work decades ago, when I had a non-malignant inflammatory condition.
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mstein1970- I'm still relatively new to this breast cancer learning curve. I was diagnosed the second week of December in 2017. I'm hormone negative and her2 positive. I've already had a BMX with one positive lymph node and clean margins. I just finished Round 4 of tchp. So far minimal side-effects. I am very interested in learning about the different types of testing and how it impacts are treatment and recurrence rates Could you please explain ANA?
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I didn't' know either so I googled my favorite medical site for general information. Below is just one sentence. Lots of information out there.
Your doctor is likely to order an ANA test for a suspected autoimmune disease such as lupus, rheumatoid arthritis or scleroderma.
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minus2-thanks for the explanation. Hope you are feeling well.
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