once again, ER+her2+ breast cancer is found to behave differently than ER-her2+

[Lani]

and I am sure they will find subtypes within it--this article refers to one subset with a better prognosis which may not need chemo

REVIEW
Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers
Rita Nahta and Ruth M. O’Regan


Abstract
There is considerable pre-clinical and clinical evidence demonstrating that HER2-positive breast cancers that express estrogen receptor (ER) exhibit intrinsic resistance to endocrine therapy. Therefore, in general, chemotherapy in combination with HER2-directed agents is recommended for all but the smallest HER2-positive early stage breast cancers regardless of ER status. This paradigm has recently come into question when responses to neo-adjuvant HER2-directed regimens were noted to vary based on ER expression, and pathologic complete response was noted not to be prognostic for ER-positive, HER2-positive breast cancers. These and other data suggest the possibility that a subset of HER2-positive, ER-positive breast cancers are driven primarily by ER, and biologically behave more like HER2-negative, ER-positive breast cancers. Identification of this subset of HER2-positive breast cancers is essential to avoid over-treatment of patients with small HER2-positive, ER-positive breast cancers, who may be optimally treated with endocrine therapy alone, or in combination with a HER2-directed agent, thereby avoiding the use of chemotherapy. Crosstalk between the ER and HER2 pathways has been established as playing a role in both intrinsic and acquired resistance to endocrine agents. Emerging data suggests that crosstalk between these pathways is also involved in resistance to HER2-directed agents. Unraveling the role of the ER pathway in resistance to HER2-directed agents could potentially result in therapeutic approaches that can improve outcome for patients with ER-positive, HER2-positive breast cancer.
Keywords Estrogen receptor – Human epidermal growth fact

[Sandra in GA]

I wonder how many of these questions will be answered in ten years. I feel that the next ten years will bring changes in treatments for all cancers that are unimaginable today.

[caya]

Thanks for this post Lani - for the small subset of us that are triple+, or at least ER+Her2+, it is gratifying to know that studies are continually being done to better treat us.

all the best
caya

[tricia keegan]

I'd echo Caya's thoughts and thank you for posting this Lani!

['lizbeth]

Lani,

Another article that seems very promising. It really seems all the hard years of research are slowly starting to reveal more answers.

I look forward to seeing more of your upcoming posts.

[karen z]

Thank you for the interesting and informative post.

[carolanno]

My primary tumor in 1998 was ER-, recurrent tumor in 2001 was ER-. Malignant lymph node 10 years later in 2011 was ER+, 50-100%, intermediate intensity. This info never got to my treatment team so they went with the cytology result of ER- and considered it a second recurrence. In June of this year, another breast tumor appeared that was also ER- from biopsy results. Once I discovered node was actually ER+, I asked to have breast tumor sample tested and it came back weakly ER+. A retest of the node was 11-50%, weak intensity. So the questions are: 1) Was this a new primary? 2) How stable and reliable is ER status? 3) Did my tumor cells find something else to drive them when HER2 was weakened by treatment? 4) Will I benefit from hormone therapy? Two oncologists feel that Her2 status is the defining marker so it's probably all the same disease. A third oncologist suggested my progression acted like an ER+ tumor progression and thought the primary must have been ER+ too. Given my experience, your post caught my eye. I'm not sure where I fall prognostically now. Can you tell me where I can read that article? Do you have any other references? Anyone else out there have changes or inconsistencies in ER status? Thanks!

[Lani]

I have posted many times before on how mets can differ from primary tumor with respect to ER PR and even her2 status

I have even posted how Stephanie Jeffrey @ Stanford with her MagSweeper technology for CTC identification and typing has shown tremendous heterogeneity of CTCs in patients--even triple negative CTCs floating around in the blood of her2+Stage IV breast cancer patients on herceptin

There are many ways this can come about. If you apply weed killer to a lawn, those plants not susceptible to it will take over and not have any competition for nutrients. It is not as if the weeds (cancer cells with different ER PR and/or her2 status ) weren't there before, they were just out-competed. Another way this can occur is by new mutations (takes much longer actually) or by epigenetic silencing ie, a glob of methylation groups or acetylation groups grabs onto the DNA just at the point where a specific gene is located and needs to be "read" by mRNA to be turned into a protein (DNA is the recipe, mRNA is the cook, protein is the cake or souffle) If the ER gene or PR gene or her2 gene is covered in goop the cook can't read the recipe and that ingredient gets left out of the cake/souffle)

The last way to explain it and this week some Stanford scientists from Irving Weissman's lab and Staphen Quake's lab found that cancer stem cells probably are not an entity that develops overnight but rather the result of a series of mutations that occur stepwise in a normal stem cell and finally in the end result in a cell out of control. This is felt to explain why cancer usually happens in older people as it takes quite a while for just the specific step mutations to occur in sequence to end up with that result.

There are treatments which have resulted in ER- patients becoming er+ and thus treatable with antihormonals. I think I may even have posted something about it on this board.

Hope this helps.

Feel free to put "conversion estrogen receptor negative to estrogen receptor postitive breast cancer" and "conversion of receptor or ER status" into entrez pubmed and see what you come up with.

Good luck

[Lani]

the Stanford article is about leukemias but there is no obvious reason it shouldn't hold for breast cancer as well:


AUG. 29, 2012

Researchers prove that leukemias arise from changes that accumulate in blood stem cells

BY CHRISTOPHER VAUGHAN




Imagine that a police bomb squad comes upon a diabolically designed bomb controlled by a tangled mass of different wires, lights and switches, some of which have a real function while others are decoys. The police don’t know how to begin defusing the bomb because they don’t know which parts are important. Then imagine the police discover the bomb-making factory and are able to see hundreds of these bombs at various stages of construction. With this information, they can reconstruct how the bomb was put together, and therefore how to disarm it.

For a team of researchers at the Stanford University School of Medicine, the bombs they need to defuse are killer leukemias. The researchers report that they have used advanced techniques to survey what’s in the “bomb factory:” the stem cells that produce all blood cells. In the process, they have proven a controversial theory that blood cancers — and perhaps all cancers — arise only when mutations accumulate over long periods of time in stem cells.

The research, published Aug. 29 in Science Translational Medicine, also sets the stage for the discovery of more effective therapies for defeating deadly cancers.

People with acute leukemias — cancers of the blood — are especially difficult to cure. Although doctors can drive leukemias into remission with chemotherapy, most of these cancers eventually come roaring back. About 60 percent of those who get acute myelogenous leukemia will ultimately die from it, a statistic that has improved little in the past 30 years.


Cancer is caused in part by genetic mutations, but cancer cells are often full of these mutations, some of which are important and some not. “Each cancer-causing mutation is potentially a therapeutic target because we might be able to fix or block it, but we have to know which mutations to focus on,” said Ravi Majeti, MD, PhD, assistant professor of hematology and a co-principal author of the paper. His fellow principal co-authors are bioengineering professor Stephen Quake, PhD, and professor of pathology Irving Weissman, MD, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford.

The researchers decided to test a hypothesis Weissman made more than a decade ago: That the progression from a normal stem cell to a leukemia stem cell occurs mostly in blood stem cells.

Weissman hypothesized that rare mutations and gene translocations accumulate in a line of blood stem cells to the point that the cancer or leukemia can break free of growth constraints and spread, eventually leading the altered blood stem cell to produce a progenitor cell from which leukemia arises. This hypothesis was investigated by graduate students Max Jan and Ryan Corces-Zimmerman, and postdoctoral scholar Thomas Snyder, the three co-first authors who conducted genetic analyses of 80-500 individual blood stem cells from each of six leukemia patients.

In the leukemia patients, even normal-seeming blood stem cells had one or more mutations because the cells were part way through the process of accumulating the mutations and other heritable changes in gene expression to become highly malignant. When the researchers compared mutations in these seemingly normal blood stem cells with the leukemia cells, they could reconstruct exactly which mutations led to the leukemia, and the order in which the mutations arose. They did this by looking for blood-forming stem cells with a single mutation, which they knew must be the first, then finding other stem cells with that first mutation plus one other, which they could then identify as the second. They continued to do this until they found examples of stem cells at each stage of mutation accumulation, leading up to the full set of mutations found in the actual leukemia cell.

The research confirms a once controversial theory. The traditional view has been that any blood cell could turn cancerous if it picked up the “right” mutations. Stanford scientists like Weissman have suggested that, in reality, only blood stem cells could accumulate enough of the those mutations to become cancerous. That’s because when blood stem cells divide into two, one cell retains its stem cell properties in order to self-renew, while the “daughter” cell continues to divide. The blood stem cells are therefore are present throughout life, while the stem cells’ progeny have life spans from days to weeks only.

“The natural mutation rate is slow enough that only the stem cells are around long enough to accumulate all of the necessary mutations and other inherited changes in gene expression to develop the cancer,” said Weissman. “I guarantee that in any room there are people who have blood cells with a cancerous mutation, but it doesn’t matter because in almost every case those cells die out naturally before they get the whole set of mutations that will give rise to an actual leukemia.”

Majeti, who is also a member of the Stanford Cancer Institute and the Institute for Stem Cell Biology and Regenerative Medicine, pointed out that having the correct model of how leukemias arise is important because it helps determine what kind of therapy might be most effective. “Because relapse is a clinical problem, we need to know if chemotherapy has somehow not killed all the leukemia cells, or perhaps it did kill all the leukemia cells, but new leukemias are arising from this pool of stem cells with preleukemic mutations,” Majeti said. “In the first case, we would want to do a better job of killing the leukemia cells, but in the latter case, for some patients it wouldn’t matter how well you do at killing leukemia cells if you don’t eliminate the mutated blood stem cells.” The next phase of the team’s research will focus on answering such questions, he added.

And although the research deals with leukemia, the implications could be much broader, Weissman said. “This confirms the hypothesis that for leukemias, all of the early mutation events occur in blood-forming stem cells, but it opens the possibility that the same will be true for other cancers, and perhaps all cancers. The progression to the cancer might occur in the normal stem cells of any particular tissue, and the cancer would only emerge as the full set of mutations accumulate.”

The leukemia findings are not only significant medically, but also showcase the benefits of conducting interdisciplinary research, said Quake, who located part of his advanced bioengineering research group to Stanford’s Lokey Stem Cell Research Building so that studies like this could be done more often. “This research highlights how advances in high technology and advances in stem cell research can complement each other to address difficult problems, such as human leukemias, which could not be answered by technology or medicine alone,” he said.

The research was funded by the Steinhart-Reed Foundation, the Howard Hughes Medical Institute, the National Institutes of Health, the Ellison Medical Foundation, the Ludwig Foundation, the Lucille P. Markey Charitable Trust, the National Science Foundation, the Burroughs Wellcome Fund and the New York Stem Cell Foundation.

PRINT MEDIA CONTACT
Krista Conger | Tel (650) 725-5371
kristac@stanford.edu
BROADCAST MEDIA CONTACT
M.A. Malone | Tel (650) 723-6912
mamalone@stanford.edu
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu/.

['lizbeth]

Lani,

A little off topic, but I was at the Uro gyn for irregular periods. The doctor mentioned not using Estrogen since I was a breast cancer survivor, but recommended an IUD with progesterone.

I fail to understand why I shouldn't be avoiding Progesterone with a breast cancer history as well. What am I missing?

[carolanno]

Thanks a lot, Lani. I'm new to the forum so I'll look at some of your older posts on this topic. So I guess this means that estrogen emerged as a stronger growth factor for my cancer cells after being dormant for 10 years. Even though it appears that my cells are at least partially resistant to Herceptin, my onc. says there is evidence that it can still be effective w/another chemo agent (Navelbine). I will consider an AI after that, but at 54 already have severe osteoporosis in lumbar spine so I'm not too keen on that idea...I had been trying to avoid osteoporosis drugs...
I'm so grateful to have this forum and access to people like you who are so knowledgeable and up on the latest research. Are you trained in the medical/research field?

[Lani]

A friend of mine who is a librarian in Denmark asks how I find all this stuff--
and tells me I should have been a librarian!

Lizbeth-- progestins and progesterone are two different things. The former has been shown , especially in combination with estrogen to predispose some to breast cancer.

I have seen a poster presentation from a researcher at UCLA five years ago or so @ ASCO or AACR showing an antiprogesterone, RU486 (controversial in US because of its use as a morning after pill) is synergistic with herceptin in the lab/petri dish setting.

I really don't think anyone understands all this, but they are working towards it.

How old are you? DId you have chemo and what was its effects on your periods? Are you on/have you been on Tamoxifen? Have you had a pelvic ultrasound to see how thick your endometrial lining of your uterus is? I am sure your doctor asked you all of these-- perhaps you could ask him if there is any other alternative ie, IUD without the progesterone ? I have no idea and am not qualified to even be commenting on any of this but perhaps I can help you formulate your questions.

Hope this helped

['lizbeth]

Thanks Lani,

I'm having the pelvis ultrasound next Friday. I just turned 49. My periods ceased during chemo, then starting coming back, 1 a year, 2 a year, 3 a year, now 4-5 heavy lengthy (last 2 1/2 weeks) patooty kicking periods per year.

I was ER-/PR- so no Tamoxifen.

I googled the IUD and it said it contained a progestogen which is a group of hormones including progesterone on wikipedia. It also gave me the impression it increased Androgens, and since I had Pagets a small study showed 88% of Paget's patients where overexpressed on Androgen receptors. That makes me nervous - since I'm having weird pain & stuff going on with the nipple on the remaining breast. I thought the doctor was saying progesterone - but I didn't ask many questions because I was in so much fricking pain from the biopsy - which I was not expecting.

[Lani]

sorry';lizbeth but this is the first time you mention a biopsy.

Went back and looked at your original question and saw nada about it.

Was that an endometrial biopsy? As I understand it they usually do the pelvic US first and then a biopsy if it seems warranted. Was it some other type of biopsy(eg your "weird" nipple on your normal breast

Am confused

['lizbeth]

You're confused, I'm confused. My oncologist put in a referral since I was having irregular periods. I figured I would just be having a pelvis exam and maybe a blood test.

The front desk said they scheduled me with Uro-gyn because they had openings. The resident interviewed me, then said he would do an endometrial biopsy. The way he explained it, well it seemed like some minor test where they would take just a little of the endometrial lining. Being a clueless patient, I filled out the consent form expecting something about as painless as a pinch. After all the word pipette seemed innocuous to me.

The pain was excruciating.

Immediately afterwards I went into the doctor's office, a Lt. Col - who was quite intimidating. He was enthusiastically telling me the options about a hysterectomy, ablation or the IUD. He also offered to roto rooter my urinary tract - if a future test showed I had a blockage (I have frequent urination). I was still reeling from the pain and in my little zone where I know that I'm close to passing out. My thoughts at that point were it's better to put up with the heavy prolonged periods and the frequent urination than to let these doctors anywhere near my pelvis again.

When I said I wasn't that worried about the heavy periods but I didn't want periods that continued on over 2 weeks babbling on about a couple of them - the Lt. Col. hit the ceiling, was pissed off thinking I only had a couple prolonged periods and brought the appointment to an abrupt end. He had been talking about blood tests, the urine test, etc.

So now I've managed to piss off another doctor, but I was afraid of him anyway.

The pelvic US is this friday. And the doctor is so annoyed he's put off my follow-up to October 1st.

[Lani]

Sounds like you need info so you feel secure in where you should and shouldn't go with this as personalities are involved

Since the Drs are leut colonels I guess they don't have many female gyns--how about any female nurse practitioners?

I unfortunately have had 3 pelvic ultrasounds myself. The first part is no big deal, they just put the ultrasound probe on your belly and move it around inspecting you from the outside in with ultrasound.

Part two which has lasted between 35 and 45 minutes (I watch the clock to decide how to psyche myself into lasting the whole time) consists of inspecting you from the inside out. The "wand" is hard. solid and of considerable diameter. This is the same procedure many states are trying to legislate every woman considering abortion undergo. The examination is performed by an ultrasound "wand" placed in the vagina which is moved around in order to look right, left, backwards, forwards to identify the uterine walls, ovaries and anything else it can see (eg babies, tumors etc)

The first tech told me she had refused to have that part done when she needed to have a pelvic ultrasound herself. Says a lot. She invited me to insert it myself.

The second tech (for the second ultrasound about 6 years later)admitted after I asked, had had one herself while she was pregnant and was understanding but kept not letting me know what percent of the procedure was already behind us (that helps me psyche myself into tolerating it as long as I know when it will end)

When I told the third tech about the first techs comment she laughed. She was not as slow and did not attempt to be as gentle as the secon in how she moved the wand, but after some banter I got her to be more thoughtful in how she carried out the procedure and finally, finally got her to say when we were more than 75% done. Don't know why that is so hard. I know they don't know exactly how hard each part will be fore them and how long it will be before they get all things into view, but I was only asking for an estimate based on their considerable previous experience. No guarantees to be given or implied!



It is definitely doable. But as in most things having the information ie, knowing that they will be Ultrasounding from the inside out and not just from the
outside in helps you psyche yourself into it. They do use lubricating jelly and you need to be in control about telling them to slow down, let you help with the
insertion if you don't trust them to be slow, gentle and listening to you. Ask them to do it where you can see the clock and ask them to estimate what percentage of the procedure is over.

One needs to drink lots of water one hour before AND NOT LET YOURSELF GO to the bathroom or they have to cancel the procedure and reschedule. Not so easy, if as in your case you have frequent urination.

Call back and ask to talk either with a nurse practioner in the gyn department or someone in the ultrasound division of the radiology department and discuss your concerns.

It is definitely doable there is no discomfort that lasts and the information the gain can tell them if the endometrial lining is thickened, if there are fibroids and/or a polyp and if an endometrial biopsy is likely to be needed...but//ooops...you already had that.

Blind endometrial biopsies are around 94% accurate for catching endometrial cancer. Biopsies done under hysteropic observation (a telescope looking up there which usually requires anaesthesia) seem to be the next step if you don't want to go to hysterectomy.

I tried to read about the topic just like you seem to (starting at wikipedia and proceding to pubmed), but I had to experience the pelvic ultrasound myself to comprehend the nitty gritty of how it is done, what it feels like, how to use the clock and questioning of the tech to psyche myself through it and that there is remarkably little soreness even a few minutes thereafter.

None of this seem well covered on the web (another reason to start that board/thread I suggested earlier about procedures (gammaknife/cyberknife/lumbar puncture/bone marrow aspirate/etc) to help prepare others

The part about not urinating was not explained to me the first time and poorly the second (and so much time had elapsed between the two I really hadn't thought much about it)

Those who have had lots of children may have an entirely different experience and as with everything , everyone experiences things differently and tolerates things differently.

Again, perhaps we could add this to the list of procedures we LIST in a thread for those inquiring what they are like (like the gamma knife'cyberknife procedure)... Starting with the official NIH description for patients and then adding personal experiences

This is one procedure I DO know about. My experiences may not be (and probably are not) typical. It is certainly very low down on my list of discomforts suffered in life, but even so, information helps one tolerate it and cooperate to ensure the most information is gained from the test.

Anyone else want to chime in?