chance ER+/PR+ HER2- might benefit from immunotherapies?

skyfly

Hey all,

My mother was diagnosed with de novo metastatic breast cancer this month. First, I'd like to thank everyone on this forum for their contributions. I've probably spent 40 hours on here, reading and reading.

Anyway, its seems that the most promising advances are in immunotherapies, but it also seems that most of these advances are for Tnbc and her2+ patients. As er+pr+/her2- makes up most of the patients, I'm sure theres research going on. Anyone know of any, or is immunotherapy really not in the cards for everyone

blainejennifer

There are several trials that use canny techniques to amplify HER2 in a ER/PR+, HER2- patients.

When searching for trials, read the summary to find out what the investigators are planning to do overcome the immunilogical "coldness" of plain vanilla breast cancer, like mine.

I am investigating one at the University of Virginia where they are specifically using a HER2 technique on HER2- patients. They are training the T Cells to target the HER2 that every patient has. HER2+ patients just have lots more.

I am not aware of therapies addressing TNBC patients that can extrapolate to the ER/PR+ crowd, but I don't know everything.

skyfly

Thanks BlaineJennifer! I actually wrote this question after reading a very insightful comment you made in another topic yesterday about immunotherapy. You are very well informed

Meow13

I asked my oncologist last year, he said nothing for me but her2 trial vaccine results are very exciting.

skyfly

Imsad to hear that Meow13. It is disheartening to see that all the best outcomes seem to be reserved for a small segment of the population, but maybe their successes will lead to a breakthrough for all breast cancer patients.

pajim

So immunotherapies seem to work better in non-breast cancers. Not cure why. My onc told me that they believe the reason that immunotherapy works in some triple-negative women is that those cancers 'look an awful lot' like melanoma. I assume he means biologically.

So far these therapies haven't done much for ER+ women. Them's the breaks.

As an ER+ person I'm disappointed for myself but happy these new therapies are working for women who previously have had a much worse prognosis than I. Same thing with HER+. That used to be considered the 'worst' cancer to have but now they have many many new drugs and are outliving the rest of us. I admit to a small amount of jealousy.

skyfly

Hey pajm, I think you’re right it’s good for them that their fortunes have changed and those are just the breaks. Maybe it’s a sign that breakthroughs are always possible

blainejennifer

I still think that the ER/PR+ has a shot at immunotherapy. Keep in mind, the only "cure" so far was in a ER/PR+, HER2- patient, Judy Perkins. She was lucky in that her cancer expressed a protein that this trial had a bullet for. We have no data on how much of our cohort (vanilla cancer) expresses this protein. It wasn't looked for before in genomic profiling. I'll bet it is now.

For example, I got my Foundation One report back, and I have ten mutations. Unless my ten is the same as lots of people in my population's ten, we are going to have a little trouble getting grant money to address these proteins.

A lot of the immunotherapy grant money poured into TNBC and HER2 because these pathologies are squirming with low hanging protein targets. But, some researchers are looking for ways to get we vanilla folk to over express pieces of those proteins to get the same benefit from treatment, without having the exact pathology.

For those of us thinking that immunotherapy is a walk in the park, treatment-wise, it still has some issues. Off the top of my head, you can develop a cytokine storm - back in the ancient history of immunotherapy (ten years ago-ish), this could kill you. Now, everyone knows what to look for, and they can tamp it down with steroids. Small bummer in that steroids depress the immune system, reducing the effect of treatment, but still better than death, right? You can develop a hospital grade infection from being near all the bad bugs in a weakened state. We've all heard of MRSA and C-Diff, and they are still killing folk. Not a lot, but enough to pay attention to. And, don't forget, we can't do conventional treatment during these trials (with few exceptions), and these trials last about 6 - 8 months. If the trial isn't treating your disease, that's a loooong time to go without effective treatment. You can also develop auto-immune diabetes, hepatitis, and a few other pancreas, liver, gallbladder sillinesses that can be treated, but are a pain in the heinie.

For the trial I'm looking at, OS for ER/PR+, HER2- is median 27 months. For HER2+, 54 months. That's a big difference. However, I've been doing stage 4 for 6.25 years now. I might be lucky to get 27 more months. In other trials like this, no one has achieved a durable remission (except for three people from the Judy Perkins trial), but they keep tweaking the T Cell stew, and tumor assay studies are showing increased tumor response as they lurch from trial to trial.

skyfly

Again BlaineJennifer, totally blown away by your expertise. The tale of Judy Perkins is kind of what got me on this immunotherapy trai. It is a bit ironic that while as a cohor, immunotherapy is least effective for er/pr+ her2-, she seems to have been the biggest success. Very frustrating that such important work has to scratch and claw for funding. Can you tell me about how you got your sample over to Foundation One? Did you have to do another biopsy? My mom had one three weeks ago and even if insurance were to cover it I doubt I could talk her into getting one again so soon. I wonder if the biopsy samples are kept around for a period of time.

Wow, you've had incredible success! I hope you experience much more. It's still hard for me to read these OS numbers without getting a lump in my throat, but I try to console myself that maybe Ibrance is just a harbinger for hormone therapy and they will keep coming out long enough for us to push back progression for my mom and all the other people suffering from this terrible illness. I really think immunotherapy sounds promising and I’m glad people like you are on the frontline of these trials.

Cure-ious

Skyfly- There is no reason, apriori, that ER-positive HER2-negative MBC should not respond to immunotherapy, they just have to find the right combination of drugs or a way to increase tumor infiltrating lymphocytes to our 'cold' cancers. Indeed, it was reported last year that CDK4,6 inhibitors, like Ibrance or Abemaciclib, greatly increase the activity of the immune system towards the cancer- there are several different ways the drugs do this, but the overall effect, at least in mice, is a large synergy in the effectiveness of checkpoint inhibitors when combined with Ibrance.

Here is some of that press:

https://www.ncbi.nlm.nih.gov/pubmed/28813415

https://www.cell.com/cell-reports/pdf/S2211-1247(18)30234-1.pdf

https://blog.dana-farber.org/insight/2018/02/cdk46...

There is one clinical trial testing a combination of Abemaciclib with Keytruda, but not the Abemaciclib-Keytruda-Femara/faslodex combination we would like to see...

skyfly

Hey Cure-ious,

Thanks for the reply and taking the time to find these. I’m going to dive on these once I’m home from work. I'm sure it will take me a while to even get the gist of the academic papers. I know some of you kind folks must have a life science background. I'm an engineer but spent three years in college thinking about med school; this stuff is greek to me.

Although I suppose in just a month I've learned a ton about cancer so I guess necessity is the mother of education. Anyway, thanks again for answering my question and filling my heart with a little hope.

Cure-ious

SkyFly- Ask away, I enjoy researching the treatments coming along. In addition to the checkpoint immunotherapies and CAR-T, you might enjoy reading about the vaccine research coming along at Stanford; early days, but promising.

https://www.sfgate.com/bayarea/article/Chemotherap...

skyfly

Cure-ious,

Interesting article. I wonder what two drugs they are combining in this study and if it could be effective against “cold” tumors. Also he mentioned the FDA approval time would be a year or two! I understand why they want to exercise caution. I've read about the high dose + bone marrow transplant craze of the 80s. Just super frustrating that when so many folks are counting on this the timeline is still so slow. Anyway, I'm sure you feel that frustration far more acutely than me so I'll shut up.

I saw another vaccine like therapy on the front page of reddit this week. Melanoma and very early stage, 54 mice, but seems kinda related at least in that it is immuno related

https://www.drugtargetreview.com/news/35232/anti-pd-l1-cancer-vaccine/

Cure-ious

Sky- As you see, there is a lot of exciting research going on, just keep in mind that your mom may well go for years on her first line treatment, with the state of the field changing rapidly for all of that time. To keep up with the research announcements and meeting abstracts, pay attention to the big meetings: in early December, we get the San Antonio Breast Cancer Symposium (SABCS), the biggest breast CA-specific meeting for clinical trial result updates- and in the spring we get AACR and ASCO, the former has more the basic research and the latter the clinical trials, and of course those cover all kinds of cancers. Some specific information can come from surprising places- for example, the quarterly reports of the pharma company involved, or even just a twitter search - not only patients but investors may have early insights into the approach or therapy you are interested in. Lastly it can be insightful to search clinical trials.gov to keep track of new drugs starting in phase 1, and to become familiar with what types of preconditions that the trials often impose. The good news is you likely won't need any of the information you learn for years to come,for me it gives me a lot of hope for the future, despite how long it takes something to get thru a clinical trial ...

snooky1954

what is a "cold tumor"?

blainejennifer

A cold tumor is one that doesn't have very many interesting mutations. Standard amount of mutations for plain old vanilla breast cancer (ER/PR+, HER2 -) is around 10. We are considered cold. Fewer unique identifier targets to train T Cells to hunt and destroy.

That is what I recall from grilling MO after I got my Foundation One report.

snooky1954

Thank You Bljen.  So  it's better to have a hot tumor

skyfly

blainejennifer,

have you read of any interesting advances in immunotherapy recently

blainejennifer

Skyfly,

Do you mean immunotherapy trials for vanilla MBC, hormone receptor positive, Her2 negative?

Funny you should ask. After being all thrilled about that trial at MSK,it turns out that I might not be producing enough mesothelin to be included in the trial. The blood test from Mayo had me at 1, but MSK's test has me at .7. Blurg.

The real key to this trial door is whether the tumor produces enough mesothelin. As per Dr. Modi, you can have it in your bloodstream from the tumor, but your mileage may vary as to your actual tumor being chock full of mesothelin. Some people's immune systems destroy the mesothelin once it enter the bloodstream - I think.

That's what I'm waiting on. To find out what my actual tumor is up to. According to the nurse in charge of the trial, it will be at least a week more before the test results come back in.

Skyfly, that's my long winded way of telling you that the most viable trial I have found for ER/PR+, Her2- (this one), is very mesothelin dependent. In their defense, they are targeting mesothelin, so if you aren't making enough of it, it's rather a waste of their time and money.

There's a trial in Virginia, https://clinicaltrials.gov/ct2/show/NCT03272334, that is targeting Her2 stem cells, which everyone has. It's only when they grow up that they count as Her2+. They are getting a PFS of about 24 months for vanilla MBC, but 57 months for Her2+. Still, I wouldn't sneeze at two years.

Here's another interesting one for vanilla MBC, "Pembrolizumab and Carboplatin in Treating Patients With Circulating Tumor Cells Positive Metastatic Breast Cancer, NCT03213041."

Here's the summary: "The purpose of the study is to evaluate the impact on progression-free survival (PFS) with the combination carboplatin - pembrolizumab in patients with CTC (circulating tumor cells) positive, HER2 negative metastatic breast cancer previously treated with anthracyclines and taxanes. Previous studies have indicated that recurrent breast cancers are more resistant to chemotherapy and maybe associated with a weak immune system. This study is investigating the use of an immune therapy drug, pembrolizumab, that has the ability to restore the capacity of controlling and killing cancer cells of an important component of your immune system called T-cells. Pembrolizumab has been found effective in other types of cancer and has already been approved by FDA for those indications, but the efficacy in breast cancer is still unknown. In this study, pembrolizumab will be combined with chemotherapy to increase the cancer cell killing. There is no control or placebo treatment in this study." The bolding is mine, to point out that being heavily pre-treated doesn't seem to be exclusionary, and everyone gets the drugs. The exclusionary criteria most likely to bite one on the fanny: "Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent."

The next one that looks good is, "Type I-Polarized Autologus Dendritic Cell Vaccine With Tumor Blood Vessel Antigen-Derived Peptides in Metastatic Breast Cancer Patients, NCT02479230".

"The vaccine is made up of natural cells found in the blood, called dendritic cells, and peptides, or small fragments of protein which are loaded onto the dendritic cells. This combination may help activate the immune system against stromal cells, which are cells that help cancer cells survive in the body." They use the Gemcitabine hydrochloride to tamp down the patient's immune system before they administer the vaccine, so that it can get right to work, and - maybe - not be gobbled down by the patient's own immune system. It's not CAR-T, but is a very interesting approach.

Stuff that could exclude you: Patients must be human leukocyte antigen (HLA)-A2+. Good news: There is no limit to the number of prior systemic treatment regimens.

I'd have to look, but I think I'm the wrong kind of HLA, from having a go at a trial at the Roswell Institute.

Because I'm getting tired, I'll just give the NCI # on this one: NCT02453620. It's a novel combination of immunotherapy drugs, and an easy read. It's not personalized, like CAR-T or vaccines.

This trial, NCT02188745, is to see if they can't resensitize hormone sensitive tumors that start behaving like triple negative, leaving the patient eligible for more endocrine therapies. For example, I'm 95% ER+, 80% PR+, but I've have gotten no use from any of the endocrine therapies, with the exception of Faslodex, which I did great on. To be honest, this is an approach you should be able to sweet talk your MO into, but I'm glad they are getting reproducible data on the process.

I realize that I've twisted your question from if I've read anything interesting about advances in immunotherapy to what trials would be good for ER/PR+, Her2- people. Here are some articles I was so moved as to keep handy:

https://medicalxpress.com/news/2019-04-relapse-can...

https://www.sciencedaily.com/releases/2019/04/1904...

https://medicalxpress.com/news/2019-02-potentially...

https://www.sciencemag.org/news/2017/12/old-drug-a...

Hope that helps.

Jennifer

skyfly

Hey blainejennifer,

I meant vanilla MBC, but advances in all the variation are very interesting and promising. I have my fingers crossed that you're able to participate in the mesothelin dependent trial. I read a little bit about the protein, and it makes sense that they'd want to target it, as it seems to be overrepresented in many different types of tumors.

That trial in Virginia seems really promising! I think that these efforts to supercharge the immune system are very interesting. I don't understand the details, but if they're at 24 months now, maybe with some refining they could unlock further PFS.

Wow, there are so many promising findings just in this month. The in situ vaccine seems very promising. I wonder if this has any potential to be combined with the TIL therapies. immunotherapy + X (which from the last article might be Antabuse?). My goodness, if there's evidence from decades ago that this might slow progression, even moderately, why is it not given to every MBC patient? How is there no serious study with this.

Do you know why they (whoever "they" is) aren't pouring more resources into the TIL and CAR-T trials, which so far have yielded the only actual persistent positive outcome. I figured that would happen after the big announcement last year.

Thanks for these articles and sharing your perspective. They were all vey heartening. I really want to believe the combination is out there. Sometimes when I get really down thinking about what the future holds for my mom, I think about how in 1995, a year before ARTs were introduced, the prognosis for HIV was also very bleak.

blainejennifer

Skyfly,

The problem with solid tumors and immunotherapy is finding the right target. You have to look for something that exists within your cancer that is fairly unique to the cancer and not to the rest of your body. That little problem is what caused those few deaths in the beginning era of CAR-T (read up on cytokine storms). Chemo has the same problem in that it kills off rapidly dividing cells, like cancer cells, but also like bone marrow cells, and hair follicle cells.

The infusion center I go to just got a machine that circulates cold water over a patient's scalp to mitigate baldness. I refused it because skull mets are real, and I haven't read enough data that this protocol doesn't affect the skull. Plus, I wish they had spent the money on the same machine, but for hands and feet because neuropathy is a big deal. But, guess what? They don't even make a machine that does that, as per the infusion center manager. What the what? If so, it means that vanity triumphs over daily living skills. Walking remains more important than hair for me.

Immunotherapies are working well for liquid cancers (ie: blood borne), but are having problems addressing a solid tumor. It likes to kill off the outside of a lesion. I have to work harder on getting a biopsy of my liver monster that demonstrates that its center is necrotic, meaning that my immune system is attacking the tumor, but then the lesion just continues to build from the necrotic tissue, like a scaffold. It means something good, but the data escapes me now. I'll get back to you about it, as soon as I re-find it.

So far, the Triple Negatives and the Her2+ patients seem to have a boatload of cool genomic mutations in their cancers to target with immunotherapy. We vanilla MBCers, not so much.

The two targets that I have seen are mesothelin and HLA type 2. I'm waiting on the mesothelin results, and didn't not have the correct HLA type when tested at Roswell Park for a trial there. I have asked my MO for a retest on the HLA, as it is the target for at least 2 dendritic cell vaccines that I have read about.

How is your Mom doing?

Jennifer

edited because grammar is hard, my dog is sick, and I'm so tired.

skyfly

That targetting problem is so freaking troubling it seems to be the most serious challenge for solid tumors and immunotherapy. I very much hope that the clever minds who work on this stuff are able to find the magic key to unlock this problem. I know metastasized cancer is a very devious adversary, but I need to believe it can be defeated! Surely there is something unique about them which isn’t present in healthy cells.

Im sorry your infusion center’s priorities are so out of whack. Were you able to get the HLA test? How is your dog doing?

My mom is well she is at 7 months on ibrance/femara. Her second set of scans are stable, all her bone mets are “gone” and she is planning to have her mastectomy surgery this summer.