Fulvestrant Resistance / Aggressive Cancer Development

Deb30

Hi,

I am new to this forum; just created an account today. I have been receiving monthly injections of Faslodex (Fulvestrant) since 8/2019 and have recently developed skin lesions on my left breast. Originally I thought they may be some sort of skin reaction but a a biopsy confirmed that the cells are 100% ER+/PR+ breast cancer. A small cluster initially appeared quite suddenly and have since further migrated throughout the bottom, left and upper portions of my breast over a course of about 6 weeks. They appear to literally migrate daily. I was originally diagnosed with breast cancer back in 12/2009 and in 3/2018 a MRI showed that the cancer had spread to a portion of my thoracic spine. In all those years, I have never developed any skin lesions during any previous treatment.

For anyone undergoing treatment with Fulvestrant, have you developed any skin lesions or noticed any rapid change/development especially around the source of your original tumor?

Also, while doing research on-line, I was quite alarmed when I read the title to a research article. Below is the link to the title and an excerpt.

"Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions

Our data demonstrate that the development of fulvestrant resistance in two breast cancer cell lines, MCF7 and T47D, is accompanied by an augmented migratory and invasive phenotype in vitro and overexpression of the HGF/SF receptor, c-Met. Importantly, upregulated c-Met expression in these cells facilitates their stimulation by HGF/SF-secreting stromal fibroblasts, leading to the activation of Src, Akt and ERK1/2 and a profound enhancement of their aggressive phenotype in vitro."

I was never told when this treatment was recommended that it could result, after cancer cells become resistant to Fulvestrant, in the development of an aggressive phenotype. This has me very concerned and frightened. While I don't know for certain if my skin lesions relate to this aggressive phenotype, I cannot help but wonder if they may be.

Has anyone seen or heard about this study?

moth

You might want to ask this question also on the Stage IV faslodex thread. https://community.breastcancer.org/forum/8/topics/...

I sort of thought it was assumed that pretty much all treatments had potential to cause mutations. We progress because our tumors become mutated enough to develop resistance to whatever treatment we're on....

but the peeps there might have more info for you. I wonder if there are any tests you could have to check for what mutations you have acquired? The genomic panels like foundation or tempus, either from a mass or liquid biopsy.

eta - hi & welcome to the boards There are a lot of knowledgeable and supportive people here so come hang with us.

Deb30

Thanks, Moth, for the info and link. Also my oncologist did mention genomic testing but only after I asked for options since the development of the skin lesions. So thank you for listing the types of testing. :-)

I didn't know that a mutated form of cancer could develop; it was never communicated in the way you did. (Actually I don't think my oncologist has ever been full transparent and honest about the side effects, risks and efficacy of the treatments unless I probe with questions and some of those questions actually go unanswered. She actually will refuse to respond especially if the response will negatively reflect in any way on the treatment. But that's a whole other issue.)

So all I knew is that the cancer would eventually become resistant but I didn't equate that with the development of a more aggressive type of cancer cell. Looking back, I have serious regrets. I find myself wanting to return to the time prior to treatment with Fulvestrant. If I would have known that an aggressive type of cancer would develop, I probably would have refused this treatment. I really don't think it did much if anything to slow down my cancer anyway. So now I am worse off.

moth

Are your bone mets stable or have you been progressing there too?

Deb30

Bone mets are stable. It's attributed to the radiation and Xgeva injections. They were stable prior to Fulvestrant when my oncologist started me on Arimidex.

buttonsmachine

Deb30, can you post the link to the study you found? I'm interested to read it. I've had significant progression on Faslodex alone, and also on Faslodex/Ibrance.

moth

This is the study I believe Hiscox et al 2006. https://erc.bioscientifica.com/view/journals/erc/1...

The entire thing is in vitro. As I read it, it's not describing a new phenomenon, it's trying to describe the mechanism of a known phenomenon. We *know* tumor cells tend to have high mutation rates and inhibition of cellular growth control mechanisms, & frequently develop resistance to treatment. That's why stage iv is a whack a mole game - you hit it, it mutates, you hit it with something else and hope for as long as possible on each treatment.

These types of studies are interesting from a biopharmaceutical perspective because they give potential targets - proteins on cells which could be inhibited externally and which would stop/slow the growth of the tumor (& in this study, specifically invasion of the stromal tissue). I don't really see any clinical application from this atm.

Deb30

Hi buttonsmachine,

I'm so sorry to hear of your progression. I feel for you. I am so emotionally distressed with the migration of these skin lesions which seem to occur practically daily. And my oncologist never informed me that studies have indicated this outcome after cancer cells become resistant to Fulvestrant.

I attempted originally to include the link but I received a message stating that links are not allowed. If you copy the title of the research article in Google, the results will show the links. There are actually two articles:

1) The Exposure of Breast Cancer Cells to Fulvestrant and Tamoxifen Modulates Cell Migration Differently

2) Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour–stroma interactions

Below is an excerpt from the last paragraph of the second listed study, which clearly states that, "...frequently results in tumours of an aggressive phenotype....marked increase in their migratory and invasive capacity..."

"The use of endocrine therapy in breast cancer is limited by the development of resistance, which frequently results in tumours of an aggressive phenotype. In this report, we show that chronic exposure of breast cancer cells to fulvestrant results in acquisition of an endocrine-resistant state, overexpression of the c-Met receptor and a marked increase in their migratory and invasive capacity in vitro."

I forwarded both articles to my oncologist who only acknowledged them and went on to say that cancer can take a different turn/course in time. Her response was close to meaningless for me. She wasn't even open to further discussing even a possibility of this. I have since contacted the FDA and AstraZeneca because the prescribing/patient information does not indicate this outcome after cancer cells become resistant to Fulvestrant.

Deb30

Thanks Moth. For me, though, if I had known, and/or it was clearly communicated, that an aggressive phenotype would develop, I would have refused this treatment. The treatment with Fulvestrant, I don't believe, was worth this outcome. If my oncologist withheld this from me assuming that it is a known, than shame on her to say the least. A medical professional should never assume anything about a patient's knowledge. She deceived me, whether intentionally or not, I will probably never know. Also, I recognize that the findings occurred "in vitro" but it still proves a possibly certainly deserving further investigation and definitely a published warning in the prescribing/patient information for anyone considering this treatment.

ShetlandPony

Mbc mutating and becoming more aggressive is a given. When it gets around a treatment, it is by definition more aggressive. To echo what moth said above, these studies are addressing the question of how bc mutates under particular treatments — exactly what happens biologically — in order to figure out a good next treatment. Mutating is how mbc develops resistance and makes itself not curable.

So what are we to do? If we reject the treatments we have available, we are likely to have a shorter survival time. A treatment that eventually stops working (because of new mutations) is better than no treatment. So it is not that anyone withheld information from you, unless they promised Faslodex would work forever. “Aggressive phenotype" to me just means that mbc is a sneaky, bad disease that is a moving target. I doubt the skin lesions are particularly related to fulvestrant itself, but just to the fact that as we go along, cancer mutates and we have to change treatments to stay on top of it.

What would be the point of discussing those articles extensively? What I would focus on is to find out what you can about the current profile of the cancer. Does a biopsy show it is still ER+ and Her2-? Can you get genomic testing of the tumor as moth suggests, through Tissue biopsy or liquid biopsy (blood test) in order to characterize the cancer and see what next treatment may or may not work?

It seems to be that there is misunderstanding here, but not deception. I hope you can talk it through with your onc and move forward with more confidence in her.

Deb30

Hi ShetlandPony,

I get what you are saying but I see things differently and without knowing my full experience with my oncologist, no one can, with any certainty, can say that she didn't deceive me. My oncologist at the very least should have informed me.

But anyway, the biopsy revealed 100% ER+/PR+ breast cancer. My oncologist is recommending Letrozole in combination with Verzenio. I have a consistently low WBC count and chronic asthma so I am concerned due to treatment with Verzenio can cause a decrease in WBC and development of lung inflammation when I already have both. So I will be at further risk of complications if either should worsen while on this treatment. And the oncologist did not respond to my safety concerns and instead only said that I can move forward with Letrozole as a stand-alone treatment if I don't feel "comfortable" with Verzenio. That response didn't do anything to address and/or ease my safety concerns with Verzenio.

moth

Can you use filgrastim to increase your WBC? I have always struggled to keep my counts up so I've always been on filgrastim during treatment.

WC3

Hi Deb30:

I'm so sorry your cancer has progressed. It must have come as a horrible shock. I realize you feel you were not sufficiently informed concerning the nature of progression. I do agree that your MO should have communicated that better to you. Drug resistance and the subsequent development of aggressive forms of cancer in the metastatic setting is not specific to any one drug though, and while I understand you might feel cheated out of an informed decision, or maybe are just upset at feeling like you have been kept in the dark, which I can certainly relate to, I'm not sure any choices available to you would have provided you with a better outcome due to the reasons the others have already explained. I recognize that you feel your MO has deceived you. I think it's important to keep in mind that your MO is on your team though and it is her goal to keep you alive and comfortable for as long as possible. However I also think it's important for good communication between doctor and patient and if you feel your relationship with your MO lags in this area then I think it is worth addressing, either by asking more questions or finding an MO whom you are comfortable with and whom you feel explains things sufficiently.

Deb30

Hi Moth. Thank you. :-) I never hear of Filgrastim. I will look it up.

Deb30

Thank you WC3. I so appreciate your understanding and validating my feelings and perspective. I have started to work with a patient advocate at the medical facility where I get treatment. There's so much uncertainty now for me. I'll see how things go with the patient advocate; hopefully I'll get someone with whom I feel comfortable and will take time to answer my questions and thoroughly.