Endocrine resistance and alternative hormonal approaches

Longtermsurvivor

Back in January 2016 I posted the following story at bco's Femara topic.

Many of you may not have read it then.

Again, I always hesitate to tell my story, because it's complicated and more a cautionary tale on what not to do, then guidelines for what might help you

This time, I'm providing article links so those interested in these alternative approaches can do further research. Also, some commentary in italics.

very much loving kindness, Stephanie

RE. Endocrine resistance...

Surprised to see so many mets members here and wonder if my Femara story might be helpful. It's very long and includes a bit of my advanced breast cancer history.

Though I haven't wanted to share my story at bco, I will share it here, because it's unusual...unique in the extreme and irreproducible.

My advanced breast cancer has changed ER, PR and even HER2 status during the past 25 years.

I've always pursued unconventional use of conventional treatments, as well as CAM and holistic approaches. Additionally, I've had lots of surgery and am not including that here.

Was originally diagnosed with bilateral breast cancer in 1990-1991, at age 34 and around 1993, I tried tamoxifen for advanced ER+ breast cancer. Since the cancer was growing on my breastless chest, I could see that it wasn't working and feel the unwanted effects of the drug, so I quit after some months. Same thing happened with Megace. This was pre-AIs and I was pre-menopausal, though didn't choose to have ovaries removed or take ovary suppressing drugs.

Radiation in 1995 got rid of many of the tumors, but they began to regrow within months. My next conventional approach was chemotherapy, Adriamycin, but same thing - tumors grew, I felt ill, so stopped. Iscador and anthroposophic medicine came to my rescue and though I still grew tumors, it was at a slower rate and my overall health and well-being have steadily improved. I've engaged this medicine for nearly 20 years and it's worked miracles for me.

Around the time AIs came on the scene, my tumors were ER-.

In 1999 I got learned of my first lung tumor, but because of more major health concerns and not wanting a biopsy, I chose to wait until it caused a problem to act on it. It didn't until early 2008 when I developed pleural mets and effusion. A tumor biopsy then showed ER+ again.

I was post-menopausal then and chose to try Femara. The unwanted effects were relieved with holistic measures. Had great response for about 3 years before big progression in pleura/lung. I then quickly ran through Aromasin, Faslodex and even Herceptin (pleural fluid was HER2+ for about a minute). Nothing doing. In 2011 had a VATS pleurodesis that controlled the symptoms effusion, though tumors remain.

This is where things get interesting.

I next tried estrogen, estradiol pills that I dissolved under my tongue. http://jama.jamanetwork.com/article.aspx?articleid... I used 1-2 mg daily, rather than the suggested 6 mg daily because the higher dose hit me too hard. I've been anti-drug, pro-homeopathic for 30+ years, so I'm more sensitive to medications than most folks. Again, don't do as I've done!

This got me to stable for about 2 years. In early 2014 diagnosed with a dozen tumors in my liver (never had biopsied, so don't know their nature).

I next tried topical testosterone for the cancer which seemed to help control it somewhat. http://www.ncbi.nlm.nih.gov/pubmed/24596374

I continue to take a small dose of Androgel, topical testosterone, to help with cachexia, the muscle wasting of advanced cancer. http://www.lifeextension.com/protocols/health-conc...

I forget when I tried Femara again for about 1-2 months, but remember deciding, I'd rather die than feel this way. So I stopped.

In early 2015 developed ascites and tumors in belly/peritoneum and outside of liver. So, I retried Femara for a third time four years after it had stopped working in 2011.

And it's worked somewhat - at least to control the pleural mets. The liver & ascites, not so much.

I'm now on hospice and continue to take Femara (with no unwanted effects this time around).

This is more of my story than I ever meant to tell at bco, but I think it may be helpful for someone who's really willing to push the envelope of hormonal and anti-hormonal treatments. Also, to understand that cancer nature changes over time and there are even variations within a single tumor. I think of it like mosquito abatement or antibiotic resistance. Cancer is a life form that develops resistance and sensitivity to different agents. I've been fortunate to have found combinations of various treatments that have served me well giving me both quantity and quality of life.

I hope this is helpful to others on this topic - now and in the future.

Healing regards always, Stephanie

annieoakley

Stephanie, this is so very helpful! Thank you so much for sharing it with us and for all you do for everyone here.

Hugs, Annie

Faith-840

Stephanie, thanks for sharing your story with us and for sharing all your knowledge about this never ending disease. I am still learning so much. Even though I'm 76 and I think I should just let the Drs. make all the decisions sometimes, that's just not my nature. I've been called a control freak on occasion, but we know ourselves best and what feels right. You are always in my thoughts and prayers.

Lots of hugs,

Faith

Longtermsurvivor

Press release about use of estrogen in ER+ breast cancer:

PUBLIC RELEASE: 11-DEC-2008

Estrogen pills can benefit women with metastatic breast cancer

WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

VIDEO: A NEW STUDY AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS HAS SHOWN THAT ESTROGEN THERAPY CAN SHRINK TUMORS IN SOME WOMEN WITH METASTATIC BREAST CANCER. ESTROGEN WORKS AGAINST... view more

For breast cancer survivors, the idea of taking estrogen pills is almost a taboo. In fact, their doctors give them drugs to get rid of the hormone because it can fuel the growth of breast cancer. So these women would probably be surprised by the approach taken by breast cancer physician Matthew Ellis, M.B., Ph.D., associate professor of medicine at Washington University School of Medicine in St. Louis -- he has demonstrated that estrogen therapy can help control metastatic breast cancer.

In a study presented at the 31st annual San Antonio Breast Cancer Symposium, he showed that for about a third of the 66 participants -- women with metastatic breast cancer that had developed resistance to standard estrogen-lowering therapy -- a daily dose of estrogen could stop the growth of their tumors or even cause them to shrink. The study was funded by the Avon Foundation through the National Cancer Institute and included six cancer centers in the United States.

Ellis believes that estrogen therapy offers an appealing alternative to chemotherapy for metastatic breast cancer that has become resistant to estrogen-lowering agents called aromatase inhibitors, such as exemestane, anastrazole and letrozole. These drugs deplete the body of estrogen and are standard treatments for hormone-receptor positive breast cancers, which account for about 75 percent of breast cancer cases.

"By stabilizing or shrinking tumors in some women with metastatic breast cancer, estrogen therapy can relieve pain and other symptoms of cancer and can potentially prolong lives," says Ellis, an oncologist with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. "And unlike chemotherapy, estrogen enhances the quality of life. For many of our patients, their hot flashes disappear, and they lose other symptoms of menopause. It's a natural treatment for breast cancer. Not only that, it's much cheaper than chemotherapy, costing less than a dollar a day."

Furthermore, estrogen seems able to return metastatic tumors to a vulnerable state in which they again can be affected by aromatase inhibitors. "We thought acquired resistance to aromatase inhibitor therapy was permanent," Ellis says. "But now we've shown that in some patients giving estrogen can make it possible to cycle back to aromatase inhibitors, and they can work again."

About 40,000 women die of metastatic breast cancer each year, and estrogen therapy potentially could help thousands of women with hormone receptor-positive disease, Ellis says.

The study measured how many women with aromatase inhibitor therapy-resistant metastatic breast cancer responded to estrogen therapy. All study participants had estrogen-receptor positive tumors that had spread to their bones, livers or lungs. The women were postmenopausal with an average age of 59.

Coming into the study, all the participants were taking aromatase inhibitors to slow or stop the growth of their tumors. But their tumors had stopped responding to the treatment and had begun to grow again. Half of the patients got a high dose of estrogen (30 milligrams a day) and half got a low dose (6 milligrams a day).

Ellis points out that decades ago, high-dose synthetic estrogen was an accepted breast cancer therapy and was only abandoned when the estrogen-blocker tamoxifen came along in the 1970s and proved just as effective with fewer side effects. The high dose in the current study was based on the amount given to breast cancer patients in many of those earlier regimens.

Both the high- and low-dose treatments led to stabilization or shrinkage of metastatic tumors in about 30 percent of the participants. But the high-dose regimen had significant side effects such as nausea, vomiting, vaginal bleeding, fluid retention or calcium imbalances. In contrast, the low-dose regimen had few side effects and was well tolerated.

The researchers found that if study participants eventually experienced disease progression on estrogen, they could go back to an aromatase inhibitor that they were previously resistant to and see a benefit -- their tumors were once again inhibited by estrogen deprivation. That effect sometimes wore off after several months, but then the tumors might again be sensitive to estrogen therapy. In fact, some patients have cycled back and forth between estrogen and an aromatase inhibitor for several years, thereby managing their metastatic disease.

The researchers also found that PET (positron emission tomography) scans could predict whose tumors would respond to estrogen therapy. They measured tumor glucose uptake before starting the women on estrogen and again 24 hours later. The patients whose tumors showed an increased glucose uptake, called a PET flare, were the same patients who benefited from estrogen therapy.

It's too early to know why estrogen has a negative effect on metastatic breast cancer tumors. But Ellis has found one clue -- estrogen reduces the amount of a tumor-promoting hormone called insulin-like growth factor-1 (IGF1).

"I think that in order for breast cancer cells to survive in the absence of estrogen (when patients are on aromatase inhibitors), the cells have to learn to alter their cellular programs to utilize alternative growth signals like IGF1," Ellis says. "In theory, when you give estrogen back, IGF1 decreases and cancer cells die as a consequence. But surviving cancer cells prefer to switch back to living on estrogen -- to them it's like eating out at McDonald's every day instead of foraging on roots and berries. These cells eventually reappear as estrogen dependent tumors and the cycle starts over."

Ellis plans to continue to follow metastatic breast cancer patients to quantify the response rate to retreatment with aromatase inhibitors when estrogen therapy stops working.

Longtermsurvivor

A subsequent press release about using estrogen in MBC. Final paragraph about resensitization of tumors so AIs work again! This happened for me with Femara. love, Stephanie

PUBLIC RELEASE: 18-AUG-2009

Low-dose estrogen shown safe and effective for metastatic breast cancer

WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

When estrogen-lowering drugs no longer control metastatic breast cancer, the opposite strategy might work. Raising estrogen levels benefited 30 percent of women whose metastatic breast cancer no longer responded to standard anti-estrogen treatment, according to research conducted at Washington University School of Medicine in St. Louis and collaborating institutions.

The results are reported in the Aug. 19, 2009, issue of the Journal of the American Medical Association. Not only did estrogen treatment often stop disease progression, in some patients metastatic tumors became resensitized and again responded to anti-estrogen treatments.

"The women in the study had all experienced a relapse while on estrogen-lowering drugs, and their disease was progressing," says lead author Matthew J. Ellis, M.D., Ph.D., an oncologist with the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital. "So they were faced with undergoing chemotherapy. We found that estrogen treatment stopped disease progression in many patients and was much better tolerated than chemotherapy would have been."

About 40,000 women die of metastatic breast cancer each year, and estrogen therapy could potentially help thousands of women, Ellis says. Furthermore, he points out that the therapy is inexpensive, costing less than a dollar a day.

Sixty-six postmenopausal women with breast cancer that had spread beyond the breast participated in the study. All participants were originally diagnosed with estrogen receptor positive (ER ) breast tumors, meaning estrogen stimulated tumor growth. Seventy-five percent of breast cancer cases are ER . All participants had received aromatase inhibitor treatment, which severely lowers estrogen levels, but their metastatic tumors had later reappeared or resumed growing.

The study compared a high 30-milligram daily dose of estrogen to a low 6-milligram daily dose, and evaluated how well the treatments controlled the women's metastatic cancers and how the treatments affected their quality of life. The high dose results in estrogen levels in the blood comparable to that of pregnant women, while the low dose gives estrogen levels similar to that of women who are ovulating, Ellis indicates.

In both the high- and low-dose groups about 30 percent of participants experienced a clinical benefit -- their tumors either shrank or stopped growing. Interestingly, the researchers demonstrated that they could predict fairly accurately which patients would have this positive response. They conducted standard positron emission tomography (PET) scans before estrogen treatment and 24 hours later. If metastatic tumors flared, or glowed more brightly, in the PET scans after estrogen was started, they were much more likely to be affected by estrogen therapy. In 80 percent of women with PET flare reactions, tumors responded to estrogen therapy, and in 87 percent of women without PET flares, tumors did not respond to estrogen.

The participants filled out questionnaires to indicate whether they had adverse reactions to estrogen during the study. Adverse reactions could include headaches, bloating, breast tenderness, fluid retention, nausea and vomiting. Patients receiving the high estrogen dose had more severe side effects.

"The older women in the study were, the fewer estrogen-related symptoms they had," says Ellis also professor of medicine in the Division of Oncology. "But overall, we demonstrated clearly that the low dose was better tolerated than the high dose and was just as effective for controlling metastatic disease."

In the 30 percent of participants who responded to estrogen, tumors often began to grow again after a period of months or years. But in a third of these recurring cases, the researchers showed that the women's tumors had become resensitized to anti-estrogen therapy. The tumors shrank or stopped growing when the patients went back on their original aromatase inhibitor treatment.

Longtermsurvivor

Earlier bco thread about the anti-hormonal drug Megace (Megestrol acetate) for MBC:

https://community.breastcancer.org/forum/8/topics/...

love & light, Stephanie

Longtermsurvivor

Aromatase inhibitors in breast cancer

free full text article. Yes, it's from 2004, but it's a good basic introduction and presents the historical building blocks for the third generation AIs femara/letrazole, arimidex/anastrozole, aromasin/exemestane. There's also some good history on megace, tamoxifen and other endocrine approaches.

hope this shines a clarifying light on the topic, Stephanie

JFL

Longterm, thanks for sharing. This is helpful and provides some additional options to consider. I think I will ask to try some of these things down the road.

zarovka

Thank you. This is very timely for several people on this forum who are just beginning to show resistance to AI's.

>Z<

Longtermsurvivor

Hi Zarovka,

Yes, I'm aware of several members with MBC & AI resistance now.

Many will move onto Xeloda and infused chemotherapy, but some may want to try these alternative hormonal approaches.

Remember, these approaches used to be state of the art along with Halsted radical mastectomies and nearly catastrophic wide field radiation. Shudder!

I'm so grateful that my years of conversation and observation and reflection of evolving cancer treatments & their effects on us!!

Happy to report to the younger generation.

Your historian and archivist friend, Stephanie

Heidihill

Thanks for sharing your story, Stephanie! It is interesting to see where yours dovetails with mine a bit. I never took estrogen but took drug holidays which would have had the effect of increasing estrogen endogenously. My oncologist gave me the idea when he mentioned a clinical trial for early stage, the Study on Letrozole Extension (SOLE). The premise of the trial is that a 3 month annual break after 5 years of continuous treatment resensitizes the body to estrogen. The trial had a fundraiser last year so it is likely still in progress. I didn't go for three months but a month in the summer with abundant Vitamin D production seemed reasonable. This helped me get through my Femara stint. I could always look forward to my break.

Then there's the testoterone. Again I didn't take any testosterone pills but started progressive weight training. Apart from doing something for my bones I read there might be some benefit from the resulting testosterone spike (side effect alleviation and recurrence prevention).

http://www.breastcancer.org/research-news/20130928...

Now that I think about it, since I am now on tamoxifen the testosterone spikes I get from exercise are probably increasing my estrogen levels as I have enough aromatase to do that. So it may be worth switching back to an AI at some point.

ShetlandPony

This is fascinating. Before I started taxol following tamoxifen failure, I expressed concern about hormonal effects of the steroid pre-med Decadron. My onc said something to indicate that any change in the hormone situation could have a benefit.

zarovka

At the moment, my problem is that the AI (letrozol) is working to control the cancer but it is making me weak and tired and I am in some pain. I am not ready to back off of the estrogen suppression, even with the side effects. I am 9 months into treatment with rapidly shrinking tumors. However, I am trying to figure out what to do long term. The testosterone treatment is really intriguing. That study published in 2013. I am wondering if they have more results or if anyone is actually doing testosterone treatments ...

>Z<

Longtermsurvivor

Hi Z.

I hope you have access to medical journal articles through your medical or public libraries. The cost of articles behind paywalls hovers around $30 each, but I get them at no cost through the UCSF patient library. I doubt they extend the courtesy to non-patients, but there may be a medical school or library in NM that's willing to email PDFs to patients - for personal use only!

I've also found that some proud authors will share their articles with interested patients - like all humans, they appreciate the interest in their work!

Here's another abstract of interest:

Therapeutic activity of testoterone in metastatic breast cancer.

Boni C(1), Pagano M, Panebianco M, Bologna A, Sierra NM, Gnoni R, Formisano D, Bisagni G.

Author information:

(1)Department of Oncology, Oncology Unit, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, viale Risorgimento 80, 42123 Reggio Emilia, Italy. boni.corrado@asmn.re.it.

Anticancer Res. 2014 Mar;34(3):1287-90.

BACKGROUND: Hormone therapy plays an important role in the management of breast cancer. In the past, testosterone was the most common line of hormonal therapy for this disease, but its use has been almost completely abandoned in the past 40 years. However, because of earlier reports on favorable therapeutic results, we re-evaluated its use for treatment of hormone-responsive patients who have become refractory to other lines of hormonal therapy.

PATIENTS AND METHODS: Fifty-three consecutive patients with positive metastatic breast cancer who had become refractory to treatment with other hormones and whose disease was progressing, were treated with testosterone propionate, 250 mg once every two weeks, twice, and then once every four weeks until disease progression, drug toxicity, or death.

RESULTS: Regression of disease was seen in 9 patients (17%; 2% complete and 15% partial). Stabilization of disease was seen in 22 patients (41.5%). In the remaining 22 patients (41,5%), the disease progressed. Median overall survival was 12 months from beginning of testosterone treatment. Hirsutism and dysphonia were noted occasionally, but were not distressing enough to mandate cessation of treatment. There was no major toxicity except for two non-fatal pulmonary emboli.

CONCLUSION: Testosterone showed a significant therapeutic activity in previously hormone-treated patients with metastatic breast cancer who were no longer responding to such treatment and whose disease was progressing. These results warrant consideration of testosterone use as treatment for patients with hormone-sensitive metastatic breast cancer.

PMID: 24596374 [PubMed - indexed for MEDLINE]

Longtermsurvivor

Zarovka, I forgot to mention, you still have many hormonal options to cycle through before deciding about estrogen - you may never need to consider it.

Femara and Arimidex are non-steroidal aromatase inhibitors. Aromasin is a steroidal aromatase inhibitor. Faslodex has a completely different mode of action.

Part of the strategy of taking estrogen is to resensitize the cancer to AIs, so it makes sense to exhaust those options first.

Testosterone is likely more interesting to you, because it can affect muscles and cachexia.

I think you've read this thread, because you posted there, but it is about another hormonal approach to MBC Androgen Receptor Testing & Treatment

And there are a wide variety of chemotherapy agents available at different dosing amounts & frequencies. It's impossible to know how any individual will respond to those agents, but some who try them are able to function better with than without treatment.

I'm interested in your process! Thank you for sharing it with us.

Zarovka, I do enjoy your research and thinking. Have you really only been living with mets and posting at bco for a few months? You're a quick study & I always look forward to your posts. Thank you!

well wishing, Stephanie