Reversing Tamoxifen Resistance

new_direction

Reversing Tamoxifen Resistance

new_direction

1. Tamoxifen leads to resistance and causes the tumor to turn into PR negative status.

2. Combination of Tamoxifen and inhibition of Growth factor receptor will prevent this.

- Does anyone know a way to inhibit the Growth factor receptor in a natural/dietary way?

Here are some links about combination of Tamoxifen with other drugs:
http://www.ncbi.nlm.nih.gov/pubmed/25175082
These results demonstrate that sorafenib and nilotinib act via ER and ER-associated proteins, indicating that these kinase inhibitors in combination with tamoxifen may be potential new treatments for tamoxifen‑resistant breast cancer.

http://www.ncbi.nlm.nih.gov/pubmed/24928945
HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER(+) ductal carcinoma in situ lesions.

Heidihill

I don't think this is generally true or they wouldn't be prescribing Tamoxifen as often as they do. In some cases, patients do become resistant to Tamoxifen. Drinking coffee might help make Tamoxifen more effective. Melatonin, too. I don't know if these are growth factor inhibitors. I'm saving HCQ for next time I'm on Tamoxifen again.

http://www.sciencedaily.com/releases/2013/04/130425091345.htm

http://tulane.edu/news/releases/pr_072514.cfm

One way to check if Tamoxifen is working for you is to compare breast density through a mammogram.

http://www.eurekalert.org/pub_releases/2013-04/ki-mrr041713.php

My breast density was reduced about 95% after taking Femara for 2 years. I am NED 7 years now, with two years of Tamoxifen between Femara and Arimidex. I'm having a mammo next week so will be curious to see about any changes in breast density.

Bounce

Dear new direction

You wrote:

1. Tamoxifen leads to resistance and causes the tumor to turn into PR negative status.

Please can you include a link to some research that proves this or explains in what circumstances this happens.

It does not appear to be the norm for most people.

Thanks

new_direction

Hi Here is an article http://jnci.oxfordjournals.org/content/97/17/1254.long and some quotes from it;

Clinical data indicate that estrogen receptor–positive/progesterone receptor–negative (ER⁺/PR⁻) breast cancers are less sensitive to tamoxifen than are ER⁺/PR⁺ tumors.

31 415 patients with ER⁺/PR⁺ tumors were compared with those of 13 404 patients with ER⁺/PR⁻ tumors.

lack of PR expression in ER⁺ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.

Later, it was recognized that ER and PR status are not always stable phenotypes and that they can in fact change over the         natural history of the disease or as a consequence of endocrine treatment (4). During tamoxifen therapy, levels of both PR and ER decrease but PR levels decrease more dramatically than ER levels, with up to half of the tumors completely losing PR expression as they develop tamoxifen resistance (5). In patients with such tumors, the loss of PR translates into a more aggressive disease and worse overall survival, suggesting that other alterations in the molecular machinery driving tumor growth accompany the loss of PR receptor expression (6). 

 there was little difference in the recurrence rate of PR⁺ versus PR⁻ tumors in patients who were treated with anastrozole.

Several clinical reports have suggested that high growth factor signaling may be associated with decreased PR levels in breast                  cancer

The cumulative data raise the possibility that PR loss is a surrogate marker for excessive growth factor receptor activation,                  which translates into reduced tamoxifen benefit.

PR levels are a surrogate for the level of activity in the signaling cascade generated by HER-1 and/or HER-2 activation

 ER levels are considerably lower in ER⁺ tumors that lack PR and also have abundant HER-1 or HER-2. Lower levels of ER are associated with less benefit from tamoxifen                      (44).

Transcription factors in the AP-1 family are activated by several external cellular stimuli including stress, cytokines, and growth factor receptor signaling.

cross-talk between ER and growth factor receptor signaling pathways in response to estrogen or tamoxifen can in part account for tamoxifen resistance. Tamoxifen, like estrogen, can directly activate the HER-1 and HER-2 tyrosine kinases and induce tumor growth when these membrane receptors are abundant (45

The results raise the possibility that overexpression of only HER-1 and/or HER-2 affects tamoxifen response substantially only when PR is negative.

if the hypothesis that lack of PR expression is a reflection of active signaling in the HER family is correct, then the response to trastuzumab or other small-molecule HER-2 inhibitors might be different in the PR⁺ and PR⁻ subsets

 if the link between PR negativity and  high growth factor receptor signaling can be confirmed as a cause of tamoxifen resistance, then therapies targeting the growth factor pathways in combination with tamoxifen should be investigated in patients with ER⁺/PR⁻ tumors in future clinical trials.

new_direction

 I just found what I was looking for...

The way I read it I think it's safest to assume we all develop tamoxifen resistance and it will be best to take precautions and try to postpone it by trying to block the EGFR ?

http://foodforbreastcancer.com/news/epidermal-growth-factor-receptor-(egfr)-expression-associated-with-worse-breast-cancer-prognosis

Arugula Blueberries Bok choy Carrots, purple Broccoli Brussels sprouts Cabbage Cauliflower Celery Cherries Collard greens Cranberries Flaxseed Grapes, red Green tea Horseradish

Hot peppers Kale Mustard Mustard greens Parsley Pomegranates Raspberries Red cabbage Red onions Saffron Seaweed, brown Soybeans Sweet potatoes, purple Tofu Turmeric Watercress

 

new_direction

http://meeting.ascopubs.org/cgi/content/abstract/24/18_suppl/514

These results support the hypothesis that ER+PR- breast cancer is growth factor dependent and constitutes a unique subgroup   of ER+ patients which may be more likely to benefit from EGFR inhibition.

I wonder if  there is an over the counter drug which does this?

new_direction

IGF (insulin-like growth factor) is a hormone that is secreted from many cell types.  IGF-1R (insulin-like growth factor receptor) is a receptor tyrosine kinase, similar to EGFR.  When IGF-1 binds to IGF-1R, it initiates signals that stimulate cell proliferation and prevent apoptosis (cell death).  Increased levels of both IGF and IGF-1R have been found in cancer patients (24).  In addition, IGF-1R signaling is often implicated in the development of resistance to EGFR inhibitors: IGF-1R is able to activate PI3K in the absence of EGFR signaling, allowing the cell proliferation signal to persist (65).

cp418

new direction - a topic about high hormone levels was discussed in another forum along with Tamoxifen. Too add to the confusion or unknowns Androgens pertaining to breast cancer have been in the news lately.

What I wonder about is the role of Androgens in breast cancer. I recall some recent articles discussing androgen receptors present in about 80% of hormone positive breast cancer.

http://www.sciencedaily.com/releases/2014/06/14062...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC341058...

http://www.ncbi.nlm.nih.gov/pubmed/23647561

new_direction

It does get a little tricky now but I think the main conclusion is that the tumor cells need to be targeted from more than one angle.
If cruciferious act as natural EGFR inhibitors it supports the findings of another article i read months ago about the synergistic effect of tamoxifen and DIM.

This is a very elaborate information about estrogen and it also shows how androgens lead to estradiol production.

http://www.fusionhealthstudio.com/estrogen-the-good-the-bad-and-the-ugly/ VERY interesting, just a few examples:

Decrease body fat

More body fat the higher the levels of aromatase  enzyme that turns testosterone to estrogen

 

Block Aromatase from Converting Testosterone to Estrogen

Blocking aromatase is key to reducing the buildup of estrogen in the body

Selenium, melatonin, zinc, green tea and citrus flavones such as oranges and grapefruits are effective at inhibiting aromatase

katcar0001

This is kind of an old article (2011), but it's interesting and relevant to this thread.

Researchers have identified how the hormones progesterone and estrogen interact to increase cell growth in normal mammary cells and mammary cancers, a novel finding that may explain why postmenopausal women receiving hormone replacement therapy with estrogen plus progestin are at increased risk of breast cancer.

The discovery that both estrogen and progesterone must be present for the increased production of the protein amphiregulin, which binds to mammary cells and promotes cell growth, could lead to new treatment methods for the disease, said Sandra Haslam, director of Michigan State University's Breast Cancer and the Environment Research Center and lead researcher on the project.

The study, funded by the Department of Defense's Breast Cancer Research Program and published in Hormones and Cancer, looked at why progesterone combined with estrogen may contribute to increased breast cancer risk. In the study, researchers used both the native hormone, progesterone, and a synthetic compound, progestin – obtaining the same results.

The finding might help explain earlier results from the groundbreaking Women's Health Initiative showing the risk of breast cancer is significantly greater for postmenopausal women who received hormone replacement therapy with combined estrogen plus progestin compared to women receiving estrogen alone.

"Also, breast cancers that develop in women receiving estrogen plus progestin are more invasive and deadlier," Haslam said. "What is the progestin doing to increase the risk of tumor growth?"

Along with co-investigator Anastasia Kariagina, a colleague in the College of Human Medicine and Department of Physiology, Haslam identified theprotein amphiregulin and its receptor as one potential culprit.

"Amphiregulin – acting through its receptor, epidermal growth factor receptor – along with progesterone leads to the activation of intracellular pathways that regulate cell growth," Haslam said. "When activated, this promotes normal cell growth and the growth of tumors."

The study was performed in rats because breast cancers in rats contain receptors for estrogen and progesterone – similar to the human breast – and tumor growth is hormone-dependent, as are the majority of human breast cancers. The research team also confirmed the same phenomenon in human breast cancer cell cultures.

In addition, the research team found that Iressa, a cancer drug that blocks the epidermal growth factor receptor, effectively stopped the proliferation caused by amphiregulin. While those studies were done only in cell cultures and not on tumors growing in animals, the results are promising, Haslam said.

"The results indicate that the interactions between estrogen, progesterone and epidermal growth factor receptor pathways may be considered relevant targets for the treatment of hormone-dependent breast cancers," she said. "This may be especially important in premenopausal breast cancer because women produce their own estrogen and progesterone.

"A combined approach of inhibiting both the hormones and the epidermal growth factor receptor may be beneficial for some women in treating hormone-dependent breast cancer."

Explore further: Team discovers new inhibitors of estrogen-dependent breast cancer cells

More information: The article can be viewed atwww.springerlink.com/content/2442385375833472/fulltext.pdf

mkkjd60

I am persuaded by new direction's information. My mom passed away 2 years ago of bc. Initially she was highly er and pr positive. In her case, since she was past menopause, she was placed on arimidex. Almost 5 years later, she became metastatic. Interestingly, her "status" at that point was highly er positive BUT pr negative. Thank you for shedding some light on this subject. Mary

LMMax

KatCar0001 in response to your post about HRT "hormones progesterone and estrogen interact to increase cell growth in normal mammary cells and mammary cancers, a novel finding that may explain why postmenopausal women receiving hormone replacement therapy with estrogen plus progestin are at increased risk of breast cancer."

Why is no one standing on top of buildings shouting about this? Why have I received more information about treatments for post menopausal issues from my ONCOLOGIST? Why do I keep seeing advertisements on TV for "bio-identical hormone replacement therapy" by Suzanne Sommers? WHY...$$$, the almighty dollar. The line from the medical community is that "there have been no definitive studies, blah, blah, blah." One simple question to every doctor prescribing hormone replacements to post-menopausal women would solve the issue, "how many of YOUR patients receiving hormone replacements have been diagnosed with estrogen positive breast cancer." What is the answer, there is your #(&*#^#! study.

In the space of 2 months I been diagnosed with bi-lateral (right ductal - 3 tumors, 3 lymph glands; left lobular-1 huge un-detectable tumor, 8 lymph glands) breast cancer, had a double-mastectomy, and now face chemotherapy and radiation. No I guess I am not dealing with this very well, every time a doctor touches me, it gets worse and worse, they find things that they didn't know were there. But going back to the original issue of the HRT, not one doctor I was seeing, NOT ONE, ever suggested to me that I shouldn't be taking the bio-identical HRT. But then that would put a lot of other doctors out of business, now wouldn't it?

katcar0001

I am so sorry, LMMAX. It sucks, plain and simple. My (former) doctor really peddles the bioidentical hormones. I had no idea that they had the same risks as the conventional ones. I remember very clearly having a discussion with her about the various types of estrogen ("good" versus "bad" estrogen) and that bioidentical estriol with a small amount of estradiol would be safe (no estrone as she labeled it the "bad" type). I have emails to her telling her I was developing more pain and lumps since on the estrogen therapy. She replied that it had to be the progesterone. Well, I was fine on just progesterone for a couple of years. It was not until we added them together that I started having problems. I have been told other clients of hers also were diagnosed with breast cancer. I don't know any details about what hormones they were taking, however, I can only speak for my own case. Yes, it needs to be screamed for the rooftop (and it was after the WHI study), but that was for progestin (synthetic) with estrogen therapy. Now, if you google bioidentical hormone replacement therapy, you'll see a top hit from Mayo Clinic stating "natural" hormones are no safer than traditional HRT. The date of this publication is Dec. 5, 2014 (ironically, one day after my mastectomy). I can assure you that this information was not at the top when I googled it a year prior. It was all happy news from naturopaths and other doctors promoting bioidentical hormones for a huge laundry list of symptoms. I drank the Kool-aid.

Are "bioidentical" or "natural" hormones safer and more effective than hormones used in traditional hormone therapy for menopause symptoms?

Answers from Shannon K. Laughlin-Tommaso, M.D.

No, they aren't. According to the Food and Drug Administration (FDA) and several medical specialty groups, the hormones marketed as "bioidentical" and "natural" aren't safer than hormones used in traditional hormone therapy, and there's no evidence they're any more effective.

Here's a crazy read for you: http://www.tahomaclinicblog.com/estriol-hot-flashe.... I don't know what to make of it. This one claims that estradiol is "potent" (apparently it was for me) but that estriol can fight breast cancer. Here's a quote for you, "...some researchers are even starting to admit that maybe, just maybe, estriol in its natural form might work as well (even better than) synthetic drugs like tamoxifen." Talk about confusing! But I know I will never be touching the stuff again.

I am so sorry about your diagnosis and encourage you to keep reading and posting here. You'll get tons of support and help. There are threads specifically for chemo and radiation by month, so you can bond with others going through the same treatments.