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Nov 8, 2018 11:46AM
Almost all the oncology people are completely mixed up and against Progesterone because they think the ARTIFICIAL Progestins which cause cancer in all the Research Literature are the same as the Bioidentical Progesterone. They need to do their homework. Thoroughly....
Taking a potential new breast cancer treatment from the lab to the clinic
Category: Science blog May 5, 2017 Emma Smith5 comments
In 2015, we wrote about some fascinating research from one of our scientists based at our Cambridge Institute, Dr Jason Carroll.
Carroll and his team uncovered a possible explanation for why women whose breast cancer cells carry two key molecules – called the oestrogen and progesterone receptors – do better than those whose cells only carry the oestrogen receptor. Even when they receive the same treatment.
They revealed that when signals were sent through the progesterone receptor it slowed down the growth of breast cancer cells. To find out if this had potential as a treatment, the researchers tested a new combination of hormone therapies and found it slowed down tumour growth in mice.
This was a really important study, but had only been carried out in mice, so it was too early to say whether it could help treat women with breast cancer.
Now, just 2 years after the discovery from Carroll's team, 3 clinical trials are set to open that will test this new approach in people.
From lab beginnings
Carroll's study was instrumental in understanding how the progesterone receptor works in breast cancer, and how it can act as a handbrake on cancer cells' growth. The team's results have now led to a possible new approach for stopping double positive breast cancer cells growing.
Normally, women whose breast cancer cells carry the oestrogen receptor (so-called ER positive) are treated with drugs that cut off oestrogen or directly block the oestrogen receptor. This will either be tamoxifen or aromatase inhibitors, depending on whether the woman is pre- or post-menopausal.
Dr Jason Carroll
But Carroll's results showed that treating mice with those oestrogen-blocking drugs and a dose of the hormone progesterone had an even bigger effect compared to the oestrogen-blocking drugs alone.
Progesterone changes the genes that oestrogen turns on and off by forcing the oestrogen receptor to sit in different positions in the genome, and according to Carroll this means the combined treatment offers a safety net.
"It's like a double blow," he says. "We cut off oestrogen, and as an insurance policy we use progesterone to pull the oestrogen receptor away from the genes that support cancer's growth."
This was the evidence that was needed to take the research into early clinical trials.
When the results were published, they caused quite a stir. Carroll says they challenged how people thought these different types of breast cancer worked at the time.
"For years there'd been a lot of confusion over whether progesterone encourages cancer to grow, and this has largely come from population studies looking into hormone replacement therapy (HRT)," he says
Some women choose to take HRT to ease symptoms caused by the menopause. There are different types, and the combined form contains a man-made version of progesterone called medroxyprogesterone acetate (or similar versions).
It's this combined form of HRT in particular that is linked to an increased risk of developing breast cancer.
"This led to the popular belief that progesterone encourages breast cancer to grow," says Carroll. "But it's not that simple. Different versions of man-made progesterone seem to have different effects on cells compared to the natural hormone.
"Plus we were trying to understand what role progesterone plays after a breast cancer has developed, rather than looking at how it affects risk of cancer beginning in the first place."
Into the clinic
Just 6 months after the findings were published, Carroll was approached by Dr Richard Baird, a clinical trials specialist based at our Cambridge Centre, to discuss possible trials.
Because the drugs we want to test have been used by doctors for years for a variety of reasons, we know they are safe and what doses to use them at. Plus they have the benefit of being cheap.
– Dr Jason Carroll
"A clinical trial from Brazil showed that around 40% of women whose cancer had stopped responding to standard oestrogen-blocking therapies, including tamoxifen and anastrozole, still responded to a man-made progesterone called megestrol acetate," says Carroll.
Their idea was to try the combination of oestrogen-blocking drug and progesterone as the first therapy women receive. And setting up the trial was surprisingly simple.
"Because the drugs we want to test have been used by doctors for years for a variety of reasons, including in the treatment of late stage metastatic breast cancer, we know they are safe and what doses to use them at. Plus they have the benefit of being cheap," says Carroll.
The Pioneer trial is being led by Carroll and Baird, and will start enrolling women with early stage breast cancer in June 2017.
Women joining the trial will still get the gold standard of care treatment that all women with early breast cancer receive, but the team will test the combination in a gap that exists between diagnosis and surgery.
"What happens is there's normally a few weeks' wait between a women having a biopsy and then having surgery to remove her tumour.
"In our trial, we're going to ask women to take the combination of an oestrogen-blocking drug – in our case anastrozole – and the man-made progesterone (megestrol acetate) during this wait. Then we can study the biopsy sample and a sample of the tumour removed during surgery to see the effects of the combination treatment on the cancer cells."
Not 1, but 3 trials
Carroll and Baird are focusing on post-menopausal women in their trial, but there are 2 other trials that have been set up in partnership that look at slightly different things.
One of the trials, led by Dr Carlo Palmieri at the University of Liverpool, is being funded by us. The approach is similar to that of Carroll and Baird, but Palmieri's trial will involve pre-menopausal women who will be given a combination of tamoxifen and man-made progesterone instead.
The third trial will be opening in Australia, testing a combination of aromatase inhibitors and natural progesterone in post-menopausal women.
If the trials show that the combination treatment is effective by studying tumour samples, the next steps would be extending the studies into larger trials so women are given the combination after surgery too, to see if it improves survival and doesn't cause any harms in the long-term.
Another interesting angle to the trials is finding out if adding progesterone to oestrogen-blocking drugs helps reduce the side effects of treatment.
"For the maximum effect, women should take oestrogen-blocking drugs for the recommended time period after surgery," says Carroll. "But unpleasant side effects mean many women stop their treatment early, and this increases the risk of their cancer returning.
"As part of this trial, we're also finding out if a lower dose of progesterone routinely used to alleviate menopausal symptoms works as well as the higher dose. This could make the side effects of hormone therapy more manageable and improve the fraction of women that stay on their standard treatments."
The clinical trials are only just opening, so we'll need to wait until they've got some results before knowing if this will benefit women with double positive breast cancer and could be made widely available.
But thanks to some excellent lab research by Carroll and his team, and our funding, the trials are up and running and we're another step closer to an
July 8, 2015
https://www.eurekalert.org/pub_releases/2014-07/pf-hab072314.phpSkip to main contentADVANCED SEARCH
PUBLIC RELEASE: 23-JUL-2014 Hormones after breast cancer: Not fuel for the fire after all?
Natural hormones reduce breast cancer tumors and have positive effects on cardiac and bone health
PARSEMUS FOUNDATION SHARE
IMAGE: MICE ON HORMONES EXERCISED MORE THAN ONES ON THE CURRENT TREATMENT, ESTROGEN BLOCKERS, LEADING TO BETTER OVERALL HEALTH. view more
CREDIT: ARUMUGAM ET AL., 2014
A new study supports a growing body of research suggesting a safe and effective role for natural steroid hormones in treating postmenopausal breast cancer, with fewer detrimental side effects and improved health profile than with standard anti-hormone therapies. The study will be published in final format today in the open-access journal Reproductive Biology and Endocrinology.
Breast cancer is the most frequently diagnosed cancer in women in the United States. Approximately 70% of breast cancers are diagnosed in postmenopausal women. Major clinical trials and experimental studies showed that a class of anti-estrogen drugs called aromatase inhibitors (AIs) is effective against postmenopausal breast cancer. Yet despite their effectiveness in reducing tumor recurrence, aromatase inhibitors have adverse effects on the cardiovascular system and increase osteoporosis and bone fractures, which may explain their lack of overall survival improvement versus the older treatment, tamoxifen. These effects, together with undesirable side effects such as incontinence and bone and joint pain, cause many women to discontinue using AIs. Alternatives are needed.
In their study, researchers at the Center of Excellence in Cancer Research at the Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, set out to explore a radical and counterintuitive hypothesis: Could an optimal choice of hormones lead to improved survival factors and quality of life, enough to outweigh any negative effect on tumor recurrence? Radical--because current standard of practice considers hormone treatment of any type absolutely contraindicated following hormone-receptor-positive breast cancer. Counterintuitive-- because estrogen-blocking aromatase inhibitors, a nearly opposite treatment, are the current adjuvant treatment for women after hormone-sensitive breast cancer.
Results from this study in a mouse model suggest the answer to their question is "yes,"--well-chosen hormones could improve both survival and quality of life.
"We are at a very preliminary stage. Our study's results are promising, but we need to know much more. This study provides a good direction," said Rajkumar Lakshmanaswamy, PhD, lead investigator for the study and research director of the Center of Excellence in Cancer Research.
The study was funded by Parsemus Foundation, a nonprofit foundation focused on reproductive health.
HORMONES: NOT ALL THE SAME
In the experiments, the researchers used the same type of hormones present in the body, because bioidentical hormones have been shown to possess a more positive risk-benefit profile than molecularly altered hormones. In the landmark Women's Health Initiative study, a negative risk-benefit profile was seen with oral equine estrogens plus oral synthetic medroxyprogesterone acetate (PremPro), an older drug combination that continues to dominate the market in English-speaking countries. Estradiol and progesterone delivered non-orally were selected for the experiments in part because of an extensive literature indicating more favorable outcomes.
The results showed that the right combination of hormone treatments reduced the risk of osteoporosis and cardiovascular disease, undesirable health effects associated with estrogen deficiency following menopause. Adding a little testosterone helped even more. Estrogen, progesterone, and testosterone, together (E plus P plus T treatment) was associated with greater physical activity, improved cognition, and better cardiovascular and bone health in the mouse model, and demonstrated the potential significance of hormone treatment in postmenopausal women.
Giving any sort of estrogen after hormone-sensitive breast cancer would generally be considered "throwing fuel on the fire." But the results were counterintuitive: tumor growth was reduced the most by E plus P plus T treatment. Long term, only in one group--the lowest-dose E plus P group--did addition of hormones result in tumor volumes slightly worse than in the control animals, noted Lakshmanaswamy.
"In this study, the aromatase inhibitor did indeed reduce recurrence as expected. However, recurrence rates in the aromatase inhibitor group bounced back up after the 5-year-equivalent treatment period, and the overall improved health outcomes in the hormone groups meant a trend towards greater survival in those groups. Even more notably, two of the regimens were even better than the aromatase inhibitor at preventing tumor growth," said Arunkumar Arumugam, first author of the study.
To date, epidemiological plus animal and laboratory evidence combined suggest that though the recurrence picture is complicated, the majority of women post-breast-cancer will do better on optimized hormones than on anti-hormones, because of better global outcomes, added Elaine Lissner, executive director of the Parsemus Foundation and second author.
"This study indicated that certain hormone regimens, especially adding testosterone, may even result in lower recurrence rates than aromatase inhibitors, on top of better global health outcomes, survival and quality of life. It's another piece of evidence that hormones don't always work the way we assume," said Lissner.
PART OF A LARGER PUZZLE
V. Craig Jordan, OBE, PhD, DSc, a scientist specializing in medications that treat and prevent breast cancer at the Lombardi Comprehensive Cancer Center, Georgetown University, considers the study an intriguing contribution to a scientific area now receiving a lot of interest. Jordan is widely considered the "father" of tamoxifen, a selective estrogen receptor modulator (SERM) that changed the field of breast cancer treatment. He also proved the anti-cancer effects of raloxifene, another SERM that blocks the effects of estrogen in breast tissue. He now studies how cancer cells can be killed by estrogen after being super-sensitized to it by those very same estrogen-blocking drugs.
The results of this study are consistent with those found in his lab. "This paper has all of the right results for the tumor and the right results for the mouse. It all lines up as far as I'm concerned." The only downside, according to Jordan, is the four-month treatment period for the mice--when women are treated for decades, and tumors are "clever and can change in a heartbeat." "Things happen short term in labs all the time; it's a very hard sell to go from experiments to outside the lab," he said.
The four-month period for mice was designed to be equivalent to five years in a woman's lifespan, and is the same time period used in aromatase inhibitor pre-approval studies. But the trend is towards ever-longer treatment periods with aromatase inhibitors, ten years or more, despite impacts on quality of life.
So should women be asking their doctors for hormone treatment rather than anti-hormone treatment after breast cancer? Could the right hormones be more effective at preventing recurrence than aromatase inhibitors, with better quality of life? For the time being, this will remain radical, says Lissner, and only the most open-minded oncologists will be willing to consider the data--despite epidemiological evidence that women who take hormones after breast cancer have much better survival rates than ones who don't.
The next step, according to Lakshmanaswamy, is to determine the hormone dose that is efficient and provides the maximum benefit with the fewest side effects, if any. But with little profit potential and no pharmaceutical company involvement, those studies are unlikely to get done unless the public pushes for taxpayer-funded research. "Our results show that using natural hormones in appropriate combinations suppresses tumor growth and has beneficial effects on cardiac and bone health, along with better tumor reduction than with current treatments. Many lines of research are coming together now, all pointing in the same direction, but only clinical trials would tell for sure."
The final version of the study is accessible online: http://www.rbej.com/content/12/1/66
About Parsemus Foundation:
Parsemus Foundation works to advance innovative and neglected medical research. The foundation supports small proof-of-concept studies and then seeks to raise awareness of results, to ensure that they change treatment practice rather than disappear into the scientific literature. Many of the studies the foundation supports involve low-cost approaches that are not under patent, and thus unlikely to be pursued by pharmaceutical companies due to limited profit potential. More information on Parsemus Foundation and the work presented here can be found at: http://www.parsemusfoundation.org/questioning-aromatase-inhibitors/
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