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A Role for Progesterone in Breast Cancer Treatment?

June 20, 2017By Lisa DeFerrariin Research ProgressTags: Cancer Clinical Trials, Hormone Receptor-Positive Breast Cancer, Tamoxifen, Targeted Therapies3 Comments

Back in August 2015, I wrote about an article in the journal Nature on some interesting new discoveries about the role of the hormone progesterone in hormone receptor-positive breast cancer.

The research suggested that adding progesterone to standard treatment with tamoxifen or an aromatase inhibitor could increase the effectiveness of treatment for this subtype of breast cancer, while possibly also lowering toxicity.

Cancer Research UK reports that these findings are now going to be investigated in three clinical trials that are set to begin.

In addition to possibly increasing the effectiveness of existing anti-estrogen therapies, and maybe also lowering toxicity, another benefit of this potential treatment approach is that it involves existing drugs that are already well understood and widely used–and whose cost is low.

It's encouraging to see these studies going forward. I'll be following developments in these trials with interest. In the meantime, I'm attaching below my earlier post, which includes some background on the role of the progesterone receptor and what the researchers found.

Hormone Receptor Positive Breast Cancer: A Look At New Research Findings

About two out of three women diagnosed with breast cancer have the sub-type that is referred to as hormone receptor-positive breast cancer. This means that when tumor cells (from a biopsy or surgery) are examined under a microscope they're found to have receptors for the hormone estrogen (they are "ER-positive") and/or the hormone progesterone (they are "PR-positive).

The prognosis generally tends to be somewhat better for this type of breast cancer, and there are several targeted hormonal therapies available. These treatment options, which include tamoxifen and aromatase inhibitors, focus on the sensitivity of this type of breast cancer to the hormone estrogen. These drugs work in slightly different ways, but the goal is to "starve" tumor cells of the estrogen they need to survive and grow.

For hormone-positive metastatic breast cancer as well, there are a number of hormonal therapies available. These include tamoxifen and aromatase inhibitors and several newer drugs. All of these treatments work by interfering with the ability of estrogen to fuel the growth of breast cancer cells.

But there are no therapies widely used today that target progesterone or its receptor in either early stage or metastatic breast cancer. Why do we even measure this characteristic at all if it doesn't have any role in determining treatment?

Role of the Progesterone Receptor

Delving into this question a little, I found that the role of the progesterone receptor in hormone-positive breast cancer has been somewhat controversial. The information about PR status has mostly been used to help determine prognosis. That is, a higher level of PR positivity (a numerical level is assigned) has been associated with a somewhat better outcome. And a lower PR level or lack of PR receptors ("PR-negative" breast cancer) is generally not as good a prognosis.

Beyond this role in determining prognosis though, there is disagreement. Some believe that PR status has no role in determining treatment, and that there really is no need to continue measuring it. However, others are of the view that PR status is useful as a biomarker to help identify patients whose ER-positive breast cancer is most likely to respond to specific types of anti-estrogen treatments and to help in choosing the most beneficial treatments for these patients.

Progesterone Receptor Study

In this new study, researchers set out to learn more about how the progesterone receptor actually works. Conducting experiments in cell lines (human breast cancer cells grown in the lab), the researchers found that there is "cross-talk" between the progesterone receptors and the estrogen receptors on breast cancer cells. In other words, they found that the receptors are communicating with each other.

And what was really interesting was that the more of this communication that was going on the better–this was because signals from the progesterone receptor served to tone down the pro-cancer activity of the estrogen receptor.

In another set of experiments, the researchers implanted hormone-positive human breast cancer tumors into mice. They found that exposing the mice to estrogen caused the tumors to grow, while exposing the mice to both estrogen and progesterone actually caused the tumors to shrink. They also found that treatment that included the hormone progesterone, in addition to anti-estrogen therapy (tamoxifen), was more effective than just tamoxifen in reducing the size of the tumors.

What These Findings Could Mean For Patients

These findings will of course need to be confirmed in additional studies including clinical trials. And the possible side effects of combining the hormonal treatments would have to be evaluated.

Hopefully, that follow-up will happen.

The lead researcher on the study, quoted in Medical News Today said the findings provide "a strong case for a clinical trial to investigate the potential benefit of adding progesterone to drugs that target the estrogen receptor, which could improve treatment for the majority of hormone-driven breast cancers."

An interesting aspect of this approach is that it would use an existing drug that is currently available as a generic.

Finally, when talking about progesterone, there's an important distinction to be aware of. The Nature article points out that there's compelling evidence that including progesterone as part of hormone replacement therapy (HRT) increases the risk of breast cancer. However, the authors say the increased risk is mostly attributed to the synthetic form of progesterone that's used in HRT. That increased risk, they said, is not significant when natural progesterone is used.

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3 responses

1. thesmallc says:June 20, 2017 at 10:43 amThank you for this information. I have always had a curiosity about how progesterone contributes to BC. I had very high level of progesterone (87%) and estrogen (99%) on my pathology report. But now they are saying progesterone may actually be helpful? This is all interesting and I look forward to knowing what researchers find out.
   • Lisa DeFerrari says:June 23, 2017 at 9:31 amHi, Rebeca. I'm very interested too in seeing what they find out. I always wondered what the purpose was in measuring the level of the progesterone receptor because it didn't seem like a whole lot was done with that information. Perhaps some new insights will come out of this that will be valuable for patients. Thanks as always for reading and for your comments!
2. Eileen says:June 29, 2017 at 3:10 amAlmost seems counter intuitive. Fascinating though. Who knew?

Welcome! I'm a cancer research advocate who was diagnosed with breast cancer in 1993 at the age of 35. I'm a graduate of the National Breast Cancer Coalition's Project LEAD program, which trains advocates in the fundamentals of breast cancer science. I've also served on numerous panels reviewing cancer research proposals for government funding. Please join us as we follow the progress that's being made in cancer research, care and prevention.
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I just wanted to make sure women know what their real options are, and that Bioidentical Progesterone is safe and Good For our Health in so many ways.

So their is a lot of discussion around Bioidentical Progesterone, whether or not women should use a cream such as Emerita Pro-Gest, or is the presciption strength Specially Compounded Prescription Bioidentical Progesterone Capsules, or Prometrium Bioidentical Progesterone Tablets better than the cream . The oral forms of Progesterone are Prescription only, whereas the Progesterone Creams are available OTC, and online.

With the oral forms of Progesterone it is more certain of the dosing you are getting, while the cream absorption varies, and application sites need to be rotated. Oral Progesterone is better for sleep for one thing. The cream skips the first pass metabolism effects. I kind of wonder if oral is better, or a bit of both oral and topical in some kind of combination would be better. I keep reading up on it, but still feel not 100% one way or the other, although I am on the oral form mostly because I wanted to make sure I am keeping my Uterine lining stable since I am on twice weekly Vagifem Estradiol.

Hi Rah2464, and MoonGirlJess, glad to spread the word. I just love the Bioidentical Progesterone I use. Helps with sleep and growing back my hair. AND it has anticancer benefits too! What's not to like?

I hope that more people read this info about Bioidentical Progesterone and share this info, with their doctors and fellow suffers. A grassroots support for education and healthy relief of symptoms associated with "treatment ".

About time Quality of Life became an important facet of bc industry "care"

Isn't that sad, MoonGirlJess and Yaniza, that your oncologists are unwilling to educate themselves.

Still, you can look around and find other doctors who can help you improve your quality of life safely, and possibly lower your risk of reoccurence.

https://www.cemcor.ca/ask/bewildered-bio-identical-hormones

Every time a doctor discusses ARTIFICIAL Progestins side effects, being the same as what occurs with Bioidentical Progesterone, I want them EDUCATED!

Their ignorance is not Bliss, it's actually incredibly harmful. ..............That's why I share this info, there is so much bc industry medical lack of knowledge.

We all suffer needlessly way, way too much. Men wouldn't stand for it.

Hi dtad, regular MD 's will occasionally do it, but otherwise I would suggest either a Naturopath or a Functional or Integrative Medicine MD or ARNP. Look at the following Article on Bioidentical Hormones by an Integrative Medicine MD on Osteoporosis.

• ..................................................................................................................................
• What You Don't Know About Osteoporosis
• We'll look at one of the most controversial and misunderstood treatments for osteoporosis -- hormone replacement therapy. We'll also answer whether being obese can actually reduce the risk of osteoporosis.
• By Joseph Sciabbarrasi, M.D., ContributorJoseph Sciabbarrasi, M.D. has been a pioneer and practitioner of Integrative Medicine for over 30 ye ...03/18/2010 05:12am ET | Updated November 17, 2011This post was published on the now-closed HuffPost Contributor platform. Contributors control their own work and posted freely to our site. If you need to flag this entry as abusive, send us an email.This time we'll look at one of the most controversial and misunderstood treatments for osteoporosis -- hormone replacement therapy. We'll also answer the question as to whether being obese can actually reduce your risk of osteoporosis.Bioidentical Hormones for WomenPrior to the publication of the Women's Health Initiative (WHI) study, hormone replacement therapy was the first choice in preventing and reversing osteoporosis. After WHI the bisphosphonates became number one (such as Fosamax, Boniva, Actonel and for those with bone cancers, Zometa). And this is for good reason. These drugs are effective in reducing risks of fracture in well conducted studies.
  
  But long term studies of bisphosphonates have also revealed side-effects which, though only occurring in a small minority of patients, can be serious. These include jaw bone deterioration and ulceration of the esophagus. One comprehensive long term study of over 12,000 women with osteoporosis also showed it would be necessary to treat approximately 66 women to prevent one fracture (1).Other, though possibly less effective, medications are also available for use if the bisphosphonates are unsuccessful.But what about hormones? Why did they fall out of favor when they consistently helped prevent fractures?Well, it was reported they also resulted in increased risks of blood clots, strokes and breast cancer, as was reported in the WHI studies. But a large part of the problem wasn't the hormones -- it was the study itself. There were major flaws in the WHI trials. Such prestigious institutions as the University of Massachusetts Medical Center, journals such as the Annals of the New York Academy of Sciences and even the WHI researchers themselves have criticized almost every aspect of the WHI studies done (2-4).That certainly let a lot of air out of the balloon. Even so, there still is good evidence that women who use the synthetichormones doincrease their risks of side-effects and adverse events.The one area which was not criticized, however, was the 30% reduction in all types of fractures and the 40% reduction in hip fractures in particular with the use of HRT (hormone replacement therapy) (5).But who wants to risk adverse effects if these can be reduced?Did you notice I wrote synthetic hormones have increased risks associated with their use? Synthetic hormones such as Premarin, Estratest, FemHRT, Prempro and Provera are all molecules which have been altered. They are not found in nature, nor are they made in our body. It is this alteration which most researchers believe accounts for the significant differences causing increased risks and adverse effects experienced with the synthetics in many women.As it turns out, the risks associated with synthetic hormones are notseen to the same significance with the Bioidentical hormones as shown in a number of excellent studies.Bioidentical hormones are the exact hormones which our bodies produce. To the last atom, they are identical in every way to that which nature gives us.
  
  Bioidentical hormones have a much different -- and safer profile. This evidence comes for example, from studies which have looked at the risks of breast cancer with synthetic HRT to the significantly reduced risks with bioidentical hormones (6-7).There is also good evidence that transdermal estrogen (patch or cream applied to the skin) has no increased risk of causing breast cancer or blood clots -- especially potentially fatal blood clots which can travel to the lungs, heart or brain (8-9).Moreover, comprehensive reviews of the safety and effectiveness of Bioidentical HRT have also concluded that, from all the clinical evidence we have to date, they are an excellent choice for protecting against fractures in women with osteoporosis (10-11).Bottom Line: Bioidentical hormone replacement therapy for women is a valid and viable option for protecting against osteoporotic fractures. There will always be a need for further studies to add to our knowledge, but the track record to date is excellent. They must be used by a knowledgeable practitioner, accompanied by periodic testing and all preventive medicine care. I appease my obsessive need to keep patients safe by tracking these things rather closely. And any hormone therapy should always be used at the lowest effective dose, using estrogen and progesterone together. This combination of the bioidenticals offers the best benefit and protection against problems.In my clinical practice -- over 15 years of experience in the use of Bioidentical hormone replacement therapy -- I regularly see that we not only halt, but we reverse osteoporosis. For women, I require annual gynecological evaluations, mammograms and pelvic ultrasound as well as periodic lab testing to ensure we are achieving optimal ranges of therapy. Bone mineral density evaluation is also periodically required as appropriate.Most importantly, you want to know you are in safe hands while benefiting from all the positives of this exceptional therapy. Therapy should be individualized and tailored to the specifics of each patient's needs and risk profile.Well, that's great for women. But what about men and testosterone replacement for bone health? Which would also be terrific for the libido in older guys.
  
  Except for one big problem. Doesn't testosterone cause prostate cancer? So for all the good it does, aren't men just helping one part and hurting another? Bummer. What's a guy to do?Testosterone, Osteoporosis and the Risk of Prostate CancerIn a comprehensive review of the subject, we see not only an increase in bone density, but significantly fewer fractures in older men with osteoporosis who are treated with testosterone replacement therapy. Moreover, this can be donewith no evidence of any increased risk of prostate cancer (12).
  
  Did we hear this right? No increased risk?Well, quoting these authors:"So far, there is no compelling evidence that testosterone has a causative role in prostate cancer."And this review echoes literally a multitude of studies which have concluded exactly the same findings over the last 20 years. Testosterone replacement therapy does not increase a man's risk of prostate cancer.Bottom Line: All men over the age of 50 should be screened for the possibility of bone loss with blood tests as well as bone mineral density testing where appropriate. Testosterone replacement therapy should be considered as first line therapy for men with bone loss or osteoporosis along with regular follow-up testing for optimal levels and a physical exam. Prostate health should be followed, these studies notwithstanding.Moreover, men with a history of prostate cancer are not necessarily excluded from receiving testosterone therapy. In my practice, I work closely with prostate oncologists to carefully select and follow these individuals while they receive testosterone replacement.Sweet. So now, what's the story on weight, obesity and osteo?ObesityThere are many potential causes for osteopenia and osteoporosis. This is not one of them. Despite the fact that there are a host of diseases which anyone with obesity is at increased risk for -- such as hypertension, diabetes, high cholesterol and coronary heart disease, there are no studies which show that obesity will increase anyone's risk of developing osteoporosis. But, of course, there is a catch.Obesity is also associated with an increased risk of falls. And even though the bone mineral density of many obese individuals is normal, there is an increased risk of fractures of the forearm, legs and spine. You heard it right. You can have a normal bone density and no osteoporosis and still have a significantly higher risk of breaking a bone if you are obese. This does not seem to be true for hip fractures, however, where there seems to be no increased risk with obesity (13 - 16).What seems to be most likely is that the protective effect of increased body size is due to the amount of muscle we have on our bodies -- not just how obese we are. This lean tissue as it is called seems to be the most important factor in obese people which protects against fractures (17).Bottom Line: If you are obese, start or continue working out to build muscle. Obesity will not cause osteoporosis. But it will increase your risk of breaking a bone whether or not your bone density is normal.Remember: Osteoporosis is a reversible disease. And so is your risk of fractures due to obesity.In our next and final installment on osteoporosis, we'll take a closer look at why I think my bones are better than my vegetarian buddy Jason's; the mineral Strontium; Vitamin K; fish oils (for stronger bones?); and the good, the bad and the surprising side of alcohol. Stay tuned!Joseph Sciabbarrasi, M.D., has practiced Integrative Medicine in West Los Angeles since 1993. In addition to his work with Osteoporosis, Bioidentical hormone replacement therapy, Cardiovascular and Chelation therapies, he also lectures, writes and celebrates his weekends with his wife, Kathleen and their 8 year old son, Kieran. Join him at his website: www.drjosephmd.comReferences1. Wells GA, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.Cochrane Database Syst Rev. 2008 Jan 23;(1):CD001155.2. Klaiber EL, et al. A critique of the Women's Health Initiative hormone therapy study. Fertil Steril. 2005 Dec;84(6):1589-601.3. Mastorakos G, et al. Pitfalls of the WHIs: Women's Health Initiative. Ann N Y Acad Sci. 2006 Dec;1092:331-40.4. Manson JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007 Jun 21;356(25):2591-602.5. Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12.6. Fournier A, et al. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Epub 2007 Feb 27.7. Fournier A, et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005 Apr 10;114(3):448-54.8. Opatrny L, et al. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG. 2008 Jan;115(2):169-75; discussion 175.9. Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007 Feb 20;115(7):840-5.10. Moskowitz D. A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Altern Med Rev. 2006 Sep;11(3):208-23.11. Holtorf K. The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med. 2009 Jan;121(1):73-85.12. Bassil N, et al. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009 Jun;5(3):427-48. Epub 2009 Jun 22.13. Premaor MO, et al. Obesity and Fractures in Postmenopausal Women. J Bone Miner Res. 2009 Oct 12.14. Pirro M, et al. High weight or body mass index increase the risk of vertebral fractures in postmenopausal osteoporotic women. J Bone Miner Metab. 2009 Jul 4.15. El Maghraoui A, et al. Body mass index and gynecological factors as determinants of bone mass in healthy Moroccan women.Maturitas. 2007 Apr 20;56(4):375-82. Epub 2006 Nov 28.16. Barrera G, et al. A high body mass index protects against femoral neck osteoporosis in healthy elderly subjects. Nutrition. 2004 Sep;20(9):769-71.17. Travison TG, et al. The relationship between body composition and bone mineral content: threshold effects in a racially and ethnically diverse group of men. Osteoporos Int. 2008 Jan;19(1):29-38. Epub 2007 Jul 28.Suggest a correctionMORE:HEALTHY LIVINGHEALTHWOMENOSTEOPOROSISBONE HEALTHMILKBONESWELLNESSMEDICINEWOMEN'S HEALTHJoseph Sciabbarrasi, M.D., ContributorJoseph Sciabbarrasi, M.D. has been a pioneer and practitioner of Integrative Medicine for over 30 years.

Bioidentical Progesterone helps me sleep more deeply. Anyone else notice that?

You're right dtad, most of the bc providers know next to nothing about the need for hormonal balance to have a decent quality of life and health.

I too feel there will eventually be a complete turn around in regards to the use of Bioidentical hormones in care of women after bc. Eventually they will wake up and realize they have been doing most of this terribly wrong.

There are providers, even now in oncology, who are at the forefront of this new/old thinking, that properly balanced hormones are crucial for good health. If we keep pushing for more knowledge like this to be shared, to educate the doctors, we can only help ourselves, and the poor women who will come after us.