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edge

Chief of Research
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Reply with quote  #1 

Breast Cancer Chemoprevention: Tamoxifen versus Raloxifene

The Current State-of-the-Art

 

 

I have been asked to briefly present the current state-of-the-art in breast cancer chemoprevention with the two SERMS, tamoxifen (Nolvadex) versus raloxifene (Evista).  The state of chemoprevention until recently has been such that despite a clear indication and FDA approval for use of tamoxifen to prevent breast cancer, relatively few eligible women actually are at present on tamoxifen as a preventive strategy, in part because physicians in a position to prescribe tamoxifen for chemoprevention are frequently non-oncologists and so have relatively little familiarity with the drug, and more importantly also because of concerns about thromboembolism and toxic effects. 

 

The STAR Trial Findings in Brief

The best evidence comes from the prospective, double-blind randomized trial STAR (Study of Tamoxifen and Raloxifene) Trial, the largest breast cancer prevention trial ever conducted, which compared tamoxifen, 20 mg/d, vs raloxifene, 60 mg/d, over 5 years, reporting results after a median follow-up of 4 years.  In short, both drugs reduced the risk of developing invasive breast cancer by about 50 percent, and hence both were equally effective at preventing invasive breast cancer in women at high risk for the disease, and mortality in the two groups was similar, but thromboembolic events occurred significantly less often in the raloxifene vs tamoxifen group (the raloxifene group experiencing fewer pulmonary embolisms and deep vein thromboses), and raloxifene had a more favorable adverse risk profile. It is important to remember here that these results are restricted to estrogen receptor-positive but NOT estrogen receptor-negative breast cancer, and only in postmenopausal women.

 

So raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer; the significance, if any, of a nonstatistically significant higher risk of noninvasive breast cancer is not clear. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. Thus both  treatments were not associated with differences in death from any cause, other invasive cancers, cardiovascular risk (no differences in incidence of ischemic heart disease for myocardial infarction, severe angina, and acute ischemic syndrome), or osteoporotic fractures. Raloxifene was also associated with slightly fewer thromboembolic events, cataracts, and cataract surgeries. Although women receiving raloxifene had significantly less uterine hyperplasia, there was not a statistically significant difference between groups in the incidence of endometrial cancer; that is, women on raloxifene had 36 percent fewer uterine cancers, but again remember the difference was not statistically significant; and 29 percent fewer blood clots than the women who were assigned to take tamoxifen. As many women know, uterine cancers, especially endometrial cancers, are a rare but serious side effect of tamoxifen. Both tamoxifen and raloxifene are known to increase a woman's risk of blood clots. Thus, the quality of life and the adverse-effect burden of raloxifene and tamoxifen are comparable. 

 

My Interpretation of the Data

But my own sense of these findings is that although raloxifene, if not superior to tamoxifen, is indeed more acceptable and tolerable, and the trend, even though not statistically significant, of lower incidence of endometrial cancer and thromboembolic events (blood clots, pulmonary embolisms and deep vein thromboses), and cataracts, is still an important differentiating factor in raloxifene's (Evista) favor; in addition, teasing out certain other underreported differences, it's also my sense that women who wish to avoid leg cramps or vaginal bleeding/discharge might also prefer raloxifene.

 

Their benefits include prevention of breast cancer in postmenopausal women at increased risk and, in the case of raloxifene, reduction of fractures related to osteoporosis.  As to anti-osteoporotic benefit, one study suggested that In postmenopausal women with low bone density, improvements in BMD and markers of bone turnover were substantially greater during treatment with alendronate compared to raloxifene (Philip Sambrook at the University of Sydney).  However, as to the most critical aspect of osteoporosis protection, reduction of hip fracture (mortality from hip fracture is higher than that from breast cancer), the efficacy of both drugs on hip fractures (-20 to -60%), however, appears to be comparable, and despite inconsistencies across trials, WHO researchers Serge Ferrari and RenĂ© Rizzoli reviewing the evidence to date earlier this year argued convincingly that there is no decisive data suggesting one agents superiority over the other, so raloxifene (Evista) remains an excellent choice for anti-osteoporotic protection.

 

Summary, and A Look Forward

All told, therefore for estrogen receptor-positive postmenopausal women at high risk of breast cancer, including those with significant family history and / or with known BRCA mutation, raloxifene Evista) at this time remains the foremost prospect for the chemoprevention of breast cancer, and for this category of high-risk women, raloxifene display a favorable risk-to-benefit ratio.  Three things to remember:

 

1.      prevention is not solely chemoprevention, so this should be part of a comprehensive breast cancer risk reduction program that includes exercise, dietary and weight control and caloric restriction modalities, as well as emerging CAM (complementary and alternative medicine) interventions (high-dose Vitamin D3 for example among others);


2.      there is some future prospect, I would speculate, of tamoxifen resurging in interest and benefit over raloxifene if the efficacy of LD-TAM (low-dose tamoxifen at 5mg / daily) is confirmed in the chemoprevention setting, as that reduces or removes the major adverse events associated with tamoxifen; and


3.      several other new SERMS currently in clinical trial, as well as other classes of agents like the Retinoids, are being explored and showing considerable promise for breast cancer chemoprevention, so it is unlikely that any one electing to begin chemoprevention with raloxifene (Evista) would remain on this agent indefinitely, switching over to better agents as they appear and are proven in safety and efficacy.

 


 

Constantine Kaniklidis
Medical Researcher
 

edge@evidencewatch.com 

csp

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Reply with quote  #2 
Constantine ,
Thank you so much. You answered many questions for me.
I found your post easy to understand and very useful.
What is bothering me though is I was told by my oncologist
that I am pre menopausal. Why has the onc perscribed this
for me then ?? I have been on it for a month now.

__________________
courage does not always roar. sometimes courage is the quiet voice at the end of the day
saying.. i will try again tomorrow.
~maryanne radmacher
edge

Chief of Research
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Posts: 1,129
Reply with quote  #3 

I too am concerned and I would strongly advise you to discuss this seriously with your oncologist, as raloxifene (Evista) has no approval or sanction for use in  premenopausal women, and there is no compelling evidence suggesting either safety or efficacy in this context. Although Brazilian researcher Benedito Borges da Silva and his colleagues have found preliminary evidence that raloxifene significantly reduces the proliferative activity of normal breast tissue in premenopausal women, that is normal tissue, not tumor tissue, and NCI researcher Jessica M. Faupel-Badger and her colleagues found raloxifene to raise estradiol levels in otherwise healthy women at high risk for breast cancer.  Raloxifene is shown to be safe and effective solely in high-risk postmenopausal women. 

 

I should note in this connection the RAZOR study indeed explored (trial completed but findings not yet released) raloxifene plus ovarian suppression via the LHRH/GnRH analog goserelin (Zoladex) to placebo in premenopausal women who may be carrying a BCRA-type gene mutation, but this serves to prove the point: the effect of the ovarian suppression is to render the women effectively postmenopausal (comparable to an oophorectomy), in which case the RAZOR study is in fact  studying raloxifene in postmenopausally-induced populations. 

 

Given the above considerations, there is no warrant to presume either the safety or efficacy of raloxifene in premenopausal populations; use in premenopausal women can only be considered safe if menopause is induced, either surgically (oophorectomy) or medically by ovarian suppression.    

 

Constantine Kaniklidis
Medical Researcher
 

edge@evidencewatch.com
csp

Moderator
Registered:
Posts: 1,940
Reply with quote  #4 
I just went to the onc this month and he told me my blood test came back that  I am pre menopausal.
I double check with my husband to make sure that is what he said. I have
been dx'd Multifocal LCIS,ALH and ADH w/ microcalcifications. I have
first degree family history of breast cancer and first degree family history
uterine cancer. I will most definitely be calling the onc . Thank you so much
for you information Constantine. I checked the patient information and you
are 100% right about the use with only post menopausal woman.
 
Carrie

__________________
courage does not always roar. sometimes courage is the quiet voice at the end of the day
saying.. i will try again tomorrow.
~maryanne radmacher
csp

Moderator
Registered:
Posts: 1,940
Reply with quote  #5 

Constantine,I put a call into my onc. They pulled my file and Yep I am pre menopausal !  He told me to stop the Evista immediately.

 
Thank you Edge, Who knows what would happened if I had
not questioned this, and stayed on the Medication
for the next 6 months until my next follow up.
 
Hugs,
Carrie

__________________
courage does not always roar. sometimes courage is the quiet voice at the end of the day
saying.. i will try again tomorrow.
~maryanne radmacher
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