18 February, 2013:

A recent review [1] was intriguing, since it brought again to our attention the search for a desired molecule which should have optimal dual characteristics: inducing estrogen-like effects on menopause-related symptoms on the one hand, but avoiding the potentially serious adverse effects of postmenopausal hormone therapy on the other hand. Here is an Abstract of this review:

Vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women. Although other SERMs have antagonistic effects on the vagina, ospemifene exerts an estrogen-like effect on the vaginal epithelium. The review focuses on data demonstrating the antiestrogenic activity of ospemifene in several unique breast cancer animal models, and the implications for utilizing ospemifene in patients with breast cancer suffering from VVA.

Comment

Two drugs – tamoxifen and raloxifene, both SERMs – are currently approved for chemoprevention of breast cancer. Tamoxifen's prevention approval dates back to 1998, after results from the Breast Cancer Prevention Trial (BCPT) [2] showed a 49% reduction in the incidence of invasive, estrogen receptor-positive breast cancer in high-risk women. Likewise, raloxifene, a SERM used in osteoporosis treatment, reduced breast cancer risk by 50%, according to the Study of Tamoxifen and Raloxifene (STAR) [3]. The STAR trial, which compared tamoxifen with raloxifene showed that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer. On the basis of that result, the US Food and Drug Administration approved raloxifene for breast cancer prevention in 2007. So this is the upside of cancer prevention by those drugs, while a downside was recorded in regard to endometrial cancer. Risk of endometrial cancer increased following tamoxifen therapy for invasive breast cancer [4]. The annual hazard rate through all follow-up was 0.2/1000 in the placebo group and 1.6/1000 in the randomized, tamoxifen-treated group; the relative risk of endometrial cancer for the latter versus the former group was 7.5. The rates were 84% less in the raloxifene-treated group than in the tamoxifen-treated group. By the end of the day, however, since benefit outweighed the risk, the issue of uterine cancer did not prevent the approval for the breast cancer prevention indication.

The above SERMs may induce or worsen menopausal symptoms to some extent because of their antiestrogenic properties. As an example, a study which investigated the consequences of switching from long-term transdermal estradiol to raloxifene resulted in worsening of vaginal atrophy assessed by the vaginal maturation value, although it was not clinically perceived by the patients [5]. However, increases in dyspareunia and urinary leaks were reported, and menopausal complaints related to vasomotor symptoms worsened in the raloxifene-treated group and persisted throughout the study period. The development of the new SERM, ospemifene, was the result of its innovative estrogen-like effects on vaginal atrophy. Data from phase I and phase II clinical trials revealed that ospemifene was having a favorable estrogenic effect in the vaginal epithelium and clinically insignificant effects on the endometrium, and therefore the focus of phase III development became the treatment of postmenopausal vulvovaginal atrophy [6]. This randomized, double-blind, phase III study (n = 826) recruited postmenopausal women having 5% or less superficial cells on the vaginal smear (maturation index), vaginal pH greater than 5.0, and at least one moderate or severe symptom of vulvovaginal atrophy. After 12 weeks of use, ospemifene was statistically significantly superior to placebo in inducing positive changes in each of the above parameters at the 60-mg dose. Ospemifene was well tolerated and demonstrated a favorable safety profile. Hot flushes were reported by 8% of women in the active study arm, versus 3% in the placebo group; the corresponding changes from baseline in endometrial thickness were 0.72 mm and -0.02 mm.

So now we have a soon-to-be-approved oral medication for a situation which has been traditionally treated locally rather than systemically. The intriguing question is whether this new SERM will have a breast cancer chemopreventive effect similar to tamoxifen or raloxifene. The new review by Wurz and colleagues [1] is encouraging at least from the perspectives of animal data. The authors' conclusion is that ospemifene does not have any stimulatory or estrogen agonist effects on breast tissue at a dose equivalent to the designated 60 mg in humans. In fact, preclinical data point at antiestrogenic properties similar to the older SERMs. Considering the higher incidence of vaginal atrophy and associated quality-of-life issues in breast cancer patients, and the currently available sub-optimal therapeutic solutions, a new SERM which combines breast and bone protection with positive effects on the vaginal epithelium, but only insignificant uterine or vasomotor problems on the other hand, seems to be the ideal medication. Whether or not ospemifene will prove to be such candidate, time and future studies will tell.

Amos Pines

Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

References

1. Wurz GT, Soe LH, Degregorio MW. Ospemifene, vulvovaginal atrophy, and breast cancer. Maturitas 2013 Jan 15. Epub ahead of print.

http://www.ncbi.nlm.nih.gov/pubmed/23332519 

2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–88.

http://www.ncbi.nlm.nih.gov/pubmed/9747868 

3. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727-41.

http://www.ncbi.nlm.nih.gov/pubmed/16754727 

4. Fisher B, Costantino JP, Redmond CK, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527-37.

http://www.ncbi.nlm.nih.gov/pubmed/8133536 

5. Checa MA, Garrido A, Prat M, et al. A comparison of raloxifene and calcium plus vitamin D on vaginal atrophy after discontinuation of long-standing postmenopausal hormone therapy in osteoporotic women. A randomized, masked-evaluator, one-year, prospective study. Maturitas 2005;52:70-7.

http://www.ncbi.nlm.nih.gov/pubmed/16143228 

6. Bachmann GA, Komi JO. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 2010;17:480–6.

http://www.ncbi.nlm.nih.gov/pubmed/20032798 

Content updated 18 February 2013