Is local estrogen therapy safe for breast cancer survivors?

Current clinical evidence suggests that local estrogen therapy is both safe and effective for treating the vaginal and urinary symptoms of estrogen decline in menopausal women. But is it safe for breast cancer survivors?

The natural decrease in estrogen levels during menopause causes vaginal atrophy (also known as atrophic vaginitis, or vulvovaginal atrophy), which is a thinning and inflammation of the vaginal walls. It can also cause effects on the urinary system. These changes can result in symptoms including vaginal dryness, irritation and pain during sex, as well as incontinence and recurrent urinary tract infections. Collectively these symptoms are known as the Genitourinary Syndrome of Menopause (GSM). As many as 50% of postmenopausal women experience vaginal and urinary symptoms of estrogen decline to some degree.

While the incidence of GSM in postmenopausal women is high, in breast cancer survivors it appears to be even more common.

In fact, the data suggests that the incidence of GSM is twice as high in postmenopausal breast cancer patients treated with aromatase inhibitors than it is in the general population (ref1). The combination of chemotherapy and hormone therapy also appears to induce early onset menopause in as many as 80% of premenopausal breast cancer survivors within a year of diagnosis (ref2).

Treatment options for vaginal and urinary menopause symptoms in breast cancer survivors

The vaginal and urinary symptoms of menopause can be addressed using a variety of approaches, albeit with varying degrees of success. These include vaginal moisturizers and lubricants, pelvic floor physiotherapy (for both pain during intercourse and incontinence), and local estrogen therapy – which may take the form of estriol, estradiol, promestriene, or conjugated equine estrogens. For a more comprehensive discussion of treatment options please see our post “Managing the vaginal and urinary symptoms of menopause in breast cancer survivors”.

Current health recommendations advise against local estrogen therapy for breast cancer survivors. So while breast cancer patients are at greater risk of developing vaginal and urinary symptoms of menopause, their recommended options for treatment are more limited.

Is this recommendation warranted?

A conservative approach to treating vaginal and urinary symptoms in menopausal women without breast cancer would begin with lower-risk therapies such as vaginal lubricants and pelvic floor physiotherapy, before graduating to local estrogen therapy. Could the same conservative approach be considered for breast cancer survivors?

Low-dose local estrogen therapy for breast cancer survivors

The typical recommendation against local estrogen therapy for breast cancer survivors has its origins in very well-known studies linking systemic (rather than local) hormone replacement therapy (commonly called “hormone therapy”) to breast cancer.

Treating the symptoms of menopause using systemic hormone replacement therapy is very effective, but a small number of very influential studies have suggested that this therapy may increase the risk of breast cancer in heathy women (ref3), and may significantly increase the risk of new breast cancer events in breast cancer survivors (ref4). Consequently, systemic hormone therapy is now more rarely prescribed to menopausal women (in favour of local estrogen therapy and other treatments), and is strongly avoided for breast cancer patients.

Is it fair to apply the same recommendation against systemic hormone therapy to low-dose local estrogen therapy for breast cancer survivors?  

Low-dose local estrogen therapy is usually delivered as a vaginal cream, vaginal tablet, or vaginally-inserted ring. The benefits of local vaginal delivery are two-fold:

1. It can be more effective than systemic therapy for treating vaginal and urinary symptoms.
2. The levels of estrogen used is a fraction of that required for systemic hormone therapy.

A variety of studies show that, as expected, low-dose local estrogen therapy produces very low levels of circulating serum estrogen in the blood stream. In one notable study, 10 mcg 17 b-estradiol vaginal tablets resulted in blood serum levels of estradiol within the normal range of serum estradiol levels found in postmenopausal women (ref5). In another recent small phase I study, a 0.03 mg ultra-low dose “Gynoflor” estriol and Lactobacillus tablet appeared not to increase blood serum estradiol and estrone levels at all (ref6).

These studies suggest that the risk of breast cancer recurrence posed by this type of local estrogen therapy should in theory be reduced (for low-dose preparations), or perhaps nearly eliminated (for ultra-low dose formulations), compared to systemic hormone therapy.

How much does local estrogen therapy reduce the risk of breast cancer recurrence compared to systemic hormone therapy?

Local estrogen therapy likely reduces the risk of breast cancer recurrence in breast cancer survivors considerably. But by how much is a difficult question to answer, for three reasons:

1. More clinical studies are needed. Only a limited number of small studies have examined the effects of local estrogen therapy on breast cancer survivors. Most of these studies were designed to examine the efficacy of local estrogen therapy for treating menopause symptoms, and/or examined the resulting levels of circulating blood serum estrogens, rather than investigate the risk of breast cancer recurrence.
2. Patient cancer history is a factor. The risk posed by local hormone therapy should in part depend on the type of breast cancer the patient had. Patients with hormone-receptor-negative tumors (which are not very responsive to estrogen) would in theory be less at risk of hormone therapy-induced breast cancer recurrence than those whose tumors were hormone-receptor positive.
3. Patient cancer treatment is a factor. Postmenopausal breast cancer patients treated with aromatase inhibitors may be particularly sensitive to hormone therapy. Aromatase inhibitors severely deplete estrogen levels, which may actually hyper-sensitize tumor cells to estrogen. From my own experiences and those of countless others working with both cancer and normal cells, stimulus deprivation often results in an accumulation of cell receptors designed to detect that stimulus (although in some instances the exact opposite may occur). Indeed, numerous studies suggest that estradiol deprivation causes an increase in the number and activity of estrogen and other growth factor receptors, and in turn, hypersensitivity to estrogen and other growth factors. So patients taking aromatase inhibitors may in fact be hypersensitive to even small amounts of circulating estrogen, which makes low levels of estrogen more risky than one might otherwise assume.

So should I take local estrogen therapy to manage my menopausal symptoms?

Local estrogen therapy is currently not recommended for treating menopausal symptoms in breast cancer survivors, especially for those being treated with aromatase inhibitors.

Conservative treatment options for the vaginal and urinary symptoms of menopause should be exhausted before local estrogen therapy is considered. The benefits and risks of local estrogen therapy should be discussed in detail with your physician, and if you do decide to use it, choose the lowest dose and use it for the shortest duration of time that is still effective for alleviating your symptoms.

Conservative treatment of my menopause symptoms isn’t working, but I’m not comfortable taking local estrogen therapy. Is there hope for new treatments?

This is an active area of research, and new developments are likely on the way. In addition to ultra-low dose local estrogen therapy formulations, a variety of new drugs are under investigation (ref8), the most promising of which may be ospemifene.

Ospemifene, known by the registered trade name “Osphena” is an estrogen receptor modulator similar in structure to tamoxifen (it’s the same class of drug). It was approved by the U.S. FDA in 2013 for the treatment of vaginal atrophy in postmenopausal women who are not candidates for local estrogen therapy. It is not yet available in Canada.

The manufacturers of Osphena include a cautionary statement in their packaging that states that patients with estrogen-dependent cancers should not take this drug. This warning speaks to a lack of clinical data rather than contraindicating evidence. The class of drugs ospemifene belongs to typically have neutral or anti-estrogenic effects on breast cells, and some very early mouse studies suggest that opemifene may actually act like tamoxifen to prevent breast cancer development (ref9).

Osphena has the potential to be a safe and effective treatment for vaginal atrophy in breast cancer survivors, but clinical data on its safety is still absent.

References

1. Chollet JA. Update on alternative therapies for vulvovaginal atrophy. Patient Prefer Adherence. 2011; 5:533-6.
2. J. Goodwin, M. Ennis, et al. Risk of menopause during the first year after breast cancer diagnosis. Journal of Clinical Oncology. 1999; 17(8):2365–2370.
3. Chlebowski R.T., Anderson G.L. et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010; Oct 20;304(15):1684-92.
4. Holmberg L., Iversen O.E., et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst. 2008; Apr 2;100(7):475-82.
5. Eugster-Hausmann M., Waitzinger J. et al. Minimized estradiol absorption with ultra-low-dose 10 microg 17beta-estradiol vaginal tablets. Climacteric. 2010; Jun;13(3):219-27.
6. Donders G., Neven P., et al. Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety and efficacy phase I clinical study. Breast Cancer Res Treat. 2014; Jun;145(2):371-9.
7. Santen R.J., Song R.X., et al. Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells. Adv Exp Med Biol. 2008;630:19-34.
8. Chollet J.A. Update on alternative therapies for vulvovaginal atrophy. Patient Prefer Adherence.2011; 5: 533–536.
9. Wurz G.T. Soe L.H., et al. Ospemifene, vulvovaginal atrophy, and breast cancer. Maturitas. 2013 Mar;74(3):220-5.