SUBJECTS STILL TABOO
Vaginal Health of Breast Cancer Survivors.
Dana Sawan MD2., Barbara Hersant MD, PhD1,2.
1 Henri Mondor Breast Center, Henri Mondor University Hospitals, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France.
2 Department of Maxillo-facial Surgery, Plastic and Reconstructive, Henri Mondor University Hospitals, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France.
Dana Sawan: email@example.com
Barbara Hersant: Barbara.firstname.lastname@example.org
Most breast cancers are hormone-sensitive or hormone-dependent on estrogen.
The therapeutic strategy is therefore to wean the body from its oestrogen supply, which induces an early menopause in patients who are often still young and genitally active.
The menopause is accompanied by a series of general and local manifestations.
These can be summed up in the urogenital sphere as a so-called genitourinary menopause syndrome (vaginal dryness, atrophy, dyspareunia, dysuria, etc.).
The treatment of this syndrome gives the main role to oestrogens. However, oestrogen carries a risk of recurrence in patients with a history of breast cancer.
It is therefore imperative to find alternatives to hormonal treatment. This work aims to do away with these means.
Keywords: genito-urinary menopausal syndrome – breast cancer – hormone therapy – alternatives – sex life.
Breast cancer is the most common cancer and the leading cause of cancer death in women. The ¾ of breast cancers express estrogen receptors, including Estrogen Receptor alpha (ERα)1-4.
Tumours that do not express oestrogen receptors often express epidermal growth factor receptor (EGFR).
The latter has been correlated with larger tumours and metastatic forms5.
The hormone sensitivity and hormone dependence of breast cancers makes hormone therapy one of the main means of treating these cancers.
It consists of weaning them from the oestrogenic intake that maintains their growth, either by suppressing endogenous production (chemotherapy or irradiation of the ovaries), or by administering an anti-estrogenic substance systemically.
Advances in breast cancer detection technology now make it possible to detect tumours at an earlier stage than before and, as adjuvant chemotherapy is associated with ovarian failure,6 an increasing proportion of breast cancer survivors are becoming postmenopausal at an earlier age after cancer treatment7. In addition, estrogen levels gradually decline as menopause approaches, leading to genital and urinary symptoms in affected women8.
Hormone replacement therapy (HRT) is known to be effective and recommended in the control of menopausal symptoms such as hot flashes, sleep disorders, sexual dysfunction or vaginal atrophy and even the prevention of osteoporosis and cardiovascular disease9,10.
In general, systemic estrogen therapy is recommended for women with general symptoms, while local estrogen therapy is recommended for those suffering from Vulvo-Vaginal Atrophy (VVA) or Genito-Urinary Menopausal Syndrome (GUMS)11.
However, HRT is risky in breast cancer survivors. Indeed, it has been shown that current and former HRT users have a higher risk of developing breast cancer because estrogen plays a central role in the development of breast cancer12. Thus, women who have received primary treatment for early breast cancer may have a recurrence of the disease after HRT13.
Clinicians must therefore consider the goals of systemic endocrine therapy and the safety of this treatment modality in healthy women and those with a history of breast cancer11.
Given the safety concerns regarding the use of HRT in women with a history of breast cancer, this document examines alternatives to estrogen replacement therapy that may help address specific survivorship issues such as GUMS in this group of women.
Alternatives to Hormone Replacement Treatment
Several alternatives to the use of hormone replacement therapy have been proposed for women with a previous diagnosis of breast cancer.
1.1. Platelet-rich autologous plasma and hyaluronic acid (Cellular Matrix)
A multicentre, randomised, controlled, open-label study of 144 women found that hyaluronic acid vaginal gel was effective in improving vaginal dryness in postmenopausal women14.
A recent phase 2 clinical study suggested that intraperitoneal administration of a combination of autologous platelet-rich plasma and hyaluronic acid appeared to improve GUMS in women with a previous diagnosis of breast cancer15.
Researchers reported a significant increase in the volume of vaginal secretions after the start of treatment.
The quality of sexual life of the participants was also significantly improved, as evidenced by a decrease in the female sexual distress score one, three and six months after treatment with platelet-rich autologous plasma and hyaluronic acid15.
The Patient’s Platelet Rich Plasma combined with Hyaluronic Acid for Skin and Mucosa Regeneration.
TREATMENT OF GENITOURINARY SYNDROME OF MENOPAUSE (GSM)
New vascularization stimulated by vascular endothelial growth factor (VEGF) release.
Increase in elasticity thanks to new synthesis of collagen and elastin.
Overall decrease in pain and discomfort.
GSM Refers to a collection of symptoms and signs associated with a decrease in estrogen :
Genital symptoms: – Dryness – Burning – Irritation
Sexual symptoms: – Lack of lubrication – Discomfort/pain – Impaired function
Urinary symptoms: – Urgency – Dysuria – Recurrent urinary infections
Cellular Matrix is also evaluated for Lichen Sclerosus, Bartholinitis, Post C-‐section scar, Episiotomy scars, Stretch marks treatments.
1.2. Vaginal Carbon Dioxide Laser Therapy
Laser therapy has recently been proposed as a viable treatment for SGUM. The use of vaginal carbon dioxide laser for menopausal symptoms is somewhat new and very few studies have explored its effectiveness as recently as 12 weeks after therapy16-18.
A single-arm pilot study showed that the vaginal carbon dioxide laser improved VVA symptoms and sexual function16.
In addition, a systematic review of six non-randomized studies suggested that the vaginal carbon dioxide laser may improve vaginal health in women diagnosed with breast cancer19.
The CO2 laser used to redraw the vaginal epithelium activates heat shock proteins which in turn activate growth factors that increase vascularization, collagen, extracellular matrix production and vaginal mucosal thickness20.
Recently, the VeLVET trial was conducted to compare the safety and efficacy of laser therapy with vaginal estrogen after six months of follow-up21.
Investigators found that women in the laser-treated group and the vaginal estrogen group had comparable improvements in SGUM symptoms and sexual function at six months follow-up.
About 70-80% of women in both groups reported being satisfied or very satisfied with their treatment option. No serious adverse events were reported by the participants.
The erbium laser: YAG has also been satisfactorily tested in the SGUM, showing greater long-term efficacy than oestriol22.
1.3. Intravaginal use of estrogen gels or creams
The use of estrogen gels and creams provides significant relief for patients suffering from SGUM.
The main concern is the safety of this treatment, as the systemic passage of estrogen occurs through the vaginal mucosa.
Several studies suggest the safety of this treatment23,24.
Indeed, systemic estrogen levels remain very low and the risk of cancer recurrence is not significantly high for estradiol doses of 0.25 mg and estradiol doses between 12.5 and 25 µg.
Aspects that some patients are dissatisfied with are the « messy » nature of the administration, the unhygienic reusable applicator and the approximate dosage, as there is often no dosing device, which is problematic in our population25. Administration is usually daily for the first two weeks and then bi-weekly for the maintenance period.
Intra-vaginal estradiol ova dosed at 4µg are also safely used in breast cancer survivor25
They offer the advantage of accurate dosing and easier application.
Similarly, vaginal rings are available that release estradiol at a sustained release rate of 7.5µg per day and can remain in place for up to 90 days25.
This local hormone therapy should only be used when non-hormonal methods do not work, and if possible for a limited period of time. Long-term use can be made in patients on tamoxifen or raloxifene 22,26,27.
The latter block the possible oestrogenic effect in case of significant systemic passage.
Hormone therapy should be avoided in any patient with unlabelled vaginal bleeding. Similarly, bleeding that appears under intravaginal hormone therapy should be investigated seriously (imaging, endometrial biopsy).
1.4. Specific oestrogen receptor modulators (SERMs)
These molecules are non-steroidal agents that exert a plethora of estrogen agonist or antagonist effects on target organs.
Only ospemifene is currently used in the management of MUMS (60 mg/day), particularly in the treatment of moderate to severe dyspareunia. It improves the maturation of the vaginal mucosa and acidifies the pH25.
Tamoxifen, on the other hand, has a variety of effects on the vagina and can cause dyspareunia, increased white discharge or vaginal dryness28.
Raloxifene and bazedoxifene do not have a direct effect on the vagina.
However, when combined with equine estrogen (20/0.45 mg per day), they have significantly improved the signs and symptoms of MUMS without causing endometrial hyperplasia29.
1.5. Vaginal dehydroepiandrosterone (DHEA)
DHEA is a pro-hormone in the biosynthesis of testosterone and estradiol.
Tests have shown its effectiveness on the symptoms of SGUM (dyspareunia, vaginal maturation index, pH).
DHEA exerts its vaginal effects through in situ conversion to testosterone and oestradiol.
Serum levels are not elevated because these products are locally inactivated30.
It is therefore a safer alternative to local estrogen in breast cancer survivors.
In addition, since aromatase does not exist in the endometrium, DHEA has no proliferative effect on the endometrium31.
2. Non-medical means
Women need to be educated about the changes that occur as a result of the decrease in estrogen. Many patients are unaware of these changes and therefore cannot seek appropriate medical help. They need to know that the symptoms and signs of MUMS will not regress spontaneously and to be aware of the various treatment options available to them25.
2.2 Vaginal lubricants and humidifiers
They offer an immediate solution to the problem of pain at the intromission which is the result of vaginal dryness.
Lubricants are used at the time of intercourse while humidifiers are used remotely32. There are water-based and silicone-based lubricants. The former do not stain and are better tolerated than the latter.
However, the effectiveness of lubricants depends on their osmolarity.
An osmolarity higher than 1200 mOsm/kg is associated with irritation, contact dermatitis and cytotoxicity32.
Humidifiers increase moisture in the vaginal mucosa by adhering to it, mimicking vaginal secretions. They also contain additives that lower the pH and affect osmolarity32.
2.3. Use of vibrators and vaginal dilators
They help maintain sexual function by stretching the vaginal and vulvar tissues. In fact, they stimulate these tissues and increase blood flow to them, whether or not the patient has a sexual partner25.
Women who have vaginismus can use these devices for conscious relaxation to facilitate the resumption of penetrative sexual activity33.
2.4. Pelvic floor re-education
Physiotherapy should ideally be guided by a professional specialising in pelvic pathology.
It is indicated for women with pelvic muscle hypertonia caused by painful sexual activity secondary to GUMS34.
2.5 Topical Lidocaine
4% aqueous lidocaine applied in the vulval vestibule a few minutes before intercourse significantly reduces the pain of penetration.
It can be used as an adjunct to other measures (lubricants, humidifiers, rehabilitation)35.
Genitourinary menopausal syndrome is a consequence of breast cancer treatment that deprives the body of its estrogen supply.
It poses a management problem because all modalities including estrogen must either be ruled out or carefully weighed on the risk/benefit balance.
However, there are many other options available that allow most patients to find the right formula for them.
Najim O, Huizing M, Papadimitriou K, Trinh XB, Pauwels P, Goethals S, Zwaenepoel K, Peterson K, Weiler J, Altintas S, van Dam P and Tjama W. The prevalence of Estrogen Receptor 1 mutation in advanced breast cancer : The estrogen receptor 1 study (EROS 1). Cancer tratment and Research Communications. 2019 ;19, 100123.
Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg contre anastrozole 1 mg pour le cancer du sein avancé avec récepteurs hormonaux positifs (FALCON) : un essai international de phase 3, randomisé, en double aveugle. Lancet Lond Engl. 2016;388(10063):2997-3005. doi:10.1016/S0140-6736(16)32389-3.
Réseau national global de lutte contre le cancer. Lignes directrices de pratique clinique en oncologie du NCCN : Breast Cancer. Ver. 2.2016. Fort Washington, PA ; 2016. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Consulté le 31 mars 2020.
Spring LM, Gupta A, Reynolds KL, et al. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer : A Systematic Review and Meta-analysis. JAMA Oncol. 2016;2(11):1477-1486. doi:10.1001/jamaoncol.2016.1897.
Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN and Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012. 136 :331-345.
Bedoschi G, Navarro PA, Oktay K. Les lésions ovariennes induites par la chimiothérapie : mécanismes et impact clinique. Futur Oncol. 2016;12(20):2333-2344. doi:10.2217/fon-2016-0176.
Passildas J, Collard O, Savoye A-M, et al. Impact of Chemotherapy-induced Menopause in Women of Childbearing Age With Non-metastatic Breast Cancer – Preliminary Results From the MENOCOR Study. Clin Cancer du sein. 2019;19(1):e74-e84. doi:10.1016/j.clbc.2018.10.003.
Gersak K, Gersak ZM, Turcin A. Reproductive Aging: Périménopause et symptômes psychopathologiques. Processus des neurodégénérateurs de l’hormone sexuelle Dis. Mai 2018. doi:10.5772/intechopen.74159.
Le comité consultatif de la déclaration de position sur l’hormonothérapie NAMS 2017. La déclaration de position sur l’hormonothérapie 2017 de la Société nord-américaine de la ménopause. Menopause N O N. 2017;24(7):728-753. doi:10.1097/GME.0000000000000921.
US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: Déclaration de recommandation de la US Preventive Services Task Force. JAMA. 2017;318(22):2224-2233. doi:10.1001/jama.2017.18261
Collège américain des obstétriciens et gynécologues. L’utilisation des œstrogènes vaginaux chez les femmes ayant des antécédents de cancer du sein dépendant des œstrogènes. Avis du Comité n° 659. Obstet Gynecol. 2016;127:e93-6.
Groupe de collaboration sur les facteurs hormonaux dans le cancer du sein. Type et calendrier du traitement hormonal de la ménopause et risque de cancer du sein : méta-analyse des preuves épidémiologiques mondiales par les participants individuels. The Lancet. 2019;394(10204):1159-1168. doi:10.1016/S0140-6736(19)31709-X.
Pan H, Gray R, Braybrooke J, et al. 20 Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830.
Chen J, Geng L, Song X, Li H, Giordan N, Liao Q. Evaluation of the efficacy and safety of hyaluronic acid vaginal gel to ease vaginal dryness : a multicenter, randomized, controlled, open-label, parallel-group, clinical trial. J Sex Med. 2013;10(6):1575-1584. doi:10.1111/jsm.12125
Hersant B, SidAhmed-Mezi M, Belkacemi Y, et al. Efficacité de l’injection d’un concentré de plaquettes combiné à de l’acide hyaluronique pour le traitement de l’atrophie vulvovaginale chez les femmes ménopausées ayant des antécédents de cancer du sein : étude pilote de phase 2. Ménopause. 2018;25(10):1124-1130. doi:10.1097/GME.0000000000001122.
Pearson A, Booker A, Tio M, Marx G. Vaginal CO2 laser for the treatment of vulvovaginal atrophy in women with breast cancer: Étude pilote LAAVA. Breast Cancer Res Treat. 2019;178(1):135-140. doi:10.1007/s10549-019-05384-9.
Mothes AR, Runnebaum M, Runnebaum IB. Traitement ablatif au laser Erbium: YAG à deux phases des symptômes vaginaux liés à l’atrophie chez les survivantes post-ménopausées d’un cancer du sein en omettant le traitement hormonal. J Cancer Res Clin Oncol. 2018;144(5):955-960. doi:10.1007/s00432-018-2614-8
Pieralli A, Fallani MG, Becorpi A, et al. Fractional CO2 laser for vulvovaginal atrophy (VVA) dyspareunia relief in breast cancer survivors. Arch Gynecol Obstet. 2016;294(4):841-846. doi:10.1007/s00404-016-4118-6.
Knight C, Logan V, Fenlon D. A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors. ecancermedicalscience. 2019;13. doi:10.3332/ecancer.2019.988.
Stefano S, Stavros A, Massimo C. The use of pulsed CO2 lasers for the treatment of vulvovaginal atrophy. Curr Opin Obstet Gynecol. 2015;27(6):504-508.
Paraiso MFR, Ferrando CA, Sokol ER, et al. Un essai clinique randomisé comparant la thérapie vaginale au laser à la thérapie vaginale aux œstrogènes chez les femmes atteintes du syndrome génito-urinaire de la ménopause: L’essai VeLVET. Menopause N O N. 2020;27(1):50-56. doi:10.1097/GME.0000000000001416
Gaspar A, Brandi H, Gomez V, Luque D. Efficacy of Erbium: YAG laser treatment compared to topical estriol treatment for symptoms of genitourinary syndrome of menopause. Lasers Surg Med. 2017;49(2):160-168.
Dew JE, Wren BG & Eden JA.A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer,Climacteric. 2003; 6:1, 45-52, DOI: 10.1080/cmt.184.108.40.206
Biglia N, Peano E, Sgandurra P, Moggio G, Panuccio E, Migliardi M, Ravarino N, Ponzone R & Sismondi P.Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study,Gynecological Endocrinology. 2010; 26:6, 404-412, DOI: 10.3109/09513591003632258.
Faubion SS, Sood R and Kapoor E. Genitourinary syndrome of menopause: management strategies for the clinician. Mayo Clin. Proc., 92 (2017), pp. 1842 -1849, 10.1016/j.mayocp.2017.08.019.
Le Ray I, Dell’Aniello S, Bonnetain F, Azoulay L, Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study. Breast Cancer Res Treat. 2012; 135(2):603-609.
O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst. 2001; 93(10):754-762.
Pinkerton JV, Stanczyk FZ. Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy. Menopause. 2014;21(3):309-319.
Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause. 2010;17(2): 281-289.
Labrie F, Archer DF, Koltun W, et al; VVA Prasterone Research Group. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016;23(3):243-256.
Portman DJ, Labrie F, Archer DF, et al; other participating members of VVA Prasterone Group. Lack of effect of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women. Menopause. 2015; 22(12):1289-1295.
Farrell, Elizabeth. Genitourinary syndrome of menopause [online]. Australian Family Physician, Vol. 46, No. 7, Jul 2017: 481-484. Availability: <https://search.informit.com.au/documentSummary;dn=919889601806011;res=IELIAC> ISSN: 0300-8495.
Zarski AC, Berking M, Fackiner C, Rosenau C, Ebert DD. Internet-based guided self-help for vaginal penetration difficulties: results of a randomized controlled pilot trial. J Sex Med. 2017;14(2):238-254.
Faubion SS, Shuster LT, Bharucha AE. Recognition and management of nonrelaxing pelvic floor dysfunction. Mayo Clin Proc. 2012;87(2):187-193.
Goetsch MF, Lim JY, Caughey AB. A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2015;33(30):3394-3400.