Management of genitourinary syndrome of menopause in breast cancer survivors: An update

Table 1 Non-hormonal treatments (Classic moisturizers and lubricants and innovative preparations) in breast cancer survivors: Summary of studies and their outcomes

Ref.	Yr	n1	Design	Treatment	Conclusion
Loprinzi et al[119]	1997	45	A double-blind, crossover, randomized clinical trial	Vaginal lubricating preparation, (Replens®)	Both Replens and the placebo appear to substantially ameliorate vaginal dryness and dyspareunia in breast cancer survivors
Lee et al[129]	2011	44 vs 42	Randomised controlled trial, double blinded	pH balanced gel vs placebo for 12 wk	Vaginal pH balanced gel could relieve vaginal symptoms
Juraskova et al[137]	2013	25	Prospective, observational study	polycarbophil-based vaginal moisturizer + olive oil as a lubricant during intercourse	Significant improvements in dyspareunia, sexual function, and quality of life over time
Goetsch et al[130,131]	2014 2015	46	Double-blind rct	4% aqueous lidocaine vs saline	Significative and safe reduction in dyspareunia
Hickey et al[128]	2016		In a single-center, randomized, double-blind, ab/ba crossover design	Water- vs silicone-based lubricants	Total sexual discomfort was lower after use of silicone-based lubricant than water-based
Juliato et al[126]	2017	25 vs 25	Randomised trial	Polyacrylic acid vs lubricant	Polyacrylic acid was superior to lubricant
Marschalek et al[136]	2017	11 vs 11	Randomised controlled trial, double blinded pilot study	Vaginal lactobacillus capsules vs placebo	Lactobacillus improves microbiota in BCSs
Hersant et al[139]	2018	20	Prospective, comparative (before/after) pilot study	A-PRP and evaluated at 0,1,3 and 6 mo	A-PRP improves vaginal mucosa in 6 mo treatment according VHI criteria
Chatsiproios et al[125]	2019	128	Open, prospective, multicentre, observational study.	oil-in-water emulsion during 28 d	This treatment seems to improve VVA symptoms with a short treatment
Carter et al[122]	2021	101	Single-arm, prospective longitudinal trial	Hyaluronic acid (HLA) vaginal gel for 12 wk	HLA moisturization improved vulvovaginal health/sexual function of cancer survivors

¹Cases vs control/placebo/other treatment. BC: Breast Cancer, BCSs: Breast cancer survivors; A-PRP: Autologous platelet-rich plasma; VHI: Vaginal Health Index.

Table 2 Systemic hormonal treatments in breast cancer survivors: summary of studies and their outcomes

Ref.	Yr	n1	Design	Treatment	Conclusion
Holmberg et al[147,149]	2004 2008	221 vs 221	Randomized, non-placebo-controlled noninferiority trial	Oral estradiol hemihydrate and Norethisterone (cyclic or continuous) vs control	In BCSs, an increased risk of new breast cancer events and adverse events were observed after 2 yr of therapy (HR = 2.4)
von Schoultz et al[150]	2005	188 vs 190	Randomized, non-placebo-controlled noninferiority trial	2 mg estradiol for 21 d with addition of 10 mg medroxyprogesterone acetate for last 10 d; or 2 mg estradiol for 84 d with 20 mg medroxyprogesterone acetate for last 10 d; or 2 mg estradiol valerate daily	No increased risk of breast cancer recurrence; trial was closed early. So, HT doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer
Kenemans et al[153]	2009	1556 vs 1542	Prospective randomized placebo controlled	Tibolone 2.5 mg daily or placebo	Trial was closed early. Tibolone had a significantly increased risk of breast cancer recurrence
Cai et al[168]	2020	1728 vs 3456	Retrospective matched cohort study	Incidence rate in ospemifene users vs untreated patients	No differences were observed in the BC incidence and recurrence rates in ospemifene users compared with matched controls

¹Cases vs control. BC: Breast cancer, BCSs: Breast cancer survivors.

Table 3 Local hormonal treatments in breast cancer survivors: summary of studies and their outcomes

Ref.	Yr	n1	Design	Treatment	Conclusion
Dew et al[178]	2003	69	Retrospective Cohort study	Estriol 0.5 mg cream and pessaries (33); Estradiol 25 μgtablets (n = 33)	VET does not seem to be associated with increased RR of BC
Kendall et al[190]	2005	7	Prospective before-after analysis	Estradiol 25 mg daily for 2 wk	Vaginal estradiol tablet significantly raises systemic estradiol levels. This reverses the estradiol suppression achieved by AIs in women with BC and is contraindicated
Biglia N et al[179]	2010	26	Prospective study	Estriol cream 0.25 mg (n = 10) or estradiol tablets 12.5 microg (n = 8) polycarbophil-based moisturizer 2.5 g (Replens®) (n = 8)	VET is effective in improving symptoms and objective evaluations in BCSs
Pfeifer et al[180]	2011	10	Prospective before-after analysis	0.5 mg vaginal estriol daily for 2 wk	Increase in FHS and LH may indicate systemic estradiol effects
Whiterby et al[201]	2011	21	Phase I/II pilot Before-After study	Testosterone cream daily for 28 d. 300/ 150 μg	Vaginal testosterone was associated with improved signs and symptoms of vaginal atrophy related to AI therapy without increasing estradiol or testosterone levels
Wills et al[49]	2012	24 vs 24	Prospective clinical trial	25 mcg estradiol vaginal tablet or ring vs control	VET treatment increases E2 levels. Should be used with caution
Le Ray et al[187]	2012	13479TAM (n = 10806) or AIs (n = 2673)	Retrospective, nested case-control study	Vaginal cream and tablets containing estrogen	Use of VET is not associated with increase in BC recurrence in those treated with TMX or AI
Dahir et al[202]	2014	13	Pilot before-after study	Testosterone cream daily for 28 d, 300 μg	Improvement in FSFI scores
Donders et al[181]	2014	16	Open label bicentric phase I pharmacokinetic study	0.03 mg Estriol + Lactobacillus	Estriol + Lactobacillusis safe in BCpatients andimprovessymptoms
Melisko et al[204]	2016	69	Randomised non-comparative study	Estradiol ring 7.5 ng vs Testosterone cream at 1% concentration: 1.5 mg/wk	Transient increase in E2 that finally reached normal levels. Meets the primary safety endpoint
Davis et al[203]	2018	44	Double-blind, randomised, placebo-controlled trial	Testosterone cream daily for 26 week/ 300 μg vs placebo	Testosterone improves sexual test items compared to placebo

¹Cases vs control. BC: Breast cancer, BCSs: Breast cancer survivors; TAM: Tamoxifen; AIs: Aromatase inhibitors; VET: Vaginal estrogen treatment; FSFI: Female Sexual Function Index.

Table 4 Vaginal laser therapy in breast cancer survivors: Summary of studies and their outcomes.

Ref.	Yr	n1	Design	Treatment	Conclusion
Pieralli et al[223]	2016	50	Prospective Before-after study	3 sessions of Fractional Microablative CO2 Laser every 30 d	The treatment seems to be feasible and effective
Pagano et al[221]	2016	26	Observational retrospective study	3 sessions of Fractional Microablative CO2 Laser every 30 d	The treatment seems to be effective and with good tolerance
Gambacciani et al[218]	2017	43	Pilot before-after study	3 sessions of Vaginal Erbium Laser every 30 d	The treatment seems to be effective
Pagano et al[214]	2018	82	Observational retrospective study	3 sessions of Fractional Microablative CO2 Laser every 30 d	The treatment seems to be effective
Mothes et al[225]	2018	16	Retrospective study	1 session of Vaginal Erbium YAG Laser	The treatment seems to be effective
Pearson et al[222]	2019	26	Single-arm pilot study Before-After study	3 sessions of Fractional Microablative CO2 Laser every 30 d	The treatment seems to improve sexual function and vaginal atrophy
Areas et al[224]	2019	24	Open, prospective study	3 sessions of Vaginal Erbium YAG Laser every 30 d	The treatment seems to improve sexual function and vaginal atrophy

¹Cases.

Table 5 Treatment options for management of genitourinary syndrome of menopause in specific patient populations: Consensus recommendations of the The North American Menopause Society[65]

General guidelines
Individualize treatment, taking into account risk of recurrence, severity of symptoms, effect on QoL, and personal preferences
Moisturizers and lubricants, pelvic floor physical therapy, and dilator therapy are firstline treatments
Involve treating oncologist in decision making when considering the use of local hormone therapies1
Ospemifene, an oral SERM, has not been studied in women at risk for breast cancer and is not FDAapproved for use in women with or at high risk for breast cancer
Offlabel use of compounded vaginal testosterone or estriol is not recommended
Laser therapy may be considered in women who prefer a nonhormonal approach; women must be counseled regarding lack of longterm safety and efficacy data
Women at high risk for breast cancer2
Local hormone therapies are a reasonable option for women who have failed nonhormonal treatment
Observational data do not suggest increased risk of breast cancer with systemic or local estrogen therapies beyond baseline risk
Women with ERpositive breast cancers on tamoxifen
Tamoxifen is a SERM that acts as an ER antagonist in breast tissue; small transient elevations in serum hormone levels noted with local hormone therapies in women on tamoxifen are less concerning than in women on AIs
Women with persistent, severe symptoms who have failed nonhormonal treatments and who have factors suggesting a low risk of recurrence may be candidates for local hormone therapy
Women with ERpositive breast cancers on AI
AIs block conversion of androgen to estrogen, resulting in undetectable serum estradiol levels; transient elevations in estradiol levels may be of concern
GSM symptoms are often more severe
Women with severe symptoms who have failed nonhormonal treatments may still be candidates for local hormone therapies after review with the woman’s oncologist vs consider switching to tamoxifen
Women with triplenegative breast cancers
Theoretically, the use of local hormone therapy in women with a history of triplenegative disease is reasonable, but data are lacking
Women with metastatic disease
QoL, comfort, and intimacy may be a priority for many women with metastatic disease
Use of local hormone therapy in women with metastatic disease and probable extended survival may be viewed differently than in women with limited survival when QOL may be a priority

¹Local hormone therapies are vaginal estrogen and intravaginal DHEA (prasterone).

²Lifetime risk > 20%, carriers of the BRCA mutation, atypical ductal hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ. AI: Aromatase inhibitor; ER: Estrogen receptor; GSM: Genitourinary syndrome of menopause; QoL: Quality of life; SERM: Selective estrogen-receptor modulator.