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Managing genitourinary symptoms – breast cancer recurrence
Evidence review B2
NICE Guideline, No. 23
Managing genitourinary symptoms – breast cancer recurrence
Review question
Are treatments for managing genitourinary symptoms associated with the menopause safe for women with a personal history or high inherited risk of breast cancer?
Introduction
Genitourinary symptoms associated with menopause can be severe and debilitating, normally treated by localised vaginal oestrogens. For women with a personal history of breast cancer (including those on no adjuvant therapy, tamoxifen or aromatase inhibitors) a difficult decision has to be made due to uncertainty over whether localised vaginal oestrogens can increase the risk of breast cancer recurrence, leaving women with potentially less effective options for treatment.
Summary of the protocol
For further details see the review protocol in Appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A and the methods document (Supplement 1).
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
Effectiveness evidence
Included studies
Overall, 4 studies were included in this review, 1 prospective cohort study (Cold 2022) and 3 retrospective cohort studies (Dew 2003, Le Ray 2012 and O’Meara 2001).
All studies included women with a history of breast cancer and compared the use of vaginal oestrogens to no treatment.
The included studies are summarised in Table 2.
See the literature search strategy in Appendix B and study selection flow chart in Appendix C.
Excluded studies
Studies not included in this review are listed, and reasons for their exclusion are provided in Appendix J.
Summary of included studies
Summaries of the studies that were included in this review are presented in Table 2.
See the full evidence tables in Appendix D and the forest plots in Appendix E.
Summary of the evidence
For this review outcomes have been judged for clinical importance based on statistical significance. Please see Supplement 1 for further details.
Vaginal oestrogen versus no treatment
Very low-quality evidence showed no important difference for breast cancer recurrence between vaginal oestrogen and no treatment in a population of women with a history of breast cancer, that used adjuvant treatment and those that did not. There was no evidence in people at high risk of developing breast cancer, for example due to genetic risk, but no previous history of breast cancer.
Very low-quality evidence, in a population of women not using adjuvant treatment for breast cancer, showed no important difference in the risk of breast cancer recurrence for those who used local vaginal oestrogens, and those that did not.
Low quality evidence showed no important difference in the risk of recurrence in women using local vaginal oestrogens if they were using tamoxifen therapy for breast cancer, compared to those that did not use local vaginal oestrogens. Low quality evidence from one study showed that for women taking aromatase inhibitors or aromatase inhibitors in sequence with tamoxifen, the use of local vaginal oestrogens increased the risk of breast cancer recurrence. However, there was very low-quality evidence showing no difference from a separate study between use of local vaginal oestrogens or not, in those women that used either tamoxifen or aromatase inhibitors for breast cancer.
All of the evidence was downgraded for risk of bias, mainly due to not enough information available on adherence to treatment, and some issues around controlling for confounders. There were also concerns around imprecision.
There was no evidence for the outcomes incidence of ovarian cancer, or incidence of endometrial cancer.
See Appendix F for full GRADE tables.
Economic evidence
Included studies
A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.
A single economic search was undertaken for all topics included in the scope of this guideline. See Supplement 2 for details.
Excluded studies
Economic studies not included in this review are listed, and reasons for their exclusion are provided in Appendix J.
Summary of included economic evidence
No economic studies were identified which were applicable to this review question.
One UK economic evaluation was identified for evidence review B1 (Dymond 2021). This study compared ospemifene plus lubricant or moisturiser to lubricant or moisturiser alone to treat genitourinary symptoms associated with the menopause transition in women contraindicated for local oestrogen treatment. This contraindication included those for which local oestrogen treatment was not medically appropriate (including those with a history of breast cancer), was inconvenient or had previously been ineffective including because of adverse events. Although the population of the study did not match that required for inclusion in this evidence review this study was considered by the committee in forming recommendations.
The study took a UK NHS perspective and reported outcomes in terms of cost per QALY. It found ospemifene plus moisturiser/lubricant to be cost effective at a £20,000 per QALY threshold compared to moisturiser/lubricant alone. This conclusion was robust to alternative assumptions. The study was directly applicable with minor methodological limitations in respect to review question B1. Given the population of the study it is only partially applicable to this review question.
Dymond 2021 is summarised in full in evidence review B1.
Economic model
No economic modelling was undertaken for this review. An economic model of treatments for genitourinary symptoms associated with the menopause transition, which did not exclude the population considered by this review, was developed for evidence review B1. This model was used to influence recommendations made for this review. The model is reported in full in evidence review B1. Whilst the population for the economic model include this population group it is not exclusive to it and results from the model are therefore only partially applicable to this review question.
The committee’s discussion and interpretation of the evidence
The outcomes that matter most
The committee chose the outcome incidence or recurrence of breast cancer as the critical outcome for this review. The committee agreed that women who experience genitourinary symptoms such as vaginal dryness with a history of breast cancer are faced with a difficult choice as to whether it is safe for them to use local vaginal oestrogens. Vaginal oestrogen is absorbed into the blood stream, but to a lesser degree than systemic oestrogen. Systemic HRT is contraindicated because of absorption of oestrogen, and therefore the impact of vaginal oestrogen on breast cancer recurrence was considered particularly important.
The committee chose incidence of ovarian cancer and incidence of endometrial cancer as important outcomes for this review. The committee agreed that women with a history of breast cancer, or at an increased risk of developing breast cancer, may also have an increased risk of developing ovarian and endometrial cancer. They therefore wanted to consider the safety of using local vaginal oestrogens on the risk of developing these cancers, too.
The quality of the evidence
The quality of the evidence was assessed with GRADE and ranged from very low to low quality. All the evidence was downgraded for risk of bias. This was due to the studies not adjusting for all the appropriate confounders, such as BMI and age at menopause. There were also concerns around deviations from the intended intervention not being investigated or taken into consideration, as successful intervention implementation was based on the assumption that all those who received a prescription for local vaginal oestrogens did go on to use the treatment. The evidence was also downgraded for concerns around imprecision.
There was a lack of evidence on ospemifene, prasterone and transvaginal laser therapy, and no evidence was identified for the outcomes: incidence of ovarian cancer or incidence of endometrial cancer.
Benefits and harms
The committee discussed the evidence on local vaginal oestrogens and the risk of breast cancer recurrence and agreed that the limitations of the evidence would need to be carefully considered when making recommendations. The committee discussed that some of the evidence had been downgraded in quality due to a lack of adjustment for important confounders regarding the prognostic variables of breast cancer, which would have an impact on the risk of recurrence. There were some uncertainties around the effect size of outcomes with wide confidence intervals making results potentially consistent with no difference, a small increase or a small decrease in breast cancer recurrence. The committee also discussed the possibility of potential bias by indication, where clinicians may prescribe local vaginal oestrogens to people who were at a lower risk of breast cancer recurrence. Given these factors, along with the relatively short length of follow-up in some studies, the committee agreed to be cautious when making recommendations.
The committee discussed the evidence comparing vaginal oestrogen to no treatment in women with a history of breast cancer. Most of the evidence showed no difference in breast cancer recurrence between women who used and did not use local vaginal oestrogens on breast cancer recurrence. There was evidence that was stratified according to whether people had used adjuvant treatment or not, and this showed no difference in breast cancer recurrence between users and non-users of local vaginal oestrogens in a population of those not using adjuvant treatment. The committee discussed the concerns around imprecision for this evidence and the wide confidence intervals around the effect estimates. The committee also discussed some of the evidence on a combined population of women who had and had not used adjuvant treatment for breast cancer, that showed no difference in risk of recurrence when using local vaginal oestrogens. The committee discussed their concerns regarding the small sample sizes of the two studies that were driving this effect, which contributed to the uncertainty in the size of this effect. There were also concerns around insufficient information in relation to any adjuvant treatment from the study characteristics related to the groups of people receiving the intervention and comparison treatment. The committee agreed that the quality of the evidence meant they could not be confident around the safety of local vaginal oestrogens. They agreed on the importance of a discussion between the clinician and the person on all available treatments. The committee agreed that they would make a recommendation that people should be given non-hormonal local options as a first line treatment of genitourinary symptoms, as the uncertainty around local vaginal oestrogen safety (in terms of effect size and evidence quality) may mean that this would be the option with the least risk.
The committee felt the evidence for local vaginal oestrogens was inconclusive in giving a clear direction of effect, therefore they decided that local vaginal oestrogens should be considered only when non-hormonal options have been ineffective, and the person is still troubled by the genitourinary symptoms. The committee were mindful that whilst there may be a small uncertain impact of local vaginal oestrogen on increased or decreased risk of breast cancer recurrence, it would need to be balanced against any reduction in quality of life due to the symptoms experienced. The committee noted that people may not realise that non-hormonal moisturisers and lubricants could also be used in combination with vaginal oestrogen, so they agreed to highlight this.
The committee discussed the evidence related to use of local vaginal oestrogens in those taking adjuvant treatment for breast cancer, specifically tamoxifen and aromatase inhibitors. The committee discussed the evidence for tamoxifen, which showed a possible reduction in the risk of breast cancer recurrence with local vaginal oestrogen use compared with no use, however this did not reach statistical significance. The committee acknowledged that this was unlikely to be a true effect of the local vaginal oestrogens, and more likely a result of adherence to treatment. They discussed that tamoxifen use is associated with fewer genitourinary symptoms due to the mechanism of action, compared with aromatase inhibitors and therefore may lead to a decreased adherence to vaginal oestrogen and increased adherence to tamoxifen treatment.
The committee went on to discuss the evidence around the risk of breast cancer recurrence with vaginal oestrogen in people who also use aromatase inhibitors as an adjunct treatment for their breast cancer. The committee discussed that the evidence available was for a combination of aromatase inhibitors used as an adjunct to breast cancer treatment either alone, or in sequence with tamoxifen. They acknowledged that there was no evidence for aromatase inhibitor use alone. The committee agreed that the mechanism of action of aromatase inhibitors which makes genitourinary symptoms more likely, could describe why the evidence suggested an increased risk of breast cancer recurrence seen in this combined (aromatase inhibitor and/or tamoxifen) group, and not in the tamoxifen only group which has a mechanism of action which makes genitourinary symptoms less likely. It is possible that this may have led to lower adherence related to the adjuvant aromatase inhibitor treatment which was then impacting on breast cancer recurrence rather than necessarily being a direct effect of vaginal oestrogen. However, they discussed that the number of women was much smaller in this group, and also noted the overall low quality of the evidence, and therefore agreed they could not reach a conclusion regarding the effect of local vaginal oestrogens on breast cancer recurrence risk in those using aromatase inhibitors.
The committee agreed that overall, they could not be confident in the evidence with regard to the safety of local vaginal oestrogens in those taking either tamoxifen or aromatase inhibitors as adjuvant therapy for breast cancer, due to the concerns around the quality of the evidence, and lack of data on aromatase inhibitor use only. However, using their expertise the committee agreed that when vaginal oestrogen is considered for people on aromatase inhibitors, advice from an oncology specialist should be sought about treatment options which could include switching from adjuvant treatment with aromatase inhibitors to tamoxifen may be an option for those who want to use local vaginal oestrogens. .
The committee discussed, based on experience, that treatment decisions including considerations related to safety of vaginal oestrogen would need to be tailored to each person. Some people have a lower risk of breast cancer recurrence than others (as covered by NICE’s guideline on early and locally advanced breast cancer). The committee decided that this was an important factor because it is worse to potentially add to the risk of those who already have a high risk than those who have a low risk of recurrence. They also noted that vaginal oestrogen is absorbed locally. Some of it is absorbed systemically, that is, further into the body, but, compared to systemic HRT, the amount is minimal, and so it may or may not be an amount that would affect breast cancer recurrence. This makes it difficult to assess the safety of vaginal oestrogen with respect to breast cancer recurrence.
In someone with an oestrogen-receptor negative breast cancer, oestrogen does not affect the growth of cancer cells, but in someone with an oestrogen-receptor positive breast cancer, it boosts it. The committee discussed that in someone with an oestrogen-receptor positive breast cancer taking adjuvant treatment if this treatment inhibits the production of oestrogen (in the ovaries or in fat or muscle tissues), it will have no effect on any oestrogen coming from a source outside the body, and this oestrogen would then be able to bind to cancer cells and stimulate their growth but if this treatment stops oestrogen from binding to oestrogen receptors (regardless of whether the oestrogen is produced by the body or absorbed from some treatment), it will stop oestrogen, regardless of source, from binding to receptors on cancer cells and so their growth will not be stimulated.
The committee acknowledged that the population in the evidence referred to people with a history of breast cancer rather than people at a high risk of breast cancer by being a carrier of a genetic variant associated with a higher breast cancer risk (such as BRCA1/2). They therefore could not comment on populations with a high inherited risk of breast cancer but noted that this population would be included in the analysis review question on the effectiveness of treatments for genitourinary symptoms and would be reported as a subgroup if relevant data were identified.
The committee agreed that the uncertainty within the evidence (and the relatively small amount of identified evidence) of the effects of vaginal oestrogen on breast cancer recurrence warranted a research recommendation which was formulated to address the gaps in the evidence (for details see Appendix K).
Cost effectiveness and resource use
The recommendations for this topic mirror current practice. There may be a small increase in the use of local oestrogens if women with a history of breast cancer decide on this treatment after non-hormonal approaches have been ineffective and possible risks discussed and considered. This would lead to an increase in resource use although economic evidence from the model for review question B1 strongly suggested that such treatments were cost effective when compared to non-hormonal moisturisers and lubricants.
Other factors the committee took into account
The committee discussed that the decision to use local vaginal oestrogens for the treatment of genitourinary symptoms, in those with a personal history of breast cancer, should be made together with the person and the healthcare professional. They agreed that the evidence needed to be considered together with each individual person’s risk of recurrence, and that this discussion should be a shared decision. Therefore, they agreed to cross refer to the NICE guideline on shared decision making and the NICE guideline on early and locally advanced breast cancer.
Recommendations supported by this evidence review
This evidence review supports recommendations 1.5.13 to 1.5.18 and research recommendations 5 on the impact of vaginal oestrogen on breast cancer recurrence in the NICE guideline.
The committee noted that there is 1 recommendation in the NICE guideline that is relevant to all women regardless of whether or not they have a history of breast cancer (recommendations 1.5.17 – on vaginal laser treatment) but this was underpinned by evidence and discussions in evidence review B1 – managing genitourinary symptoms (network meta-analysis).
References – included studies
Cold 2022
Cold, Soren; Cold, Frederik; Jensen, Maj-Britt; Cronin-Fenton, Deirdre; Christiansen, Peer; Ejlertsen, Bent; Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study.; Journal of the National Cancer Institute; 2022 [PMC free article: PMC9552278] [PubMed: 35854422]Dew 2003
Dew, J E; Wren, B G; Eden, J A; A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer; Climacteric: the journal of the International Menopause Society; 2003; vol. 6 (no. 1); 45- [PubMed: 12725664]Le Ray 2012
Le Ray, Isabelle; Dell’Aniello, Sophie; Bonnetain, Franck; Azoulay, Laurent; Suissa, Samy; Local estrogen therapy and risk of breast cancer recurrence among; Breast Cancer Res. Treat.; 2012; vol. 135 (no. 2); 603–609 [PubMed: 22903687]O’Meara 2001
O’Meara ES, Rossing MA, Daling JR et al. (2001) Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. Journal of the National Cancer Institute 93(10): 754–762 [PubMed: 11353785]Dymond 2021
Dymond, A; Holmes, H; McMaster, J; Craig, J; Davies, H; Mealing, S. and Perard, R; 2021. Economic Evaluation of Senshio®(Ospemifene) for the Treatment of Vulvovaginal Atrophy in Scotland. Applied Health Economics and Health Policy, 19, pp.123–132. [PubMed: 32390072]
Effectiveness
Economic
Appendices
Appendix A. Review protocols
Appendix B. Literature search strategies
Appendix C. Effectiveness evidence study selection
Appendix D. Evidence tables
Appendix E. Forest plots
Appendix F. GRADE tables
Appendix G. Economic evidence study selection
Study selection for review question: Are treatments for managing genitourinary symptoms associated with the menopause safe for women with a personal history or high inherited risk of breast cancer?
A single economic search was undertaken for all topics included in the scope of this guideline. See Supplement 2 for further information.
Appendix H. Economic evidence tables
Economic evidence tables for review question: Are treatments for managing genitourinary symptoms associated with the menopause safe for women with a personal history or high inherited risk of breast cancer?
No evidence was identified which was applicable to this review question.
Appendix I. Economic model
Economic model for review question: Are treatments for managing genitourinary symptoms associated with the menopause safe for women with a personal history or high inherited risk of breast cancer?
No economic analysis was conducted for this review question.
Appendix J. Excluded studies
Excluded studies for review question: Are treatments for managing genitourinary symptoms associated with the menopause safe for women with a personal history or high inherited risk of breast cancer?
Excluded effectiveness studies
Table 6Excluded studies and reasons for their exclusion
| Study | Code [Reason] |
|---|---|
| Areas, Fernanda, Valadares, Ana L R, Conde, Delio Marques et al. (2019) The effect of vaginal erbium laser treatment on sexual function and vaginal health in women with a history of breast cancer and symptoms of the genitourinary syndrome of menopause: a prospective study. Menopause (New York, N.Y.) 26(9): 1052–1058 [PubMed: 31453969] |
- Outcome Reported outcomes do not match the review protocol |
| Barton, Debra L, Shuster, Lynne T, Dockter, Travis et al. (2018) Systemic and local effects of vaginal dehydroepiandrosterone (DHEA): NCCTG N10C1 (Alliance). Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 26(4): 1335–1343 [PMC free article: PMC5823730] [PubMed: 29164377] |
- Outcome Reported outcomes do not match the review protocol |
| Barton, Debra L, Sloan, Jeff A, Shuster, Lynne T et al. (2018) Evaluating the efficacy of vaginal dehydroepiandosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance). Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 26(2): 643–650 [PMC free article: PMC5754227] [PubMed: 28921241] |
- Outcome Reported outcomes do not match the review protocol |
| Becorpi, Angelamaria, Campisciano, Giuseppina, Zanotta, Nunzia et al. (2018) Fractional CO2 laser for genitourinary syndrome of menopause in breast cancer survivors: clinical, immunological, and microbiological aspects. Lasers in medical science 33(5): 1047–1054 [PubMed: 29492713] |
- Outcome Reported outcomes do not match the review protocol |
| Biglia, Nicoletta, Peano, Elisa, Sgandurra, Paola et al. (2010) Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 26(6): 404–12 [PubMed: 20196634] |
- Outcome Reported outcomes do not match the review protocol |
| Bruyniks, N, Biglia, N, Palacios, S et al. (2017) Systematic indirect comparison of ospemifene versus local estrogens for vulvar and vaginal atrophy. Climacteric : the journal of the International Menopause Society 20(3): 195–204 [PubMed: 28267367] |
- Population Not breast cancer or high risk population |
| Chambers, Laura M, Herrmann, Alyssa, Michener, Chad M et al. (2020) Vaginal estrogen use for genitourinary symptoms in women with a history of uterine, cervical, or ovarian carcinoma. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 30(4): 515–524 [PubMed: 32075898] |
- Population Women had a previous history of cervical, endometrial or ovarian cancer - not breast cancer. Less than 33% (18%) had a history of ovarian cancer. |
| Crandall, Carolyn J; Diamant, Allison; Santoro, Nanette (2020) Safety of vaginal estrogens: a systematic review. Menopause (New York, N.Y.) 27(3): 339–360 [PubMed: 31913230] |
- Population Systematic review - no included studies in women with/at risk of breast cancer |
| Crandall, Carolyn J, Hovey, Kathleen M, Andrews, Christopher A et al. (2018) Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause (New York, N.Y.) 25(1): 11–20 [PMC free article: PMC5734988] [PubMed: 28816933] |
- Population Not women with breast cancer or at high risk |
| Di Donato, Violante, Schiavi, Michele Carlo, Iacobelli, Valentina et al. (2019) Ospemifene for the treatment of vulvar and vaginal atrophy: A meta-analysis of randomized trials. Part II: Evaluation of tolerability and safety. Maturitas 121: 93–100 [PubMed: 30509754] |
- Population Not breast cancer or high-risk population |
| Gambacciani, Marco and Levancini, Marco (2017) Vaginal erbium laser as second-generation thermotherapy for the genitourinary syndrome of menopause: a pilot study in breast cancer survivors. Menopause (New York, N.Y.) 24(3): 316–319 [PubMed: 28231079] |
- Outcome Reported outcomes do not match the review protocol |
| Gardner, Alyssa N and Aschkenazi, Sarit O (2021) The short-term efficacy and safety of fractional CO2 laser therapy for vulvovaginal symptoms in menopause, breast cancer, and lichen sclerosus. Menopause (New York, N.Y.) 28(5): 511–516 [PubMed: 33399322] |
- Outcome Reported outcomes do not match the review protocol |
| Gittens, Paul and Mullen, Gregory (2019) The effects of fractional microablative CO2 laser therapy on sexual function in postmenopausal women and women with a history of breast cancer treated with endocrine therapy. Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology 21(3): 127–131 [PubMed: 29883233] |
- Outcome Reported outcomes do not match the review protocol |
| Harris, Benjamin S, Bishop, Katherine C, Kuller, Jeffrey A et al. (2020) Hormonal management of menopausal symptoms in women with a history of gynecologic malignancy. Menopause (New York, N.Y.) 27(2): 243–248 [PubMed: 31738735] |
- Study design Systematic review checked for relevant studies |
| Hirschberg, Angelica Linden, Sanchez-Rovira, Pedro, Presa-Lorite, Jesus et al. (2020) Efficacy and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial. Menopause (New York, N.Y.) 27(5): 526–534 [PMC free article: PMC7188038] [PubMed: 32049923] |
- Outcome Reported outcomes do not match the review protocol |
| Hocke, C, Diaz, M, Bernard, V et al. (2021) [Genitourinary Menopause Syndrome. CNGOF and GEMVi clinical practice guidelines]. Gynecologie, obstetrique, fertilite & senologie [PubMed: 33757926] |
- Language Not English language |
| Jha, Swati; Wyld, Lynda; Krishnaswamy, Priyanka H (2019) The Impact of Vaginal Laser Treatment for Genitourinary Syndrome of Menopause in Breast Cancer Survivors: A Systematic Review and Meta-analysis. Clinical breast cancer 19(4): e556–e562 [PubMed: 31227415] |
- Outcome Reported outcomes do not match the review protocol |
| Knight, Charity; Logan, Vera; Fenlon, Deborah (2019) A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors. Ecancermedicalscience 13: 988 [PMC free article: PMC6974376] [PubMed: 32010212] |
- Outcome Reported outcomes do not match the review protocol |
| Lethaby, Anne; Ayeleke, Reuben Olugbenga; Roberts, Helen (2016) Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database of Systematic Reviews 8(8): cd001500 [PMC free article: PMC7076628] [PubMed: 27577677] |
- Population Not breast cancer or high risk |
| Li, Bohan, Duan, Hua, Chang, Yanan et al. (2021) Efficacy and safety of current therapies for genitourinary syndrome of menopause: A Bayesian network analysis of 29 randomized trials and 8311 patients. Pharmacological research 164: 105360 [PubMed: 33307219] |
- Outcome Reported outcomes do not match the review protocol |
| Lyytinen, H.; Pukkala, E.; Ylikorkala, O. (2006) Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstetrics and Gynecology 108(6): 1354–1360 [PubMed: 17138766] |
- Population Not women with/ at risk of breast cancer |
| Mension, Eduard; Alonso, Inmaculada; Castelo-Branco, Camil (2021) Genitourinary Syndrome of Menopause: Current Treatment Options in Breast Cancer Survivors - Systematic Review. Maturitas 143: 47–58 [PubMed: 33308636] |
- Study design Systematic review checked for relevant studies |
| Moegele, M, Buchholz, S, Seitz, S et al. (2012) Vaginal estrogen therapy in postmenopausal breast cancer patients treated with aromatase inhibitors. Archives of gynecology and obstetrics 285(5): 1397–402 [PubMed: 22212649] |
- Study design Systematic review checked for relevant studies |
| Mothes, A R; Runnebaum, M; Runnebaum, I B (2018) Ablative dual-phase Erbium:YAG laser treatment of atrophy-related vaginal symptoms in post-menopausal breast cancer survivors omitting hormonal treatment. Journal of cancer research and clinical oncology 144(5): 955–960 [PubMed: 29487993] |
- Outcome Reported outcomes do not match the review protocol |
| Pagano, Tiziana, De Rosa, Pasquale, Vallone, Roberta et al. (2018) Fractional microablative CO2 laser in breast cancer survivors affected by iatrogenic vulvovaginal atrophy after failure of nonestrogenic local treatments: a retrospective study. Menopause (New York, N.Y.) 25(6): 657–662 [PubMed: 29286986] |
- Outcome Reported outcomes do not match the review protocol |
| Pavlovic, R T, Jankovic, S M, Milovanovic, J R et al. (2019) The Safety of Local Hormonal Treatment for Vulvovaginal Atrophy in Women With Estrogen Receptor-positive Breast Cancer Who Are on Adjuvant Aromatase Inhibitor Therapy: Meta-analysis. Clinical breast cancer 19(6): e731–e740 [PubMed: 31522958] |
- Outcome Reported outcomes do not match the review protocol |
| Pearson, Antonia, Booker, Andrew, Tio, Martin et al. (2019) Vaginal CO2 laser for the treatment of vulvovaginal atrophy in women with breast cancer: LAAVA pilot study. Breast cancer research and treatment 178(1): 135–140 [PubMed: 31377895] |
- Outcome Reported outcomes do not match the review protocol |
| Pieralli, Annalisa, Fallani, Maria Grazia, Becorpi, Angelamaria et al. (2016) Fractional CO2 laser for vulvovaginal atrophy (VVA) dyspareunia relief in breast cancer survivors. Archives of gynecology and obstetrics 294(4): 841–6 [PubMed: 27170261] |
- Outcome Reported outcomes do not match the review protocol |
| Quick, Allison M, Hundley, Andrew, Evans, Cynthia et al. (2022) Long-Term Follow-Up of Fractional CO2 Laser Therapy for Genitourinary Syndrome of Menopause in Breast Cancer Survivors. Journal of clinical medicine 11(3) [PMC free article: PMC8836519] [PubMed: 35160226] |
- Outcome Reported outcomes do not match the review protocol |
| Saeaib, Nungrutai, Peeyananjarassri, Krantarat, Liabsuetrakul, Tippawan et al. (2020) Hormone replacement therapy after surgery for epithelial ovarian cancer. The Cochrane database of systematic reviews 1: cd012559 [PMC free article: PMC7027384] [PubMed: 31989588] |
- Intervention No relevant interventions |
| Sanchez-Rovira, Pedro, Hirschberg, Angelica Linden, Gil-Gil, Miguel et al. (2020) A Phase II Prospective, Randomized, Double-Blind, Placebo-Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone Receptor-Positive Postmenopausal Women with Early Stage Breast Cancer in Treatment with Aromatase Inhibitor in the Adjuvant Setting. The oncologist 25(12): e1846–1854 [PMC free article: PMC8108054] [PubMed: 32459035] |
- Outcome Reported outcomes do not match the review protocol |
| Simon, James A, Altomare, Corrado, Cort, Susannah et al. (2018) Overall Safety of Ospemifene in Postmenopausal Women from Placebo-Controlled Phase 2 and 3 Trials. Journal of women’s health (2002) 27(1): 14–23 [PMC free article: PMC5771532] [PubMed: 29064335] |
- Population Not breast cancer or high risk |
| Tranoulis, Anastasios; Georgiou, Dimitra; Michala, Lina (2019) Laser treatment for the management of genitourinary syndrome of menopause after breast cancer. Hope or hype?. International urogynecology journal 30(11): 1879–1886 [PubMed: 31321465] |
- Outcome Reported outcomes do not match the review protocol |
| Wills, S;Ravipati, A;Venuturumilli, P. et al. (2012) Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. Journal of Oncology Practice 8(3): 144–149 [PMC free article: PMC3396801] [PubMed: 22942807] |
- Outcome Reported outcomes do not match the review protocol |
| Zuo, Stephanie Wang; Wu, Harold; Shen, Wen (2018) Vaginal estrogen and mammogram results: case series and review of literature on treatment of genitourinary syndrome of menopause (GSM) in breast cancer survivors. Menopause (New York, N.Y.) 25(7): 828–836 [PubMed: 29533365] |
- Population The case series excluded women with history of breast cancer |
Excluded economic studies
No economic evidence was identified for this review. See Supplement 2 for further information.
Appendix K. Research recommendations – full details
Tables
Table 1Summary of the protocol (PICO table)
| Population | Women with genitourinary symptoms associated with the menopause transition and a personal history of breast cancer or otherwise at high risk of developing breast cancer (for example BRCA1/2 carriers) |
|---|---|
| Intervention |
|
| Comparison |
|
| Outcome | Critical
|
Table 2Summary of included studies
| Study | Population | Intervention | Comparison | Outcomes |
|---|---|---|---|---|
|
Prospective cohort study Denmark |
N=8328 women with breast cancer Age <65 years - number (%): Vaginal oestrogen therapy (VET): 1327 (68%) Never-users: 4047 (64%) Age ≥65 years - number (%): VET: 630 (32%) Never-users: 2297 (36%) | Vaginal oestrogen | No vaginal oestrogen |
|
|
Retrospective cohort study Australia |
N=1472 women with breast cancer Age, mean (range): only reported by group rather than overall:
| Vaginal oestrogen | No vaginal oestrogen |
|
|
Retrospective cohort study UK |
N=10933 women with breast cancer Used tamoxifen or aromatase inhibitors Age, mean (SD) years: 63.1 (13.7) | Vaginal oestrogen | No vaginal oestrogen |
|
|
Retrospective cohort study United States |
N=869 women with breast cancer Age, mean (SD) years: NR (overall or by group) | Vaginal oestrogen | No vaginal oestrogen |
|
NR: not reported; SD: standard deviation
FINAL
Evidence reviews underpinning recommendations 1.5.13 to 1.5.18 and research recommendations 5 in the NICE guideline
These evidence reviews were developed by NICE
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.