Management of Menopausal Symptoms for Breast Cancer Survivors 1) The case involves a 55-year-old breast cancer survivor who is experiencing worsening menopausal symptoms four years after her periods stopped. 2) Hormonal therapy could be an option to alleviate her vasomotor symptoms if recurrence risk is low, which it likely is given 16 years have passed since her original diagnosis. 3) Phytoestrogens are not recommended to relieve her hot flashes due to conflicting data on their safety and efficacy for breast cancer survivors. Non-hormonal options like antidepressants should be considered first.

1. Management of Menopausal Symptoms
for Breast Cancer Survivors
TEVFİK YOLDEMİR MD. BSc. MA. PhD.
tevfikyoldemir
yoldemirtevfik

2. CASE
• The patient, Jale is now 55. She had found a lump near her nipple at the age of
39.
• She had no family history and was surprised when identified as having a grade
3 cancer. This was node negative.
• She had had two lumpectomies (as excision margins were not initially clear),
five (of six) courses of chemotherapy, radiotherapy and then tamoxifen for five
years.
• During this treatment, her periods never stopped and remained regular until
just over two years ago.
• She has had menopause-related symptoms for the past four years, and they
have become progressively worse and more intrusive and is now at the end of
her tether.

3. Q1
• Could hormonal therapy be an option for this women in
alleviating her vasomotor symptoms, and if so in which
condition(s)?

4. • At 16 years, since their original diagnosis, recurrence risk from
their original cancer can be reasonably expected to be very low.
We cannot say that it does not exist, but it is implausible that
metastasized breast cancer cells will have remained dormant
for that length of time in women with menstrual cycles.
• A second primary is a more likely possibility, but there is
nothing to suggest that this is greater than the population level
risk.

5. • The women had periods all through treatment. She will have
already been exposed to fluctuating endogenous estrogen and
progesterone at levels that are greater than we would expect
from HRT.

6. Main features and results of observational studies of
HT in breast cancer survivors
Gynecological Endocrinology,2017 33:1, 10-15

7. Breast cancer risk – results from RCTs of
conventional HT and tibolone
Gynecological Endocrinology,2017 33:1, 10-15
A higher proportion of women with node positive breast cancer in the HABITS trial, more women treated
with tamoxifen in Stockholm trial, the differences in the HT (NETA versus AMP) and the regimens used
(continuous versus sequential), and that the Stockholm trial was specially design to reduce the
progesterone doses, are few of the facts to be considered as responsible of the differences in the risk of
recurrence of breast cancer between both studies. Neither of them found an increased mortality from
breast cancer in HT group
Patients with ER negative tumors had no increased risk of recurrence (HR 1.15; 95% CI 0.73–1.80; p =0.058)
by contrast with patients with ER positive tumors (HR 1.56; 95% CI 1.22–2.01; p =0.0005)

8. oncologic impact of hormone replacement therapy
in premenopausal breast cancer survivors
3.2. Risk of breast cancer recurrence with HRT in young women
At the time of early discontinuation the LIBERATE trial [17]
demonstrated a significant increased risk of any breast cancer
recurrence in breast cancer survivors taking tibolone vs placebo
4. Discussion
The impact and management of treatment-induced menopause
in young women with breast cancer is a significant survivorship
concern. Despite this, our study demonstrates very limited data to
Table 3a
Breast cancer recurrences by age in the randomized controlled trial.
Paper Hazard ratio for any recurrence (local/distant) compared to placebo by age
<40 40e49 50e59 60e69 70
Kenemans et al. 2009 [17] 1.28 (95% CI 0.54e3.05) 1.56 (95% CI 1.10e2.19) 1.45 (95% CI 1.08e1.94) 1.06 (95% CI 0.61e1.84) 1.33 (95% CI 0.33e5.32)
Table 3b
Breast cancer recurrences by age in the cohort studies.
Paper Sample size Any Recurrence by age Estrogen receptor negative recurrences
50 years (% of total) 50 years (% of total)
Marttunen et al. 2001 [24] I 88 5 (5.7%) 2 (2.3%) 3
C 43 3 (7.0%) 2 (4.7%) 2
Ursic-Vrscaj et al. 1999 [25] I 21 4 (19%) 0 (0%) 2
C 42 5 (11.9%) 0 (0%) 3
Beckmann et al. 2001 [26] I 64 1 (1.6%)a
5 (7.8%) 1
C 121 4 (3.3%) 10 (8.3%) 3
I ¼ Intervention, C ¼ Control; a
From unpublished data by author correspondence
Y. Wang et al. / The Breast 40 (2018) 123e130128
3.2. Risk of breast cancer recurrence with HRT in young women
At the time of early discontinuation the LIBERATE trial [17]
demonstrated a significant increased risk of any breast cancer
recurrence in breast cancer survivors taking tibolone vs placebo
(HR 1.4 [95% CI 1.14e1.70, p ¼ 0.001]). Women in the 40e49 age
group had the highest risk of recurrence HR 1.56 [95% CI 1.1e2.2],
4. Discussion
The impact and management of treatment-induced menopause
in young women with breast cancer is a significant survivorship
concern. Despite this, our study demonstrates very limited data to
guide clinicians treating this unique population. In this review,
focusing specifically on breast cancer survivors younger than 50,
Table 3a
Breast cancer recurrences by age in the randomized controlled trial.
Paper Hazard ratio for any recurrence (local/distant) compared to placebo by age
40 40e49 50e59 60e69 70
Kenemans et al. 2009 [17] 1.28 (95% CI 0.54e3.05) 1.56 (95% CI 1.10e2.19) 1.45 (95% CI 1.08e1.94) 1.06 (95% CI 0.61e1.84) 1.33 (95% CI 0.33e5.32)
Table 3b
Breast cancer recurrences by age in the cohort studies.
Paper Sample size Any Recurrence by age Estrogen receptor negative recurrences
50 years (% of total) 50 years (% of total)
Marttunen et al. 2001 [24] I 88 5 (5.7%) 2 (2.3%) 3
C 43 3 (7.0%) 2 (4.7%) 2
Ursic-Vrscaj et al. 1999 [25] I 21 4 (19%) 0 (0%) 2
C 42 5 (11.9%) 0 (0%) 3
Beckmann et al. 2001 [26] I 64 1 (1.6%)a
5 (7.8%) 1
C 121 4 (3.3%) 10 (8.3%) 3
I ¼ Intervention, C ¼ Control; a
From unpublished data by author correspondence
Y. Wang et al. / The Breast 40 (2018) 123e130128
0.01 0.1 1 10 100
Favou rs HRT Favou rs Con trol
Y. Wang et al. / The Breast 40 (2018) 123e130 129
The Breast 40 (2018) 123-130

9. Recurrence and Mortality Data –HRT BCS
HORMONE REPLACEMENT THERAPY REVIEW
Table 1. Recurrence and Mortality Dataa
Initial authorb
Type of study
Statistics for
recurrencea
Statistics for
mortality
1 Holmberg (2004) RCT RH = 3.5 (1.5–8.1) No analysis
2 Holmberg (2008) RCT RH = 2.2 (1.0–5.1) No analysis
3 Fahlen (2013) RCT HR = 3.6 (1.2–10.9) No significant
findings
4 Marsden (2000) RCT No analysis No data
5 Decker (2003) Prospective Descriptive data t-test; p .03
6 Peters (2001) Prospective Descriptive data No analysis
7 Vassilopoulou-
Sellin (1999)
Prospective Descriptive data No analysis
8 Brewster (2007) Retrospective HR = 2.10 (1.21–3.64)
HR = 1.78 (1.27–2.50)
No analysis
9 Dew (2003) Retrospective No significant findings No analysis
10 Le Ray (2012) Retrospective No significant findings No data
11 O’Meara (2001) Retrospective No significant findings No significant
findings
12 Durna (2002) Retrospective RR = 0.18 (0.04–0.75) No significant
findings
13 Beckmann (2001) Retrospective No significant findings No significant
findings
14 DiSaia (2000) Retrospective No data Kaplan-Meier
p = .003
Note. RCT = randomized controlled trial; RH = relative hazard; HR = hazard ratio.
a
Only the values of statistically significant relative hazards and hazard ratios are
J Adv Pract Oncol 2015;6:322–330

10. Q2
• What is the recommended algorithm for the management of
the vasomotor symptoms?

11. Proposed algorithm for the management of vasomotor
symptoms in young breast cancer survivors.
een conducted.
toms has the potential to
fe and increase compli-
ications for breast can-
proposes an algorithmic
deal” treatment of VMS
est available data.
Therapies
ancer survi-
e therapies
eatment for
In addition
ntioxidants,
bal antican-
c remedies,
as phytoes-
dong quai)
nts for VMS.
f action of
t clear, their
ve induced
nd lowered
animals. In
an antipro-
d a positive
ity (BMD).
omeopathic
n the treat-
hesis mutus,
is, Sulphur,
d Amylium
andomized
have evalu-
c medicine
51,52
efficacy of these therapies in breast cancer patients
have been conducted.
Chinese Herbs: Dong quai is a traditional Asian
herbal preparation made from the root of Angelica
sinensis and used to treat menopausal symptoms. It
can be employed as a general blood tonic for puri-
fying and increasing blood flow and as a valuable
remedy for anemia. It is also a common traditional
Premenopausal breast cancer survivor with hot flashes
If symptoms are mild:
• Lifestyle changes such as wearing light clothes,
keeping room temperature low, avoiding alcohol
and spicy foods, smoking cessation, and consuming
cold beverages
• Yoga and behavioral therapy
Gabapentin 300 mg/d
or
Venlafaxine 37.5 mg/d
or
Fluoxetine 20 mg/d
After 4 weeks,
evaluate efficacy
If no relief
of symptoms
If effective and
symptoms resolve,
continue
October 2012, Vol. 19, No. 4 Cancer Control 323
addition, they may also have an antipro-
liferative effect on breasts and a positive
effect on bone mineral density (BMD).
Homeopathy: Many homeopathic
medicines have been used in the treat-
ment of VMS, including Lachesis mutus,
Belladonna, Sepia officinalis, Sulphur,
Sanguinaria canadensis, and Amylium
nitrosum.50
To date, two randomized
placebo-controlled studies have evalu-
ated the use of homeopathic medicine
either alone or in combination.51,52
Jacobs
et al51
analyzed 83 breast cancer survi-
vors (mean age, 55 years), and Thompson
et al52 evaluated 45 breast cancer survi-
vors (mean age, 52 years) who received
either an individualized medicine, a for-
mulaic complex remedy containing three
medicines — Amyl nitrate 3 × [1:1,000
dilution], Sanguinaria canadensis 3 ×
[1:1,000 dilution], and Lachesis 12 ×
[1:1,000,000,000,000 dilution] — or a
placebo. They reported no significant
difference in the severity or frequency of
hot flashes. Of note, women taking the
combination homeopathic remedy did
experience increased headaches. Fig 2. — Proposed algorithm for the management of vasomotor symptoms in young breast cancer survivors.
Gabapentin 300 mg/d
or
Venlafaxine 37.5 mg/d
or
Fluoxetine 20 mg/d
If side effects or no efficacy,
stellate ganglion block
After 4 weeks,
evaluate efficacy
and side effects
If no relief of symptoms,
Gabapentin 300 mg twice a day × 3 days
then 300 mg 3 times a day × 22 days
or
Venlafaxine 75 mg/d × 21 days
If effective and
symptoms resolve,
continue
Cancer Control October 2012, Vol. 19, No. 4 : 317- 329

12. Q3
• Should there be any cautions to consider if the women were to
be on tamoxifen or AI at the present?

13. Recommendations
1. For breast cancer patients being treated with tamoxifen:
a. The use of venlafaxine, citalopram, clonidine, gabapentin and
pregabalin be considered effective in treating hot flashes
(grade B recommendation).
b. The use of paroxetine and fluoxetine be avoided, given that
they may reduce the efficacy of tamoxifen
(grade D recommendation).
Support Care Cancer (2013) 21:1461–1474
DOI 10.1007/s00520-013-1732-8

14. Recommendations
2. For breast cancer patients not being treated with tamoxifen:
a. The use of venlafaxine, paroxetine, citalopram, clonidine,
gabapentin and pregabalin be considered effective in treating hot
flashes
(grade B recommendation).
b. Fluoxetine not be used to treat hot flashes, given that there is
insufficient evidence for its therapeutic efficacy
(grade D recommendation).
3. For breast cancer survivors, sertraline, phytoestrogens (including
isoflavones and other phytoestrogen derivatives), black cohosh and
St. John’s wort not be used to treat hot flashes
(grade A recommendation). Support Care Cancer (2013) 21:1461–1474
DOI 10.1007/s00520-013-1732-8

15. TMX interactions
• Fluoxetine and paroxetine, and to a much lesser extent,
possibly sertraline, citalopram and escitalopram, are inhibitors
of the cytochrome P450 isoform CYP2D6
SpringerPlus (2015) 4:65 DOI 10.1186/s40064-015-0808-y

16. Q4
• Can phytoestrogens be an option for the relief of HF for this
women?

17. Summary of Human Studies about Effects of Phytoestrogens
on Menopausal Symptoms in Breast Cancer survivors
isoflavone from the product did not have any consequence
on this effect.
More recent works also present conflicting data. In a
randomized clinical trial conducted by Levis et al in 2011,
no improvement in MS was found after a 2-year period of
consumption of soy isoflavone-containing tablets in 122
(Thomas et al., 2014).
TreatmentOptionsforMenopausalSymptoms
in Breast Cancer Survivors
In 1997, a consensus development conference on
0
25.0
50.0
75.0
100.0
osedwithouttreatment
gnosedwithtreatment
ersistenceorrecurrence
Remission
None
Chemotherapy
Radiotherapy
currentchemoradiation
Table 1. Summary of Human Studies about Effects of Phytoestrogens on Menopausal Symptoms in Breast
Cancer survivors
First author- Pub
year-type of study
Purpose of study: as-
sessment of …
Number of cases Type/ dose of PE used Results
Quella et al. 2000
RCT, cross over
design
Effect of soy PE on HF
in BCS
149 BCS divided in
2 groups
soy tablets 150 mg soy/d or
placebo; 2 periods of treatment
for 4 w with 1 w rest in between
for cross over
No significant dif-
ference between 2
groups
Van Patten et al.
2002
RCT
Effect of soy PE on HF
in BCS
59 cases,
64 controls
500 mL of a soy or placebo
beverage
No significant dif-
ference between 2
groups
Nikander et al. 2003
- RCT, cross over
design
Effects of PE on MS
and QOL in BCS
56 BCS divided in
2 groups
PE tablets 114 mg
isoflavonoid/d or placebo;
2 periods of treatment for 3 m
with 2 m rest in between for
cross over
No significant dif-
ference between 2
groups
MacGregor et al.
2005 - RCT
Effects of soy PE on
MS and QOL in BCS
33 cases, 35 con-
trols
12 w of soy capsules (overall 70
mg/d of soy PE) or placebo
No significant dif-
ference between 2
groups
Gold et al. 2006
(WHEL*) - multi-
center RCT
Association of MS with
soy food, and effects of
soy PE on MS, in early
stage BCS
Overall 2198 BCS Soy-rich food in cases, regular
diet in controls
No association
between use of PE
and MS
Dorjgochoo et al.
2011 - Cohort
Association of MS with
soy food
4842 Chinese BCS Habitual dietary intake of soy
foods was assessed**
No significant asso-
ciation between soy
PE intake and MS
Pruthi et al. 2012 -
RCT
Effects of flaxseed***
on HF
88 cases, 90 con-
trols ****
Flaxseed bar (providing 410 mg
of lignans) for 6 w, or placebo
No significant dif-
ference between 2
groups
Pub=publication, PE= phytoestrogen, RCT= randomized controlled (clinical) trial, HF=hot flashes, BCS=breast cancer survivors, d= day, w=week,
MS= menopausal symptoms, QOL= quality of life, m= month. *WHELstudy =Women’s Healthy Eating and Living **This study included participants
of the Shanghai Breast Cancer Survival Study (SBCSS) *** the richest source of lignans (one of the major classes of phytoestrogens) ****half in
Asian Pac J Cancer Prev, 16 (8), 3091-3096

18. Summary of Human Studies about Effects of Phytoestrogens
on Breast Cancer Prognosis
drug with minimal side effects and low risks to treat
MS in patients surviving breast cancer, hence clinicians
have been considering non-hormonal drugs to ameliorate
MS (Biglia et al., 2003); serotonin reuptake inhibitors,
clonidine, veralipride, gabapentin, black cohosh, primrose
In2002,afterimplantingMCF-7cellsinovariectomized
athymic mice, Ju et al assessed interactions between
genistein (as a soy isoflavone) and tamoxifen on the
growth of these estrogen- dependent breast cancer
cells. They found out that genistein lowered the effect of
Table 2. Summary of Human Studies about Effects of Phytoestrogens on Breast Cancer Prognosis
Author, year of
study, type of study
Purpose of study: assessment
of…
Number
of cases
studied
Type/ dose of
PE used
Median
Follow
up time
Results
Shu et al., 2009
Cohort, longitudinal
Association of soy food with
BC mortality and recurrence
in BCS
5042
BCS
soy foods com-
monly used in
Shanghai
3.9 y
after Dx
Significant decreased mortality
and recurrence with higher soy
food intake
Guha et al., 2009
(LACE*) --Cohort
Association of soy food with
BC recurrence in BCS
1954
BCS
Several kinds
of soy-contain-
ing foods
6.31 y
after
enroll-
ment
Non-significant decreased
recurrence with higher soy
food intake
Kang et al., 2010
Cohort
Association of soy food with
BC mortality and recurrence
in BCS
508
BCS
under
adjuvant
HT
Several kinds of
soy-containing
foods
5.1 y
after Dx
Significant decreased recur-
rence with higher soy food
intake in postm with ER+,
PR+ BC
Caan et al., 2011
following
(WHEL**) study-
Cohort
Effects of soy foods on BC
prognosis in BCS
3088
early
stage
BCS
Several kinds of
soy-containing
foods
7.3 y
after
enroll-
ment
Significant decreased mortality
with higher soy food intake,
but non-significant highest
level of intake
Zhang et al., 2012
Cohort
Association of soy food with
BC mortality and recurrence
in BCS
616
BCS
Several kinds of
soy-containing
foods
52.1 m
after Dx
Significant decreased mortality
and recurrence with higher soy
food intake esp. in ER+ BC
Nechuta et al., 2012
(ABCPP***)- 2
US and 1 Chinese
cohort, pooled
analysis
Association of soy food with
BC mortality and recurrence
in BCS
9514
BCS
Several kinds of
soy-containing
foods
7.4 y
after Dx
Non-significant decreased mor-
tality and significant decreased
recurrence with higher soy
food intake
Pub=publication, PE=phytoestrogen, postm= post-menopausal, BC= Breast Cancer, BCS= breast cancer survivors, y=year, Dx= diagnosis, RCT=
randomized controlled (clinical) trial, PE= phytoestrogen, HT=hormone therapy, ER+=estrogen receptor positive, PR+=progesterone receptor
positive, m=month, esp.=especially. *LACE = Life After Cancer Epidemiology study, **WHEL= Women’s Healthy Eating and Living study***
Asian Pac J Cancer Prev, 16 (8), 3091-3096

19. Purified pollen extract
Review
Table 4. PPE for HFs treatment.
Author, year of
publication and
type of study
Number of pa-
tients (N) and type
of treatment
Type of
measurement
Main results
Efficacy
in healthy
women
Winther et al [34]
Double-blind,
placebo-controlled
trial
N = 64
PPE 2/day per 3
months
- MRS
- 15 QoL parameters
- 65% HFs reduction in the PPE
group versus 38% in the placebo
group (p 0.006)
- Improvement in the QoL parameters
(tiredness, dizziness, mood, libido,
headache, irritability, mood swings
and sensitiveness) in the PPE group
compared to baseline (p 0.031)
Safety in
breast cancer
survivors
No oestrogenic
activity
Hellstrom et al [35]
In vitro study
- High-performance liquid
chromatography analyses of
phytoestrogens in PPE
- Oestrogenic activity evalua-
tion in the immature female rat
uterotrophic bioassay with PPE
- PPE in the high dose of 500 mg
kg/day contains low, subeffective
concentrations of daidzin, daidzein
and genistin. Genistein, formonone-
tin and biochanin could not be
detected.
- No uterine growth in female rats
with PPE
Seeger et al [36]
In vitro study
- MCF-7 and T47D cells were
transfected with PGRMC1
- Different concentrations of PPE
alone and in combination with
E2 or growth factor were tested
- Proliferation was determined by
the MTT test
- Apoptosis was determined by
CDD ELISA kit
PPE was neutral in the cell lines alone
or in combination with E2 or growth
factors in terms of cell proliferation
and cell apoptosis, both in cells trans-
fected with PGRMC1 or not
Winther et al [34]
Double-blind,
placebo-controlled
trial
N = 64
PPE 2/day per 3
months
- 15 QoL parameters
- Diary of AUB
- Blood samples for FSH, E2, TT,
SHBG
- No changes in vaginal dryness
parameter
- No AUB
- No change in blood levels of FSH,
E2, TT, SHBG
No interference
with CYP2D6
enzyme
Goldstein et al [37]
In vitro study
Test for potential inhibition of
CYP2D6 enzyme by PPE at high
concentrations in pooled human
liver microsome with Quinidine as
a reference.
Negligible inhibition of CYP2D6 with
PPE (6.53% to 10.67%), whereas
Quinidine completely inhibited the
CYP2D6.
PPE = Purified pollen extract; MRS = Menopause Rating Scale; HFs = hot flushes; QoL = quality of life; PGRMC1 = progesterone receptor membrane com-
ecancer 2019, 13:909; DOI:10.3332/ecancer.2019.909

20. Black cohosh
ecancer 2019, 13:909; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2019.909 9
Data from the WHI trial in healthy women show that weight loss determines a reduction in HFs [57]. Two RCTs confirm these findings, sug-
gesting that weight loss is associated in overweight or obese healthy women with a reduction in HFs [58, 59]. In breast cancer survivors,
prevention of weight gain after diagnosis can help in controlling HFs, whereas the role of intentional weight loss after diagnosis on vasomotor
symptoms is still not defined [60].
Table 5. Black cohosh for HFs treatment.
Black cohosh versus placebo Outcome
HFs frequency and intensity - No statistically significant difference in systematic reviews and meta-analysis [43, 44]
- Same results in RCTs in BCSs [51, 52]
Night sweats frequency - No statistically significant difference in systematic reviews and meta-analysis [43, 44]
- In an RCT in BCSs significant improvement [51]
Menopausal symptom score
(KI, GCS and MRS)
No statistically significant difference in systematic reviews and meta-analysis [43, 44]
Safety profile - Good safety profile in the general population [38, 45]
- No endometrial thickness increase [41, 42]
- No detrimental effect on recurrence rate in BCSs [54] and unlikely interaction with tamoxifen [38]
KI = Kupperman Index; GCS = Green Climacteric Scale; MRS = menopause rating scale; RCT = randomised controlled trial; BCSs = breast cancer survivors
ecancer 2019, 13:909; DOI:10.3332/ecancer.2019.909

21. Q5
• What are the management options if she had cumbersome
vaginal dryness and severe sexual pain?

22. TMX / AI
amoxifen experience more vaginal bleeding and
arge; patients on AIs have a higher incidence of
etal disorders, which typically include arthralgia
of osteoporosis and fractures; tamoxifen leads
centage of days with a filled prescription available was 87%. In
a subset of 492 patients with long-term data, filled prescrip
tions were available for only 50% of days during the 4 years o
treatment. Adherence rates were lower in patients younge
than 45 years and older than 85 years [23]. In another claimed
ence of the most frequent/serious effects of tamoxifen and aromatase inhibitors. Additional frequent/serious side effects that are present wit
py include cardiovascular, cognitive dysfunction and fatigue [2,3,18].
Expert Review of Anticancer Therapy,
DOI: 10.1080/14737140.2018.1520096

23. Treatment Options to Consider for Vaginal Dryness and
Sexual Pain in Cancer SurvivorsTABLE 2. Treatment Options to Consider for Vaginal Dryness and Sexual Pain in Cancer Survivorsa
Treatment type and specific therapyb
Examples and dosages Notes References
Nonprescription
Lubricants d Used as needed for sexual activity d
Moisturizers d Used several times per week to maintain vaginal
moisture
102
Hyaluronic acid gel d Used intravaginally every 3 d 106,107
Nonhormone
Topical lidocaine 4% aqueous lidocaine Applied to the vulvar vestibule as needed several
minutes before penetration
125
Hormonec
Low-dose vaginal estrogen Available in vaginal cream,
10-mg tablet, or ring
Low-level systemic absorption of unclear clinical
significance is possible with existing local vaginal
estrogen products; not recommended in patients
with a history of breast cancer taking aromatase
inhibitors
102,108-110
Intravaginal DHEA 3.25 or 6.5 mg of 0.5%
intravaginally daily
Long-term safety data in breast cancer survivors are
lacking, but no evidence of increased estradiol levels
in patients taking aromatase inhibitors
112-114
Ospemifene (oral SERM) 60 mg/d by mouth Not FDA approved for use in women with or at high
risk for breast cancer
115-118
a
DHEA ¼ dehydroepiandrosterone; FDA ¼ Food and Drug Administration; SERM ¼ selective estrogen receptor modulator.
b
Nonprescription treatments are first-line therapies; nonprescription and nonhormonal treatment options are preferred in survivors of hormonally responsive cancers.
c
Use with caution in survivors of hormonally responsive cancers.
MAYO CLINIC PROCEEDINGS
Mayo Clin Proc. 2016;91(8):1133-1146

24. Q6
• Could hormonal therapy be an option for relief of genitourinary
syndrome of menopause, if her main complaint was so?

25. Local estrogen therapy
Systemic absorption of LET can be relevant especially for women
with contraindication to hormonal treatments, such as BCSs.45
In
particular, BCSs who receive AIs, which completely deprive the
female body of estrogens, even a small increase in systemic serum
levels might have a detrimental effect on the risk of recurrence.
can alleviate urogenital symptoms associated with VVA, without an
increase of serum levels of estrogens.47-53
In a study that included
only 6 postmenopausal BCSs treated with AIs who received estra-
diol tablets at a standard dose (25 mg), serum estradiol levels
increased from baseline levels 5 pmol/L to a mean of 72 pmol/L
Table 1 Studies on LET in BCSs
Reference
Type of
Study Study Population Main Outcome Treatment
Study
Period Results
O’Meara
et al, 200148
Retrospective
case-control
study
43% (75 patients) of
174 BCSs using HRT
(compared with 2581
BCSs not using HRT)
Recurrence and
mortality
LET (CEE
and dienestrol)
457 person-
years
Risk of recurrence or mortality
not increased
Dew et al.,
200349
Cohort study 69 BCSs treated for VVA
(compared with 1403
BCSs who did not require
treatment for VVA)
Recurrence 36 BCSs vaginal estriol
creams and pessaries;
33 BCSs estradiol
25-mg tablets
1 year (median
time; range,
0.1-5)
No increase in the
recurrence rate
Kendall
et al, 200647
Prospective
clinical study
7 Postmenopausal
BCSs treated with AIs
Serum E2, FSH,
LH levels
Vaginal estradiol
25 mg tablets
12 weeks Serum E2 levels increase from
baseline levels 5 pmol/L to a
mean 72 pmol/L at 2 weeks;
however, a decrease to a mean
of 16 pmol/L was observed after
1 month; significant further
increases were seen in 2 BCSs
Biglia et al,
201050
Prospective
clinical study
26 Postmenopausal
BCSs using SERMs or
AIs (BCSs receiving AIs
were excluded from LET
administration)
Efficacy: improvement
of VVA evaluated
using the Vaginal
Symptoms Score,
Profile of Female
Sexual Function,
Vaginal Health Index,
and Karyopycnotic
Index
Safety: endometrial
thickness and serum
FSH, LH, E2, E1, TT
and SHBG levels
10 Women, vaginal
estriol cream 0.25 mg;
8 women, vaginal
estradiol tablets
12.5 mg; 8 women,
nonhormonal
polycarbophil-based
vaginal moisturizer
(2.5 g)
12 weeks Efficacy: low-dose LET is
effective for VVA relief, and
nonhormonal moisturizer only
provides transient benefit
Safety: minimal increase of
serum hormone levels with LET
Wills et al,
201251
Prospective
study
48 Postmenopausal
BCSs and women at risk
Serum E2 levels 24 Control participants
(receiving AIs only); 14
3 Months LET increases E2 levels, regardless
of whether the preparation is by
Clinical Breast Cancer doi: 10.1016/j.clbc.2015.06.005

26. Local estrogen therapy
201050
clinical study BCSs using SERMs or
AIs (BCSs receiving AIs
were excluded from LET
administration)
of VVA evaluated
using the Vaginal
Symptoms Score,
Profile of Female
Sexual Function,
Vaginal Health Index,
and Karyopycnotic
Index
Safety: endometrial
thickness and serum
FSH, LH, E2, E1, TT
and SHBG levels
estriol cream 0.25 mg;
8 women, vaginal
estradiol tablets
12.5 mg; 8 women,
nonhormonal
polycarbophil-based
vaginal moisturizer
(2.5 g)
effective for VVA relief, and
nonhormonal moisturizer only
provides transient benefit
Safety: minimal increase of
serum hormone levels with LET
Wills et al,
201251
Prospective
study
48 Postmenopausal
BCSs and women at risk
of breast cancer during
AI or SERM treatment
Serum E2 levels 24 Control participants
(receiving AIs only); 14
women, intravaginal
25 mg estradiol tablet;
10 women intravaginal
estradiol ring (7.5 mg/d)
3 Months LET increases E2 levels, regardless
of whether the preparation is by
tablet or slow-release ring. Mean E2
levels before insertion and 12
weeks after insertion in BCSs who
were using the ring were significantly
greater than in control participants;
levels before insertion for BCSs who
were receiving tablets were not
increased compared with control
participants, suggesting that E2
increases with use of tablets might
not be continuously sustained
Donders
et al, 201452
Phase I
clinical study
16 Postmenopausal
BCSs who were
receiving AIs
Serum E1, E2,
E3 levels
Ultraelow-dose estriol
0.03 mg and
Lactobacillus acidophilus
vaginal tablets
3 Months Small and transient increase in
serum E3 level, but not in
E1 or E2 levels; VVA resolved or
improved in all women
Pfeiler et al,
201153
Prospective
randomized
clinical study
10 BCSs who were
receiving AIs
Serum E2 or
E3 levels
Vaginal 0.5 mg estriol 2 Weeks Serum levels of E3 and E2
were not increased
Abbreviations: AI ¼ aromatase inhibitor; BCS ¼ breast cancer survivor; CEE ¼ conjugated equine estrogens; E1 ¼ estrone; E2 ¼ estradiol; E3 ¼ estriol; FSH ¼ follicle-stimulating hormone; HRT ¼
hormone replacement therapy; LET ¼ local estrogen therapy; LH ¼ luteinizing hormone; SERM ¼ selective estrogen receptor modulator; SHBG ¼ sex hormone-binding globuline; TT ¼ testosterone;
VVA ¼ vulvovaginal atrophy.
Clinical Breast Cancer Month 2015 - 3
Clinical Breast Cancer doi: 10.1016/j.clbc.2015.06.005

27. hormone receptor-positive breast cancer patients
on aromatase inhibitor therapy - LETTable 2 Summary of prospective clinical studies evaluating vaginal estrogen products
Reference PM patients N Median
age (years)
Treatment arms
(s)
E2 assay
(LLOQ)
Median E2
concentration
Efficacy Study
location
Wills, JOP,
2012
ER ? BC or at
high risk of
BC taking an
AI or a
SERM for
C14 days
with atrophic
vaginitis
48 VE: 68
(53–79);
Control:
60
(49–67)
VagifemÒ
25
mcg tablets
(N = 14) OR
EstringÒ
(N = 10) for
C90 days
RIA after
DEE
extraction
(0.82 pg/
ml)
Median values: Control:
0.817 pg/ml (range
0.82–2.10 pg/ml);
VagifemÒ
preinsertion (12 h
prior): 0.82 pg/ml
(range
0.82–1.34 pg/ml)
and VagifemÒ
post-
insertion (12 h post):
12.26 pg/ml (range
5.18–24.24); EstringÒ
(24 h prior): 4.09 pg/
ml (range
0.82–5.18 pg/ml)
and EstringÒ
(60 days
post): 4.09 pg/ml
(range
0.82–9.53 pg/ml)*
NR London,
UK
Donders, Br
Can Res
Treat, 2014
NSAIs for at
least
6 months
with
symptomatic
vaginal
atrophy
16 Reported
in mean
age: 57
(52–63)–
GynoflorÒ
1
tablet daily
94 wks
followed by 3
tablets per wk
98 wks
GC/MS
method
(1.0 pg/
ml)
1.0 pg/ml at baseline
and at 0.5 and 24 h
post-insertion on D1
and D28 in all
patients except 1
patient (1.19 pg/ml)
Improvement
in symptoms:
75 and 94 %
patients at
Wk 2 and Wk
4,
respectively
Antwerpen,
Belgium
Pfeiler, HR ? BC who 10 65 (50–77) Ovestin 0.5 mg ECL OR 10 pg/ml at baseline Improvement Vienna,
Breast Cancer Res Treat
Breast Cancer Res Treat
DOI 10.1007/s10549-016-3827-7

28. hormone receptor-positive breast cancer patients
on aromatase inhibitor therapy - LET
(range
0.82–9.53 pg/ml)*
Donders, Br
Can Res
Treat, 2014
NSAIs for at
least
6 months
with
symptomatic
vaginal
atrophy
16 Reported
in mean
age: 57
(52–63)–
GynoflorÒ
1
tablet daily
94 wks
followed by 3
tablets per wk
98 wks
GC/MS
method
(1.0 pg/
ml)
1.0 pg/ml at baseline
and at 0.5 and 24 h
post-insertion on D1
and D28 in all
patients except 1
patient (1.19 pg/ml)
Improvement
in symptoms:
75 and 94 %
patients at
Wk 2 and Wk
4,
respectively
Antwerpen,
Belgium
Pfeiler,
Climacteric
2011
HR ? BC who
had been
receiving AI
for at least
1 year
10 65 (50–77) Ovestin 0.5 mg
tablets daily
for 14 days
ECL OR
GC/MS
(10.0 pg/
ml)
10 pg/ml at baseline
and 2 weeks of
therapy
Improvement
of vaginal
dryness: 5 of
6 BC (83 %);
Relief of
dyspareunia:
3 out of 5
(60 %)
Vienna,
Austria
Kendall,
Annals of
Oncology,
2006
On adjuvant AI
therapy for
early BC with
severe
atrophic
vaginitis
7 52 (51–59) VagifemÒ
25
mcg tablets
daily 92 wks
then twice
weekly
(N = 6);
PremarinÒ
cream
(N = 1)
RIA after
DEE
(0.82 pg/
ml)
Baseline: B1.362 pg/
ml*; D14: 19.613 pg/
ml (0.817–63.198)*;
D28: 4.358 pg/ml
(0.817–10.896)*; Wk
7–10: 4.631 pg/ml
(0.817–59.657)*;
Wk [ 12: 0.817 pg/
ml* (for 2/7 patients)
Improvement
in symptoms:
5 of 6 (83 %)
London,
UK
AI aromatase inhibitor; BC breast cancer; Br Can Res Treat-Breast Cancer Research and Treatment; d/D day; DEE diethyl ether extraction; E2
beta-estradiol; ECL Electro-chemiluminescence immunoassay; ER? estrogen receptor-positive; GC/MS gas chromatography-mass spectrometry
method; h hour; HR? hormone receptor-positive; JOP Journal of Oncology Practice; LLOQ lower limits of quantitation; mcg microgram; mg
milligram; ml milliliter; N number; NR not reported; NSAI non-steroidal aromatase inhibitor (letrozole or anastrozole); NC no control; NR not
reported; pg picogram; PK pharmacokinetic; PM postmenopausal; RIA radioimmunoassay; SD standard deviation; SERM selective estrogen
receptor modulator; UK United Kingdom; VE vaginal estrogen; Wk week
* Data was converted from pmol/l to pg/ml
Breast Cancer Res Treat
DOI 10.1007/s10549-016-3827-7