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Treatment of Perimenopausal Women with Breast cancer
Alison L Jones
Royal Free and UCLH
November 2014
Oestradiol levels in a female lifetime
1000pmol
150pmol
12 years 36 years 51 years
Definition of menopause1
Menopause
Bilateral prior oophorectomy
Age >60 years Age <60 years
Amenorrhoea for
>12 months
Post-menopausal
FSH and oestradiol
concentrations
• Cannot assign menopausal status to women on
LHRH analogue therapy
• Amenorrhoea ≠ menopause on chemotherapy
1. Breast cancer. NCCN practice guidelines in oncology v.3; 2012.
Many women fall into the perimenopausal range…
…and may become postmenopausal during their treatment Cancer Research UK http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/incidence/uk-breast-cancer-incidence-statistics Last accessed 10 Jan 2013.
Average Number of New Cases Per Year and Age-Specific Incidence Rates per 100,000 Population, Females, UK, 2008–2010
Chemotherapy - Induced Amenorrhea Rates
Agents “Younger”
Women (≤40 y)
“Older”
Women (>40 y)
Alkylating 18% to 61% 61% to 97%
Anthracyclines ~ 32% ~ 88%
Taxanes (+Anthac.) ~ 61% ~ 84%
Walshe JM, et al. J Clin Oncol. 2006;24(36):5769-5779
Goodwin PJ, et al. J Clin Oncol. 1999;17(8):2365-2370.
Mathematical Model of Risk of Menopause:
First Year After Diagnosis
0.2
0.4
0.6
0.8
1.0
0.0
25 30 35 40 45 50 55
None
Horm Only
Chem Only
Both
Age at Diagnosis, years
Esti
mate
d P
rob
ab
ilit
y
Our patient
NICE guidelines for endocrine therapy
in pre/peri-menopausal ABC • Offer tamoxifen and ovarian suppression as first-line treatment to
premenopausal and perimenopausal women with ER-positive advanced breast cancer not previously treated with tamoxifen
• Offer ovarian suppression to premenopausal and perimenopausal women who have previously been treated with tamoxifen and then experience disease progression
NICE clinical guideline 81, 2009.
Use of AIs in Perimenopause: Royal Marsden Experience
45 women
Median age 47 (39-52) years with CT induced amenorrhea
Treated with AIs (33 biochemically confirmed ovarian suppression)
– Recovery of ovarian function: 12 (27%)
– Pregnancies 1
– Median duration of amenorrhea: 12 (4-59) months
– Median time on AI: 6 (3-18) months
Smith IE, et al. J Clin Oncol. 2006;24(16): 2444-2447.
Biochemical Monitoring of Ovarian Function in Perimenopause
• Single measurement of FSH, (LH), E2, beta inhibin reflects function only at that time point, but is not predictive
• Tests used for E2 measurements are highly unreliable in perimenopause, as they do not extract or purify E2 from plasma
• Measurement in patients receiving a steroidal AI cross-react even with most specialized immunoassays
Smith IE, et al. J Clin Oncol. 2006;24(16):2444-2447.
FSH, follicle-stimulating hormone; LH, luteinizing hormone
Mrs A F (aged 49)
• 2010 Carcinoma right breast
– T2 N1 (2/9) M0
– 2.5 cm Grade 2 IDC with clear margins
• ER + Quick score 7/8
• PR + Quick score 4/8
• HER 2 Negative (IHC 0)
• No co-morbidities
• Mastectomy and axillary node clearance
Mortality estimations with Adjuvantonline
Addition of Chemotherapy to Endocrine in ER+ EBC EBCTCG 2005
Mrs AF; Adjuvant treatment
• She receives 3 cycles of FEC (100)
followed by 3 cycles of docetaxel which
she tolerates well
Q2: Initial Endocrine therapy option?
1. Decision based on FSH/E1 levels
2. Tamoxifen started
3. An Aromatase Inhibitor started
4. A combination of LHRH-Ag and AI
5. A combination of LHRH-AG and Tamoxifen
44 years; Last menses < 9 months; pT2,N1, M0
IDC, Grade III, ER/PgR [+], HER2 negative
Tamoxifen Efficacy Does Not Differ
Significantly According to Patient Age
Annual Risk Ratio ± SE
Breast Cancer
Recurrence Rate
Breast Cancer
Death Rate
Risk Ratio SE Risk Ratio SE
For all age groups 0.59 0.03 0.66 0.04
Age, years
<40 0.56 0.10 0.61 0.12
40-49 0.71 0.07 0.76 0.09
50-59 0.66 0.05 0.76 0.07
60-69 0.55 0.05 0.65 0.06
≥70 0.49 0.12 0.63 0.15
Parton M, et al. J Clin Oncol. 2008;26(5):745-752 after Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2005:365(9472):1687-1717.
Q2: Initial Endocrine therapy option?
1. Decision based on FSH/E1 levels
2. Tamoxifen started
3. An Aromatase Inhibitor started
4. A combination of LHRH-Ag and AI
5. A combination of LHRH-AG and Tamoxifen
Patient case
30 months had gone
No relapse
Patient still on Tamoxifen
Good tolerance (Hot flashes first year)
Amenorrhea maintained (38 months)
Q3: Is it time for switching endocrine therapy?
1. No discussion – switch to Exemestane
2. Exemestane but measuring FSH/E1 levels
3. Tamoxifen maintained for 5 years and then we
will see
Coombes RC et al, Eur J Cancer Suppl. 2009;7(2): Abstract 5010.
Tamoxifen
R A N D O M I
ZE
Exemestane
(2-3 years)
Tamoxifen
(2-3 years)
Post-treatment follow-up
Diagnosis
Median follow-up from randomization = 91
months (June 2009)
Start of
study
Total 5 years
endocrine therapy
Total follow-up available from randomization at June 2009 analysis = 32296 women years
2-3 years
Intergroup Exemestane Study Design
Long term results from the IES Study
Coombes RC et al, Eur J Cancer Suppl. 2009;7(2): Abstract 5010.
If Use of AIs Is Considered in Perimenopause (Age <55 Years)
• Serial monthly measurement of FSH and E2
– For at least 6 months – For AI after tamoxifen situation even longer
• If E2 remains >10 pmol/L = AI is not fully effective
– Switch back to tamoxifen – Surgical ovarian ablation
• Instruct patients to contact clinician if menstrual bleed recurs or hot flushes
stop abruptly
• Adequate contraception should be practiced during monitoring period
• Anti Müllerian Hormone (AMH) is most reliable indicator of residual follicular function
Smith IE, et al. J Clin Oncol. 2006;24(16):2444-2447.
Normal menopausal transition
• If postmenopausal
status cannot be
confirmed, treatment
with AIs alone is
contraindicated.
• Monitor E2 and
gonadotrophin levels
(ie, every 3-6 months)
to allow an AI when
postmenopausal
status is confirmed.
• The added value of
ovarian suppression
remains to be defined.
TREATMENT-NAÏVE:
NATURAL MENOPAUSAL
TRANSITION
TREATMENT-INDUCED AMENORRHOEA
Women of uncertain menopausal status who may be or may become eligible for an
adjuvant AI
CHEMOTHERAPY- INDUCED
WHILE ON TAMOXIFEN
AGE < 40: AI ALONE IS
CONTRAINDICATED
AGE > 40
Start with tamoxifen
Monitor E2 and FSH every
3-6 months
Consider an AI as soon as
menopausal status is confirmed
If E2 and FSH levels are post-menopausal by reliable & valid measure start AI
Monitor hormones at 3, 6 months and q6 during treatment
• The effects of chemotherapy on ovarian function vary
• The likelihood of resumed ovarian function diminishes as a woman approaches the mean age of natural menopause (51 years)
• Women with CIA who are younger than 40 are more likely to resume ovarian function and should not receive an AI alone
Chemotherapy-induced amenorrhea (<40)
TREATMENT-NAÏVE: NATURAL MENOPAUSAL
TRANSITION
TREATMENT-INDUCED
AMENORRHOEA
Women of uncertain menopausal status who may be or may become eligible for an
adjuvant AI
CHEMOTHERAPY-
INDUCED
WHILE ON TAMOXIFEN
AGE < 40:
AI ALONE IS
CONTRAINDICATED
AGE > 40
Start with tamoxifen
Monitor E2 and FSH every 3-6 months
Consider an AI as soon as menopausal status is confirmed
If E2 and FSH levels are post-menopausal by reliable & valid measure start AI
Monitor hormones at 3, 6 months and q6 during treatment
• In older women if E2
and FSH levels are
consistent with
postmenopausal status,
an AI can be started
• Undertake serial
monitoring at 3 and 6
months and then at
intervals of six months
during treatment
• If reliable testing is not
available, AIs should be
used with great caution
TREATMENT-NAÏVE: NATURAL MENOPAUSAL
TRANSITION
TREATMENT-INDUCED
AMENORRHOEA
Women of uncertain menopausal status who may be or may become eligible for an
adjuvant AI
CHEMOTHERAPY-
INDUCED
WHILE ON TAMOXIFEN
AGE < 40: AI ALONE IS
CONTRAINDICATED
AGE > 40
Start with tamoxifen
Monitor E2 and FSH every 3-6 months
Consider an AI as soon as menopausal status is confirmed
If E2 and FSH levels are post-menopausal by reliable & valid measure start AI
Monitor hormones at 3, 6 months and q6 during treatment
Chemotherapy-induced amenorrhea (>40)
• If the patient is a
candidate for
switching to an AI
first check E2 and
FSH levels
• Measurements
should be made at
baseline and then
serially (eg, every
3-6 months) during
treatment
Women of uncertain menopausal status who may be or may become eligible for an
adjuvant AI
Cessation of menses on tamoxifen
TREATMENT-NAÏVE: NATURAL MENOPAUSAL
TRANSITION
TREATMENT-INDUCED
AMENORRHOEA
CHEMOTHERAPY- INDUCED
WHILE ON
TAMOXIFEN
AGE < 40: AI ALONE IS
CONTRAINDICATED
AGE > 40
Start with tamoxifen
Monitor E2 and FSH every 3-6 months
Consider an AI as soon as menopausal status is confirmed
If E2 and FSH levels are post-menopausal by reliable & valid measure start AI
Monitor hormones at 3, 6 months and q6 during treatment
Issues for ‘perimenopausal’ women started
on an aromatase inhibitor
• Contraception
• Hot flashes
• Sexual dysfunction and dyspareunia
• Bone Heath
Serum estradiol levels in women receiving concurrent aromatase inhibitors and Vagifem.
Kendall A et al. Ann Oncol 2006;17:584-587
Avoid use of vaginal oestrogen preparations in women on aromatase inhibitors
Bone health
• A baseline measurement of bone mineral density (BMD)
is recommended to guide future management.
• Advice on exercise, cessation of smoking and
moderation of alcohol should be provided.
• Adequate calcium (1g/day) and vitamin D (400-800 i.u.)
is advised in all postmenopausal women.
• Women with BMD T score of <-2 or <-1 and annual bone
loss > 4%/year should be considered for bisphosphonate
treatment
DM Reid et al. Cancer Treatment Reviews 34, Suppl 1, S3-S18, 2008.
P Hadji et al. Annals of Oncology 2008; 19: 1407-1416.
Summary
• When menopausal status is uncertain, starting endocrine therapy with tamoxifen rather than an AI provides effective treatment while allowing a period during which the patient’s menopausal status may become clearer. If in doubt wait!
• However, given the benefit certain women may gain from receiving an AI rather than continuing on tamoxifen, it is important regularly to monitor the hormonal status of perimenopausal patients so that treatment can be switched when appropriate.
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