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Article history:
Received 24 March 2010
Received in revised form 21 May 2010
Accepted 25 May 2010
Keywords:
Adjuvant therapy
Aromatase inhibitors
Breast cancer
Menopause
Perimenopause
Tamoxifen
s u m m a r y
Menopausal status is a major consideration in adjuvant breast cancer therapy. The variable onset and
duration of the menopausal transition and the poor predictive value of bleeding patterns and hormone
levels mean many women fall naturally into a perimenopausal category. Women becoming amenorrhoeic during cytotoxic or endocrine treatment are also of uncertain status since ovarian function
may resume even in older patients after several months without menses. The recent St. Gallen panel
acknowledged that aromatase inhibitors (AIs) should form part of standard endocrine therapy for postmenopausal women with receptor-positive tumours. Among perimenopausal women at sufciently high
risk of recurrence, there may also be a case for adjuvant AIs either up-front or after tamoxifen. Such treatment should be initiated only after careful consideration of the patients age, menstrual history and the
effects of tamoxifen (which may make hormone levels an unreliable guide to ovarian function). In treatment-nave women whose postmenopausal status cannot be conrmed by reliable, serial hormone measurements, treatment should start with tamoxifen. Serial monitoring of hormone levels may enable an AI
to be started if postmenopausal status is conrmed. In women with treatment-induced amenorrhoea,
any decision to start an AI requires baseline hormone levels consistent with postmenopausal status;
and continuation of treatment requires that hormone levels remain postmenopausal during regular
monitoring.
2010 Elsevier Ltd. All rights reserved.
Introduction
While the median age at diagnosis of breast cancer is 61 years,
13% of cases in the US occur in women younger than 45 years and
22% between the ages of 45 and 54.1 The average age of menopause
in women of Caucasian/European origin is around 51 years.2,3
Breast cancer therefore affects a substantial number of women
who are either premenopausal or within the typical perimeno-
98
Methods
On the basis of clinical relevance, a number of key unresolved
issues were identied relating to the hormonal treatment of the
perimenopausal breast cancer patient. Having identied these issues, a literature search was conducted independently of the
authors using appropriate keywords and phrases. These included
(in various combinations) aromatase inhibitors; breast cancer;
chemotherapy-induced amenorrhoea; endocrine therapy; oestradiol; oestrogen level, measurement and receptors; follicle stimulating hormone; luteinising hormone and luteinising hormone
agonists; menopausal transition; ovarian function suppression;
and peri-, post- and premenopausal. Articles were selected for consideration if they had been published within the last 10 years and
addressed one or more of these issues: differentiating between
peri- and postmenopausal breast cancer patients, hormonal measurement or other means of determining menopausal status, and
treatment recommendations for breast cancer patients of different
menopausal status. Following discussion of this evidence, the writing committee (O. Ortmann, O. Pagani, A. Jones, N. Maas, and D.
Noss) sought to achieve consensus on a series of recommendations.
These recommendations were then put to a review committee (H.
Rugo, C. van de Velde, M. Aapro, and R. Coleman) whose contributions were incorporated into the nal manuscript.
99
100
Prior to the diagnosis of breast cancer, she had noticed that her
menstrual cycle had changed: the interval between menses was
21 days rather than the previous 28. After starting tamoxifen, her
menses became less regular and stopped 12 months after beginning adjuvant treatment.
At 2-year follow-up, a hormone prole indicated that she was
postmenopausal. The options for endocrine treatment were discussed with her again and she elected to switch to an AI. Her hormone prole 3, 6 and 12 months after starting the AI remained
postmenopausal and she completed 5 years of endocrine therapy
uneventfully.
Case 2
A woman aged 42 years underwent surgery and then adjuvant
chemotherapy for a ductal breast carcinoma that was pT2 pN1a
MO. The tumour was moderately positive for oestrogen and progesterone receptors and HER2-negative.
101
Fig. 1. Recommendations on the assessment of menopausal status in women with early breast cancer who are to have adjuvant endocrine therapy.
102
optimal endocrine therapy in view of the recurrence risk associated with her node-positive disease. She therefore elected to undergo a laparoscopic oophorectomy and continue on the AI. At
24 months, her BMD had fallen and she was started on an oral bisphosphonate. She completed 5 years of adjuvant endocrine
treatment.
Discussion
Perimenopausal women with early breast cancer can be divided
into at least three separate categories:
1. Treatment-nave women undergoing a natural menopausal
transition.
2. Women with treatment-induced amenorrhoea (TIA), who can
be further subdivided into:
a) patients with chemotherapy-induced amenorrhoea (CIA);
b) patients with cessation of menses while taking tamoxifen.
The present paper is not intended to provide clear-cut clinical
recommendations on the use of AIs in perimenopausal women.
These are difcult to make and are still a matter of debate. In general, however, at least some of these women, i.e. those at increased
risk of relapse, may be candidates for AIs either up-front or as
sequential treatment following tamoxifen. Goss et al. have recently
presented (data not yet formally published) a subset analysis of the
MA17 trial relating to women who were premenopausal at diagnosis and became menopausal because of oophorectomy or during
adjuvant tamoxifen or chemotherapy.40 This retrospective analysis
suggests that these women beneted as much as patients who
were postmenopausal at diagnosis from being randomised to extended letrozole following completion of 5 years of tamoxifen.
However, there are certain caveats when recommending an AI to
perimenopausal women.
First, the reduced feedback of oestrogen to the hypothalamus
and pituitary can lead to increased secretion of gonadotrophins
which in turn can cause resumption of oestrogen production by
the ovaries. In both the natural and treatment-induced perimenopause (especially the latter), resumption of ovarian function can
occur even in women aged 50 years and above, and even after
many months of amenorrhoea.33
Secondly, tamoxifen has diverse effects on the ovary. One potential effect is stimulation of ovarian function with increases in
circulating E2. Hormone proles may therefore be an unreliable
reection of true ovarian function and should be interpreted with
caution.
Thirdly, single measurements of FSH, LH, E2 and inhibin-B reect ovarian function only at the time they are taken and therefore
are not useful for predicting the potential for ovarian recovery.
The combination of an AI plus a GnRH analogue (which is not a
standard treatment but is sometimes considered in selected cases)
suppresses plasma oestrogen levels more profoundly than either
GnRH analogues alone41 or the combination of GnRH analogue
and tamoxifen.42 Nevertheless, resumption of ovarian function
has been reported even when an AI is given in combination with
a GnRH analogue. GnRH analogues do not always lead to complete
suppression of ovarian function and combination treatment with
an AI is therefore safe only if it can be established (and periodically
Box 1. Recommendations of the expert panel on the assessment of menopausal status in women with early breast cancer
who are to have adjuvant endocrine therapy (summarised in
Fig. 1).
(1) Treatment-nave women undergoing a natural menopausal transition.
In women whose postmenopausal status cannot reasonably be confirmed by available tools, treatment
with AIs alone is contraindicated and tamoxifen should
be given. E2 and gonadotrophin levels should be monitored serially (i.e. every 36 months) to allow an AI to
be started as soon as postmenopausal status is confirmed. The added value of ovarian suppression
remains to be defined.
(2) (a) Women with chemotherapy-induced amenorrhoea.
The effects of chemotherapy on ovarian function vary
with the agent(s) used, the duration of treatment, ovarian reserve, and the age of the patient. 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. In older women, provided that
validated and reliable testing is available, E2 and FSH
levels should be measured at baseline. If levels are
consistent with postmenopausal status, an AI can be
started. One reasonable approach is to undertake serial
monitoring at 3 and 6 months and then at intervals of
6 months during treatment. However, if reliable testing
is not available, AIs should be used alone only with
great caution.
(b) Women with cessation of menses while taking
tamoxifen.
In women who develop amenorrhoea while taking
tamoxifen and who are candidates for switching to an
AI, it is advisable first to check E2 and FSH levels. Measurements should be made at baseline and then serially (e.g. every 36 months) during treatment.
In 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 patients
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.
Box 2.Contraception.
Following adjuvant chemotherapy or endocrine treatment
for breast cancer, menstrual cycles may become irregular
or cease. However, ovulation may occur.
In women who were pre- or perimenopausal at diagnosis,
contraception should be offered even in the absence of
menses until postmenopausal status is confirmed. (It is
worth remembering that tamoxifen was originally
designed as a fertility drug.)
Contraception should be non-hormonal.
Funding
This project was made possible by an unrestricted grant from
Pzer Inc.
Acknowledgement
Rob Stepney PhD (medical writer, Charlbury, UK) assisted in the
drafting of this paper. Editorial assistance was provided by TRM
Oncology (The Hague, The Netherlands).
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