VOLUME 34 NUMBER 14 MAY 10, 2016

JOURNAL OF CLINICAL ONCOLOGY O N C O L O G Y G R A N D R O U N D S

Is Estradiol Monitoring Necessary in Women

Receiving Ovarian Suppression for Breast Cancer?
Antroula Papakonstantinou, Theodoros Foukakis, Kenny A. Rodriguez-Wallberg, and Jonas Bergh, Karolinska Institutet and
University Hospital, Stockholm, Sweden
See accompanying articles on pages 1584, 1594, and 1601

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case
presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a
summary of the authors suggested management approaches. The goal of this series is to help readers better understand how to
apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own
clinical practice.

A 36-year-old premenopausal woman had been diagnosed with stage III breast cancer. After an initial biopsy
conrmed breast cancer, she underwent mastectomy and axillary node dissection for a left-sided breast
cancer, measuring 7 cm. The tumor had lobular histology and was considered grade 2 of 3. Metastatic
carcinoma was identied in 10 of 13 axillary nodes. Immunohistochemical studies showed that the tumor
was strongly positive for estrogen and progesterone receptor expression and had a Ki-67 score of 15%
(> 20% is considered high according to a Swedish quality control study and the St Gallen Expert
Consensus).1,2 There was no amplication of the HER2/neu gene. Staging scans were negative for metastatic
disease. In the adjuvant setting, she received three cycles of anthracycline-cyclophosphamide combi-
nation chemotherapy followed by three cycles of taxane chemotherapy and then locoregional radiotherapy.
After completion of chemotherapy, she developed amenorrhea. As adjuvant endocrine therapy, she began
monthly goserelin administration to achieve ovarian function suppression (OFS), in combination with the
aromatase inhibitor (AI) exemestane. She experienced menopausal symptoms including hot ashes, vaginal
dryness, and sexual dysfunction. After two monthly treatments with goserelin and exemestane, a sensitive assay for
serum estradiol was checked and returned at 16 pg/mL (61 pmol/L); postmenopausal range for sensitive assay is
less than 15 pg/mL (< 50 pmol/L). The patient has now been referred to our unit to discuss further management.

ovarian follicle development, and subsequent increase of plasma

CHALLENGES IN DIAGNOSIS AND MANAGEMENT
The diagnosis and given therapy for the patient just described must
be put in context in relation to the present armamentarium of
available endocrine therapies and their adverse effects, including new
emerging concerns. Tamoxifen has for decades been the cornerstone
for management of early and metastatic breast cancer for both pre-
and postmenopausal women. Treatment with adjuvant AIs for 5 years
reduces relative 10-year breast cancer mortality rates by approximately
15% compared with tamoxifen in postmenopausal women.3 There-
fore, an AI should be the preferred option for postmenopausal
patients, whereas the optimal adjuvant endocrine treatment of pre-
menopausal women is still controversial.3 OFS with gonadotropin-
releasing hormone agonists (GnRHa) in combination with AIs became
an appealing approach to further improve survival in premenopausal
women, as demonstrated for the postmenopausal group.3,4
The inhibition of estrogen biosynthesis by AIs, in pre-
menopausal women, could stimulate the hypothalamus/pituitary
pathway, inducing follicle-stimulating hormone (FSH) release,
estradiol levels (Fig 1).5 Addition of GnRHa is believed to hamper this
effect, but too little is known about the interaction between AIs and
GnRHa when administered concurrently in women with residual
ovarian function. There are still controversies regarding the methods
to dene residual ovarian function after chemotherapy, the timing of
the sampling of hormone levels, what monitoring should be per-
formed during treatment, if any, and the role of body mass index
(BMI). Should ultra-low but detectable estradiol levels be considered
as sign of suboptimal ovarian suppression able to affect survival? How
sensitive should estradiol assays be, and what cutoff levels of estradiol
are clinically meaningful? Using the wrong assay to measure estradiol
levels could lead to erroneous treatment decisions.6
SUMMARY OF THE RELEVANT LITERATURE
Endocrine Treatment
Tamoxifen administered for 5 years reduces breast cancer
mortality by one third, and tamoxifen administered for 10 years

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Copyright 2017 American Society of Clinical Oncology. All rights reserved.
 Papakonstantinou et al
Normal Inhibition with GnRHa
premenopausal status
Hypothalamus
or ovarian ablation
combined with
GnRH additional endocrine
agents
Anterior
pituitary FSH Anterior
pituitary
LH
Positive
feedback k
No follicle
stimulation
Stimulation of
+E2 follicle
development
Ovary Ovary
No follicle
Developing follicles
stimulation and no
and ovulatory follicle
produce E2 E2 production
further reduces the risk of breast cancer recurrence (relative risk
[RR], 0.75; 95% CI, 0.62 to 0.90), breast cancerspecic mortality
(RR, 0.71; 95% CI, 0.58 to 0.88), and overall mortality (RR, 0.79;
95% CI, 0.68 to 0.92).7-10 A signicant absolute 10-year overall
survival (OS) gain of 2.7% with AIs compared with tamoxifen
made AIs the standard adjuvant endocrine treatment of the majority
of postmenopausal women.3 Ovarian suppression with goserelin has
a similar effect to ovarian ablation in premenopausal women with
metastatic breast cancer.11-15 Reversible ovarian suppression using
GnRHa may be preferred over permanent ovarian ablation with
bilateral oophorectomy or radiation-induced ablation because treat-
ment can be stopped if the patient experiences intolerable symptoms.16
The use of AIs in premenopausal women is hampered by aro-
matization occurring in both the ovaries and peripheral tissues.
Hence, complete and sustained suppression of residual ovarian
function might not be achieved by AIs alone in premenopausal
women, and addition of GnRHa might be needed to inhibit the
release of gonadotropins and subsequent ovarian stimulation.
The Suppression of Ovarian Function Trial (SOFT) reported
that premenopausal women younger than 35 years old and with high
risk for breast cancer relapse who received adjuvant chemotherapy
received a larger benet from OFS combined with tamoxifen
(freedom from breast cancer rate at 5 years, 78.9%; 95% CI, 69.8%
to 85.5%) when compared with tamoxifen alone (67.7%; 95%
CI, 57.3% to 76.0%), and the benet was further enhanced by
exemestane (83.4%; 95% CI, 74.9% to 89.3%) in combination
with OFS.17 Ovarian suppression in SOFT and the Tamoxifen and
Exemestane Trial (TEXT) was achieved either by medical treatment
with the GnRHa triptorelin, bilateral oophorectomy, or ovarian
irradiation, and 16% of the patients underwent bilateral oopho-
rectomy or bilateral irradiation at some time point during the trial.18
A combined analysis of the SOFT/TEXT trials and an analysis of the
SOFT trial alone demonstrated improved 5-year disease-free survival
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Copyright 2017 American Society of Clinical Oncology. All rights reserved.
Hypothalamus
GnRHa
Peripheral
FSH tissue
Androstenedione
Aromatase Fig 1. Hormonal regulation of ovarian
inhibitors estrogen production in the premenopausal
woman and mechanisms of adjuvant endo-
crine treatment of breast cancer. E2, estradiol;
E2 FSH, follicle-stimulating hormone; GnRH,
gonadotropin-releasing hormone; GnRHa,
gonadotropin-releasing hormone agonist; LH,
luteinizing hormone.
E
Estrogen
re
receptor
Tamoxifen,
Fulvestrant
(DFS) with exemestane plus OFS versus tamoxifen plus OFS.17,18
However, this did not translate to an improved OS (Table 1).
By contrast, the Austrian Breast and Colorectal Cancer Study
Group 12 (ABCSG-12) trial reported no signicant difference in
DFS rates between premenopausal women treated with anastrozole
plus goserelin versus those treated with tamoxifen plus goserelin after
3 years of therapy in both arms, with or without zoledronate.20 A
worse OS in the anastrozole plus goserelin group was seen with
longer follow-up (hazard ratio, 1.63; 95% CI, 1.05 to 1.45; P 5.030).19
The lack of OS benet in the SOFT/TEXT trials combined with
worse OS in the ABCSG12 trial suggests that the combination
of AIs with GnRHa may not be the ideal combination for pre-
menopausal women. The underlying reasons for failing to improve
survival are at present unknown, but genetic variations (eg, in the
aromatase-encoding genes) could be involved.21,22 Poor adherence
to AI treatment as a result of increased adverse effects or incomplete
inhibition of aromatase by AIs could also be related to the less
favorable outcome.23,24 The studies have used different AIs, but this
is probably of minor importance, given that the effect of AIs in the
adjuvant postmenopausal setting was superimposable.3
Another possible explanation for the lack of survival benet
could be incomplete ovarian suppression by GnRHa. The Takeda
Adjuvant Breast Cancer Study with Leuprorelin Acetate (TABLE)
trial demonstrated approximately 7% hormonal escape in 299
women treated with leuprorelin, with a cutoff value of 30 pg/mL.25
In addition, in the accompanying article by Bellet et al,26 the
investigators report that during the rst year of exemestane plus
triptorelin, 17% of the patients had estradiol levels greater than the
threshold of 2.72 pg/mL (10 pmol/L).
On the basis of these data, we believe it is advisable to ensure
that complete ovarian suppression is achieved by monitoring of
estradiol levels serially in women beginning ovarian suppression
and AI therapy. Appropriate management should be based on the
JOURNAL OF CLINICAL ONCOLOGY
 www.jco.org
Table 1. Summary of Studies Investigating the Effect of GnRHa Plus Tamoxifen or GnRHa Plus AI as Adjuvant Treatment in Premenopausal Women With Hormone ReceptorPositive Early Breast Cancer
No. of Treatment Follow-Up Absolute 5-Year HR for DFS Absolute 5-Year OS
Trial Patients Treatment Duration (years) Time (months) DFS (%; 95% CI) (95% CI) (%; 95% CI) HR for OS (95% CI)
ABCSG-1219 1,803 3 99.4 1.13 (0.88 to 1.45) 1.63* (1.05 to 2.52)
OFS 1 tamoxifen NR NR
OFS 1 anastrozole NR NR
SOFT17 2,033 5 67 0.83 (0.66 to 1.04) 0.64 (0.42 to 0.96)
Tamoxifen alone 84.7 (82.2 to 86.9) 90.9 (87.9 to 93.2)
OFS 1 tamoxifen 86.6 (84.2 to 88.7) 94.5 (92.0 to 96.2)
SOFT/TEXT18 combined 4,690 5 68 0.72 (0.6 to 0.85) 1.14 (0.86 to 1.51)
Analysis
OFS 1 tamoxifen 87.3 (85.7 to 88.7) 96.9 (96.0 to 97.6)
OFS 1 exemestane 91.1 (89.7 to 92.3) 95.9 (94.9 to 96.7)

Abbreviations: ABCSG-12, Austrian Breast and Colorectal Cancer Study Group 12 trial; AI, aromatase inhibitor; DFS, disease-free survival; GnRHa, gonadotropin-releasing hormone agonist; HR, hazard ratio; NR, not
reported; OFS, ovarian function suppression; OS, overall survival; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial.
*P , .05.
Patients who received chemotherapy.
P , .001.
Adjuvant Endocrine Therapies for the Premenopausal

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2016 by American Society of Clinical Oncology
1575
 Papakonstantinou et al

hormone levels because GnRHa may not cause complete ovarian
suppression in some patients.25,26
Chemotherapy-Induced Amenorrhea
Chemotherapy regimens used in breast cancer therapy can cause
permanent or transient amenorrhea, which is considered to account
for some of the chemotherapy effect.27,28 Chemotherapy-induced
amenorrhea (CIA) may occur with varying incidence, depending on
the agents and dosage used. For example, alkylating agents such as
cyclophosphamide have been reported to cause CIA in 18% to 61% of
women younger than 40 years old and up to 97% of women older
than 40 year old.29,30 A correlation between increasing cumulative
dose and dose-intensive therapies and the risk of CIA has also
been demonstrated.28,31-34 Induction of CIA and/or recovery of
ovarian function inuences the estradiol and FSH levels, and
therefore, it would have been interesting to have detailed descriptions
of the regimens used, including doses delivered, in the SOFT study.
Recovery of Ovarian Function
Generally, establishing menopausal status after chemotherapy is
burdensome, and prolonged amenorrhea should not be regarded as
equivalent to a postmenopausal status. Even in natural menopause,
estradiol levels remain greater than postmenopausal levels for up to a
year after amenorrhea.35 Swain et al36 report CIA as an independent
factor for improved survival, and recovery of ovarian function has been
reported in up to 32% of women younger than 48 years treated with an
AI after developing CIA.36-39 This nding is supported in another study
where reduced DFS was reported among women with recovery of
ovarian function (HR, 9.3; 95% CI, 3.3 to 48.0; P 5 .04), supporting
the apprehension regarding suboptimal ovarian suppression as dis-
cussed in this article.38 In the presence of incomplete ovarian sup-
pression by GnRHa, treatment with an AI can stimulate the residual
ovarian function, leading to an increase in plasma estrogen levels.37
Further data are required, however, to determine whether biochemical
recovery of ovarian function, at subclinical levels, affects prognosis.
Even in the absence of menstruation, other clinical signs of
residual ovarian function, such as breast tenderness, uid reten-
tion, discomfort in the lower abdomen and lower spine, or
increased vaginal discharge, should raise concerns.
Factors associated with recovery of ovarian function are
ambiguous, but younger age, type of chemotherapy, high BMI, and
time from treatment completion seem to signicantly inuence the
incidence of recovery of menses.32,40,41 This, in turn, can be related
to increased levels of estradiol seen in postmenopausal women with
high BMI treated with AIs.42 Similar results are shown among
overweight postmenopausal women treated with anastrozole and
letrozole in the Arimidex, Tamoxifen, Alone or in Combination
(ATAC) and Breast International Group (BIG) 1-98 trials,
respectively.43,44 Contradicting data are reported in the accom-
panying article by Krekow et al,45 where no relationship between
BMI and ovarian function recovery was seen. However, these
ndings are based on only 173 patients.45
Biochemical Monitoring
The optimal method to measure plasma concentration of
estradiol is still debated. High sensitivity and specicity are required
to measure low hormone concentrations.6,46 High-sensitivity assays
and purication of the estradiol from the plasma are required for
trustworthy monitoring, but these methods may not be widely
accessible.37 In addition, measurement of estradiol levels for patients
receiving exemestane is unreliable as a result of nonspecic cross-reactions
in immunoassays, unless a specialized purication method is used.47
In addition to the methodologic controversies, dening the
ideal timing to collect samples to assess whether a patient has

Endocrine Therapy for Hormone ReceptorPositive Early Breast Cancer

*After initial chemotherapy, when indicated

Clinical and Laboratory (E2, FSH, LH)

Assessment of Menopause Status

Premenopausal Perimenopausal Postmenopausal

Fig 2. Assessment of menopausal status

and choice of endocrine treatment of women
GnRHa/AI - AI with hormone-positive early breast cancer. AI,
Low risk High risk and/or - Tamoxifen if low risk
or aromatase inhibitor; E2, estradiol; FSH, follicle-
< 35 years GnRHa/tamoxifen stimulating hormone; GnRHa, gonadotropin-
Tamoxifen or or tamoxifen releasing hormone agonist; LH, luteinizing
GnRHa/ alone
GnRHa/AI hormone.
tamoxifen

E2, FSH, LH every Repeated clinical and

3-6 months laboratory evaluation

If insufficient Switch to AI when

suppression: permanent
- Switch to GnRHa/ postmenopausal
tamoxifen status is
- Or ovarian ablation established

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 Adjuvant Endocrine Therapies for the Premenopausal
optimal OFS is also challenging. Data on estradiol or estrone serum
levels during treatment with AI plus ovarian suppression are scarce
with limited follow-up.48,49 In their accompanying article, Bellet
et al26 demonstrate that at least 34% of the women (27 of 79
women) in a small substudy of the SOFT trial regained ovarian
function with detectable estradiol levels within the rst year after
random assignment. A retrospective study found that mean adjusted
estradiol level during natural menopause was 5.4 pg/mL (95% CI,
5.3 to 5.6 pg/mL).50 Although the clinical signicance of detecting
ultra-low estradiol concentrations is unclear, the increased risk of
death seen for the combination of anastrozole and GnRHa at the
long-term follow-up in the ABCSG-12 trial together with the lack of
OS benet in the SOFT/TEXT trials raises concern (Table 1).
Anti-Mullerian hormone, inhibin B, and FSH, measured
together with estradiol levels, could possibly predict recovery of
ovarian function during AI treatment after development of CIA,
but more data are needed.51-53 Both estradiol and inhibin B are
stimulated by FSH, and single time point measurements are not
reliable given that many patients are in a perimenopausal situation
or can gain recovery of ovarian function months after completion
of chemotherapy.37,54,55 Notwithstanding these methodologic
limitations, we believe that dynamic and serial monitoring should be
performed to ensure suppressed ovarian function. We acknowledge
that it remains unproven that such monitoring will identify which
patients will or will not benet from GnRHa and AI treatment and
that neither the ideal time points for monitoring nor the stand-
ardized laboratory criteria have been established.37,55
Duration of OFS Treatment and Quality of Life
The optimal length of OFS with GnRHa is not well estab-
lished; however, the panel in St Gallen in 2007 recommended a
treatment duration of 5 years.56 The SOFT/TEXT combined
analysis showed no difference in global quality of life between
patients treated with exemestane plus OFS and tamoxifen plus OFS
after 2 years of treatment.57 However, the adverse effects were
distinct between tamoxifen and AIs, with signicantly more hot
ashes and sweats in the tamoxifen plus OFS group and major
problems with joint pain, vaginal dryness, and loss of sexual
interest.57 In the SOFT trial quality-of-life substudy, OFS added to
tamoxifen, versus tamoxifen alone (only descriptive information
for OFS plus AI), resulted in increased endocrine symptom burden
with worse hot ashes during the rst 24 months and declined
sexual interest for the whole observation period, as reported in the
accompanying article by Ribi et al.58 Similar ndings were reported
in an earlier but smaller study.59
Adherence to endocrine treatment is negatively inuenced by
adverse effects, and nonadherence impacts breast cancer survival,
especially in young women.60 The increased rate of treatment dis-
continuation in the SOFT trial (19% of patients discontinued
tamoxifen and 21% discontinued triptorelin) as a result of substantial
symptoms highlights the need for symptom relief.58 Both pharma-
cologic and nonpharmacologic approaches have been tested.61-64
SUGGESTED APPROACHES TO MANAGEMENT
We recommend treatment with AI plus GnRHa for 5 years in
high-risk patients younger than age 35 who have received
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chemotherapy.1 We initiate therapy and monitor endocrine
function as outlined in Figure 2.
For women with high-risk breast cancer in whom treatment
with an AI is desirable but adequate ovarian suppression cannot
be achieved, treatment possibilities include switching endocrine
treatment to tamoxifen plus ovarian suppression with GnRHa for
at least 5 years or bilateral oophorectomy. An Early Breast Cancer
Trialists Collaborative Group meta-analysis demonstrated that
ovarian ablation increased survival in women younger than age
50 years, and other studies have reported improved survival with
oophorectomy and tamoxifen among premenopausal women with
early breast cancer.65-67 Among patients older than age 35, we
prefer tamoxifen alone for some patients, especially considering the
increased adverse effects of the combined treatment.
Measuring estradiol or gonadotropin levels immediately before
the monthly administration of GnRHa could be used to assess the
optimal treatment interval. A low peak response of GnRHa-
stimulated luteinizing hormone value of less than 3 mIU/mL
could indicate that adequate suppression of the hypothalamic-
pituitary axis has been achieved, but this test is currently expen-
sive and demanding.68,69 Theoretically, detectable levels of estradiol
or gonadotropins just before the next planned GnRHa treatment
could provide evidence on whether inhibition is sufcient or
indicate the necessity for more denitive suppression of ovarian
function, perhaps on a different GnRHa schedule.
Given the effectiveness of ovarian suppression in the SOFT
trial, which did not require monitoring of endocrine function,
the basic question is whether to recommend such testing and, if
so, how to respond to persistent, measurable levels of estradiol.
We believe the accompanying article by Bellet et al26 proves the
importance of this testing. Accordingly, we recommend mea-
surements of estradiol and FSH at baseline, before a patient
initiates treatment with GnRHa and AIs.37,55 Given the risk of
recovery of ovarian function or insufcient ovarian suppression,
we also recommend serial biochemical monitoring every 3 to
6 months during treatment, especially for patients younger than
50 years (Fig 2).37,55
In our patient discussed at the beginning of the article, given
the high-risk stage at presentation, we recommended ovarian ablation
and continuation of an AI. The patient was unwilling to consider
surgical oophorectomy at the time, and we recommended intensied
treatment with goserelin. Two months later, she accepted laparo-
scopic oophorectomy, and she can now safely receive treatment with
an AI, on the basis of the advanced stage at diagnosis.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Financial support: Jonas Bergh
Administrative support: Jonas Bergh
Manuscript writing: All authors
Final approval of manuscript: All authors
2016 by American Society of Clinical Oncology 1577

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DOI: 10.1200/JCO.2015.65.3493; published
online ahead of print at www.jco.org on
March 7, 2016.
2016 by American Society of Clinical Oncology 1579
 Papakonstantinou et al

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Is Estradiol Monitoring Necessary in Women Receiving Ovarian Suppression for Breast Cancer?
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCOs conict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Antroula Papakonstantinou Kenny A. Rodriguez-Wallberg
No relationship to disclose No relationship to disclose
Theodoros Foukakis Jonas Bergh
Research Funding: Roche (Inst) Research Funding: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Merck
Patents, Royalties, Other Intellectual Property: UpToDate (Inst), Pzer (Inst), Roche (Inst), Sano (Inst)
Royalties: UpToDate

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 Adjuvant Endocrine Therapies for the Premenopausal

Acknowledgment

Supported by grants from the Swedish Cancer Society, the Wallenberg Fund, the research funds at Radiumhemmet, the Breast Cancer
Research (BRECT) Consortium, Karolinska Institutet, and Stockholm County Council. We thank Helen Eriksson for her ne
administrative support.

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