VOLUME 36 • NUMBER 19 • JULY 1, 2018

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Gonadotropin-Releasing Hormone Agonists During

Chemotherapy for Preservation of Ovarian Function and
Fertility in Premenopausal Patients With Early Breast Cancer:
A Systematic Review and Meta-Analysis of Individual
Patient–Level Data
Matteo Lambertini, Halle C.F. Moore, Robert C.F. Leonard, Sibylle Loibl, Pamela Munster, Marco Bruzzone, Luca
Boni, Joseph M. Unger, Richard A. Anderson, Keyur Mehta, Susan Minton, Francesca Poggio, Kathy S. Albain,
Douglas J.A. Adamson, Bernd Gerber, Amy Cripps, Gianfilippo Bertelli, Sabine Seiler, Marcello Ceppi, Ann H.
Partridge, and Lucia Del Mastro

Author affiliations and support information

(if applicable) appear at the end of this A B S T R A C T
article.
Purpose
Published at jco.org on May 2, 2018.
The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa)
Processed as a Rapid Communication during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal
manuscript.
women remains controversial. This systematic review and meta-analysis using individual
A.H.P. and L.D.M. are co-last authors. patient–level data was conducted to better assess the efficacy and safety of this strategy in patients
Clinical trial information: PROSPERO with early breast cancer.
registration number CRD42014015638.
Methods
Corresponding author: Matteo
The trials in which premenopausal women with early breast cancer were randomly assigned to
Lambertini, MD, Institut Jules Bordet and
Université Libre de Bruxelles, Boulevard
receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion.
de Waterloo 121, 1000 Brussels, Belgium; Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy
e-mail: [email protected]. rate. Disease-free survival and overall survival were secondary end points. Because each study
© 2018 by American Society of Clinical represents a cluster, statistical analyses were performed using a random effects model.
Oncology
Results
0732-183X/18/3619w-1981w/$20.00 A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and
30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P , .001). A total of 37
(10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the
control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in
disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival
(adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups.
Conclusion
Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with
GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced
POI and potentially improve future fertility in premenopausal patients with early breast cancer.

J Clin Oncol 36:1981-1990. © 2018 by American Society of Clinical Oncology

associated with gonadotoxicity.2 Age of the patient at

INTRODUCTION
the time of treatment, type of chemotherapy regi-
men administered, and use of adjuvant endo-
Breast cancer is the most commonly diagnosed crine therapy are crucial factors affecting the risk
ASSOCIATED CONTENT
malignancy in premenopausal women, and its of developing this side effect.2 Chemotherapy-
See accompanying Editorial
on page 1895
treatment often results in long-term sequelae induced premature ovarian insufficiency (POI)
and impaired quality of life.1 Given the improved can have a substantial negative impact on pa-
Data Supplement
DOI: https://doi.org/10.1200/JCO.
prognosis of patients with breast cancer over the tients’ quality of life and is associated with
2018.78.0858 past years, survivorship issues are becoming more several side effects, such as vasomotor symp-
DOI: https://doi.org/10.1200/JCO.2018. important.1 The use of anticancer therapies in toms, sexual dysfunction, and fertility-related
78.0858 premenopausal patients with breast cancer is problems.3

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 Lambertini et al

International guidelines recommend to counsel all young pa- of all possible pertinent trials. The search strategy was then repeated before
tients newly diagnosed with breast cancer about the potential risk of final analysis on August 31, 2017 to confirm the retrieval of all possible
chemotherapy-induced POI and infertility.4,5 Failure to address trials. Eligible studies were randomized trials evaluating the efficacy of
adding GnRHa to chemotherapy as a strategy to reduce the occurrence of
these issues can negatively influence patients’ psychosocial health
chemotherapy-induced POI in premenopausal women with early breast
and their adherence to the proposed anticancer treatments, po- cancer receiving (neo)adjuvant chemotherapy.
tentially affecting disease-related morbidity and mortality.1 Embryo For all participants enrolled in each of the included trials, individual
and oocyte cryopreservation are the current standard strategies for patient–level data (baseline patient and tumor characteristics, administered
fertility preservation in young women with breast cancer.4,5 How- treatments, and data on ovarian function after chemotherapy, pregnancies
ever, these approaches do not prevent the risk of developing after breast cancer diagnosis, adverse events during treatment, and survival
chemotherapy-induced POI. To date, temporary ovarian suppres- outcomes) were collected. Data from each of the included trials were
carefully checked and verified for consistency with their original publica-
sion obtained by administering gonadotropin-releasing hormone tions; discrepancies were discussed and resolved with the authors before
agonists (GnRHa) during chemotherapy is the only medical in- pooling the data in the final unified database used for analysis.
tervention with the potential to preserve ovarian function in pre-
menopausal patients receiving cytotoxic systemic therapy.2 Because
of the conflicting results reported in randomized studies, the role of Outcomes
This study aimed to evaluate both the efficacy (ie, preservation of
this option remains controversial, and it is still considered an ex-
ovarian function and fertility) and the safety (ie, toxicity and survival
perimental technique by major international guidelines.4,5 outcomes) of temporary ovarian suppression with GnRHa during che-
In 2015, we performed a systematic review and meta-analysis on motherapy in premenopausal patients with early breast cancer. Primary
the basis of abstracted data from publications to investigate the end points were POI rate (according to the definition used as primary end
protective role of temporary ovarian suppression with GnRHa during point in each trial) and post-treatment pregnancy rate. Secondary end
chemotherapy in premenopausal patients with early breast cancer.6 points included amenorrhea rates 1 year and 2 years after the end of
The use of GnRHa was associated with a significantly reduced risk of chemotherapy, GnRHa-related adverse events (hot flashes, sweating, mood
changes, vaginal dryness, and headache), disease-free survival (DFS), and
chemotherapy-induced POI and amenorrhea 1 year after chemo- overall survival (OS). Prespecified subgroup analyses investigated the ef-
therapy completion, as well as an increased chance of obtaining ficacy and safety of temporary ovarian suppression with GnRHa during
a subsequent pregnancy.6 Nevertheless, no final conclusions could be chemotherapy according to age of the patients, estrogen receptor status,
drawn, mainly because of the lack of data on ovarian function beyond type and duration of chemotherapy administered, and tumor stage.
1 year after the end of chemotherapy, the limited information on the
safety of this approach, and the lack of availability at that time of the
Statistical Analysis
results of the Anglo Celtic Group OPTION (Ovarian Protection Trial All analyses were performed including the total number of patients with
in Oestrogen Non-responsive Premenopausal Breast Cancer Pa- available information for each specific end point.
tients Receiving Adjuvant or Neo-adjuvant Chemotherapy) trial,7 one For POI rate, the primary end point definition of POI used in each of
of the largest studies in this field. Furthermore, without individual the included trials was used. To apply a more homogeneous definition,
patient–level data, analyses of other efficacy and safety outcomes as amenorrhea rates (defined as absence of menses) at 1 year and 2 years after
well as the evaluation of the association between treatment effect and the end of chemotherapy were also computed. For post-treatment preg-
nancy rate, only the first reported pregnancy for each patient was con-
patient or tumor characteristics were not possible. The current study sidered independently of its outcome. Adjusted odds ratios (ORs) with
seeks to provide more conclusive clinical evidence on this contro- 95% CIs were calculated to estimate the effect size of temporary ovarian
versial topic by conducting a meta-analysis on the basis of individual suppression with GnRHa during chemotherapy. Fisher’s exact test was
patient–level data of the randomized trials that investigated the role of applied for POI and amenorrhea analyses. Incidence rate ratio (IRR)
temporary ovarian suppression with GnRHa during chemotherapy as between the GnRHa and control groups for post-treatment pregnancy rate
a strategy to preserve ovarian function and fertility in premenopausal was computed. A multivariate logistic regression analysis was performed to
investigate the effects of GnRHa treatment on the risk of developing POI,
patients with early breast cancer.
1-year and 2-year amenorrhea adjusting by age of the patients at the time of
study entry, estrogen receptor status, type, and duration of chemotherapy
administered. Because each trial represents a cluster of allegedly correlated
METHODS outcomes, a generalized linear mixed model for binary end points with
logit link was fitted to the data by adding to the model the random effect of
This systematic review and meta-analysis of individual patient–level data the study. This model allowed estimating the amount of heterogeneity
are reported according to the Preferred Reporting Items for Systematic between trials and, accordingly, it provided suitable estimates of the
Reviews and Meta-analysis guidelines.8 A protocol was developed before standard errors of the predictors (fixed effects) included in the model.
study initiation and submitted to PROSPERO (registration number GnRHa-related adverse events were dichotomized first as no adverse
CRD42014015638). event (grade 0) and adverse event of any grade (1 to 4), and then as no
adverse event (grade 0), mild (grade 1 or 2), and severe (grade 3 or 4)
adverse events. Toxicity rates were compared using Fisher’s exact test.
Identification of Studies and Collection of Data The reverse Kaplan-Meier method was used to calculate the median
Details about the systematic review of the literature were previously period of follow-up and its interquartile range (IQR). DFS interval was
reported.6 Briefly, a search using PubMed, Embase, and the Cochrane computed as the difference between the date of random assignment and
Library was conducted without any date or language restrictions up to the date of locoregional, contralateral, or distant recurrence, second
April 30, 2015. Furthermore, conference proceedings presented at the most malignancy, or death, whichever occurred first. OS was defined as the time
important international conferences from 2004 onward until April 2015 interval between the date of random assignment and the date of death from
were searched to identify unpublished studies; cross-referencing from any cause. Observation times of patients without the event were censored
relevant studies and review articles was also conducted to confirm retrieval on the date of their last follow-up visit. DFS and OS probabilities were

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 GnRHa for Ovarian Function and Fertility Preservation

computed according to the Kaplan-Meier method. To investigate the effect of DerSimonian and Laird was applied, because it is generally more ap-
of GnRHa treatment on the risk of developing DFS and OS events adjusting propriate in such situation.
by age of the patients at the time of study entry, estrogen receptor status, All statistical tests were two-sided, and P values , .05 were considered
type and duration of chemotherapy administered, and tumor stage, statistically significant. Statistical analyses were performed using STATA
a mixed effect Cox proportional hazards model was fitted to the data to 14.2 (StataCorp LP, College Station, TX).
take into account the clustering effect of each study. As estimates of
treatment effect, adjusted hazard ratios (HRs) with 95% CI were com-
puted. To check for the proportional hazards assumption, the Schoenfeld
residuals were examined. RESULTS
Subgroup analyses of both efficacy and safety end points were per-
formed by means of an interaction test to determine the consistency of the Of the 676 entries returned by the initial database search, 662 were
treatment effect on the outcomes according to age of the patients, estrogen
excluded because they did not meet the inclusion criteria (Data
receptor status, type and duration of chemotherapy administered, and
tumor stage. Likelihood ratio test was applied to test both the main effects Supplement). A total of 14 publications corresponding to 13 different
and the interaction effects of the covariates included in the statistical randomized trials were considered eligible for this study.7,9-21 In-
models. In addition, a meta-analysis procedure was applied to the data of dividual patient–level data were available for five major trials
each individual study for every end point to evaluate the consistency of the (PROMISE-GIM6 [PRevention Of Menopause Induced by chemo-
results between trials. As overall measure of the effect across studies, we therapy: A Study in Early breast cancer patients—Gruppo Italiano
computed the weighted mean of the ORi or HRi estimated from each i-th Mammella 6],9,10 POEMS [Prevention Of Early Menopause Study]/
trial, with weights proportional to the variance of ORi or HRi. The meta-
analysis was performed by means of the inverse-variance method trans-
SWOG S0230,11 Anglo Celtic Group OPTION,7 GBG [German
forming the ORi or HRi in its natural logarithm. The heterogeneity Breast Group]-37 ZORO [ZOladex Rescue of Ovarian function],12
between studies was quantified through the Higgins I2 index. In the presence Moffitt-led trial13) including 873 randomly assigned patients. Indi-
of significant heterogeneity, the random effect model following the method vidual patient–level data from 708 patients included in the remaining

Table 1. Characteristics of the Five Included Randomized Trials

Anglo Celtic Group
Characteristic PROMISE-GIM69,10 POEMS/SWOG S023011 OPTION7 GBG-37 ZORO12 Moffitt-led trial13
Type of chemotherapy CMF or E→CMF or AC or CAF or TAC or CEF CAF or CAF→T or CEF or FEC→D or EC→D or FEC AC or AC→T or FEC or
EP→CMF or ED→CMF or AC→T or CMF CEF→T or FAC or TAC or EC→D FAC
or AC or EC or FEC or or AC→D or FEC→GEM
AC→D or EC→D or
EC→P or FEC→P or
FEC→D or ED
No. of cycles of 6-8 3-8 6-8 6-8 4-8
chemotherapy
Definition of primary No resumption of Amenorrhea for the prior 6 Amenorrhea between 12 No reappearance of two No maintenance of
end point (POI) menstrual activity and months and and 24 months after consecutive menstrual menses and no
postmenopausal levels postmenopausal levels random assignment periods within 21 to 35 resumption of menses
of FSH and E2 at 12 of FSH at 24 months with elevated FSH days 6 months after at 24 months after
months after after chemotherapy chemotherapy chemotherapy
chemotherapy
Planned sample size 280 416 250 62 124
Actual sample size 281 257 227 60 48
Start of accrual October 2003 February 2004 August 2004 March 2005 July 2003
End of accrual January 2008 May 2011 December 2009 December 2007 January 2007
ER status for eligibility ER-positive and ER-negative only ER-positive and ER-negative only ER-positive and
ER-negative ER-negative ER-negative
Upper age limit for # 45 years # 49 years None # 45 years # 44 years
eligibility
Stage for eligibility I-III I-IIIA I-IIIB I-III I-III
Type of GnRHa used in Triptorelin Goserelin Goserelin Goserelin Triptorelin
the experimental group
Mode of GnRHa 3.75 mg IM started at 3.6 mg SC started at least 3.6 mg SC implant started 3.6 mg SC started at least 3.75 mg IM started at
administration in the least 1 week before 1 week before at least 1 week before 2 weeks before least 1 week before
experimental group chemotherapy and then chemotherapy and then chemotherapy and then chemotherapy and then chemotherapy and then
every 4 weeks every 4 weeks every 4 weeks every 4 weeks every 4 weeks
NCI-CTCAE version Version 2.0 Version 3.0 AE not recorded Version 2.0 AE not recorded

Abbreviations: AC, doxorubicin, cyclophosphamide; AC/EC→D, AC or EC followed by docetaxel; AC→T, AC followed by a taxane; AE, adverse events; CAF,
cyclophosphamide, doxorubicin, fluorouracil; CEF, cyclophosphamide, epirubicin, fluorouracil; CMF, cyclophosphamide, methotrexate, fluorouracil; E2, estradiol; EC,
epirubicin, cyclophosphamide; E→CMF, epirubicin followed by CMF; EC→P, EC followed by paclitaxel; ED, epirubicin, docetaxel; ED→CMF, ED followed by CMF;
EP→CMF, epirubicin, paclitaxel followed by CMF; ER, estrogen receptor; FAC, fluorouracil, doxorubicin, cyclophosphamide; FEC, fluorouracil, epirubicin, cyclo-
phosphamide; FEC→D, FEC followed by docetaxel; FEC→GEM, FEC followed by gemcitabine; FEC→P, FEC followed by paclitaxel; FSH, follicle-stimulating hormone;
GBG-37 ZORO, German Breast Group-37 ZOladex Rescue of Ovarian function; GnRHa, gonadotropin-releasing hormone agonists; IM, intramuscularly; NCI-CTCAE,
National Cancer Institute–Common Terminology Criteria for Adverse Events; NR, not reported; OPTION, Ovarian Protection Trial in Oestrogen Non-responsive Pre-
menopausal Breast Cancer Patients Receiving Adjuvant or Neo-adjuvant Chemotherapy; POEMS, Prevention Of Early Menopause Study; POI, premature ovarian
insufficiency; PROMISE-GIM6, PRevention Of Menopause Induced by chemotherapy: A Study in Early breast cancer patients—Gruppo Italiano Mammella 6; SC,
subcutaneous; TAC, docetaxel, doxorubicin, cyclophosphamide.

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 Lambertini et al

eight trials were not available because of refusal to participate for showed that only treatment with GnRHa (adjusted OR, 0.38; 95%
three trials and no success in reaching the principal investigators of CI, 0.26 to 0.57; P , .001) and younger age at diagnosis (adjusted
the other five trials despite several attempts to contact them. OR, 0.35; 95% CI, 0.24 to 0.52; P , .001) were significantly as-
Table 1 summarizes the main characteristics of the five in- sociated with a reduced risk of developing chemotherapy-induced
cluded trials. As per study inclusion criteria, only patients with POI (Data Supplement).
hormone receptor–negative breast cancer were enrolled in two One-year amenorrhea data were available in 760 (87.1%) of
trials.11,12 873 patients. In the GnRHa group, 142 (36.8%) of 386 patients
A total of 873 patients were included, of whom 436 were developed 1-year amenorrhea as compared with 151 (40.4%) of
randomly assigned to the GnRHa group and 437 to the control 374 in the control group (adjusted OR, 0.92; 95% CI, 0.66 to 1.28;
group (Data Supplement). Baseline patient and treatment char- P = .623; Data Supplement).
acteristics were well balanced between the two groups (Table 2). Two-year amenorrhea data were available in 424 (48.6%) of
Median age at diagnosis was 38 years (IQR, 34-42 years); 350 873 patients; this end point was not collected in the PROMISE-
patients (40.1%) had estrogen receptor–positive disease. GIM6 study,9,10 and in patients who developed DFS and/or OS
events between 1 and 2 years. In the GnRHa group, 39 (18.2%) of
214 patients developed 2-year amenorrhea, as compared with 63
Efficacy Results: Preservation of Ovarian Function and (30.0%) of 210 in the control group (adjusted OR, 0.51; 95% CI,
Fertility 0.31 to 0.85; P = .009; Data Supplement).
Chemotherapy-induced POI was the primary end point in all The three largest trials reported post-treatment pregnancies7,9-11;
trials; different definitions and time points for its evaluation were preservation of fertility was a preplanned secondary end point in
used (Table 1). POI data were available in 722 (82.7%) of 873 only one trial.11 Information on post-treatment pregnancies was
patients. In the GnRHa group, 51 (14.1%) of 363 patients de- available in 726 (83.2%) of 873 patients. In the GnRHa group, 37
veloped POI, as compared with 111 (30.9%) of 359 in the control (10.3%) of 359 women had at least one post-treatment pregnancy,
group (adjusted OR, 0.38; 95% CI, 0.26 to 0.57; P , .001). The as did 20 (5.5%) of 367 in the control group (IRR, 1.83; 95% CI,
meta-analysis approach showed no heterogeneity (I2 = 0%; P = 1.06 to 3.15; P = .030; Data Supplement). The meta-analysis
.726; Fig 1A). The effect of GnRHa on reducing the risk of de- approach showed no heterogeneity (I2 = 0%; P = .852; Fig 2).
veloping chemotherapy-induced POI was homogeneous among All pregnancies occurred in patients with # 40 years of age at the
the different patient subgroups (Fig 1B). Multivariate analysis time of diagnosis; 49 (86.0%) and eight (14.0%) of 57 were

Table 2. Baseline Patient and Tumor Characteristics and Treatments Administered by Study Group (N = 873)
GnRHa Group (n = 436) Control Group (n = 437)
Characteristic or Treatment No. (%) No. (%) P*
Age, years, median (IQR) 38 (34-42) 39 (35-42) .258
Age distribution, years .316
# 40 297 (68.1) 283 (64.8)
$ 41 139 (31.9) 154 (35.2)
Tumor stage .800
Stage I 76 (17.4) 78 (17.8)
Stage II 134 (30.7) 130 (29.7)
Stage III 62 (14.2) 54 (12.4)
Missing 164 (37.6) 175 (40.0)
Estrogen receptor status .782
Positive 177 (40.6) 173 (39.6)
Negative 257 (58.9) 262 (59.9)
Missing 2 (0.5) 2 (0.5)
Type of chemotherapy .196
Anthracycline only 194 (44.5) 198 (45.3)
Anthracycline plus taxane 227 (52.1) 210 (48.0)
Non-anthracycline 6 (1.4) 13 (3.0)
Missing 9 (2.1) 16 (3.7)
Cumulative cyclophosphamide dose, mg/m2, median (IQR) 4,000 (3,420 to 5,185) 3,960 (3,082 to 5,400) .585
Duration of chemotherapy .870
# 4 months 120 (27.5) 116 (26.5)
. 4 months 208 (47.7) 194 (44.4)
Missing 108 (24.8) 127 (29.1)
Use of adjuvant endocrine therapy† .578
No 8 (4.5) 5 (2.9)
Yes 126 (71.2) 116 (67.0)
Missing 43 (24.3) 52 (30.1)

Abbreviations: GnRHa, gonadotropin-releasing hormone agonists; IQR, interquartile range.

*Calculated by excluding unknown data
†The percentages were calculated on the total number of patients with estrogen receptor–positive disease (177 in the GnRHa group and 173 in the control group).

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 GnRHa for Ovarian Function and Fertility Preservation

A
GnRHa Control
Study Events/pts Events/pts OR 95% CI

PROMISE-GIM6 16/148 40/133 0.29 0.15 to 0.57

POEMS/SWOG S0230 5/66 15/69 0.33 0.10 to 1.14

Moffitt-led trial 3/26 2/21 1.17 0.14 to 9.55

GBG-37 ZORO 6/28 13/29 0.54 0.14 to 2.07

OPTION 21/95 41/107 0.41 0.20 to 0.81

Overall (I  0%,P = .726) 51/363 111/359 0.37 0.25 to 0.57

.0982 1 10.2

GnRHa better Control better

B Fig 1. Premature ovarian insufficiency (A) by

GnRHa Control P-value for trial, and (B) by patient subgroup. GBG-37 ZORO,
Subgroup Events/pts Events/pts OR 95% CI interaction German Breast Group-37 ZOladex Rescue
of Ovarian function; GnRHa, gonadotropin-
releasing hormone agonists; OPTION, Ovarian
All patients 51/363 111/359 0.38 0.26 to 0.57
Protection Trial in Oestrogen Non-responsive
Premenopausal Breast Cancer Patients Re-
Age distribution, y .139 ceiving Adjuvant or Neo-adjuvant Chemother-
apy; OR, odds ratio; POEMS, Prevention Of
 40 21/254 58/235 0.28 0.16 to 0.49 Early Menopause Study; PROMISE-GIM6,
 41 30/109 53/124 0.52 0.29 to 0.92 PRevention Of Menopause Induced by che-
motherapy: a Study in Early breast cancer
patients—Gruppo Italiano Mammella 6; pts,
Estrogen receptor status .579 patients.
Positive 30/174 52/167 0.46 0.27 to 0.79
Negative 20/187 58/190 0.31 0.17 to 0.56

Type of chemotherapy .155

Anthracycline only 32/169 56/170 0.51 0.30 to 0.87
Anthracycline plus taxane 17/188 49/174 0.26 0.14 to 0.48
Non-anthracycline 0/4 1/8

Duration of chemotherapy .769

 4 months 12/102 31/102 0.34 0.16 to 0.73
> 4 months 16/164 34/144 0.35 0.18 to 0.68

0 .2 .4 .6 .8 1 1.2

GnRHa better Control better

observed in women with estrogen receptor–negative and estrogen Concurrent administration of GnRHa and chemotherapy was asso-
receptor–positive disease, respectively (Data Supplement). ciated with a significantly higher incidence of hot flashes and sweating,
of grade 1 or 2 in the majority of the cases (Data Supplement). No
significant difference was observed in the incidence of mood changes,
Safety Results: Toxicity and Survival Outcomes vaginal dryness, and headache between the GnRHa and control groups.
GnRHa-related adverse events of any grade were recorded in three Survival outcomes were collected in all included trials but
studies,9-12 and two of them reported their severity by grade.9-11 one.13 Median follow-up time was 5.0 years (IQR, 3.0-6.3 years).

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 Lambertini et al

GnRHa Control
Study Events/pts Events/pts IRR 95% CI

PROMISE-GIM6 8/148 3/133 2.52 0.67 to 9.50

Fig 2. Post-treatment pregnancies by trial.
GnRHa, gonadotropin-releasing hormone
POEMS/SWOG S0230 22/105 12/113 1.77 0.87 to 3.57 agonists; IRR, incidence rate ratio; OPTION,
Ovarian Protection Trial in Oestrogen Non-
responsive Premenopausal Breast Cancer
OPTION 7/106 5/121 1.54 0.49 to 4.85
Patients Receiving Adjuvant or Neo-adjuvant
Chemotherapy; POEMS Prevention Of Early
Overall (I = 0%,P = .852) 37/359 20/367 1.82 1.05 to 3.14 Menopause Study; PROMISE-GIM6, PRe-
vention Of Menopause Induced by chemo-
therapy: a Study in Early breast cancer
patients—Gruppo Italiano Mammella 6; pts,
patients.

.105 1 9.5

Control better GnRHa better

Among the 809 (92.7%) of 873 patients evaluable for DFS, 136 number of post-treatment pregnancies. No heterogeneity of
events (16.8%) were observed, 69 (17.2%) of 402 in the GnRHa treatment effect between subgroups was shown. Similar DFS and
group and 67 (16.5%) of 407 in the control group. Five-year DFS OS were observed between groups irrespective of the estrogen
was 79.5% (95% CI, 74.7% to 83.5%) in the GnRHa group and receptor status of the disease.
80.0% (95% CI, 75.2% to 83.9%) in the control group (adjusted The avoidance of symptoms associated with chemotherapy-
HR, 1.01; 95% CI, 0.72 to 1.42; P = .999; Fig 3A). The meta- induced loss of gonadal function represents an important goal to be
analysis approach showed low heterogeneity (I2 = 3.1%; P = .377; achieved in young survivors of breast cancer, even in patients
Data Supplement). Subgroup analysis according to estrogen re- without the desire to have a subsequent pregnancy.22 Our study
ceptor status showed no significant interaction (Pinteraction = .867); supports the protective gonadal effect of GnRHa administration
the adjusted HRs were 1.17 (95% CI, 0.62 to 2.20) and 0.95 (95% during chemotherapy, with a significant 16.8% absolute reduction
CI, 0.64 to 1.42) in patients with estrogen receptor–positive (Fig in the incidence of chemotherapy-induced POI (adjusted OR, 0.38;
3B) and estrogen receptor–negative (Fig 3C) disease, respectively. 95% CI, 0.26 to 0.57; P , .001). The efficacy of this strategy was
The Data Supplement reports the multivariate analysis for DFS. consistent across all subgroups analyzed, including in patients with
Among the 812 (93.0%) of 873 patients evaluable for OS, 77 estrogen receptor–positive disease, and independently of their age
events (9.5%) were observed, 33 (8.2%) of 404 in the GnRHa at the time of treatment. The different definition and time point of
group and 44 (10.8%) of 408 in the control group. Five-year OS evaluation used in the trials highlights the current lack of stan-
was 90.2% (95% CI, 86.4% to 92.9%) in the GnRHa group and dardized definition of chemotherapy-induced POI. Nevertheless,
86.3% (95% CI, 82.0% to 89.7%) in the control group (adjusted the availability of individual patient–level data allowed analysis of
HR, 0.67; 95% CI, 0.42 to 1.06; P = .083; Fig 4A). The meta- ovarian function recovery on the basis of more homogeneous
analysis approach showed that heterogeneity was rather high (I2 = definitions. Using 1-year amenorrhea, the reduced absolute 3.6%
51.1%; P = .105; Data Supplement). Subgroup analysis according difference favoring the GnRHa was not statistically significant
to estrogen receptor status showed no significant interaction (adjusted OR, 0.92; 95% CI, 0.66 to 1.28; P = .623). On the
(Pinteraction = .762); the adjusted HRs were 0.79 (95% CI, 0.24 to contrary, our prior meta-analysis on the basis of abstracted data
2.59) and 0.65 (95% CI, 0.39 to 1.07) in patients with estrogen showed a significant reduction in the risk of 1-year amenorrhea
receptor–positive (Fig 4B) and estrogen receptor–negative (Fig 4C) (OR, 0.55; 95% CI, 0.41 to 0.73; P , .001) when considering the
disease, respectively. The Data Supplement reports the multivariate eight trials that reported this end point.6 The more limited number
analysis for OS. of trials included in the current analysis may explain this dis-
crepancy. Nevertheless, the benefit of concurrent administration of
GnRHa and chemotherapy became clearly evident at a longer time
DISCUSSION point, 2 years after the end of chemotherapy (11.8% absolute
reduction; adjusted OR, 0.51; 95% CI, 0.31 to 0.85; P = .009).
This meta-analysis included individual patient–level data from five However, this end point could be evaluated in a more limited
major trials that investigated the role of temporary ovarian sup- number of patients as compared with 1-year amenorrhea. This is
pression with GnRHa during chemotherapy as a strategy to pre- likely attributable to longer-term evaluation not being originally
serve ovarian function and fertility in premenopausal women with planned for most of these studies and the difficulty faced by in-
early breast cancer. Concurrent administration of GnRHa and vestigators in collecting information on end points like menstrual
chemotherapy significantly reduced the risk of developing function. These findings also highlight that even if the majority of
chemotherapy-induced POI and was associated with a higher patients experience menstrual function recovery in the first

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 GnRHa for Ovarian Function and Fertility Preservation

A B
100 100

80 80

DFS (%)
DFS (%)

60 60

40 40

20 Treatment Patients Events 5-year DFS 20 Treatment Patients Events 5-year DFS
Control group 407 67 80.0 Control group 152 18 87.6
GnRHa group 402 69 79.5 GnRHa group 154 21 85.1

0 1 2 3 4 5 0 1 2 3 4 5
Time Since Random Assignment (years) Time Since Random Assignment (years)
No. at risk No. at risk
Control group 407 352 322 268 232 172 Control group 152 145 140 129 124 110
GnRHa group 402 356 323 286 240 174 GnRHa group 154 151 144 137 123 102

C
100

80
DFS (%)

60

40

20 Treatment Patients Events 5-year DFS

Control group 254 49 73.5
GnRHa group 247 48 75.9

0 1 2 3 4 5
Time Since Random Assignment (years)
No. at risk
Control group 254 206 181 138 108 62
GnRHa group 247 204 178 148 116 71

Fig 3. Disease-free survival (DFS) in (A) the whole study population, (B) patients with estrogen receptor–positive disease, and (C) patients with estrogen receptor–
negative disease. GnRHa, gonadotropin-releasing hormone agonists.

12 months after chemotherapy, this can also occur beyond 1 year. chemotherapy had a subsequent pregnancy as compared with
Hence, an evaluation of chemotherapy-induced POI too close to those who received cytotoxic therapy alone (37 v 20; IRR, 1.83;
the end of chemotherapy might not have captured the protective 95% CI, 1.06 to 3.15; P = .030). This suggests the potential role of
effect of GnRHa that became more evident at a longer time point. this strategy also as a fertility preservation procedure. Embryo and
These findings also support the recent expert opinion–based oocyte cryopreservation remain the first options to be proposed to
suggestion to define menopausal status after chemotherapy not women interested in fertility preservation.4,5 Nevertheless, being
earlier than 2 years after the end of treatment.1 not mutually exclusive, temporary ovarian suppression with
Approximately 50% of young patients with breast cancer are GnRHa during chemotherapy can also be used in this setting after
concerned about the possible risk of infertility as a consequence of cryopreservation procedures to increase the chances of a sub-
chemotherapy use and desire to have children after the end of sequent pregnancy as well as in patients who do not have access to
treatment.23 Nevertheless, these patients are, among survivors of assisted reproductive options.25 Notably, for patients receiving
cancer, those with the lowest chances of subsequent pregnancies.4 temporary ovarian suppression with GnRHa during chemotherapy
In our analysis, less than 10% of the patients had a post-treatment after prior controlled ovarian stimulation for embryo/oocyte
pregnancy (57 patients, 7.9%), in line with the available data in the cryopreservation, the timing for administering the long-acting
literature of a pregnancy rate in survivors of breast cancer ranging GnRHa needs to be further explored, considering its potential
between 4% and 7%.24 Although the absolute numbers remain low use as trigger of final follicular maturation instead of chorionic
and the trials were not designed to address pregnancy as primary gonadotropin or short-acting GnRHa. In addition, future research
end point, a statistically significant higher number of patients who efforts should aim at clarifying the fertility outcomes of patients
underwent temporary ovarian suppression with GnRHa during who undergo temporary ovarian suppression with GnRHa during

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 Lambertini et al

A B
100 100

80 80
OS (%)

60

OS (%)
60

40 40

20 Treatment Patients Events 5-year OS 20 Treatment Patients Events 5-year OS

Control group 408 44 86.3 Control group 153 6 95.6
GnRHa group 404 33 90.2 GnRHa group 155 5 96.6

0 1 2 3 4 5 0 1 2 3 4 5
Time Since Random Assignment (years) Time Since Random Assignment (years)
No. at risk No. at risk
Control group 408 362 342 291 254 188 Control group 153 150 146 141 136 119
GnRHa group 404 370 350 313 265 199 GnRHa group 155 155 151 146 135 118

C
100

80
OS (%)

60

40

20 Treatment Patients Events 5-year OS

Control group 254 38 79.0
GnRHa group 248 28 85.0

0 1 2 3 4 5
Time Since Random Assignment (years)
No. at risk
Control group 254 211 195 149 118 69
GnRHa group 248 214 198 166 129 80

Fig 4. Overall survival (OS) in (A) the whole study population, (B) patients with estrogen receptor–positive disease, and (C) patients with estrogen receptor–negative
disease. GnRHa, gonadotropin-releasing hormone agonists.

chemotherapy after cryopreservation procedures as compared with difference between patients who received GnRHa concurrently or
those of women who access only one of the two strategies.25 sequentially to chemotherapy.28 Our study confirms the safety of
The main adverse events associated with GnRHa administration concurrent administration of GnRHa and chemotherapy in all
are vasomotor symptoms and sexual problems.26 Nevertheless, these patients with breast cancer, irrespective of the estrogen receptor
side effects are mainly of grade 1 or 2 and are reversible at the time of status of their disease. Nevertheless, of note, the majority of pa-
treatment completion. Importantly, preservation of ovarian function tients with estrogen receptor–positive disease included in this
with GnRHa use during chemotherapy may help avoid menopausal analysis derive from the PROMISE-GIM6 trial.9,10 In this study,
symptoms, including loss of bone density, in the long term; this is of approximately 70% of the patients with estrogen receptor–positive
crucial importance also in women not interested in fertility preservation. disease who had resumed ovarian function after chemotherapy
In the past, two major safety concerns on the use of temporary were treated with GnRHa as part of adjuvant endocrine therapy.10
ovarian suppression with GnRHa during chemotherapy were This further supports that the safety of ovarian function preser-
raised for women with estrogen receptor–positive disease: a po- vation in patients with hormone receptor–positive disease should
tential antagonism with concurrent administration of antiestrogen be considered in the context of subsequent ovarian function
therapy and cytotoxic systemic therapy, and the possible detri- suppression as part of adjuvant endocrine therapy.29
mental effect on prognosis of the lack of chemotherapy-induced Some limitations of the current study should be acknowl-
POI.27 These concerns have been recently dispelled by the results of edged. It was possible to include individual patient–level data
the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Sup- from only five major randomized trials, corresponding to 55.2%
pression of Ovarian Function Trial) trials showing no survival (873 of 1,581) of the eligible population for this study.

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 GnRHa for Ovarian Function and Fertility Preservation

Nevertheless, for all end points that could be evaluated also in our
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
previous meta-analysis of abstracted data, similar results were OF INTEREST
observed, with the exception of 1-year amenorrhea.6 This may
suggest that the inclusion of all studies would not have modified Disclosures provided by the authors are available with this article at
the overall findings. For the efficacy end points, major limitations jco.org.
are the lack of data on the extent of ovarian function preservation
using more sensitive biomarkers like the anti-Müllerian hor-
mone, the limited information on patients’ wish to have
a pregnancy, and on the number of women with more than one AUTHOR CONTRIBUTIONS
post-treatment pregnancy. Finally, a few baseline characteristics
and end point data were missing in some trials and for some Conception and design: Matteo Lambertini, Ann H. Partridge, Lucia Del
patients also in studies that had originally planned to collect Mastro
them. Nevertheless, there is no evidence of imbalance for these Provision of study materials or patients: Matteo Lambertini, Halle C.F.
missing data or a differential drop-out between the GnRHa and Moore, Robert C.F. Leonard, Sibylle Loibl, Pamela Munster, Richard A.
Anderson, Susan Minton, Francesca Poggio, Kathy S. Albain, Douglas J.A.
control groups; thus, it is unlikely that they may have influenced Adamson, Bernd Gerber, Gianfilippo Bertelli, Sabine Seiler, Amy Cripps,
the comparisons between randomly assigned groups. Ann H. Partridge, Lucia Del Mastro
In conclusion, our systematic review and meta-analysis of Collection and assembly of data: Matteo Lambertini, Halle C.F. Moore,
individual patient–level data provides evidence for the efficacy and Robert C.F. Leonard, Sibylle Loibl, Pamela Munster, Marco Bruzzone, Luca
safety of temporary ovarian suppression with GnRHa during Boni, Joseph M. Unger, Richard A. Anderson, Keyur Metha, Francesca
chemotherapy in premenopausal patients with early breast cancer. Poggio, Kathy S. Albain, Douglas J.A. Adamson, Bernd Gerber, Gianfilippo
Bertelli, Sabine Seiler, Marcello Ceppi, Ann H. Partridge, Lucia Del Mastro
Given the findings of our study, this strategy should be considered
Data analysis and interpretation: Matteo Lambertini, Marco Bruzzone,
as an available option to reduce the likelihood of chemotherapy- Marcello Ceppi, Ann H. Partridge, Lucia Del Mastro
induced POI and potentially improve future fertility in premeno- Manuscript writing: All authors
pausal patients with early breast cancer undergoing (neo)-adjuvant Final approval of manuscript: All authors
chemotherapy. Accountable for all aspects of the work: All authors

9. Del Mastro L, Boni L, Michelotti A, et al: Effect 17. Song G, Gao H, Yuan Z: Effect of leuprolide
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 Lambertini et al

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Affiliations
Matteo Lambertini, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Halle C.F. Moore, Cleveland Clinic
Taussig Cancer Institute, Cleveland, OH; Robert C.F. Leonard, Imperial College, London; Richard A. Anderson, University of Edinburgh,
Edinburgh; Douglas J.A. Adamson, Ninewells Hospital, Dundee; Gianfilippo Bertelli, Sussex Cancer Centre, Brighton, United Kingdom;
Sibylle Loibl, Keyur Mehta, and Sabine Seiler, German Breast Group, Neu-Isenburg; Bernd Gerber, University Hospital Rostock,
Rostock, Germany; Pamela Munster, University of California, San Francisco, San Francisco, CA; Marco Bruzzone, Francesca Poggio,
Marcello Ceppi, and Lucia Del Mastro, Ospedale Policlinico San Martino; Francesca Poggio and Lucia Del Mastro, University of Genova,
Genova; Luca Boni, Azienda Ospedaliero Universitaria Careggi, Florence, Italy; Joseph M. Unger, SWOG Statistical Center and Fred
Hutchinson Cancer Research Center, Seattle, WA; Susan Minton, Moffitt Cancer Center, Tampa, FL; Kathy S. Albain, Loyola University
Chicago Stritch School of Medicine, Maywood, IL; Amy Cripps, Nexgen Oncology, Dallas, TX; and Ann H. Partridge, Dana-Farber
Cancer Institute, Boston, MA.
Support
Supported in part by the Italian Association for Cancer Research (AIRC) Grant No. 2013:14272.
The financial sponsor of the study (AIRC) had no role in study design, data collection, or analysis, interpretation, or writing of the
report, and it had no access to the individual patient–level data.
Prior Presentation
Presented at the 2017 San Antonio Breast Cancer Symposium, San Antonio, TX, December 7, 2017.

nnn

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 GnRHa for Ovarian Function and Fertility Preservation

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients
With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient–Level Data
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Matteo Lambertini Francesca Poggio
Consulting or Advisory Role: Teva No relationship to disclose
Travel, Accommodations, Expenses: Astellas Pharma
Kathy S. Albain
Halle C.F. Moore Consulting or Advisory Role: Novartis, Pfizer, Myriad Genetics,
Research Funding: Puma Biotechnology (Inst), AbbVie (Inst) Genentech
Other Relationship: Puma Biotechnology
Robert C.F. Leonard
No relationship to disclose Douglas J.A. Adamson
Stock or Other Ownership: GlaxoSmithKline (I)
Sibylle Loibl Research Funding: Roche (Inst), Aventis Pharma (Inst), Novartis (Inst),
Research Funding: Pfizer, Roche, Celgene, Amgen, Novartis (Inst) Amgen (Inst), Pfizer (Inst), Bayer (Inst), Sanofi (Inst), Boehringer
Pamela Munster Ingelheim (Inst), Immodulon Therapeutics (Inst), Schering-Plough (Inst),
Honoraria: Sanofi, Amgen (I), AstraZeneca, EMD Serono Biocompatibles (Inst), AstraZeneca (Inst)
Consulting or Advisory Role: OncoSec Bernd Gerber
Research Funding: Merck (Inst), Pfizer (Inst), Novartis (Inst), Travel, Accommodations, Expenses: AstraZeneca, Roche
GlaxoSmithKline (Inst), OncoMed (Inst), Celgene (Inst), Andes
Biotechnologies (Inst), Incyte (Inst), Ignyta (Inst), CBT Pharmaceuticals Amy Cripps
(Inst), Merrimack (Inst), Genentech (Inst), OncoSec (Inst), Bristol-Myers Employment: NexGen Oncology
Squibb (Inst), Plexxikon (Inst), Piramal Life Science (Inst), Andes Travel, Accommodations, Expenses: Foundation Medicine
Biotechnologies (Inst), Immune Design (Inst), Biomarin (Inst)
Gianfilippo Bertelli
Marco Bruzzone Consulting or Advisory Role: Roche, Novartis Pharmaceuticals UK,
No relationship to disclose Genomic Health
Travel, Accommodations, Expenses: Roche
Luca Boni
No relationship to disclose Sabine Seiler
Consulting or Advisory Role: Hexal, Roche, Amgen, Novartis
Joseph M. Unger Travel, Accommodations, Expenses: Hexal, Roche, Novartis, Amgen
No relationship to disclose
Marcello Ceppi
Richard A. Anderson No relationship to disclose
Consulting or Advisory Role: Roche Diagnostics, HRA Pharma, NeRRe
Therapeutics Ann H. Partridge
Speakers’ Bureau: IBSA, Merck No relationship to disclose
Research Funding: Ferring Pharmaceuticals
Lucia Del Mastro
Keyur Metha Honoraria: Roche, Novartis, Takeda Pharmaceuticals, Ipsen, Eisai, Pfizer
No relationship to disclose Consulting or Advisory Role: Eli Lilly
Susan Minton
No relationship to disclose

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 Lambertini et al

Acknowledgment

Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research
Fellowship at Institut Jules Bordet in Brussels (Belgium); he received a San Antonio Breast Cancer Symposium Clinical Scholar Award for
presenting the results of this systematic review and meta-analysis at the 2017 San Antonio Breast Cancer Symposium. The authors thank all
the patients and the investigators from the Gruppo Italiano Mammella (GIM) study group, the SWOG, the Anglo Celtic Group, the
German Breast Group (GBG), and the Moffitt-led study who participated in the five included trials.

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