abstract gs4-01: pooled analysis of five randomized trials … · 2020. 12. 23. · daniela...
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Abstract GS4-01: Pooled analysis of five randomized trials investigating
temporary ovarian suppression with gonadotropin-releasing hormone
analogs during chemotherapy as a strategy to preserve ovarian function
and fertility in premenopausal early breast cancer patients
Daniela Dornelles Rosa, MD PhD
Hospital Moinhos de Vento
PPG Patologia UFCSPA
www.infomama.com.br
Porto Alegre, RS
Disclosures
Disclosure categories Industry
Grant support Roche, Lilly,
GSK, Astra
Zeneca, Sanofi,
Novartis
Run clinical trials sponsored by companies Roche, Amgen,
GSK
Lecture fees Eisai, Roche,
Novartis
Advisory board participation Novartis, Roche
Academic research grant L‘Oreal
Stock owner ----
San Antonio Breast Cancer Symposium, December 5-9, 2017
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute
Pooled analysis of five randomized trials investigating temporary ovarian
suppression with gonadotropin-releasing hormone analogs during
chemotherapy as a strategy to preserve ovarian function and fertility in
premenopausal early breast cancer patients
Matteo Lambertini1, Halle C.F. Moore2, Robert C.F. Leonard3, Sibylle Loibl4, Pamela Munster5, Marco
Bruzzone6, Luca Boni7, Joseph M. Unger8, Richard A. Anderson9, Keyur Mehta4, Susan Minton10,
Francesca Poggio6, Kathy S. Albain11, Douglas J.A. Adamson12, Bernd Gerber13, Amy Cripps14, Gianfilippo
Bertelli15, Sabine Seiler4, Marcello Ceppi6, Ann H. Partridge16, and Lucia Del Mastro6
1Institut Jules Bordet and Université Libre de Bruxelles (U.L.B.), Brussels, Belgium. 2Cleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OH.3Imperial College, London, UK. 4GBG - German Breast Group, Neu-Isenburg, Germany. 5UCSF - University of California, San Francisco, CA. 6Ospedale
Policlinico San Martino-IST, Genova, Italy. 7AOU Careggi and Istituto Toscano Tumori, Firenze, Italy. 8SWOG Statistical Center, Fred Hutchinson Cancer
Research Center, Seattle, WA. 9MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK. 10Moffitt Cancer Center, Tampa, FL. 11Loyola
University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL. 12Tayside Cancer Centre, Ninewells Hospital, Dundee, UK. 13University Hospital
Rostock, Rostock, Germany. 14Nexgen Oncology, Dallas, TX. 15Singleton Hospital, Swansea, UK. 16Dana-Farber Cancer Institute, Boston, MA.
• Fertility preservation and pregnancy-related issues are high priority areas
of concern for young women with breast cancer
• Oocyte/embryo cryopreservation are standard strategies for fertility
preservation but they do not prevent the risk of chemotherapy-induced
premature ovarian insufficiency (POI)
• Temporary ovarian suppression with GnRHa during chemotherapy has
been studied in several RCTs as a strategy to preserve ovarian function
and potential fertility
• However, data are mixed and its role remains controversial
Background
• Systematic review and meta-analysis of individual patient data from RCTs
that investigated the role of temporary ovarian suppression with GnRHa
during chemotherapy for early breast cancer patients
Study Methods
• To evaluate the efficacy (ovarian function and fertility preservation) and
the safety (survival outcomes) of GnRHa use during chemotherapy
Study objectives
• Primary endpoints
- POI rate (according to the definition used as primary endpoint in each
trial)
- Post-treatment pregnancy rate
• Secondary endpoints
- Amenorrhea rates one year and two years after the end of
chemotherapy
- Disease-free survival (DFS) and overall survival (OS)
Study endpoints
Results
Results
Study Characteristics
PROMISE-GIM61,2 POEMS/SWOG
S02303
Moffitt-led trial4 GBG-37 ZORO5 Anglo Celtic Group
OPTION6
Definition of POI No resumption of
menstrual activity and
postmenopausal
levels of FSH and E2
Amenorrhea for the
prior 6 months and
postmenopausal
levels of FSH
No maintenance of
menses and no
resumption of menses
No re-appearance of
two consecutive
menstrual periods
within 21 to 35 days
Amenorrhea with
elevated FSH
Timing of POI after
chemotherapy
12 months 24 months 24 months 6 months Between 12 and 24
months
Sample size 281 257 48 60 227
ER status for
eligibility
ER-positive and ER-
negative
ER-negative only ER-positive and ER-
negative
ER-negative only ER-positive and ER-
negative
Upper age limit for
eligibility
≤ 45 years ≤ 49 years ≤ 44 years ≤ 45 years None
Type of GnRHa Triptorelin Goserelin Triptorelin Goserelin Goserelin
Amenorrhea AmenorrheaAmenorrhea
+ FHSAmenorrhea
+ FHS
Amenorrhea
+ FHS + E2
ER-negative only ER-negative only
ResultsGnRHa group
(n=436)
No. (%)
Control group
(n=437)
No. (%)
p value*
Age, median (IQR), years 38 (34-42) 39 (35-42) 0.258
Age distribution, years
≤ 40
≥ 41
297 (68.1)
139 (31.9)
283 (64.8)
154 (35.2)
0.316
Estrogen receptor status
Positive
Negative
Missing
177 (40.6)
257 (58.9)
2 (0.5)
173 (39.6)
262 (59.9)
2 (0.5)
0.782
Type of chemotherapy
Anthracycline only-based
Anthracycline- and taxane-based
Non anthracycline-based
Missing
194 (44.5)
227 (52.1)
6 (1.4)
9 (2.1)
198 (45.3)
210 (48.0)
13 (3.0)
16 (3.7)
0.196
Cumulative cyclophosphamide dose,
median (IQR), mg/m2
4000 (3420-5185) 3960 (3082-5400) 0.585
Premature ovarian insufficiency rate
OR adjusted for age, ER, type and duration of CT
62% POI rate
No heterogeneity
Overall (I≤=0%,p=0.73) 51/363 111/359
GBG-37 ZORO
OPTION
Study
UCSF-led trial
POEMS/SWOG S0230
PROMISE-GIM6
6/28
GnRHa
21/95
Events/pts
3/26
5/66
16/148
13/29
Control
41/107
Events/pts
2/21
15/69
40/133
0.37 (0.25, 0.57)
0.54 (0.14, 2.07)
0.41 (0.20, 0.81)
OR (95% CI)
1.17 (0.14, 9.55)
0.33 (0.10, 1.14)
0.29 (0.15, 0.57)
0.37 (0.25, 0.57)
0.54 (0.14, 2.07)
0.41 (0.20, 0.81)
OR (95% CI)
1.17 (0.14, 9.55)
0.33 (0.10, 1.14)
0.29 (0.15, 0.57)
1.0982 1 10.2
GnRHa better Control better
All patients
Age distribution, y ≤ 40 ≥ 41
Estrogen receptor status Positive Negative
Type of chemotherapy Anthracycline only Anthracycline+taxane Non anthracycline
Duration of chemotherapy ≤ 4 months > 4 months
Subgroup
51/363
21/254 30/109
30/174 20/187
32/169 17/188 0/4
12/102 16/164
Events/pts GnRHa
111/359
58/235 53/124
52/167 58/190
56/170 49/174 1/8
31/102 34/144
Events/pts Control
0.38 (0.26-0.57)
0.28 ( 0.16-0.49 ) 0.52 ( 0.29-0.92 )
0.46 ( 0.27-0.79 ) 0.31 ( 0.17-0.56 )
0.51 ( 0.30-0.87 ) 0.26 ( 0.14-0.48 )
0.34 ( 0.16-0.73 ) 0.35 ( 0.18-0.68 )
OR (95% CI)
0.139
0.579
0.155
0.769
interaction P-value for
0.38 (0.26-0.57)
0.28 ( 0.16-0.49 ) 0.52 ( 0.29-0.92 )
0.46 ( 0.27-0.79 ) 0.31 ( 0.17-0.56 )
0.51 ( 0.30-0.87 ) 0.26 ( 0.14-0.48 )
0.34 ( 0.16-0.73 ) 0.35 ( 0.18-0.68 )
OR (95% CI)
0.139
0.579
0.155
0.769
interaction P-value for
1 0 .2 .4 .6 .8 1 1.2
GnRHa better Control better
Premature ovarian insufficiency rate
Post-treatment pregnancy rates
Overall (I≤=0%,p=0.85) 37/359 20/367
POEMS/SWOG S0230
PROMISE-GIM6
Study
OPTION
22/105
8/148
GnRHa
Events/pts
7/106
12/113
3/133
Control
Events/pts
5/121
1.82 (1.05, 3.14)
1.77 (0.87, 3.57)
2.52 (0.67, 9.50)
IRR (95% CI)
1.54 (0.49, 4.85)
1.82 (1.05, 3.14)
1.77 (0.87, 3.57)
2.52 (0.67, 9.50)
IRR (95% CI)
1.54 (0.49, 4.85)
1.105 1 9.5
Control better GnRHa better
GnRHa group
(n = 37)
No. (%)
Control group
(n = 20)
No. (%)
Age distribution, years
≤ 40
≥ 41
37 (100)
0 (0.0)
20 (100)
0 (0.0)
Estrogen receptor status
Positive
Negative
6 (16.2)
31 (83.8)
2 (10.0)
18 (90.0)
GnRHa Group: 37/359 (10.3%)
vs.
Control Group: 20/367 (5.5%)
IRR* 1.83 (95% CI 1.06-3.15)
p=0.030
No heterogeneity
San Antonio Breast Cancer Symposium, December 5-9, 2017
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute
0%
10%
20%
30%
40%
50%
36.8%
GnRHa group
n=386
Control group
n=374
40.4%
OR* 0.92 (95% CI 0.66-1.28); p=0.623
0%
10%
20%
30%
40%
50%
18.2%
GnRHa group
n=214
Control group
n=210
30.0%
OR* 0.51 (95% CI 0.31-0.85); p=0.009
One-Year Amenorrhea Two-Year Amenorrhea
*Odds ratio (OR) adjusted for age, estrogen receptor status, type and duration of chemotherapy
administered
Amenorrhea rates
Disease-free progression
Median follow-up = 5.0 years (IQR, 3.0 - 6.3 years)
0
20
40
60
80
100
Dis
ea
se F
ree
Su
rviv
al (%
)
402 356 323 286 240 174GnRHa group
407 352 322 268 232 172Control groupNumber at risk
0 1 2 3 4 5
Time Since Random Assignment (years)
Control group 407 67 80.0
GnRHa group 402 69 79.5
TREATMENT Patients Events DFS
All Patients
0
20
40
60
80
100
Dis
ea
se F
ree
Su
rviv
al (%
)
154 151 144 137 123 102GnRHa group
152 145 140 129 124 110Control groupNumber at risk
0 1 2 3 4 5
Time Since Random Assignment (years)
Control group 152 18 87.6
GnRHa group 154 21 85.1
TREATMENT Patients Events DFS
ER+ PatientsEstrogen receptor-positive disease
0
20
40
60
80
100
Dis
ea
se F
ree
Su
rviv
al (%
)
247 204 178 148 116 71GnRHa group
254 206 181 138 108 62Control groupNumber at risk
0 1 2 3 4 5
Time Since Random Assignment (years)
Control group 254 49 73.5
GnRHa group 247 48 75.9
TREATMENT Patients Events DFS
ER- PatientsEstrogen receptor-negative disease
HR* 1.17 (95% CI 0.62-2.20)
HR* 0.95 (95% CI 0.64-1.42)
Overall survival
0
20
40
60
80
100
Overa
ll S
urv
iva
l (%
)
404 370 350 313 265 199GnRHa group
408 362 342 291 254 188Control groupNumber at risk
0 1 2 3 4 5
Time Since Random Assignment (years)
Control group 408 44 86.3
GnRHa group 404 33 90.2
TREATMENT Patients Events OS
All PatientsMedian follow-up = 5.0 years (IQR, 3.0 - 6.3 years)
0
20
40
60
80
100
Overa
ll S
urv
iva
l (%
)
155 155 151 146 135 118GnRHa group
153 150 146 141 136 119Control groupNumber at risk
0 1 2 3 4 5
Time Since Random Assignment (years)
Control group 153 6 95.6
GnRHa group 155 5 96.6
TREATMENT Patients Events OS
ER+ PatientsEstrogen receptor-positive disease
Estrogen receptor-negative disease
HR* 0.79 (95% CI 0.24-2.59)
0
20
40
60
80
100
Overa
ll S
urv
iva
l (%
)
248 214 198 166 129 80GnRHa group
254 211 195 149 118 69Control groupNumber at risk
0 1 2 3 4 5
Time Since Random Assignment (years)
Control group 254 38 79.0
GnRHa group 248 28 85.0
TREATMENT Patients Events OS
ER- Patients
HR* 0.65 (95% CI 0.39-1.07)
Conclusions
• Administration of GnRHa during chemotherapy was associated with a
significant reduction in the risk of chemotherapy-induced POI
• A greater number of women in the GnRHa group had a post-treatment
pregnancy
• Similar DFS and OS were observed between groups irrespective of the
estrogen receptor status of the disease
• This strategy should be considered as an option to reduce the likelihood
of chemotherapy-induced POI and potentially improve future fertility in
premenopausal early breast cancer patients undergoing (neo)adjuvant
chemotherapy
Potential issues
- No individual data
- Similar results to other 5 included
Potential issues
• Studies limited to breast cancer – 3 negative studies in
hematologic diseases
• Heterogeneity of patients and chemo doses
• Younger age in hematologic studies
• Low number of patients
Thank you!