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 matteo.lambertini@bordet.be 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 matteo.lambertini@bordet.be 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!

dornellesrosa@gmail.com