What’s

new in Ovarian
Function Suppression in Pre-
menopausal Breast Cancer?
M. Yadi Permana
Fatmawati National Central Hospital
Jakarta
 Breast cancer is the 1st most common cancer in Indone

• In 2018, more than 58.000 woman has diagnosed

with breast cancer and around 22.000 women died
due to breast cancer1

• American Joint Committee of Cancer (AJCC)

recommends the collection of biomarkers, such as
hormone receptor status (Estrogen/Progesterone
Receptor (ER/PR)) and Human Epidermal Growth
Factor 2 (HER2) status, although these do not
specifically influence assigned stage of disease2
• The choice of medication is primarily determined by
patient’s menopausal status

2
Treatment Options for Pre-/perimenopausal
Women with HR+ Early Breast Cancer

§ Selective estrogen receptor modulator (SERM)

§ Cytotoxic chemotherapy
§ Ovarian ablation
• Surgery, Irradiation

• Medical ovarian suppression (GnRHa)

Ovarian Suppression in Pre-menopausal B
 Ovarian Suppression

• Luteinizing hormone-releasing hormone (LHRH) agonists were d

suppress ovarian function for the treatment of premenopausal br
time, ovarian suppression (OS) was gradually substituted OA(Ov

• The long-term use of an LHRH agonist for the treatment of HR+

was considered a new medical method of OA in the reversible fo
be seen as advantageous for the preservation of fertility in breas

5
Ovarian Suppression with LHRH Agon
 ASCO, St. Gallen, NCCN has recommended Combinati
Tamoxifen1,2,3

8
 Goserelin 3.6 mg suppresses serum oestradio
postmenopausal level by the 8th day

9
Combination of Goserelin and Tamo
 ASTRRA study(2019): Role of adding ov
function suppression to tamoxifen in young
with hormone-sensitive breast cancer who
premenopausal or resume menstruation
chemotherapy

Primary objective:
To compare 5-year DFS between Tamoxifen (5yrs) plus OFS (2yrs
alone for women who remain premenopausal or resume OF after c
neoadjuvant chemotherapy.
 Patient Characteristics I
Characteristics T only
N=647 %

Age at enrollment (years) <35 83 12.8

35-39 194 30.0

40-45 370 57.2
Median [range] 40 24-45
Mean [±SD] 39.7 ±4.1
Lymph node status Negative 289 44.7
Positive 358 55.3
Tumor size <2cm 310 47.9
≥2cm 337 52.1
Tumor grade 1 89 13.8
2 349 53.9
3 157 24.3
Unknown 52 8.0
Invasive ductal carcinoma 570 88.1
Histology
 Patient Characteristics II
Characteristics T only
N=647 % N
HER2 status Negative 362 56.0
Positive 92 14.2
Equivocal 24 3.7
Unknown/Not done 169 26.1
AC 186 28.7
Chemotherapy regimen
AC followed by taxane 330 51.0
AT 29 4.5
TAC 9 1.4
FAC 74 11.4
Other taxane based regime 7 1.1

Other non-taxane based regimen 5 0.8

Unknown 7 1.1
Surgery Total mastectomy 260 40.2
 Frequency and Pattern of OF recovery :defined as FSH<30mI
history (N=1,369)

(%)
1370 100 Premenopausal sta
the first screening
90 defined by:

Number of patients
1096 80 • serum follicular
stimulating horm
70 (FSH) levels < 3
822 60 mIU/ml.
• At 6, 12, 18, an
50 months followin
baseline assessm
548 40 ovarian function
30 to be evaluated
menstruation st
274 20 serum FSH leve
10
0 0
0 6 12 18 24
Woo Chul Noh 14
Months since enrollment
 ASTRRA (2018): Goserelin + Tamoxifen significantly i
Disease Free Survival and Overall Survival

15
Conclusion
• OF needs to be monitored longitudinally for at least 2 years af
chemotherapy to establish eligibility of OFS.

• For those who remained in premenopausal status or resumed

chemotherapy, adding 2 years of OFS to tamoxifen significant
DFS as compared to tamoxifen alone.
 Long term follow up (12 years) trial show Goserelin
provide additional benefit in reducing death &

17
 Goserelin +Tamoxifen is well tolerated and has no
safety issues1

Treatment re

Goserelin alone Go
(n = 154)

Symptoms % (n)

Hot flushes 74 (114)

Vaginal discharge 13 (20)

Vaginal soreness 18 (27)

Adverse effect on sexual activity 15 (23)

18
Absolute improvements in Freedom from Distant Recurrence
with Adjuvant Endocrine Therapies for Premenopausal
Women with HR+ HER2-negative Breast Cancer: Result from
TEXT and SOFT
 SOFT and TEXT Design

R
A
• Premenopausal HR+ Tamoxifen+OFS x 5y
N
• ≤12 wks after surgery D
TEXT (N=2672)
• Planned OFS O
• No planned chemo (40%) or M Exemestane+OFS x 5y
planned chemo (60%) I
Z
E
Tamoxifen x 5y
R
A
• Premenopausal HR+ N SOFT (n=3066) Tamoxifen + OFS x 5y
• ≤12 wks after surgery D
• No chemo (47%) or O
M
• Remain premenopausal ≤ 8
mos after chemo (53%)
I Exemestane + PFS x 5y
Z
E
Woo Chul Noh
Efficacy of OFS on DFS

All Patients

Patients with CTX

Efficacy of OFS according to HER2 status
Efficacy of E or T with OFS
 Conclusions of SOFT TEXT Analys

• Adding OFS to T results in higher DFS in preM women, especially fo

who received chemotherapy.

• Further improvement was seen with E + OFS

• For HER2- and received CTX, the benefit of E+OFS on DFS was gr
Goserelin in preserving ovarian functio
chemotherapy
 Goserelin associated with a low risk of long t
chemotherapy-induced amenorrhoea and a high c
pregnancy*

71% of patients
achieved pregnancies+
95%
Cumulative patients who resumed

94%
100% 82%
menstrual activity (%)

90%
80%
70% 54%
60%
50%
40% 21%
30%
20%
10%
0%
3 months 6 months 12 months 18 months 24 month 36 mon
26
Goserelin survival in premenopausal pati
advanced breast cancer
 Goserelin achieve similar survival to oophorectom
breast cancer

28
 GOSERELIN 10.8 MG INDICATION STARTING 2020

¡ Premenopausal Breast Cancer: Goserelin 10,8 mg is i

management of premenopausal breast cancer for hor
positive
Study (NCT00303524): multicenter, open-label, randomized, parallel group in pre-menopausal Jap
ER+ early breast cancer recruited from 29 centers across Japan

Primary end
• Age ≥ 20 years Goserelin 10.8 mg, sc • AUC E2 ser
• Histologically or cytologically (every 3 month) + the first 24 w
confirmed breast cancer and an Tamoxifen 20 mg, daily Secondary e
ER+ primary tumor n = 86 • E2 and FSH
N = 170
• Prior had radical surgery • % patients w
• PS ≤ 2 concentratio
• Pre-menopausal criteria: 1:1 • Menstruatio
• Menses within 1 year
• E2 levels ≥10 pg/ml
• DFS
• FSH levels ≤30 mIU/ml within 3 Goserelin 3.6 mg, sc • Tolerability (
weeks before randomization (every month) + laboratory t
Tamoxifen 20 mg, daily

n = 84

Exclusion criteria:
- Metastatic disease,
- prior bilateral oophorectomy or radiotherapy to the ovaries, or if breast surgery had been completed (12 weeks) before ra
- prior chemotherapy (including neo-adjuvant chemotherapy) or hormone therapy for breast cancer;
 GOSERELIN 10.8 MG
GIVEN EVERY 3
MONTHS IS AS
EFFECTIVE AS
MONTHLY GOSERELIN
3.6 MG IN ACHIEVING
• ≥98.8% patient maintain E2 serum concentration ≤30 pg/ml à within range regarded as the post-menopausal status
• All the patients experienced amenorrhea by week 12 in the 10.8 mg group and by week 16 in the 3.6 mg group

AND MAINTAINING
Endpoint Goserelin 10.8 Goserelin 3.6 mg OVARIAN
mg SUPPRESSION IN PRE-
Primary endpoint: MENOPAUSAL
AUC of E2 serum concentration WOMEN
during the first 24 weeks of treatment
18.32 pg/ml 18.95 pg/ml
AUC ratio (10.8/3.6) = 0.974
CI 95% upper limit (1.188)*
*Non-inferiority was demonstrated if the upper 95% CI limit of the E2 AUC ratio (10.8/3.6 mg) was ≤ 1.25

31
Masuda, N., Iwata, H., et al, 2011; DOI 10.1007/s10549-010-1332-y
GOSERELIN 10.8 MG ALSO HAS A SIMILAR TOLERABILITY PROFIL
GOSERELIN 3.6 MG

Inci
occ
eith
set)
 Study (NCT01073865): Phase 3, open-label, multicentre trial. Pre-menopausa
ER-positive advanced breast cancer were randomized to 3-monthly goserelin 1
monthly goserelin 3.6 mg

• Age ≥ 20 years Goserelin 10.8 mg, sc Primary endpoi

• Histologically/cytologically (3 monthly ±7 days) + • PFS rate at 24 w
confirmed BC with ER+ Tamoxifen 20 mg, daily
n = 109
• Hormone-sensitive BC
N = 222 Secondary endp
• ≥1 lesion, assessed by CT, MRI, or
plain X-Ray (RECIST V 1.1) • objective respo
• PS 0-2 • serum E2 levels
• Pre-menopausal criteria: 1:1 • safety and toler
• Menses within 1 year
• E2 levels ≥10 pg/ml Goserelin 3.6 mg, sc
• FSH levels ≤30 mIU/ml
(monthly ±7 days) +
within 4 weeks prior
randomization Tamoxifen 20 mg, daily Final assessment of effic
n = 113 time of disease progres
Exclusion criteria:
- Received hormonal therapies within the previous 24 weeks or LHRH agonist therapy within the previous 48 weeks;
- Radiotherapy or Trastuzumab/Lapatinib treatment for early BC within prev 4 weeks (or at any point for treatment of advanced BC);
- Relapse during or within 48 weeks of adjuvant hormonal therapy, or during or within 24 weeks of adjuvant chemotherapy;
- Previous non breast cancer malignancy (other than controlled basal/squamous carcinoma or cancer of the cervix);
- life-threatening metastatic disease;
- abnormal laboratory tests results;
GOSERELIN 10.8 MG IS NON-INFERIOR TO GOSERELIN 3.6 MG
MENOPAUSAL WOMEN WITH ER-POSITIVE ADVANCED BREAS

Since the lower 95 % CI was above the pre-defined margin of -17.5 %, 3-monthly goserelin 10.8 mg met
the criteria for non-inferiority compared with monthly goserelin 3.6 mg

At week 24, mean serum E2 conc

24.8 pg/mL (SD=28.1) in the gose
 SUMMARY

• ASCO, St. Gallen, NCCN has recommended Combination of Goserelin

• ASTRRA (2019): Goserelin + Tamoxifen significantly improved Disea

Overall Survival4

• Long term follow up (12 years) trial show Goserelin plus Tamoxifen pr

reducing death & recurrence and has no additional safety issues5,6

• Goserelin associated with a low risk of long term chemotherapy-induc

high chance of pregnancy7

• Goserelin achieve similar survival to oophorectomy8

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• Goserelin is Simple, One-step delivery with SafeSystem 9
HATUR NUHUN