Pregnancy after Breast Cancer

Prof. Dr. Sibylle Loibl

Chair, German Breast Group

Centre for Haematology and Oncology, Bethanien, Frankfurt

Goehte University Frankfurt

Topics

Risk of Recurrence

Treatment induces failure of ovarian function

How to measure ovarian failure

Amenorrhea as prognostic factor

Prognosis in women with pregnancy after breast cancer

GnRH to protect ovarian function

Age at TNBC diagnosis by gBRCA mutation status

Couch FJ, et al. J Clin Oncol 2015;33:304-11

POSH study OS in young patients with gBRCA

Copson E Lancet Oncol 2018

OS in TNBC with gBRCA – POSH study

Copson E Lancet Oncol 2018

n = 325r2 = 0.81

Age (in months from conception to birth; in years from birth to menopause)

Ovarian reserve

Wallace WHB, Kelsey TW. PLoS ONE 2010;5:e8772

NG

F p

op

ula

tio

n

(lo

g 10

scal

e)

Amenorrhoea rate and influence of age and chemotherpay

Petrek JA, et al. J Clin Oncol 2006;24:1045-51

>40 years

≤40 years

Ganz P, et al. J Clin Oncol 2011;29:1110-6

-- without alkylating substances-- with alkylating substances

15–24 years25–34 years

35–44 years ≥45 years

Time to menopause after treatment for Hodgkin's lymphoma by age at start of treatment

van der Kaaij MA, et al. J Clin Oncol 2012;30:291-9

Age 15-24 Age 25-34

Age 35-44 Age 45+

Chemotherapy induced ovarian insufficiency

Furlantetto J et al. Loibl S SABCS 2 2017JCO 35.15_suppl.10068017; Cancer Res 78(4 Suppl):Abstract No PD7-09 and ASCO 2017 ; J ClinOncol JCO 35.15_suppl.10068

TIMEPOINT EOT 6 M 12 M 18 M 2 M

CIOF % 85.7 62.2 54.0 43.5 38.3

CT REGIMEN dtEC-dtD PMCb iddEnPC PM P nP-EC P-EC Cz

CIOF % 95.6 95.2 94.6 93.1 89.7 82.9 81.3 29.0

gBRCA1 vs gBRCA2

Proportion of patients with induced amenorrhoea by age at diagnosis*

*All patients received chemotherapy

Valentini A, et al. J Clin Oncol 2013;31:3914-9

Mutation carriers vs noncarriers

Baseline AMH and age as predictors of amenorrhoea

Anderson RA, et al. Eur J Cancer 2013;49:3404-11

12-month landmark analysis of OS and DFS, according to amenorrhoea status

Swain SM, et al. N Engl J Med 2010;363:2268-70

4-years DFS by pre-vs post-menopausal hormone levels at EOT

• OS appeared qualitatively similar to DFS, but not significant due to less mature data

• In patients with HR-positive BC, OS almost reached statistical significance with an advantage for those patients with postmenopausal hormone levels at EOT

Overall

HR-positiveAge <30 years

84.4%

65.0%

87.8%

62.6%

92.8%

69.5%

Furlantetto J et al. Loibl S SABCS 2 2017JCO 35.15_suppl.10068017; Cancer Res 78(4 Suppl):Abstract No PD7-09 and ASCO 2017 ; J ClinOncol JCO 35.15_suppl.10068

DFS between the pregnant group and matched nonpregnant group

Azim HA Jr, et al. J Clin Oncol 2013;31:73-9

DFS depending on pregnancy outcome and interval from primary diagnosis to pregnancy

Azim HA Jr, et al. J Clin Oncol 2013;31:73-9

Schedule for planning pregnancy while still on ET

C Sibylle Loibl

18-36 months

ResumeEndocrineTherapy

Pregnancy andlactation

EndocrineTherapy

contraception

Sto

pp

En

do

crin

eh

tera

py

18-36 months2-3 months Up to two years Re

-Sta

rt e

nd

ocr

ine

ther

apy

Breast cancer-specific survival for subjects with and without a pregnancy: from date of breast cancer

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation

Survival of gBRCA carriers

Valentini A, et al. Breast Cancer Res Treat 2013;142:177-85

Lambertini M, et al. Ann Oncol 2015;26:2408-19

PROMISE-GIM62,3 POEMS/SWOG S02304 Moffitt-led trial5 GBG-37 ZORO6 Anglo Celtic Group

OPTION7

Definition of POI No resumption of

menstrual activity and

postmenopausal levels

of FSH and E2

Amenorrhoea 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

Amenorrhoea 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

Study characteristics1

1. Lambertini M, et al. Presented at SABCS 2017 (Abstract GS4-01); . Del Mastro L, et al. JAMA 2011;306:269-76; 3. Lambertini M, et al. JAMA 2015;314:2632-40; 4. Moore HCF, et al. N Engl J Med 2015;372:923-32; 5. Munster P, et al. J Clin Oncol 2012;30:533-8; 6. Gerber B et al, J Clin Oncol 2011;29:2334-41; 7. Leonard RCF, et al. Ann Oncol 2017;28:1811-6

OR* 0.38 (95% CI 0.26-0.57)

p<0.001

0%

10%

20%

30%

40%

50%

14.1%

GnRHa group

n=363

Control group

n=359

30.9%

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

Premature ovarian insufficiency rate

*OR adjusted for age, estrogen receptor status, type and duration of chemotherapy administered

Lambertini M, et al. Presented at SABCS 2017 (Abstract GS4-01) and JC Lin Oncol 2019

Meta-analysis approach

OR* 0.92 (95% CI 0.66-1.28); p=0.623

0%

10%

20%

30%

40%

50%

36.8% 40.4%

0%

10%

20%

30%

40%

50%

18.2% 30.0%

OR* 0.51 (95% CI 0.31-0.85); p=0.009

One-year amenorrhoea Two-year amenorrhoea

GnRHa group

n=214

Control group

n=210

Amenorrhoea rates

GnRHa group

n=386

Control group

n=374

*OR adjusted for age, estrogen receptor status, type and duration of chemotherapy administeredLambertini M, et al. Presented at SABCS 2017 (Abstract GS4-01)

GnRHa group: 37/359 (10.3%)

vs.

Control croup: 20/367 (5.5%)

IRR 1.83 (95% CI 1.06-3.15)

p=0.030 Meta-analysis approach

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)

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

Post-treatment pregnancy rate

Lambertini M, et al. Presented at SABCS 2017 (Abstract GS4-01) and J Clin Oncol 2019

Summary

Pregnancy after Breast Cancer should not be discouraged

Individual counselling of the women including risk of recurrence

Young women have higher risk of recurrence especially when having an HR+/HER2- tumour

Young women with TNBC are very likely gBRCA carriers

gBRCA carriers have a better prognosis

Chemotherapy induces amenorrhoea

GnRH may be used to prevent chemotherapy-induced amenorrhea

Greetings from Frankfurt