Cancer in Pregnancy Pregnancy interruption vs. Active treatment

MATERNITA E TUMORI Milan, May 16th – 18th, 2013

Hatem A. Azim Jr., MD, MSc.

Department of Medicine, BrEAST Data Centre

Institut Jules Bordet

Brussels, BE

Berry DL et al; JCO 1999

EPIDEMIOLOGY

1/1.000 pregnancies

Rising Trend of Delaying Childbearing

Mathews T & Hamilton B; NCHC 2009

Pregnancy Interruption .. Why not ?

Customs &Traditions

Precious Child

Religion Too late

Main Themes

Regret

A Woman who interrupted her pregnancy

“It does make me feel, you know, quite bad some days. It does not go”

A Woman who already completed her family and opted to continue her pregnancy

Main Themes

Anxiety & Decision Conflict

“If they said the best option is to have a termination, I think I would have had one . But I knew it would have been really hard but I’ve got other kids, I can’t sort of risk my life”

Pregnancy Interruption .. Why ?

This could improve prognosis of these patients ..

PROGNOSIS Not clear whether pregnancy impact prognosis

Stensheim H; JCO 2009

OS unadjusted

OS adjusted

Prognosis of BC during Pregnancy

Analysis adjusted for age and stage Azim HA Jr et al; Cancer Treat Rev 2012

But Does Interruption have any Therapeutic Role .. ??

Is therapeutic abortion really therapeutic !!?

Disease-free survival Overall survival

Azim HA Jr et al; Acta Oncol 2012

p=0.11 p=0.04 Adjusted HR: 0.4 (0.1 – 1.5)

Pregnancy Interruption .. Why ?

This will allow the treating physician to adequately treat the patient

This could improve prognosis of these patients ?

When a drug is administered to the mother, placental transfer of the drug could be hazardous to the fetus

Cardonick E et al; Lancet Oncol 2004

Cardonick E & Iacobucci; Lancet Oncol 2004

Chemotherapy transfer to the fetus

van Calsteren et al; Gynecol Oncol 2011

Maternal blood Maternal urine

Fetal blood Amniotic fluid

DOXORUBICIN EPIRUBICIN CYCLOPHOSPHAMIDE

van Calsteren et al; Int J Gynecol Oncol 2010 van Calsteren et al; Gynecol Oncol 2011

Number Drug detected in fetus (n) % drug detected in fetus

Doxorubicin 15 6 7.5 ± 3.2

Epirubicin 11 8 4.0 ± 1.6

Paclitaxel 11 7 1.4 ± 0.8

Docetaxel 9 0 0

Cyclophosphamide 4 3 25.1 ± 6.3

Carboplatin 7 7 57.5 ± 14.2

DOXORUBICIN EPIRUBICIN

Ring, 2005 Hahn, 2006 Peccatori, 2009 Loibl, 2012

Study type Retrospective Prospective Prospctive Prospective

Multicentric Monocentric Monocentric Registry

N. 28 57 20 197

Regimen A(E)C=16 CMF=12

FAC (100%) Weekly E (100%) A-based=178 A(E)C (n=55) Taxane=14 CMF=15

Median gestational W at chemo

W20 (15 – 33) W23 (11 – 34) W19 (16 – 30) W24 (NR)

Median gestational W at delivery

W37 (30 – 40) W37 (29 – 42) W35 (28 – 40) W37 (32 – 42)

Congenital malformations 0 3/57 (5%) 1/20 (5%) 8/179 (4.5%)

Anthracyclines in Breast Ca during Pregnancy

Ring A et al; JCO 2005, Hahn et al; Cancer 2006 Peccatori F et al; BCRT 2009, Loibl S et al; Lancet Oncol 2012

Azim HA Jr et al; Cancer Treat Rev 2010

DOXORUBICIN IN NHL DURING PREGNANCY

Long term cardiac effect of anthracyclines exposure in-utero

Exposed to anthracycline-based during pregnancy Age range: 18m-18y

Amant F et al; Lancet Oncol 2012

Anthracyclines during pregnancy NOT ALL THE SAME !!

HIGHLY LIPOPHILIC “higher placental transfer”

DAUNORUBICIN

IDARUBICIN

Azim HA Jr et al; Cancer Treat Rev 2010

Number

- Breast cancer

- Other

55

39

16

- Paclitaxel

- Docetaxel

- Both

33

19

3

Neonatal outcome

- Mean Gestational age at delivery

- Foetal weight

- Early preterm delivery

- Foetal complications

- Foetal malformations

W 36

2400 g

1 (2%)

Anaemia (n=1), neutropenia (n=1)

Pyloric stenosis (n=1)

TAXANES IN CANCER DURING PREGNANCY

Mir O et al; Ann Oncol 2010 Cardonick E et al; Ann Oncol 2012

Number

- Cisplatin

- Carboplatin

48

47

1

Regimen - Single agent (61.7%)

- Combination with bleomycin, or taxanes (38.3%)

Neonatal outcome

- Mean Gestational age at delivery

- Foetal weight

- Foetal complications

- Foetal malformations

W 33

2200 g

++ creatinin (n=1), intraventricular hge (n=1), hypoglycemia (n=1), hypotension (n=1),hearing loss (n=1)

None

PLATINUM SALTS IN CERVICAL CANCER DURING PREGNANCY

Zagouri F et al; Obstet Gynecol 2013

Number Drug detected in fetus (n) % drug detected in fetus

Doxorubicin 15 6 7.5 ± 3.2

Epirubicin 11 8 4.0 ± 1.6

Paclitaxel 11 7 1.4 ± 0.8

Docetaxel 9 0 0

Cyclophosphamide 4 3 25.1 ± 6.3

Carboplatin 7 7 57.5 ± 14.2

Clinical evidence runs in line with preclincial data on transplacental transfer of the different chemotherapeutic agents

Van Calsteren K et al; Gynecol Oncol 2011

Cardonick J et al; Cancer J 2010 Loibl S et al; Lancet Oncol 2012

Obstetric complications Fetal wt <10th percentile

Chemo No chemo Chemo No chemo

Cardonick, 2010 22/104 (22%) NR 8/104 (7.5%) 0/12 (0%)

Loibl, 2012 31/179 (17%) 15/149 (9%) 15/175 (9%) 5/139 (4%)

An increase in the risk of pregnancy complications “on average” in patients treated with chemo during pregnancy even if started after the 1st trimester

WEEKLY APPLICATION OF CHEMOTHERAPY Allow close monitoring of pregnancy Low peak plasma concentration resulting in

- Lower toxicity (more safe)

- Possible lower placental transfer & foetal exposure

Easy interruption in case of toxicity

Poor Placental Crossing of MoAB Early in Pregnancy

Pentsuk N et al; Birth Defects Research 2009

Pregnancy on trastuzumab

Pregnancy after trastuzumab

No trastuzumab

Number of pts (pregnancies) 16 (16) 33 (45) 9 (9)

Miscarriage 4 (25%) 7 (16%) 0

Induced abortion 7 (44%) 4 (9%) 3 (33%)

Completed pregnancies 5 (31%) 30 (67%) 6 (67%)

N. Live births 5 (100%) 33 (100%) 6 (100%)

N. Congenital anomalies 0 1 1

Mean Gestational week at delivery 40 39 39

Mean Apgar score at 10 min 10 9.6 9

Mean fetal weight in gm 3,485 3,397 3,197

Mean fetal length in cm 50 52 49

BRIEF REPORT

Pregnancy occurring during or following adjuvant trastuzumabin patients enrolled in the HERA trial (BIG 01-01)

Hatem A. Azim Jr. • Otto Metzger -Filho • Evandro de Azambuja •

Sibylle Loibl • Florine Focant • Ekaterina Gresko •

Mounir Arfi • Martine Piccart-Gebhart

Received: 9 February 2012/ Accepted: 11 February 2012/ Published online: 26 February 2012

Ó Springer Science+Business Media, LLC. 2012

Abstract Only few case reports describe the pregnancy

course and outcome of breast cancer patients, who were

under treatment with trastuzumab at the timeof conception

or who have completed trastuzumab therapy before

becoming pregnant. The HERA trial is a large phase III

randomized clinical trial in which patients with early

HER2-positive breast cancer were randomized to receive 1

or 2 years of trastuzumab or observation following com-

pletion of primary chemotherapy. To examine the effect of

trastuzumab on pregnancy outcome, we report all preg-

nancy events that occurred until March 2010 in patients

enrolled in the study. For the sake of this analysis, patients

were assigned to three groups: (1) pregnancy occurring

during and up to 3 months after trastuzumab exposure

(group 1); (2) pregnancy occurring [ 3 months of last

trastuzumab dose(group 2); and (3) pregnancy occurring in

patients without prior exposure to trastuzumab (group 3).

Sixteen, 45 and 9 pregnancies took place in groups 1, 2,

and 3, respectively. 25 and 16% of patients in groups1 and

2 experienced spontaneous abortion, the former being

higher than figures reported in the general population.

However, short-term fetal outcomeappeared normal across

the three groups. Only 2 congenital anomalies were

reported, one in group 2 and one in group 3. No congenital

anomalies were reported in those exposed to trastuzumab

in utero. This is the first report from a large randomized

trial assessing the effect of trastuzumab on pregnancy

course and outcome. Based on our results, trastuzumab

does not appear to affect fetal outcome in patients who

manage to complete their pregnancy. We are currently

initiating a collaboration to collect similar data from the

other large adjuvant trastuzumab trials to confirm these

findings.

Keywords Breast cancer Pregnancy Trastuzumab

Counseling Fetal outcome

Introduction

One year of adjuvant trastuzumab is the standard of care

for patients with early HER2-positive breast cancer [1–3].

As trastuzumab is not known to cause amenorrhea [4], and

given the rising trend of delaying pregnancy to later in life

[5], patients with child-bearing potential could become

pregnant during or following trastuzumab exposure.

Unlike chemotherapy, the safety profile of trastuzumab

during pregnancy is not well described and limited to few

published case reports [6–10]. The most striking observa-

tion hasbeen theapparent risk of oligo- and anhydramnios,

which resulted in premature delivery, fetal morbidity, and

This study was conducted on behalf of the HERA study team.

This study was presented as a poster presentation at the 2011 San

Antonio Breast Cancer Symposium.

H. A. Azim Jr. (& ) O. Metzger-Filho E. de Azambuja

F. Focant M. Piccart-Gebhart

Department of Medical Oncology, Institut Jules Bordet and

l’Universite Libre de Bruxelles (ULB), Boulevard de Waterloo

121, 1000 Brussels, Belgium

e-mail: hatem.azim@bordet.be

S. Loibl

Department of Medicine and Research, Klinikum Offenbach,

Offenbach, Germany

E. Gresko

F. Hoffmann-La Roche, Basel, Switzerland

M. Arfi

Frontier Science, Kincraig, Kingussie, Scotland, UK

123

Breast Cancer Res Treat (2012) 133:387–391

DOI 10.1007/s10549-012-1996-6

Author's personal copy

Regimen Oligohydramnios Congenital anomalies GW at delivery Fetal complications/death

Waterston 2006 T No No Term No

Berveiller 2008 T No No Elective abortion (ectopic)

…

Azim Jr 2009 T No No W39 No

Goodyer 2009 T No No W39 No

Trastuzumab stopped once pregnancy is discovered

Regimen Oligohydramnios Congenital anomalies GW at delivery Fetal complications/death

Watson 2005 T Yes No W37 No

Shrim 2007 T No No W37 Renal Failure

Witzel 2008 T Yes No W27 (pre-term) Res F. / death

Pant 2008 T Yes No W32 (pre-term) Transient complications

Weber 2008 T Yes No W27 (pre-term) Res F. / death

Warraich 2009 T +tam /LHRH

Yes No W37 Res F. / death

Beale 2009 T + tam Yes No W31 (pre-term) Renal & Respiratory failure / death

Mandrawa 2011 T Yes No W37 No

Trastuzumab continued to 2nd or 3rd trimester along with pregnancy

Trastuzumab & the amniotic fluid

Anhydramnios

o Trastuzumab blocks Her-2 expressed in fetal kidney

o It interferes with VEGF signaling responsible for amniotic fluid production and reabsorption

Sekar R et al: OBY GYN, 2007 Pant S et al: JCO, 2008

Setting Regimen Time Mother Pregnancy Baby

Watson 2005 A T Pre, 1st, 2nd NS Anhydramnios NAD

Fanale 2005 M T+ vinorelbine 3rd NS NS NAD

Bader 2007 M T + paclitaxel 2nd NS Anhydramnios, IUGR Transient Resp F,RF

Shrim 2007 M T Pre, 1st, 2nd -- EF NS Transient RF

Sekar 2007 M T + docetaxel 2nd, 3rd NS Anhydramnios NAD

Witzel 2008 M T Pre, 1st, 2nd, 3rd NS Anhydramnios, vag blee Resp F, died

Pant 2008 M T Pre, 1st, 2nd, 3rd NS Anhydramnios NAD

Weber 2008 M T Pre, 1st, 2nd NS Anhydramnios Resp F, died

Warraich 2009 A T + tam + LHRH Pre, 1st, 2nd , 3rd NS Anhydramnios Res. F, fetal death after 40 minutes

Beale 2009 A T + tam Pre, 1st, 2nd NS Anhydramnios, PROM Twins:

1) RF, Resp F, Death

2) Transient Resp. F

Goodyer 2009 M T 2nd None None Premature

Gottschalk 2011 M T + Carbo + Doc 2nd None Anhydramnios Fetal growth restriction

Azim HA Jr et al; Exp Rev Immunol 2010

High risk of anhydramnios and fetal morbidity/mortality secondary to trastuzumab administration during pregnancy

N = 153

• Neonatal death = 1

• Neonatal B-cell depletion = 11, neonatal infection = 4

• Congenital malformations = 2 (club foot, cardiac)

Agent Use during pregnancy

Imatinib Avoid during the first trimester. Possible

starting the second trimester

Lapatinib Only one case report. Avoid during the

whole pregnancy period

Bevacizumab and other VEGF

targeting agents

No clinical data but worrying preclinical

evidence. Avoid during pregnancy

Zoledronic acid Induce anomalies in preclinical models,

could affect uterine contraction secondary

to hypocalcemia. Should be avoided

Tamoxifen during pregnancy

Braems G et al; Oncologist 2011

When to consider pregnancy termination ? “Is when you can not balance maternal benefits and fetal risks”

• Delaying standard therapy could seriously affect maternal prognosis (e.g. diagnosis of acute leukemia during 1st trimester)

• Patient is seriously concerned on delaying standard therapy that can not be delivered during pregnancy (e.g. Ca cervix)

MAYBE PRETERM DELIVERY COULD BE THE OPTIMAL SOLUTION ..??

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

Cerebral palsy Mental retardation

Psycho disorder Disability affecting

working capacity

Full term

W34-W36

W31-W33

Norwegian National Registry ≈1 Million infant

Moster D et al; NEJM 2008

Amant F et al; Lancet Oncol 2012

Long-term cognitive function and IQ correlates with time of delivery

N=70 Median FU=22m after delivery

Each additional month of gestation is associated with 11.6 points increase in the

IQ scale !!

Conclusions

1. Offering active treatment during pregnancy is feasible and could provide adequate disease control with comparable outcomes to the non-pregnant settings

Conclusions

2. Offering standard treatments is sometimes not possible, and hence adapting tailored strategies could be needed. Hence a need to engage centres with expertise in this field

Conclusions

3. Pregnancy terminations offers

– no therapeutic advantages

– Psychological detrimental effect on the patient that can be long-lasting

Should not be routinely offered to patients except in exceptional cases

NEONATOLOGY

PSYCHOLOGY

ONCOLOGY

OBSTETRICS

PAEDIATRICS

Managing BC during pregnancy The need for a multidisciplinary approach

ACKNOWLEDGMENTS

Funding Support

Les Amis de l'Institut Bordet

C. Sotiriou M. Piccart S. Loi V. Jose S. Majjaj S. Michiels C. Desmedt D. Fumagalli M. Ignatiadis E. de Azambuja

F. Peccatori N. Rotmensz G. Pruneri E. Botteri G. Renne G. Viale A. Goldhirsch

N. Pavlidis G. Pentheroudakis