breast cancer during pregnancy and pregnancy after treatment belgian breast meeting 13-10-2006...

Breast cancer Breast cancer during pregnancy during pregnancy

and pregnancy and pregnancy after treatmentafter treatment

Belgian Breast Meeting13-10-2006

Frederic AmantGynaecologic Oncology

Multidisciplinary Breast CenterKatholieke Universiteit Leuven

‘‘To begin my life with the beginning To begin my life with the beginning of my life, I record that I was born’of my life, I record that I was born’

Ch. Dickens in : Ch. Dickens in : The personal history of David The personal history of David Copperfield, 1850Copperfield, 1850

Negative influence on Negative influence on human developmenthuman development

InfectionsInfections

TeratogensTeratogens

AlcoholAlcohol

CocaineCocaine

TobaccoTobacco

Nutritional deficiencyNutritional deficiency

Cytotoxic treatment????Cytotoxic treatment????

Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy

FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data

Pregnancy after breast cancerPregnancy after breast cancer

Study center Perinatal Study center Perinatal Epidemiology (SPE)Epidemiology (SPE)

0

10

20

30

40

50

Pe

rce

nta

ge

<20 20-24 25-29 30-34 35-39 >=40

Maternal age

Distribution of maternal age in Flanders

1988

1994

1997

2002

2004

PathologyPathology

It appears that the histopathologic and It appears that the histopathologic and immunohistochemical findings of the immunohistochemical findings of the tumors of pregnant women with BC tumors of pregnant women with BC are similar to those of non-pregnant are similar to those of non-pregnant

young women with BC. young women with BC.

It is more likely that age at diagnosis It is more likely that age at diagnosis rather than the pregnancy determines rather than the pregnancy determines

the biologic features of the tumor.the biologic features of the tumor.



Pregnancy after treatmentPregnancy after treatment

Breast cancer surgery Breast cancer surgery during pregnancyduring pregnancy

Risk of abortion is highest before 12 weeksRisk of abortion is highest before 12 weeks Majority underwent mastectomy due to fear Majority underwent mastectomy due to fear

for radiotherapyfor radiotherapy Breast conserving surgery with axillary LN Breast conserving surgery with axillary LN

dissection dissection Especially third trimesterEspecially third trimester Chemotherapy before radiationChemotherapy before radiation

Sentinel node: Tc Sentinel node: Tc Gentilini et al., Ann Oncol 2004;15:1348-51Gentilini et al., Ann Oncol 2004;15:1348-51 Keleher et al., Breast J 2004;10:492-5Keleher et al., Breast J 2004;10:492-5

Radiotherapy, Radiotherapy, Kal, Lancet Oncol 2005Kal, Lancet Oncol 2005

Breastca, supradiaphragmatic Hodgkin’ disease, Brain tumors, head– and necktumors

< 0.01 Gy exposure

DistanceShielding with lead protection

Slight increase leukemia, tumors during childhood 0.003-0.004 (nl 0.002-0.003)

0.2 Gy: effect dependent pregnancy durationMultidisciplinary approach

AnthracyclinsAnthracyclins

Doxorubicin (Adriblastina°)Doxorubicin (Adriblastina°)Epirubicin Epirubicin (Peccatori et al., Lancet Oncol 2004;5:398)(Peccatori et al., Lancet Oncol 2004;5:398)

Slightly more lipophylicSlightly more lipophylic Faster influxFaster influx Less intracellular retentionLess intracellular retention Shorter elimination half lifeShorter elimination half life Better therapeutic indexBetter therapeutic index Less systemic and cardial toxic effectsLess systemic and cardial toxic effects No fetal complications (n=14)No fetal complications (n=14)

IdarubicinIdarubicin More lipophylic More lipophylic Higher affinity for DNAHigher affinity for DNA

Doxorubicin

1

10

100

1000

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Time (h)

Co

nc

en

tra

tie

(n

g/m

l)

VK 15+19

VK 23+27

VDBP 31+35

VDBP pp

Pharmacokinetics during Pharmacokinetics during pregnancy: preliminary pregnancy: preliminary

datadata

Taxanes during Taxanes during pregnancypregnancy

Author Chemotherapy

Start chemo (w)

Delivery (w)

Status child (age,

mts)

De Santis, 2000

Docetaxel, 3 x

24 32 Nl (20)

Sood, 2001 Paclitaxel-cisplatin,

3x

30 37 Nl (30)

Mendez, 2003

Paclitaxel-carboplati

n, 6x

16 35 Nl (15)

Gadducci, 2003

Epirubicin x4,

paclitaxel x3

14 36 Nl (36)

Potluri, 2006

Doxo-cyclo x4,

docetaxel x4

14 Nl

Doxo-docetaxel

x6

14 Nl

Nieto, 2006

FEC x4, docetaxel

x4

13 NL (birth)

Trastuzumab during Trastuzumab during pregnancypregnancy

Dosage Gestational age

Complication

Outcome child

Watson et al., 2005

580mg, 3 weekly

Untill 20w

anhydramnion

Nl

Fanale et al., 2005

weekly 27w none Nl

Waterston et al., 2006

1 cycle, 523 mg

First trimester

none Nl

Chemotherapy during 2Chemotherapy during 2ndnd and 3 and 3rdrd trimester:trimester:

IUGR, premature birth, IUD, IUGR, premature birth, IUD, neonatal deathneonatal death

Pizzuto et al., Cancer Treat Rep 1980;64:679Mulvihill et al., Cancer 1987;60:1143Zemlickis et al., Arch Intern Med 1992;152:573Zemlickis et al., Am J Obstet Gynecol 1992;166:781Partridge & Garber, Sem Oncol 2000;27:712Hansen et al., Am J Obstet Gynecol 2001;97:809Peres et al., Braz J Med Biol Res 2001;34:1551Ali et al., Leuk Res 2003;27:381

Follow up in high-risk obstetrical unit to determine Follow up in high-risk obstetrical unit to determine

optimal moment of deliveryoptimal moment of delivery

Chemotherapy during Chemotherapy during pregnancy: 1966-2004pregnancy: 1966-2004 Cardonick & Iacobucci, Lancet Oncol 2004;5:283

N = 376, mostly after organogenesisN = 376, mostly after organogenesis 19 (5%) foeti and 1% neonati died19 (5%) foeti and 1% neonati died

16 in hematological malignancies16 in hematological malignancies 2/3 received idarubicine for breastca2/3 received idarubicine for breastca

28 (7%) IUGR, 18 (5%) premature birth28 (7%) IUGR, 18 (5%) premature birth 15 (4%) neonatal transient 15 (4%) neonatal transient

myelosuppressionmyelosuppression 9/11 malformations occurred after 19/11 malformations occurred after 1stst

trimester exposuretrimester exposure

Avoidance of prematurityAvoidance of prematurityZhao et al., Int J Gynecol Cancer 2006;16:8-15Zhao et al., Int J Gynecol Cancer 2006;16:8-15

Series of 22 cases of ovarian cancer Series of 22 cases of ovarian cancer during pregnancyduring pregnancy

14 deliveries14 deliveries

1 neonatal death1 neonatal death C/S at 31 weeksC/S at 31 weeks Died of respiratory distress syndromeDied of respiratory distress syndrome

Fetal maturityFetal maturity

0

10

20

30

40

50

60

70

80

90

100

24-25 26-27 28-29 30-31 32-33 34-35

mortality

hyaline membranedysplasiabronchopulmonardysplasiaintraventricularhemorrhage

18 year experience from 5 18 year experience from 5 London teaching hospitalsLondon teaching hospitals

Ring et al., J Clin Oncol 2005;18:4192-7Ring et al., J Clin Oncol 2005;18:4192-7 28 women (24 curative, 4 palliative)28 women (24 curative, 4 palliative) Chemotherapy: AC or EC (n=16) or CMF (n=12)Chemotherapy: AC or EC (n=16) or CMF (n=12) 1/28: 11/28: 1ee trim → miscarriage trim → miscarriage

medianmedian rangerange

GA, D/, wGA, D/, w 1717 4-334-33

GA, surgery, wGA, surgery, w 1616 5-295-29

GA, chemo,wGA, chemo,w 2020 15-3315-33

GA, delivery, wGA, delivery, w 3737 30-4030-40

Weight < P10Weight < P10 00

Transfer neonatoTransfer neonato 55

Last chemo-delivery: > 3w Last chemo-delivery: > 3w intervalinterval

Maternal neutropenia and thrombocytopeniaMaternal neutropenia and thrombocytopenia

Metabolisation in placenta (fœtus) versus Metabolisation in placenta (fœtus) versus inefficient neonatal liver and kidney inefficient neonatal liver and kidney functionfunction (neonate)(neonate)

Neonatal myelosuppressionNeonatal myelosuppressiono Okun et al., Med Ped Oncol 1979;7:315Okun et al., Med Ped Oncol 1979;7:315o Pizzuto et al., Cancer Treat Rep 1980;64:679Pizzuto et al., Cancer Treat Rep 1980;64:679o Reynoso et al., JCO 1987;5:1098Reynoso et al., JCO 1987;5:1098o Raffles et al., Br J Obstet Gynaecol 1989;96:1099Raffles et al., Br J Obstet Gynaecol 1989;96:1099o Avilés et al., Am J Hematol 1991;36:243Avilés et al., Am J Hematol 1991;36:243o Garcia et al., J Perinatol 1999;19:230Garcia et al., J Perinatol 1999;19:230

Long term outcomes: retrospective Long term outcomes: retrospective datadata

Avilés and Neri, Clinical Lymphoma 2001;2:173-7 Update on Aviles et al., Am J Hemat Update on Aviles et al., Am J Hemat 1991;36:243-81991;36:243-884 children 84 children Hematological malignancies (29 malignant Hematological malignancies (29 malignant lymphoma, 26 Hodgkin, 29 acute leukemia)lymphoma, 26 Hodgkin, 29 acute leukemia)38 received chemotherapy during 138 received chemotherapy during 1stst trimester trimester19 y follow up (range, 6-29 years)19 y follow up (range, 6-29 years)Normal fysical, neurological, psychological, Normal fysical, neurological, psychological, hematological and immunological function hematological and immunological function

MD Anderson dataMD Anderson dataHahn et al., Cancer 2006Hahn et al., Cancer 2006

N = 57 (32 adj CT, 25 NACT), FACN = 57 (32 adj CT, 25 NACT), FAC Survey: mail or telephoneSurvey: mail or telephone Children age (n=40): 2-157 mtsChildren age (n=40): 2-157 mts

Outcome N (%) Reported incidence general population

Down syndrome 1 (2.5) 1:700 (30-34y)

Clubfoot 1 (2.5) 1:1000

Cong bilat ureteral reflux

1 (2.5) 3-4% some uro problem

“normal development”

39 (97)

Requires special attention in school

2/18 (11)

Retrospective search of casesRetrospective search of cases ProspectiveProspective

o Standardised clinical neurologic Standardised clinical neurologic assessmentassessment

o Echocardiografy with dopplers Echocardiografy with dopplers

MethodsMethods

Results: maternal data (last Results: maternal data (last FU, 9-2006)FU, 9-2006)

DiagnosisDiagnosis NN RTRT SurgerySurgery ChemotherapyChemotherapy

Orofaryngeal ca,Orofaryngeal ca, 11 2 x cisplatin (25mg/m²) + fluoroblastin (100mg/m²)2 x cisplatin (25mg/m²) + fluoroblastin (100mg/m²) (30, 32)(30, 32)

Spinocellular Spinocellular cervixca,cervixca,

11 6 x cisplatin (75mg/m²)6 x cisplatin (75mg/m²) (17, 19, 20, 23, 24, 27)(17, 19, 20, 23, 24, 27)

BreastcaBreastca 55 443 x doxorubicin (60mg/m²) + cyclophosphamide(600mg/m²)3 x doxorubicin (60mg/m²) + cyclophosphamide(600mg/m²)

(23.4, 25.4, 28.4)(23.4, 25.4, 28.4)3 x doxorubicin (60mg/m²) + cyclophosphamide(600mg/m²) 3 x doxorubicin (60mg/m²) + cyclophosphamide(600mg/m²)

(26, 29, 32)(26, 29, 32)6 x cyclophosphamide (600mg/m²) + epirubicin (100mg/m²)6 x cyclophosphamide (600mg/m²) + epirubicin (100mg/m²)

+ 5-FU (500mg/m² ) (21, 24, 27, 30, 33, 36)+ 5-FU (500mg/m² ) (21, 24, 27, 30, 33, 36)6 x cyclophosphamide (500mg/m²) + epirubicin(100mg/m²)6 x cyclophosphamide (500mg/m²) + epirubicin(100mg/m²)

+ 5-FU (500mg/m²) (20, 23, 26, 29, 32, 35)+ 5-FU (500mg/m²) (20, 23, 26, 29, 32, 35)3 x 3 x

3 x doxorubicin + cyclophosphamide3 x doxorubicin + cyclophosphamide

ALLALL 11 HOVON 37 cycle 1 and 2 (21, 26)HOVON 37 cycle 1 and 2 (21, 26)

AMLAML 22 2 x idarubicine (12mg/m²) + cytarabine (100mg/m²) 2 x idarubicine (12mg/m²) + cytarabine (100mg/m²) (15, 20)(15, 20)

retinoinic acid started at 31wretinoinic acid started at 31w3 x idarubicine (12mg/m²) + cytarabine (100mg/m²) 3 x idarubicine (12mg/m²) + cytarabine (100mg/m²)

(15, 21, 26)(15, 21, 26)

GlioblastomaGlioblastoma 11 11 11 Temodal ( 18-21, 26, 30, 34)Temodal ( 18-21, 26, 30, 34)

HodgkinHodgkin 33 3 x ABVD3 x ABVD2 x ABVD (29, 33)2 x ABVD (29, 33)

4 x ABVD (15, 19, 23, 27)4 x ABVD (15, 19, 23, 27)

Results: neonatal and pediatric follow-up (last FU, 9-2006)(last FU, 9-2006)

NN Com-Com-plicationplications s

GA birth (w)GA birth (w) Birth weight Birth weight ((gr)gr)

Neonatal complicationsNeonatal complications FUFU(Mts)(Mts)

Outcome childOutcome child

11 34.534.5 2840 (p 79)2840 (p 79) PrematurityPrematurity 2.52.5 Asymmetric tonick nek reflex and delayed Asymmetric tonick nek reflex and delayed visual fixation visual fixation

11 3232 1715 (p 23)1715 (p 23) PrematurityPrematurityHMD I: ncpapHMD I: ncpapPneumomediastinumPneumomediastinum↑ ↑ creatinincreatinin

1616 Normal developmentNormal development

11 Sepsis Sepsis (26)(26)P-PROM P-PROM (28)(28)

28.328.3 720 (p 0.5)720 (p 0.5) PrematurityPrematurityPancytopeniaPancytopenia2 d HFO 2 d HFO -> cpap till d 31-> cpap till d 31

2121 Minor delay expressive language development Minor delay expressive language development

1 (twin)1 (twin) P-PROM P-PROM (32.4)(32.4)

3333 1630 (p 5)1630 (p 5) PrematurityPrematurityHFOHFO

3939 Autistic disorder, mental and motoric Autistic disorder, mental and motoric retardation (< unilateral polymicrogyria)retardation (< unilateral polymicrogyria)

1 (twin)1 (twin) P-PROM P-PROM (32.4)(32.4)

3333 1390 (p 0.8)1390 (p 0.8) PrematurityPrematurity 3939 Normal development Normal development

1010 1 x 1 x Sepsis Sepsis (29)(29)

34-39 34-39 (36.3)(36.3)

2743 (2140-2743 (2140-3370)3370)

4 x Prematurity 4 x Prematurity 26 26 (1-(1-66)66)

Normal developmentNormal development

PatientsPatients ControlsControls P valueP value

LVEDD/BSA (mm)LVEDD/BSA (mm) 54.2 ± 10.754.2 ± 10.7 53.2 ± 8.153.2 ± 8.1 0.820.82

LVESD/BSA (mm)LVESD/BSA (mm) 34.7 ± 6.834.7 ± 6.8 34.8 ± 6.134.8 ± 6.1 0.980.98

ILWTD/BSA (mm)ILWTD/BSA (mm) 9.1 ± 2.79.1 ± 2.7 10.0 ± 3.210.0 ± 3.2 0.480.48

FS (%)FS (%) 35.7 ± 3.435.7 ± 3.4 33.7 ±3 .433.7 ±3 .4 0.210.21

LVMI (gr/mLVMI (gr/m22)) 57.3 ± 9.357.3 ± 9.3 65.2 ± 12.965.2 ± 12.9 0.140.14

Mitral E (cm/sec)Mitral E (cm/sec) 101.4 ±19.7101.4 ±19.7 97.2 ± 11.897.2 ± 11.8 0.580.58

E/A ratioE/A ratio 2.2 ± 0.62.2 ± 0.6 2.2 ± 0.52.2 ± 0.5 0.810.81

Decceleration E (msec) Decceleration E (msec) 105.8 ± 22.3105.8 ± 22.3 119.1 ± 17.6119.1 ± 17.6 0.160.16

IVRT (msec)IVRT (msec) 47.4 ± 8.247.4 ± 8.2 51.1 ± 8.251.1 ± 8.2 0.350.35

PuVe systole (cm/sec)PuVe systole (cm/sec) 54.8 ± 6.354.8 ± 6.3 51.2 ± 4.051.2 ± 4.0 0.170.17

PuVe diastole (cm/sec)PuVe diastole (cm/sec) 61.3 ± 6.961.3 ± 6.9 64.2 ±8.3 64.2 ±8.3 0.460.46

Septal annular motion (mm)Septal annular motion (mm) 10.2 ± 2.110.2 ± 2.1 11.2 ± 1.111.2 ± 1.1 0.420.42

Lateral annular motion (mm)Lateral annular motion (mm)13.4 ± 1.513.4 ± 1.5 13.0 ± 1.313.0 ± 1.3 0.980.98

RV annular motion (mm)RV annular motion (mm) 15.8 ± 2.515.8 ± 2.5 17.0 ± 1.817.0 ± 1.8 0.140.14

Standard Standard echocardiographic dataechocardiographic data

Van Calsteren et al., J Clin Oncol 2006;24(12):e16-7

Pregnancy after Pregnancy after treatmenttreatment

No difference in survivalNo difference in survival‘‘Two year cancer diagnosis Two year cancer diagnosis anniversary’anniversary’

Higher rate of miscarriagesHigher rate of miscarriagesIndividual’s response to therapyIndividual’s response to therapy

Receptor positive: Receptor positive: Tamoxifen contraindicated (ambiguous Tamoxifen contraindicated (ambiguous genitalia, Goldenhar syndrome)genitalia, Goldenhar syndrome)After completion hormonal treatmentAfter completion hormonal treatment

Radiotherapy is possibleRadiotherapy is possibleChemotherapyChemotherapy

Short term (neonatal) safety evidenceShort term (neonatal) safety evidenceLong term outcome: retrospective data Long term outcome: retrospective data suggest safetysuggest safetyProspective trials neededProspective trials needed Larger numbersLarger numbers Longer follow upLonger follow up Thorough assessmentThorough assessment

Morbidity related to –induced- Morbidity related to –induced- prematurityprematurity

Breast cancer during pregnancy Breast cancer during pregnancy and pregnancy after treatment : and pregnancy after treatment :

conclusionsconclusions

¡¡¡ Thank you¡¡¡ Thank you!!!!!!

breast cancer during pregnancy and pregnancy after treatment belgian breast meeting 13-10-2006...

Documents

breast cancer slide

cgy slide

treatment slide

breast cancer surgery

w conception slide

radiotherapy breast

breast j

pregnancy risk of abortion