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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.
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
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
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
Pregnancy after treatmentPregnancy after treatment
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
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
Pregnancy after treatmentPregnancy after treatment
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
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
Pregnancy after treatmentPregnancy after treatment
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
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
Pregnancy after treatmentPregnancy after treatment
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)
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
Pregnancy after treatmentPregnancy after treatment
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
Breast cancer during pregnancyBreast cancer during pregnancySurgerySurgeryRadiotherapyRadiotherapyChemotherapyChemotherapy
FarmacologyFarmacologyShort term neonatal outcomeShort term neonatal outcomeLong term pediatric outcomeLong term pediatric outcomeProspective dataProspective data
Pregnancy after treatmentPregnancy after treatment
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
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