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Breast cancer during pregnancy and pregnancy after treatment Belgian Breast Meeting 13-10-2006 Frederic Amant Gynaecologic Oncology Multidisciplinary Breast.

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Presentation on theme: "Breast cancer during pregnancy and pregnancy after treatment Belgian Breast Meeting 13-10-2006 Frederic Amant Gynaecologic Oncology Multidisciplinary Breast."— Presentation transcript:

1 Breast cancer during pregnancy and pregnancy after treatment Belgian Breast Meeting Frederic Amant Gynaecologic Oncology Multidisciplinary Breast Center Katholieke Universiteit Leuven

2 ‘To begin my life with the beginning of my life, I record that I was born’ Ch. Dickens in : The personal history of David Copperfield, 1850

3 Negative influence on human development InfectionsTeratogensAlcoholCocaineTobacco Nutritional deficiency Cytotoxic treatment????

4 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after breast cancer

5 Study center Perinatal Epidemiology (SPE)

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7 Distribution of cancer in pregnant women Distribution of cancer in pregnant women Pavlidis A, Oncologist 2002;7: n of cases% n of cases% Breast29826 Cervical cancer Leukemia17415 Lymphoma Melanoma938 Thyroid454 Miscellaneous11111 Total

8 ChemotherapyRadiotherapy All-or-nothing 10cGyIUGR Central nervous system Microcephaly Eye anomalies Mental retardation Few gross anomalies, rather growth retardation 17% congenital anomalies -nasal and auditory canal abnormalities -micrognathia -limb deformities Exclusion of folate antagonists: 6% (↔ 3% general population) IUGR Premature birth IUD 10 days w 40 w Conception

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10 Pathology It appears that the histopathologic and immunohistochemical findings of the tumors of pregnant women with BC are similar to those of non-pregnant young women with BC. It is more likely that age at diagnosis rather than the pregnancy determines the biologic features of the tumor.

11 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

12 Breast cancer surgery during pregnancy  Risk of abortion is highest before 12 weeks  Majority underwent mastectomy due to fear for radiotherapy  Breast conserving surgery with axillary LN dissection  Especially third trimester  Chemotherapy before radiation  Sentinel node: Tc  Gentilini et al., Ann Oncol 2004;15:  Keleher et al., Breast J 2004;10:492-5

13 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

14 Radiotherapy, Kal, Lancet Oncol 2005 Breastca, supradiaphragmatic Hodgkin’ disease, Brain tumors, head– and necktumors < 0.01 Gy exposure Distance Shielding with lead protection Slight increase leukemia, tumors during childhood (nl )  0.2 Gy: effect dependent pregnancy duration  Multidisciplinary approach

15 Fetal dose during diagnostic procedures Chest X-ray Abdominal X-ray Pelvic X-ray IVP CT skull CT pelvis Tc (bone scan) 0,00006 cGy 0,15-0,26 cGy 0,2-0,35 cGy 0,47-0,82 cGy 0,007 cGy 2,5 cGy 0,15 cGy

16 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

17 Anthracyclins Doxorubicin (Adriblastina°) Epirubicin (Peccatori et al., Lancet Oncol 2004;5:398) Slightly more lipophylic Slightly more lipophylic Faster influx Faster influx Less intracellular retention Less intracellular retention Shorter elimination half life Shorter elimination half life Better therapeutic index Better therapeutic index Less systemic and cardial toxic effects Less systemic and cardial toxic effects No fetal complications (n=14) No fetal complications (n=14)Idarubicin  More lipophylic  Higher affinity for DNA

18 Pharmacokinetics during pregnancy: preliminary data

19 Taxanes during pregnancy AuthorChemotherapyStart chemo (w) Delivery (w)Status child (age, mts) De Santis, 2000 Docetaxel, 3 x2432Nl (20) Sood, 2001Paclitaxel- cisplatin, 3x 3037Nl (30) Mendez, 2003Paclitaxel- carboplatin, 6x 1635Nl (15) Gadducci, 2003 Epirubicin x4, paclitaxel x3 1436Nl (36) Potluri, 2006Doxo-cyclo x4, docetaxel x4 14Nl Doxo- docetaxel x6 14Nl Nieto, 2006FEC x4, docetaxel x4 13NL (birth)

20 Trastuzumab during pregnancy DosageGestational age ComplicationOutcome child Watson et al., mg, 3 weekly Untill 20wanhydramnionNl Fanale et al., 2005 weekly27wnoneNl Waterston et al., cycle, 523 mg First trimester noneNl

21 Rituximab during pregnancy DosageGestational age (w) ComplicationsOutcome child Herold et al., x R-doxo- vinblastin- prednisone 21NoneNl (4 mts) Kimby et al., x 375mg/m²conceptionNoneNl (18 mts) Decker et al., x R-CHOP14NoneNl (16 mts)

22 Imatinib during pregnancy DosageGestational age (w) ComplicationsOutcome child Ali, mg/d6weeks during organogenesis NoneNl AlKindi, mg/d 200mg/d Whole pregnancy None Nl Prabhash, mg/d Whole pregnancy None none Nl at birth Nl at 1 mt Ault, mg/d N =9 During organogenesis, 4 weeks (range, 4-9 w) Hypospadia, x1 Spontaneous abortion, x2 Elective abortion, x1 8 nl babies at a mean age of 17mts(range, 3- 53mts) Chouhary, mg/d4w during organogenis meningocoelefatal

23 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

24 Chemotherapy during 2 nd and 3 rd trimester: IUGR, premature birth, IUD, neonatal death Pizzuto et al., Cancer Treat Rep 1980;64:679 Mulvihill et al., Cancer 1987;60:1143 Zemlickis et al., Arch Intern Med 1992;152:573 Zemlickis et al., Am J Obstet Gynecol 1992;166:781 Partridge & Garber, Sem Oncol 2000;27:712 Hansen et al., Am J Obstet Gynecol 2001;97:809 Peres et al., Braz J Med Biol Res 2001;34:1551 Ali et al., Leuk Res 2003;27:381 Follow up in high-risk obstetrical unit to determine optimal moment of delivery

25 Chemotherapy during pregnancy: Chemotherapy during pregnancy: Cardonick & Iacobucci, Lancet Oncol 2004;5:283  N = 376, mostly after organogenesis  19 (5%) foeti and 1% neonati died  16 in hematological malignancies  2/3 received idarubicine for breastca  28 (7%) IUGR, 18 (5%) premature birth  15 (4%) neonatal transient myelosuppression  9/11 malformations occurred after 1 st trimester exposure

26 Avoidance of prematurity Zhao et al., Int J Gynecol Cancer 2006;16:8-15 Series of 22 cases of ovarian cancer during pregnancy 14 deliveries 1 neonatal death  C/S at 31 weeks  Died of respiratory distress syndrome

27 Fetal maturity

28 18 year experience from 5 London teaching hospitals Ring et al., J Clin Oncol 2005;18: 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: 1 e trim → miscarriage 1/28: 1 e trim → miscarriage medianrange GA, D/, w GA, surgery, w GA, chemo,w GA, delivery, w Weight < P10 0 Transfer neonato 5

29 Last chemo-delivery: > 3w interval Maternal neutropenia and thrombocytopenia Metabolisation in placenta (fœtus) versus inefficient neonatal liver and kidney function (neonate) Neonatal myelosuppression o Okun et al., Med Ped Oncol 1979;7:315 o Pizzuto et al., Cancer Treat Rep 1980;64:679 o Reynoso et al., JCO 1987;5:1098 o Raffles et al., Br J Obstet Gynaecol 1989;96:1099 o Avilés et al., Am J Hematol 1991;36:243 o Garcia et al., J Perinatol 1999;19:230

30 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

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

32 MD Anderson data Hahn et al., Cancer 2006 N = 57 (32 adj CT, 25 NACT), FAC N = 57 (32 adj CT, 25 NACT), FAC Survey: mail or telephone Survey: mail or telephone Children age (n=40): mts Children age (n=40): mts OutcomeN (%)Reported incidence general population Down syndrome1 (2.5)1:700 (30-34y) Clubfoot1 (2.5)1:1000 Cong bilat ureteral reflux1 (2.5)3-4% some uro problem “normal development”39 (97) Requires special attention in school 2/18 (11)

33 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

34  Retrospective search of cases  Prospective o Standardised clinical neurologic assessment o Echocardiografy with dopplers Methods

35 Results: maternal data (last FU, ) DiagnosisNRTSurgeryChemotherapy Orofaryngeal ca, 1 2 x cisplatin (25mg/m²) + fluoroblastin (100mg/m²) (30, 32) (30, 32) Spinocellular cervixca, 1 6 x cisplatin (75mg/m²) (17, 19, 20, 23, 24, 27) (17, 19, 20, 23, 24, 27) Breastca54 3 x doxorubicin (60mg/m²) + cyclophosphamide(600mg/m²) (23.4, 25.4, 28.4) 3 x doxorubicin (60mg/m²) + cyclophosphamide(600mg/m²) (26, 29, 32) 6 x cyclophosphamide (600mg/m²) + epirubicin (100mg/m²) + 5-FU (500mg/m² ) (21, 24, 27, 30, 33, 36) 6 x cyclophosphamide (500mg/m²) + epirubicin(100mg/m²) + 5-FU (500mg/m²) (20, 23, 26, 29, 32, 35) 3 x 3 x doxorubicin + cyclophosphamide ALL1 HOVON 37 cycle 1 and 2 (21, 26) AML2 2 x idarubicine (12mg/m²) + cytarabine (100mg/m²) (15, 20) retinoinic acid started at 31w 3 x idarubicine (12mg/m²) + cytarabine (100mg/m²) (15, 21, 26) Glioblastoma111 Temodal ( 18-21, 26, 30, 34) Hodgkin3 3 x ABVD 2 x ABVD (29, 33) 4 x ABVD (15, 19, 23, 27)

36 (last FU, ) Results: neonatal and pediatric follow-up (last FU, ) N Com- plication s GA birth (w) Birth weight (gr) Neonatal complications FU(Mts) Outcome child (p 79) Prematurity2.5 Asymmetric tonick nek reflex and delayed visual fixation (p 23) Prematurity HMD I: ncpap Pneumomediastinum ↑ creatinin 16 Normal development 1 Sepsis (26) P-PROM (28) (p 0.5) PrematurityPancytopenia 2 d HFO -> cpap till d 31 -> cpap till d 3121 Minor delay expressive language development 1 (twin) P-PROM (32.4) (p 5) PrematurityHFO39 Autistic disorder, mental and motoric retardation (< unilateral polymicrogyria) 1 (twin) P-PROM (32.4) (p 0.8) Prematurity39 Normal development 10 1 x Sepsis (29) (36.3) 2743 ( ) 4 x Prematurity 26 (1- 66) Normal development

37 PatientsControls P value LVEDD/BSA (mm) 54.2 ± ± LVESD/BSA (mm) 34.7 ± ± ILWTD/BSA (mm) 9.1 ± ± FS (%) 35.7 ± ± LVMI (gr/m 2 ) 57.3 ± ± Mitral E (cm/sec) ± ± E/A ratio 2.2 ± ± Decceleration E (msec) ± ± IVRT (msec) 47.4 ± ± PuVe systole (cm/sec) 54.8 ± ± PuVe diastole (cm/sec) 61.3 ± ± Septal annular motion (mm) 10.2 ± ± Lateral annular motion (mm) 13.4 ± ± RV annular motion (mm) 15.8 ± ± Standard echocardiographic data Van Calsteren et al., J Clin Oncol 2006;24(12):e16-7

38 Breast cancer during pregnancy SurgeryRadiotherapyChemotherapyFarmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

39 No difference in survival ‘Two year cancer diagnosis anniversary’ Higher rate of miscarriages Individual’s response to therapy Receptor positive: Tamoxifen contraindicated (ambiguous genitalia, Goldenhar syndrome) After completion hormonal treatment

40 Extended adjuvant: update Goss et al., JNCI 2005;97: Letrozole N = 2593 Placebo N= 2594 P-value Rec or contralat breast HR 0.58 (CI ) Distal recurrence HR 0.60 (CI ) Survival HR 0.82 (CI ) 0.3 Survival node pos HR 0.61 (CI ) 0.04 Bone fracture 5.3%4.6%0.25 Osteoporosis8.1%6.0%0.003 Cardiovascular5.8%5.6%0.76 Postmenopausal 5 years tamoxifen Randomisation

41 Radiotherapy is possible Chemotherapy Short term (neonatal) safety evidence Long term outcome: retrospective data suggest safety Prospective trials needed  Larger numbers  Longer follow up  Thorough assessment Morbidity related to –induced- prematurity Breast cancer during pregnancy and pregnancy after treatment : conclusions

42 ¡¡¡ Thank you!!!

43 Cisplatin during pregnancy Epithelial ovarian cancer, ovarian germ cell, cervical ca, sex-cord stromal, melanoma, neuroblastoma. Based on 21 reports: 2/21 (9.5%) IUGR 1/21 (4.5%) moderate bilateral hearing loss 1/21 (4.5%) ventriculomegaly e causa ignota 19/21 (90.5%) absence congenital anomalies and normal neurological development

44 Safety issues Safety issues Andreadis et al., Gynecol Oncol 2004;95: year-old T4cN3 breast cancer, bone metastases 5-fluorouracyl, epirubicin and cyclophosphamide before conception and during first trimester 28Gy thoracic and lumbar part at 17 weeks Diagnosis of pregnancy Normal functioning one-year-old child

45 Fetal cardiac effects after doxorubicin: case report Meyer-Wittkopf et al., Ultrasound Obstet Gynecol 2001;18: year-old T1 grade III IDA at 16 weeks Mastectomy and axillary node dissection 4 cycles doxorubicin-cyclophosphamide Serial echocardiographic measurements ventricular shortening fraction and biometry of the ventricular cavities during pregnancy till 2 year No myocardial dysfunctions were observed

46 Late cardiac effects of doxorubicin therapy for ALL in childhood Lipschultz et al., NEJM 1991;324: Acute lymphoblastic leukemia, n = doxorubicin/m² (median, 360), n = 97 Median interval was 6.4 y Results Left ventricular wall thickness: 0.68±0.20 vs 0.81±0.09 cm, P< Multivariate analysis: higher cumulative dosage and age < 4 years predicted increased afterload Doxorubicin induced loss of myocytes during childhood might result in inadequate left ventricular mass and clinically important heart disease in later years

47 Transplacental passage of anthracyclins Roboz et al., Lancet 1979;22: No detection of doxorubicin or its metabolite in amniotic fluid shortly after a dose was administered to the mother

48 Transplacental passage of anthracyclins Karp et al., Cancer Treat Rep 1983;67:773-7 Patient 2: no doxorubicin could be detected in any fetal tissue (liver, lung, kidney, heart, spleen, diaphragm, duodenum, skeletal muscle) Samples in patient 1 Doxorubicin (nmols/g of tissue) Placenta (maternal side) Placenta (proximal to cord) Umbilical cord Cord blood plasma Not detectable

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