Breast cancer during pregnancy and pregnancy after treatment

Breast cancer during pregnancy and pregnancy after treatment Belgian Breast Meeting 13 -10 -2006 Frederic Amant Gynaecologic Oncology Multidisciplinary Breast Center Katholieke Universiteit Leuven

‘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

Negative influence on human development Infections Teratogens Alcohol Cocaine Tobacco Nutritional deficiency Cytotoxic treatment? ?

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after breast cancer

Study center Perinatal Epidemiology (SPE)

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.

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

Breast cancer surgery during pregnancy Ø Ø Ø Risk of abortion is highest before 12 weeks Majority underwent mastectomy due to fear for radiotherapy Breast conserving surgery with axillary LN dissection Ø Ø Ø Especially third trimester Chemotherapy before radiation Sentinel node: Tc Ø Ø Gentilini et al. , Ann Oncol 2004; 15: 1348 -51 Keleher et al. , Breast J 2004; 10: 492 -5

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

Radiotherapy, Kal, Lancet Oncol 2005 Breastca, supradiaphragmatic Hodgkin’ disease, Brain tumors, head– and necktumors Distance Shielding with lead protection < 0. 01 Gy exposure Slight increase leukemia, tumors during childhood 0. 003 -0. 004 (nl 0. 002 -0. 003) Ø 0. 2 Gy: effect dependent pregnancy duration ØMultidisciplinary approach

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

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

Pharmacokinetics during pregnancy: preliminary data

Taxanes during pregnancy Author Chemotherapy Start chemo (w) Delivery (w) Status child (age, mts) De Santis, 2000 Docetaxel, 3 x 24 32 Nl (20) Sood, 2001 Paclitaxelcisplatin, 3 x 30 37 Nl (30) Mendez, 2003 Paclitaxelcarboplatin, 6 x 16 35 Nl (15) Gadducci, 2003 Epirubicin x 4, paclitaxel x 3 14 36 Nl (36) Potluri, 2006 Doxo-cyclo x 4, docetaxel x 4 14 Nl Doxodocetaxel x 6 14 Nl FEC x 4, docetaxel x 4 13 NL (birth) Nieto, 2006

Trastuzumab during pregnancy Dosage Gestational age Complication Outcome child Watson et al. , 2005 580 mg, 3 weekly Untill 20 w anhydramnion Nl Fanale et al. , 2005 weekly 27 w none Nl Waterston et al. , 2006 1 cycle, 523 mg First trimester none Nl

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

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

Chemotherapy during pregnancy: 1966 -2004 Cardonick & Iacobucci, Lancet Oncol 2004; 5: 283 q N = 376, mostly after organogenesis q 19 (5%) foeti and 1% neonati died § § 16 in hematological malignancies 2/3 received idarubicine for breastca q 28 (7%) IUGR, 18 (5%) premature birth q 15 (4%) neonatal transient myelosuppression q 9/11 malformations exposure occurred after 1 st trimester

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

Fetal maturity

18 year experience from 5 London teaching hospitals Ring et al. , J Clin Oncol 2005; 18: 4192 -7 n n n 28 women (24 curative, 4 palliative) Chemotherapy: AC or EC (n=16) or CMF (n=12) 1/28: 1 e trim → miscarriage median range GA, D/, w 17 4 -33 GA, surgery, w 16 5 -29 GA, chemo, w 20 15 -33 GA, delivery, w 37 30 -40 Weight < P 10 0 Transfer neonato 5

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

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

Long term outcomes: retrospective data Avilés and Neri, Clinical Lymphoma 2001; 2: 173 -7 Update on Aviles et al. , Am J Hemat 1991; 36: 243 -8 84 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

MD Anderson data Hahn et al. , Cancer 2006 n n n N = 57 (32 adj CT, 25 NACT), FAC Survey: mail or telephone Children age (n=40): 2 -157 mts Outcome N (%) Reported incidence general population Down syndrome 1 (2. 5) 1: 700 (30 -34 y) 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 pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

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

Results: maternal data (last FU, 9 -2006) Diagnosis N RT Surgery Chemotherapy Orofaryngeal ca, 1 2 x cisplatin (25 mg/m²) + fluoroblastin (100 mg/m²) (30, 32) Spinocellular cervixca, 1 6 x cisplatin (75 mg/m²) (17, 19, 20, 23, 24, 27) Breastca 5 4 3 x doxorubicin (60 mg/m²) + cyclophosphamide(600 mg/m²) (23. 4, 25. 4, 28. 4) 3 x doxorubicin (60 mg/m²) + cyclophosphamide(600 mg/m²) (26, 29, 32) 6 x cyclophosphamide (600 mg/m²) + epirubicin (100 mg/m²) + 5 -FU (500 mg/m² ) (21, 24, 27, 30, 33, 36) 6 x cyclophosphamide (500 mg/m²) + epirubicin(100 mg/m²) + 5 -FU (500 mg/m²) (20, 23, 26, 29, 32, 35) 3 x 3 x doxorubicin + cyclophosphamide ALL 1 HOVON 37 cycle 1 and 2 (21, 26) AML 2 2 x idarubicine (12 mg/m²) + cytarabine (100 mg/m²) (15, 20) retinoinic acid started at 31 w 3 x idarubicine (12 mg/m²) + cytarabine (100 mg/m²) (15, 21, 26) Glioblastoma 1 Hodgkin 3 1 1 Temodal ( 18 -21, 26, 30, 34) 3 x ABVD 2 x ABVD (29, 33) 4 x ABVD (15, 19, 23, 27)

Results: neonatal and pediatric follow-up (last FU, 9 -2006) N Complication s GA birth (w) Birth weight (gr) Neonatal complications FU (Mts) Outcome child 1 34. 5 2840 (p 79) Prematurity 2. 5 Asymmetric tonick nek reflex and delayed visual fixation 1 32 1715 (p 23) Prematurity HMD I: ncpap Pneumomediastinum ↑ creatinin 16 Normal development 1 Sepsis (26) P-PROM (28) 28. 3 720 (p 0. 5) Prematurity Pancytopenia 2 d HFO -> cpap till d 31 21 Minor delay expressive language development 1 (twin) P-PROM (32. 4) 33 1630 (p 5) Prematurity HFO 39 Autistic disorder, mental and motoric retardation (< unilateral polymicrogyria) 1 (twin) P-PROM (32. 4) 33 1390 (p 0. 8) Prematurity 39 Normal development 10 1 x Sepsis (29) 34 -39 (36. 3) 2743 (21403370) 4 x Prematurity 26 (166) Normal development

Standard echocardiographic data Patients Controls P value LVEDD/BSA (mm) 54. 2 ± 10. 7 53. 2 ± 8. 1 0. 82 LVESD/BSA (mm) 34. 7 ± 6. 8 34. 8 ± 6. 1 0. 98 ILWTD/BSA (mm) 9. 1 ± 2. 7 10. 0 ± 3. 2 0. 48 FS (%) 35. 7 ± 3. 4 33. 7 ± 3. 4 0. 21 LVMI (gr/m 2) 57. 3 ± 9. 3 65. 2 ± 12. 9 0. 14 101. 4 ± 19. 7 97. 2 ± 11. 8 0. 58 2. 2 ± 0. 6 2. 2 ± 0. 5 0. 81 105. 8 ± 22. 3 119. 1 ± 17. 6 0. 16 IVRT (msec) 47. 4 ± 8. 2 51. 1 ± 8. 2 0. 35 Pu. Ve systole (cm/sec) 54. 8 ± 6. 3 51. 2 ± 4. 0 0. 17 Pu. Ve diastole (cm/sec) 61. 3 ± 6. 9 64. 2 ± 8. 3 0. 46 Septal annular motion (mm) 10. 2 ± 2. 1 11. 2 ± 1. 1 0. 42 Lateral (mm) 13. 4 ± 1. 5 13. 0 ± 1. 3 0. 98 15. 8 ± 2. 5 17. 0 ± 1. 8 0. 14 Mitral E (cm/sec) E/A ratio Decceleration E (msec) annular motion RV annular motion (mm) Van Calsteren et al. , J Clin Oncol 2006; 24(12): e 16 -7

Breast cancer during pregnancy Surgery Radiotherapy Chemotherapy Farmacology Short term neonatal outcome Long term pediatric outcome Prospective data Pregnancy after treatment

Pregnancy after treatment 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

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

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