1. The document summarizes evidence on administering chemotherapy during pregnancy for breast cancer. Two prospective studies found that weekly regimens of epirubicin or FAC chemotherapy appeared safe for mother and neonate. 2. Data on transplacental transfer of chemotherapy in animal models found lower transfer rates for anthracyclines, paclitaxel, and docetaxel compared to cyclophosphamide and carboplatin. 3. Case reports on trastuzumab administration during pregnancy generally reported no adverse effects on the mother but increased risk of fetal complications like anhydramnios and respiratory failure.

1. BREAST CANCER DURING PREGNANCY What evidence do we have? Hatem A.Azim Jr Breast Cancer Translational Research Laboratory (BCTL) Institut Jules Bordet (IJB) Brussels, Belgium 11 th Pan Arab Cancer Congress; EASO session Casablanca; April 29 – May 1 st , 2011

2. Berry DL et al; JCO 1999 EPIDEMIOLOGY 1/3.000 pregnancies 5-10% of breast cancer < 40 y ~ 10,000 cases/year worldwide

5. Cardonick E et al; Lancet Oncol 2004

7. Adjuvant (neo) chemo in GBC ONLY 2 Prospective Studies !!

10. Age at diagnosis 33 y (24-45) Gestational age at diagnosis W 17 (2-33) Gestation age of starting chemo W 23 (14-33) Histological grade III 82% ER –ve 70% Her-2/neu +ve 30% Number of cycles 4 (1-6) Method of delivery Vaginal 60% Cesarean 40% MD Anderson - experience

14. Age at diagnosis 37 y (23-42) Gestation age of starting chemo W 19 (16-30) Node +ve 60% ER –ve 50% Her-2/neu +ve 20% Number of weeks 12 (4-16) Method of delivery Vaginal 40% Cesarean 60% IEO – experience

16. MD Anderson (57) IEO (20) FAC Regimen Weekly epirubicin 37 W Gestational age at delivery 35 W 2/57 (4%) Pre-term pregnancies 1/20 (5%) 3/57 Congenital anomalies 1/20 Maternal outcome at 38m 70% DFS 70% 77% OS 85%

19. Long-term effects of in-utero exposure to doxorubicin-based regimens Aviles A et al; Ann Oncol 2006 Hahn K et al; Cancer 2006 Median FU Number Late effects Doxorubicin-based regimens (leukemia/lymphoma) 18 Y 89 None FAC (CI Doxo) 6 Y 18 None

20. Long-term effects of in-utero exposure to weekly epirubicin (n=30) Updated Peccatori F et al; Breast Ca Res Treat 2009 Normal Development !! Age 0-1 Age 2-3 Age 4-5 Age 6-7 Age 8 N° 5 10 9 3 3

21. WHAT ABOUT OTHER CHEMOTHERAPY REGIMENS?

23. Transplacental transfer of chemotherapy in baboon models * % during the first 25h from maternal exposure Van Calsteren V et al; Gynecol Oncol 2010 Van Calsteren V et al; Int J Gynecol Cancer 2010 Drug % in fetus * Total No. (Detected) Doxorubicin 7.5 ± 3.2 15 ( 6) Epirubicin 4.0 ± 1.6 11 (8) Paclitaxel 1.4 ± 0.8 11 (7) Docetaxel 0 9 (0) Cyclophosphamide 25.1 ± 6.3 4 (3) Carboplatin 57.5 ± 14.2 7 (7)

28. HER2 plays a pivotal role in the development of different foetal organs LUNG KIDNEY INTESTINE SKIN Patel NV et al; Am J Respirol Mol Biol 2000 Kokai Y et al; PNAS 1987

30. A: adjuvant; M: metastatic; T: trastuzumab; NS: not significant; pre: preconception; EF: ejection fraction; IUGR: intrauterine growth restriction; vag blee: vaginal bleeding; PROM; premature rupture of membranes; NAD: no abnormality detected; RF: renal failure; Resp F: respiratory failure Setting Regimen Time Mother Pregnancy Baby Watson 2005 A T Pre, 1 st , 2 nd NS Anhydramnios NAD Fanale 2005 M T+ vinorelbine 3 rd NS NS NAD Waterston 2006 A T Pre NS NS NAD Bader 2007 M T + paclitaxel 2 nd NS Anhydramnios, IUGR Transient Resp F,RF Shrim 2007 M T Pre, 1 st , 2 nd EF decrease NS Transient RF Sekar 2007 M T + docetaxel 2 nd , 3 rd NS Anhydramnios NAD Witzel 2008 M T Pre, 1 st , 2 nd , 3 rd NS Anhydramnios, vag blee Resp F, died Berveiller 2008 A T Pre NS Ectopic preg., E. Aborton … Pant 2008 M T Pre, 1 st , 2 nd , 3 rd NS Anhydramnios NAD Weber 2008 M T Pre, 1 st , 2 nd NS Anhydramnios Resp F, died Warraich 2009 A T + tam + LHRH Pre, 1 st , 2 nd , 3 rd NS Anhydramnios Res. F, fetal death after 40 minutes Beale 2009 A T + tam Pre, 1 st , 2 nd NS Anhydramnios, PROM Twins: 1) RF, Resp F, Death 2) Transient Resp. F Azim Jr 2009 A T Pre NS NS NAD Goodyer 2009 M A T T 2 nd , Pre None None Premature

31. Setting Regimen Time Mother Pregnancy Baby Watson 2005 A Herceptin Pre, 1 st , 2 nd NS Anhydramnios NAD Fanale 2005 M Herceptin + vinorelbine 3 rd NS NS NAD Waterston 2006 A Herceptin Pre NS NS NAD Bader 2007 M Herceptin + paclitaxel 2 nd NS Anhydramnios, IUGR Transient Resp F,RF Shrim 2007 M Herceptin Pre, 1 st , 2 nd EF decrease NS Transient RF Sekar 2007 M Herceptin + docetaxel 2 nd , 3 rd NS Anhydramnios NAD Witzel 2008 M Herceptin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios, vag blee Resp F, died Berveiller 2008 A Herceptin Pre NS Ectopic preg., E. Aborton … Pant 2008 M Herceptin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios NAD Weber 2008 M Herceptin Pre, 1 st , 2 nd NS Anhydramnios Resp F, died Warraich 2009 A Herceptin + tamoxifen + gasorelin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios Res. F, fetal death after 40 minutes Beale 2009 A Herceptin + tamoxifen Pre, 1 st , 2 nd NS Anhydramnios, PROM Twins: 1) RF, Res. F, Death 2) Transient Res. F Azim Jr 2009 A Herceptin Pre NS NS NAD

33. Setting Regimen Time Mother Pregnancy Baby Watson 2005 A Herceptin Pre, 1 st , 2 nd NS Anhydramnios NAD Fanale 2005 M Herceptin + vinorelbine 3 rd NS NS NAD Waterston 2006 A Herceptin Pre NS NS NAD Bader 2007 M Herceptin + paclitaxel 2 nd NS Anhydramnios, IUGR Transient Resp F,RF Shrim 2007 M Herceptin Pre, 1 st , 2 nd EF decrease NS Transient RF Sekar 2007 M Herceptin + docetaxel 2 nd , 3 rd NS Anhydramnios NAD Witzel 2008 M Herceptin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios, vag blee Resp F, died Berveiller 2008 A Herceptin Pre NS Ectopic preg., E. Aborton … Pant 2008 M Herceptin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios NAD Weber 2008 M Herceptin Pre, 1 st , 2 nd NS Anhydramnios Resp F, died Warraich 2009 A Herceptin + tamoxifen + gasorelin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios Res. F, fetal death after 40 minutes Beale 2009 A Herceptin + tamoxifen Pre, 1 st , 2 nd NS Anhydramnios, PROM Twins: 1) RF, Res. F, Death 2) Transient Res. F Azim Jr 2009 A Herceptin Pre NS NS NAD

34. Setting Regimen Time Mother Pregnancy Baby Watson 2005 A Herceptin Pre, 1 st , 2 nd NS Anhydramnios NAD Fanale 2005 M Herceptin + vinorelbine 3 rd NS NS NAD Waterston 2006 A Herceptin Pre NS NS NAD Bader 2007 M Herceptin + paclitaxel 2 nd NS Anhydramnios, IUGR Transient Resp F,RF Shrim 2007 M Herceptin Pre, 1 st , 2 nd EF decrease NS Transient RF Sekar 2007 M Herceptin + docetaxel 2 nd , 3 rd NS Anhydramnios NAD Witzel 2008 M Herceptin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios, vag blee Resp F, died Berveiller 2008 A Herceptin Pre NS Ectopic preg., E. Aborton … Pant 2008 M Herceptin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios NAD Weber 2008 M Herceptin Pre, 1 st , 2 nd NS Anhydramnios Resp F, died Warraich 2009 A Herceptin + tamoxifen + gasorelin Pre, 1 st , 2 nd , 3 rd NS Anhydramnios Res. F, fetal death after 40 minutes Beale 2009 A Herceptin + tamoxifen Pre, 1 st , 2 nd NS Anhydramnios, PROM Twins: 1) RF, Res. F, Death 2) Transient Res. F Azim Jr 2009 A Herceptin Pre NS NS NAD

40. Amant F; EJC 2010

41. Sentinel node in Pregnancy Dosimetry Study in non-pregnant patients Gentilini O et al, Ann Oncol 2004 12 MBq  fetal exposure < 0.1 mGy N = 26

43. Amant F; EJC 2010

47. GBC BC controls Unpublished data All patients 65 130 Age (years) < 35 35-39 ≥ 40 20 (30.8) 33 (50.8) 12 (18.5) 41 (31.5) 61 (46.9) 28 (21.5) Match Median 36 (28-47) 36 (28-47) Year of Surgery Median 2005 (1996-2010) 2005 (1996-2009) Match pT 1 2 3 26 (39.9) 31 (47.7) 6 (9.2) 52 (39.9) 62 (47.7) 12 (9.2) Match pN 0 1 2 3 28 (43.1) 19 (29.2) 10 (15.4) 6 (9.2) 56 (43.1) 38 (29.2) 20 (15.4) 12 (9.2) Match Neoadjuvant Chemotherapy Yes No 7 (10.8) 58 (89.2) 14 (10.8) 116 (89.2) Match Surgery Quadrantectomy Mastectomy 42 (64.6) 23 (35.4) 80 (61.5) 50 (38.5) 0.676 Adjuvant Chemotherapy Yes No 44 (67.7) 21 (32.3) 81 (62.3) 49 (37.7) 0.460

48. Unpublished data GBC BC controls Pathological Subtype IDC ILC Others 58 (89.2) 0 (0) 7 (10.8) 116 (89.2) 5 (3.9) 9 (6.9) 0.171 Grade 1 2 3 4 (7.5) 18 (34.0) 31 (58.5) 4 (3.6) 43 (39.1) 63 (57.3) 0.503 Perivascular Invasion Absent Present 31 (47.7) 34 (52.3) 70 (55.1) 57 (44.9) 0.330 ER Positive Negative 43 (66.1) 22 (33.9) 98 (75.4) 32 (24.6) 0.175 PR Positive Negative 42 (64.6) 23 (35.4) 87 (66.9) 43 (33.1) 0.748 Ki-67 % < 20 ≥ 20 18 (28.6) 45 (71.4) 30 (23.4) 98 (76.6) 0.442 Her2/neu Positive Negative 11 (16.9) 54 (83.1) 24 (18.9) 103 (81.1) 0.737

49. ABORTION DOES NOT IMPROVE PROGNOSIS Unpublished data Full-term delivery (n=24) Abortion/anticipated delivery (n=38) Log-rank p=0.03

50. INFERIOR DFS AT MEDIAN FU 4 YEARS Unpublished data Disease free survival (DFS) Overall survival (OS) Log-rank p:0.01 HR 2.3 (95% CI 1.3-4.2)* * Adjusted for T, N, age, HER2, ki67, perivascular invasion Log-rank p:0.17 HR 1.7 (95% CI 0.8-3.9)* BCP BCP Controls Controls

52. Elective Systemic therapy in pregnancy Summary Consider weekly application Anthracycline-based regimen √ Taxanes 2 nd best Trastuzumab X Tamoxifen X Bisphosphonates Better postponed