EASO2011 PanArab 1 Azim

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  • EASO2011 PanArab 1 Azim

    1. 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. 2. Berry DL et al; JCO 1999 EPIDEMIOLOGY 1/3.000 pregnancies 5-10% of breast cancer < 40 y ~ 10,000 cases/year worldwide
    3. 3. POINTS TO DISCUSS <ul><li>Safety, feasibility of chemotherapy </li></ul><ul><li>Data on trastuzumab </li></ul><ul><li>Others: tamoxifen/bisphosphonates </li></ul><ul><li>Surgery & radiotherapy </li></ul><ul><li>Prognosis </li></ul>
    4. 4. <ul><li>When a drug is administered to the mother, placental transfer of the drug could be hazardous to the fetus </li></ul>Chemotherapy Safety Cardonick E et al; Lancet Oncol 2004
    5. 5. Cardonick E et al; Lancet Oncol 2004
    6. 6. Our Bench Mark !! Pregnancy-related events in the normal population ? Goldenberg R et al; Lancet 2008 <ul><li>Incidence of malformations </li></ul><ul><li>Major </li></ul><ul><li>Moderate </li></ul>2-4% 15% Incidence of spontaneous abortion 15% <ul><li>Incidence of pre-term deliveries </li></ul><ul><li>Europe </li></ul><ul><li>US </li></ul>5-9% 10-13%
    7. 7. Adjuvant (neo) chemo in GBC ONLY 2 Prospective Studies !!
    8. 9. MD Anderson - experience <ul><li>Phase II study (recruitment period: 10 years) </li></ul><ul><li>57 patients (32 adjuvant, 25 neo-adjuvant) </li></ul><ul><li>Regimen: FAC </li></ul><ul><ul><li>Cyclo : 500mg/m2 IV D1 </li></ul></ul><ul><ul><li>Doxo: 50mg/m2 CI D1-3 </li></ul></ul><ul><ul><li>5-FU: 500mg/m2 IV D1+4 </li></ul></ul>Hahn K et al; Cancer 2006
    9. 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
    10. 11. <ul><li>Fetal mortality: 0 </li></ul><ul><li>Median gestational age at delivery: 37 W </li></ul><ul><li>Median fetal birth weight: 3,000 gm </li></ul><ul><li>Congenital anomalies </li></ul><ul><ul><li>Down syndrome: 1 </li></ul></ul><ul><ul><li>Club foot: 1 </li></ul></ul><ul><ul><li>Congenital ureteral reflux: 1 </li></ul></ul><ul><li>Follow-up (2-157m): normal physical & mental development, no cardiac anomalies </li></ul>MD Anderson – experience Neonatal outcome Hahn K et al; Cancer 2006
    11. 13. IEO – experience <ul><li>Phase II study (recruitment period: 5 years) </li></ul><ul><li>20 patients (13 adjuvant, 7 neo-adjuvant) </li></ul><ul><li>Regimen: single agent epirubicin </li></ul><ul><ul><li>Epirubicin: 35mg/m2 weekly </li></ul></ul>Peccatori F et al; Breast Ca Res Treat 2009
    12. 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
    13. 15. <ul><li>No G III/IV toxicity, G II anemia: 1 patient </li></ul><ul><li>Fetal mortality: 0 </li></ul><ul><li>Median gestational age at delivery: 35 W </li></ul><ul><li>Median fetal birth weight: 3,000 gm </li></ul><ul><li>Congenital anomalies: </li></ul><ul><ul><li>Polycystic kidney: 1 </li></ul></ul><ul><li>Follow-up (2-50m): normal physical & mental development, no cardiac anomalies </li></ul>IEO – experience Neonatal outcome Peccatori F et al; Breast Ca Res Treat 2009
    14. 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%
    15. 17. <ul><li>Allow close monitoring of pregnancy </li></ul><ul><li>Low peak plasma concentration resulting in </li></ul><ul><ul><li>Lower toxicity (more safe) 1 </li></ul></ul><ul><ul><li>Possible lower placental transfer & foetal exposure 2 </li></ul></ul><ul><li>Easy interruption in case of toxicity </li></ul><ul><li>Efficacy of weekly regimens is established outside pregnancy 3 </li></ul>WHY WEEKLY ?? 1. Norton L et al; Oncologist 2005 2. Zucchetti M; personal communication 3. Ellis M et al; JCO 2011
    16. 18. EUROPEAN REGISTRY on BC during pregnancy Loibl S et al; SABCC 2010 <ul><li>Foetal outcome (chemo vs. no chemo) </li></ul><ul><li>Median birth weight at delivery: 2760 gm (vs. 2810) </li></ul><ul><li>Median gestational age at delivery: W37 (vs. W38) </li></ul><ul><li>Median HB level post-partum: 16g/dl </li></ul>Total Number of patients 315 Treated with Chemotherapy 121 (51%) Treated with anthracycline-based regimens 95 (78%) AC/EC 71 FEC 20 Single agent epirubicin/doxorubicin 4
    17. 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
    18. 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
    19. 21. WHAT ABOUT OTHER CHEMOTHERAPY REGIMENS?
    20. 22. Taxanes in GBC <ul><li>Number </li></ul><ul><li>Breast cancer </li></ul><ul><li>Other </li></ul>27 13 Paclitaxel Docetaxel Both 21 16 3 <ul><li>Neonatal outcome </li></ul><ul><li>Gestational age at delivery </li></ul><ul><li>Foetal weight </li></ul><ul><li>Median FU 18m </li></ul>W 36 2400 g No anomalies reported
    21. 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)
    22. 24. CMF in pregnancy ! <ul><li>CMF : normal outcome in 2 nd , 3 rd trimester exposure </li></ul><ul><li>However .. </li></ul><ul><li>MTX used in induction of abortion 2 </li></ul><ul><li>1 st trimester exposure = highly teratogenic 3 </li></ul><ul><li>CMF < “Anthracyclines” < “Anthra + Taxanes” 1 </li></ul>Ring A et al; JCO 2005 1. Bedard P & Cardoso F: Ann Oncol 2008 2. Say L et al; Cochrane Database 2005 3. Aebi S & Loibl L: Rec Results Cancer Res, 2008
    23. 25. CMF in pregnancy ! <ul><li>CMF : normal outcome in 2 nd , 3 rd trimester exposure (25 cases) </li></ul><ul><li>CMF < “Anthracyclines” < “Anthra + Taxanes” 1 </li></ul><ul><li>MTX used in induction of abortion 2 </li></ul><ul><li>1 st trimester exposure = highly teratogenic 3 </li></ul>Azim HA Jr et al: Cancer Treat Rev, 2010 1. Bedart & Cardoso: Ann Oncol, 2008 2. Say L et al: Cochrane Database, 2005 3. Aebi & Loibl: Rec Results Cancer Res, 2008 AVOID during PREGNANCY
    24. 26. CHEMOTHERAPY DURING PREGNANCY: PRACTICAL TIPS Azim HA Jr et al; Breast 2011 Urgently needed in 1 st trimester Discuss termination When to start W14 Pregnancy monitoring <ul><li>U/S and umbilical artery Doppler </li></ul><ul><li>At least once every month </li></ul>When to stop W34 or 35 max Chemo-delivery interval <ul><li>Preferably 3 weeks (in Q3w regimens) </li></ul><ul><li>Avoid delivery in Nadir </li></ul>Delivery Method Vaginal: faster recovery Timing of delivery Aim for W37+; try to avoid early preterm (i.e. less than W34)
    25. 27. POINTS TO DISCUSS <ul><li>Safety, feasibility of chemotherapy </li></ul><ul><li>Data on trastuzumab </li></ul><ul><li>Others: tamoxifen/bisphosphonates </li></ul><ul><li>Surgery & radiotherapy </li></ul><ul><li>Prognosis </li></ul>
    26. 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
    27. 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
    28. 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
    29. 32. Trastuzumab & the amniotic fluid <ul><li>Anhydramnios </li></ul><ul><li>Trastuzumab blocks Her-2 expressed in fetal kidney </li></ul><ul><li>It interferes with VEGF signaling responsible for amniotic fluid production and reabsorption </li></ul>Sekar R et al: OBY GYN, 2007 Pant S et al: JCO, 2008
    30. 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
    31. 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
    32. 35. POINTS TO DISCUSS <ul><li>Safety, feasibility of chemotherapy </li></ul><ul><li>Data on trastuzumab </li></ul><ul><li>Others: tamoxifen/bisphosphonates </li></ul><ul><li>Surgery & radiotherapy </li></ul><ul><li>Prognosis </li></ul>
    33. 36. Facts about tamoxifen <ul><li>Pregnancy is possible on tamoxifen … </li></ul><ul><li>Moreover, currently used in induction of ovulation and licensed in the UK for managing infertility </li></ul><ul><li>Preclinical models have shown that it causes ambiguous genitalia and ++ genital cancers in off springs </li></ul>Berthelmess & Gately; Breast 2004
    34. 38. <ul><li>Concerns </li></ul><ul><li>- Preclinical models: skeletal deformities, genital defects </li></ul><ul><li>- Maternal hypocalcemia: affect uterine contraction </li></ul>Bisphosphonates However … - A systematic review of literature till 9-2008 3 - 52 patients exposed (mainly osteoporosis): normal outcomes Patlas N et al: Teratology, 1999 Ornoy A et al: Reprod Toxicol, 2006 Djokanovic N et al: J Obstet Gynaecol Can, 2008
    35. 39. POINTS TO DISCUSS <ul><li>Safety, feasibility of chemotherapy </li></ul><ul><li>Data on trastuzumab </li></ul><ul><li>Others: tamoxifen/bisphosphonates </li></ul><ul><li>Surgery and radiation </li></ul><ul><li>Prognosis </li></ul>
    36. 40. Amant F; EJC 2010
    37. 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
    38. 42.     Number 12 Median age (range) 38 (33 – 42) Clinical stage T1N0 (7); T2N0 (5) Median gestational age at SLN (range) 17w (5-33w) SLN outcome 10 –ve; 2 +ve <ul><li>At 32 months of FU </li></ul><ul><li>Patient </li></ul><ul><li>Babies </li></ul>No axillary recurrence Normal development
    39. 43. Amant F; EJC 2010
    40. 44. POINTS TO DISCUSS <ul><li>Safety, feasibility of chemotherapy </li></ul><ul><li>Data on trastuzumab </li></ul><ul><li>Others: tamoxifen/bisphosphonates </li></ul><ul><li>Surgery & radiotherapy </li></ul><ul><li>Prognosis </li></ul>
    41. 45. DIAGNOSTIC DELAY <ul><li>Larger tumors </li></ul><ul><li>More nodal involvement </li></ul><ul><li>More mastectomies </li></ul><ul><li>More systemic therapies </li></ul>Courtesy of Fedro Peccatori
    42. 46. DO PATIENTS WITH GBC HAVE WORSE PROGNOSIS COMPARED TO MATCHED CONTROLS ? <ul><li>Around 30 published case-control trials with conflicting results !!!! </li></ul><ul><li>Limitations: </li></ul><ul><ul><li>Small-sized (lack of power) </li></ul></ul><ul><ul><li>Multi-institutional </li></ul></ul><ul><ul><li>Lack of matching according to stage - therapy </li></ul></ul><ul><ul><li>Scarce information regarding pathological features </li></ul></ul>
    43. 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
    44. 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
    45. 49. ABORTION DOES NOT IMPROVE PROGNOSIS Unpublished data Full-term delivery (n=24) Abortion/anticipated delivery (n=38) Log-rank p=0.03
    46. 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
    47. 51. Is GBC biologically different? <ul><li>Collection of FFPE of GBC </li></ul><ul><li>TMA construction </li></ul><ul><li>Central testing for pathology, IHC </li></ul><ul><li>Whole genome array </li></ul><ul><li>GGI </li></ul><ul><li>Compare to matched controls and </li></ul><ul><li>examine effect on DFS </li></ul>IEO – Jules Bordet – GBG – Katholic University Leuven – Ioannina University Azim, Peccatori, Loibl, Amant, Pavlidis, Sotiriou
    48. 52. Elective Systemic therapy in pregnancy Summary Consider weekly application Anthracycline-based regimen √ Taxanes 2 nd best Trastuzumab X Tamoxifen X Bisphosphonates Better postponed
    49. 53. TAKE HOME MESSAGE <ul><li>Treatment during pregnancy is feasible, but </li></ul>Locally advanced/ N+ Aggressive biology (e.g. TN/HER2+) 2nd trimester Early, N-ve Luminal-A W30+ “ Though the narrowness of today might reassure us that an intervention is safe, it is only with the wisdom of time that the full consequences of our actions are revealed” .. Goodman et al; NEJM 2010

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