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Prognostic value of occult breast cancer cells in blood and bone marrow

Prognostic value of occult breast cancer cells in blood and bone marrow. Gro Wiedswang Surgical unit, Ullevål University Hospital & The Micrometastasis lab, Radiumhospital-Rikshospital Oslo Norway. Rome 16.11.06. - why occult tumour cells - what is occult tumour cells

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Prognostic value of occult breast cancer cells in blood and bone marrow

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  1. Prognostic value of occult breast cancer cells in blood and bone marrow Gro Wiedswang Surgical unit, Ullevål University Hospital & The Micrometastasis lab, Radiumhospital-Rikshospital Oslo Norway Rome 16.11.06

  2. - why occult tumour cells - what is occult tumour cells - occult tumour cells in bone marrow - timing of bone marrow examination - occult tumour cells in blood - clinical trials - futher perspectives

  3. Challenge of breast cancer • Better diagnostics • Screening • Improved surgical treatment • Improved adjuvant treatment 25-30% of N0 patients die whitin 5 years 40% of N1 patients survive > 10 år Overgaard NEJM 1997

  4. Challenge of breast cancer • Therapeutic desicions • size of tumour • lymph node involvement • histological grade • hormone receptor • HER-2 status Improved prognostication! Feature of the patient??

  5. Why micrometastasis? Cancer incidence: > 2500 women/year in Norway > 1mill women/ year wordwide Still 20% 5 year mortality in Norway Current treatment strategies does not catch patients at risk / overtreat low-risk patients Micrometastasis / occult tumour cells: - prognostic tool - identify high/low risk patients - monitoring therapy - identify therapeutic targets

  6. Why micrometastasis ? Patients do relapse after removing the whole breast and negative lymph nodes Early, subclinical dissemination of tumour cells TNM staging does not catch all patients at risk Isolated tumour cells for prognostication ?

  7. Mikrometastasis • Groups of tumour cells 0.2-2mm in another tissue than primary tumour (AJCC 2002, UICC 2002) • bone marrow / lymph nodes / blood • signs of invastion and organisation(Diel & Cote, Ca Treat Reviews 2000)

  8. Occult tumour cells • disseminated tumour cells • circulating tumour cells • minimal residual disease • micrometastasis • early cancer spread

  9. Pilot studies Relapse BM- 24% 25% 23% 15% Follow-up (mnd) 48 76 77 39 Ref. Salvadori 1990 Mansi 1991 Diel 1994 Harbeck 1994 BM+ 17% 25% 45% 38% Relapse BM+ 30% 48% 77% 39% p-value ns <0.005 <0.005 <0.005

  10. Oslo Micrometastasis project • Collaboration between several hospitals in the Oslo region • aspiration of 40 ml bone marrow from crista iliaca ant and post peroperatively • 920 patients included (1995-98)

  11. Isolation of mononuclear cells

  12. Immunocytochemical detection • Single cell suspension2 x 106 cells/test • Spinns to slides • fixation - acetone • Anti-epitelial antibodyAE1/AE3 • Enzymatic visualisation of antibody -APAAP Y Y Y

  13. Tumour cell

  14. Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. Establishment of objective criteria for the evaluation of immunostained cells The European ISHAGE Working Group for Standardization of Tumor cell detection E. Borgen et al. 1999. Cytotherapy 1:377-388

  15. Histopatological datan=920 frequency Nodal status Tumor status N0 N+ T1 T2 T3-4 63% 33% 58% 29% 6% Naume et al Clin Can Res 2001;7:4122-9

  16. Detection of tumour cells BM+ Tumourstatus T1 11.2% T2 15.0% T3 22.6% N0 9.9% N+ 20.6% Nodalstatus Naume et al Clin Can Res 2001;7:4122-9

  17. Correlation of bone marrow positvity to other known prognostic characteristica 0.055 0.128 0.575 0.024 0.045 BM+ p-value ER/PgR p53 Catepsin D c-erbB2 Vascular infiltration 12.0 % 17.6 % 16.2 % 11.9 % 13.1 % 14.6 % 23.9 % 12.3 % 17.4 % 12.6 % +/-,-/+,+/+ -/- Pos Neg Pos Neg Pos Neg Yes No Naume et al Clin Can Res 2001;7:4122-9

  18. Clinical follow-up No of patients with infiltrating cancer, M0 and evaluable immunocytology Obs.time median (range) No of relapses No of systemic relapses No of locoregional relapses No died of breast cancer 817 49 (½-85) mnd 174 (21%) 127 (16%) 47 (6%) 94 (11%) Wiedswang JCO, 18; 3469, 2003

  19. Localisation of systemic relapse Frequency % Skeleton Liver Lung CNS 10.2 5.8 5.2 1.9 Wiedswang JCO, 18; 3469, 2003

  20. Survival according to bone marrow status DDFS BCSS BM- BM- BM+ BM+ p<0.001 p<0.001

  21. Survival lymph node-pos (N+) DDFS BCSS BM- BM- BM+ BM+ p=0.001 p=0.008

  22. Survival lymph node-negative (N0) BCSS DDFS

  23. Survival T1N0 without adjuvant treatment p=0.014 P<0.001

  24. Uni -& multivariat analysis • Cox-regression: • BM+ versus BM- • histological grade • T1 versus T2-4 • N0 versus N1 • hormone receptor (ER+ or/and PgR+ versus both-) • p53 • c-erbB2 • catepsinD • vascular infiltration

  25. Multivariat analysis(Cox regression)p -values breast cancer specific survival All N+ N0 T-status <0.001 <0.001 ns N-status <0.001 BM 0.018 0.015 ns hormonreceptor <0.001 <0.001 ns histologic grade 0.002 0.017 0.021

  26. Multifactorial survial analyses with BM status BM- BM- BM+ BM+ P<0.001 p=0.003

  27. Mansi et al Patient inclusion: 1981-86 Mansi et al. 1987/91/99

  28. Occult tumour cells in bone marrow and clinical outcome Braun et al, 2000, NEJM

  29. Persisting tumor cells in BM after chemotherapy - the impact on survival Braun et al. 2000

  30. Second bone marrow aspiration 3 years after surgery

  31. Second bone marrow aspiration 3 years after surgery • Pasient characteristics (n=356) • 70.2% T1 • 71.9% N0 • 80.1% hormon receptor positiv • 14.9% BM+ • correlates to nodal status and adjuvant treatment

  32. Second bone marrow aspiration 3 years after surgery • Clinical data: • 26 mnd after BM2 • 66 mnd after primary surgery • 32 relapses • 12 local • 20 systemic • 10 pasients died of breast cancer

  33. Survival according to second bone marrow status Distant disease free survival Breast cancer spesific survival p<0.001 p<0.001 Wiedswang et al Clin Ca Res 2004

  34. Breast cancer specific survival N0 (n=256) N+ (n=93) p=0.003 p=ns Wiedswang et al Clin Ca Res 2004

  35. BM1 & BM2 • n= 356 patients • 4 groups: ++ 17 patients +- 54 ” -+ 33 ” -- 231 ”

  36. BM1 & BM2 Breast cancer specific survival Distant disease free survival ++ ++ p<0.001 p<0.001 Wiedswang et al Clin Ca Res 2004

  37. ”Magasinet”, Dagbladet april 03

  38. Occult tumour cells in blood and bone marrow, correlated to clinical outcome (n=341) DFS DDFS BCSS BM- BM- BM- BM+ BM+ BM BM+ Cumulative survival Events/total no of pts: BM-: 8/293 BM+: 6/48 Events/total no of pts: BM-: 17/293 BM+: 10/48 Events/total no of pts: BM-: 23/293 BM+: 14/48 p<0.001 p<0.001 p=0.001 PB- PB- PB- PB+ PB+ PB+ PB Cumulative survival Events/total no of pts: PB-: 8/307 PB+: 6/34 Events/total no of pts: PB-: 28/307 PB+: 9/34 Events/total no of pts: PB-: 20/307 PB+: 7/34 p=0.001 p=0.002 p<0.001 Months after operation Wiedswang et al Int J Ca 2006

  39. Xenidis JCO 2006,24:3756-62

  40. Benoy et al Br J Ca 2006 RT-PCR BM and blood 147 M0/M+ pts Bone marrow superior to blood in predicting outcome

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