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MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER

EMRA against cancer 1 st Forum “ NGOs and cancer: Challenges and opportunities ” Marrakech, 18 - 19 June 2010. MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER. Introduction. Breast cancer: most common malignancy in women . Advances in clinical and translationnel research .

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MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER

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  1. EMRA against cancer 1st Forum “NGOs and cancer: Challenges and opportunities” Marrakech, 18 - 19 June 2010 MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER

  2. Introduction Breast cancer: most common malignancy in women . Advances in clinical and translationnel research. Systemic treatment: chemotherapy, targeted therapy, endocrine therapy Survival improvement

  3. Peto Meta analysis Peto et al, SABCS 2007

  4. INO Recruitement: 1985 - 2006 

  5. Breast cancer treatment Loco-regional: Surgery Radiotherapy Systemic: Chemotherapy Endocrine therapy Targeted therapy

  6. Personalize Medicine: Right Drug to the Right Patient

  7. claudin low Lum A Lum B Basal Her2 Changing Portraits Concept evolution

  8. Biology as the Framework for Progress Clinical Characteristics Biology Pathology

  9. Treatment improvement

  10. Indications of systemic treatment Adjuvant setting Primary systemic therapy Palliative chemotherapy

  11. ADJUVANT SETTING

  12. Adjuvant chemotherapyGoals Post operative Against micrometastasic spread Aim : Improve survival

  13. Adjuvant chemotherapy:Active drugs Methotrexate 5 FU Cyclophosphamide Anthracyclines Taxanes (paclitaxel, docetaxel)

  14. Adjuvant chemotherapy:Regimens 6 FAC 6 FEC 4 AC 60  4 TC 3 FEC+ 3 Docetaxel 4AC 60 + 12 Paclitaxel

  15. Adjuvant Treatment and Survival Improvement Over Past 40 Years

  16. 5 10 5 10 5 10 Peto metanalysisEBCTCG up date 2007 Taxanes > anthra > CMF > No chemotherapy Breast cancer mortality 50 10-y gain 4.3%(SE 1.0) Lorank 2p < 0.00001 10-y gain 4.3%(SE 1.0) Lorank 2p < 0.00003 10-y gain 5.1%(SE 1.6) Lorank 2p < 0.00001 Control36.4% CMF31.3% Anthr. 31.0% 40 30 CMF32.2% 20.5 19.9 Anthr.27.0% 20 15.3 Taxane25.9% %+ SE 17.8 16.5 12.8 10 Years Years Years 0 0 0 0 Peto et al, SABCS 2007

  17. Role of taxanes:Docetaxel Meta-analysis: Trials 20,698 Patients Laporte S, et al. SABCS 2009..

  18. Docetaxel Meta-Analysis: DFS and OS According to Nodal Status • Overall, the pooled HR estimate [95% CI] for DFS was 0.82 [0.75;0.89] (P<0.001) in favor of docetaxel-based chemotherapy • The overall estimated HR for OS was 0.82 [0.74;0.91] (P<0.001) Laporte S, et al. SABCS 2009.

  19. Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4 Peto et al, SABCS 2007

  20. In summary Adjuvant chemotherapy: Survival benefit in node positive and negative breast cancer Anthracyclines based regimen. Anthracyclines + Taxanes Node positif High risk node negatif (SBRIII, RH-, LVI, Her3+..)

  21. Targeted therapy Trastuzumab. HER2 over expressing tumor. Duration : 1 year.

  22. Trastuzumab trials

  23. Endocrine therapy Rôle des sécrétions hormonales dans la prolifération tumorale et site d’action des Tt anti hormonaux Hypothalamus Aromatase inhibitors LHRH Adrenal gland breast Fat TAMOXIFEN Antagonist H Hypophyse FULVESTRANT RH FSH LH Cancerous cell Ovary CASTRATION

  24. Endocrine therapy: in summary RH: positive (≥1%) Premenopausal women : Tamoxifen Post menopausal women: Aromatase inhibitors 5 years

  25. Indications Prognostic factors Predictive factors

  26. First «generation » factors • Age • Grade • Histological type • RE/RP, HER2 • Vascular invasion « 3d generation » factors: Multigenic signatures: Oncotype Dx Mammaprint Genomic grade T N M « 2d generation » factors • Proliferation index • UPA, PAI-1 • Micrometastasis • Alpha II Topoisomerase

  27. Indications: adjuvant chemotherapy Anthracycline regimens: all patients Anthracyclines + Taxanes • Node positif • High risk node negatif (SBRIII, RH-, LVI, Her3+..) Trastuzumab: Her 2 neu +++: HR +: endocrine therapy (pre vs post-menopausal)

  28. Indications : Consensus conferences NCCN 2010 St Gallen 2009 St Paul de vence Goldhirsch, Ann Oncol 2009

  29. Primary systemic Therapy

  30. Primary systemic Therapy:Goals Induction therapy, preoperative systemic therapy, neo-adjuvant chemotherapy. Down staging Breast-conservative surgery Treat early micro metastases Study of predictive factors Assess chemo sensitivity

  31. Primary systemic therapy: anthracyclines NSABP B-18 , N: 1,523 Wolmark NSABP B18 , JNCI 2001

  32. NSABP B18 update ( 2007) Tumor response Nodal response Overall Survival Disease Free Survival

  33. NSABP B18 update ( 2007) DFS and pCR OS and pCR OS and PFS benefit correlated to pCR Wolmark, NCI Meeting March 2007

  34. Taxanes: neo-adjuvant setting Slide Aberdeen trial Aberdeen, TAX 301

  35. Taxanes: neo-adjuvant setting Pathologic Complete Responses 34 16 Aberdeen, TAX 301

  36. Taxanes: neo-adjuvant setting Pathologic Complete Responses 1.0 docetaxel .9 p=0.05 Survival probability CVAP .8 Log Rank Test .7 0 10 20 30 40 50 60 time (months) Overall Survival Disease Free Survival Docetaxel  DFS and OS Smith, JCO 2002 Hutcheon, 3rd EBCC 2002

  37. SCHEDULES Sequentiel anthracyclines and Taxanes. Increase rate of pCR / successful breast conservation surgery / node negative patients by 50%. Trastuzumab is indicated for Her 2-neu +++ patients, to be continued in adjuvant setting .

  38. For whom? Inoperable breast cancer: Inflammatory breast cancer. Locally advanced breast cancer (T4Nx, TxN2-3) Operable breast cancer: Conservative surgery

  39. METASTATIC SETTING

  40. METASTATIC SETTING • Goals of therapy in MBC: • Improve survival • Delay time to disease progression • Palliate symptoms

  41. SCHEDULES Monochemotherapy : Doxorubicin Epirubicin Liposomal Doxorubicin Paclitaxel Docetaxel Gemcitabine Vinorelbine Capecitabine Cisplatine Carboplatin • Targeted therapy • Trastuzumab • Lapatinib • Bevacizumab

  42. Monochemotherapy: Fumoleau IGR 2006

  43. Targeted therapy

  44. SCHEDULES Polychemotherapy  (Her2 neu -): FAC FEC AC 60  AT AP Docetaxel + capécitabine Paclitaxel + gemcitabine Docetaxel + gemcitabine Capecitabine + Vinorelbine Capecitabine + Vinorelbine Ixabepilone + Capécitabine Bevacizumab + Paclitaxel Etoposide + Cisplatine Gemcitabine + Cisplatine Gemcitabine + Oxaliplatine Paclitaxel + Carboplatine

  45. Polychemotherapy versus monochemotherapy: Meta-analysis Fossati JCO 1998

  46. Polychemotherapy = sequentiel monochemotherapy ECOG 1193, Sledge 2003

  47. SCHEDULES in Her2 neu positive disease Trastuzumab + Docetaxel Trastuzumab + Paclitaxel Trastuzumab + Vinorelbine Trastuzumab + Capécitabine Lapatinib + Capécitabine

  48. Trastuzumab in Her2 neu positive diseaseprognosis Trastuzumab in Her2 positive disease = Her 2-

  49. Endocrine therapy Premenopausel women: Tamoxifene + castration Adjuvant Tamoxifene : no standard, recommendation : ovarien ablation± AI Menopausel women: Not pretreated by AI: Standard : 3d generation AI (anastrozole, létrozole) Exemestane Option : fulvestrant Pretreated by non stéroïdiens AI No standard Option : Fulvestrant, Exemestane, Tamoxifene

  50. INDICATIONS According to : Hormonal status Her2 status Disease agressiveness: Agressive disease  : symptomatic disease, multiple metastatic sites, visceral metastases, high tumor burden, relapse interval< 2years Non agressive disease : asymptomatic, relapse interval > 2years (5years ?), low tumor burden, few metastatic sites, slow evolutive disease

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