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MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER EMRA against cancer 1st Forum “NGOs and cancer: Challenges and opportunities” Marrakech, 18 - 19 June 2010 Introduction • Breast cancer: most common malignancy in women . • Advances in clinical and translationnel research. • Systemic treatment: chemotherapy, targeted therapy, endocrine therapy Survival improvement Peto Meta analysis Peto et al, SABCS 2007 INO Recruitement: 1985 - 2006 1200 1000 800 600 400 200 Sein Col Poumon Colo-rectum 20 06 20 05 20 04 20 03 20 02 20 01 20 00 19 99 19 97 19 95 19 93 19 91 19 89 19 87 19 85 0 Cavum Breast cancer treatment Loco-regional: Surgery Radiotherapy Systemic: Chemotherapy Endocrine therapy Targeted therapy Personalize Medicine: Right Drug to the Right Patient Chan ging Portraits Concept evolution claudin low Lum A Lum B Basal Her2 Biology as the Framework for Progress Clinical Characteristics Biology Pathology Treatment improvement Indications of systemic treatment Adjuvant setting Primary systemic therapy Palliative chemotherapy ADJUVANT SETTING Adjuvant chemotherapy Goals Post operative Against micrometastasic spread Aim : Improve survival Adjuvant chemotherapy: Active drugs • • • • • Methotrexate 5 FU Cyclophosphamide Anthracyclines Taxanes (paclitaxel, docetaxel) Adjuvant chemotherapy: Regimens 6 FAC 6 FEC 4 AC 60 4 TC 3 FEC+ 3 Docetaxel 4AC 60 + 12 Paclitaxel Adjuvant Treatment and Survival Improvement Over Past 40 Years Peto metanalysis EBCTCG 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 Control 36.4% 40 10-y gain 5.1% (SE 1.6) Lorank 2p < 0.00001 CMF 31.3% Anthr. 31.0% 30 20.5 20 % + SE CMF 32.2% 19.9 17.8 16.5 Anthr. 27.0% 15.3 12.8 10 Years Years Taxane 25.9% Years 0 0 5 10 0 5 10 0 5 10 Peto et al, SABCS 2007 Role of taxanes: Docetaxel Meta-analysis: Trials Study Nodes GEICAM 9805 N0 ECOG 2197 N0/ N+ ≤3 USO 9735 No. Pts Regimen 1060 F/U (yr) TAC vs FAC 5 1893/989 AT vs AC 5 N0/N+ 487/529 TC vs AC 7 UK TACT N0/N+ 835/3327 FEC-T vs FEC/E-CMF 5 RAPP-01 N0/N+ ≤3 627 AT vs AC 5 FinHer N+ (89%) 1010 T-FEC vs V-FEC 5 BCIRG001 N+ 1491 TAC vs FAC TAXIT 216 N+ 972 E-T-CMF vs E-CMF 5 PACS01 N+ 1999 FEC-T vs FEC 5 BIG2-98, TAX315 N+ 2887 A-T (AT)-CMF vs A(C)-CMF 5 WSG/AGO N+ ≤3 1837 EC-T vs FEC 5 HORG N+ 756 T-EC vs FEC 5 20,698 Patients 4.5 Laporte S, et al. SABCS 2009.. 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. Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence rates in years 0-4 Age ER-poor ER+ <50 0.57 (0.07) 0.51 (0.06) 50-59 0.65 (0.07) 0.75 (0.05) 60-69 0.78 ( 0.08) 0.81 (0.05) Peto et al, SABCS 2007 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+..) Targeted therapy Trastuzumab. HER2 over expressing tumor. Duration : 1 year. Trastuzumab trials Rôle des sécrétions hormonales dans la prolifération therapy tumorale etEndocrine site d’action des Tt anti hormonaux Aromatase inhibitors Hypothalamus LHRH Antagonist Adrenal gland breast Fat TAMOXIFEN H Hypophyse FULVESTRANT RH FSH LH Cancerous cell Ovary CASTRATION Endocrine therapy: in summary RH: positive (≥1%) Premenopausal Post women : Tamoxifen menopausal women: Aromatase inhibitors 5 years Indications Prognostic factors Predictive factors First « generation » factors Age Grade Histological type RE/RP, HER2 Vascular invasion « 2d generation » factors •Proliferation index • UPA, PAI-1 • Micrometastasis •Alpha II Topoisomerase « 3d generation » factors: Multigenic signatures: Oncotype Dx Mammaprint Genomic grade T N M Indications: adjuvant chemotherapy Anthracycline regimens: all patients Anthracyclines + Taxanes o Node positif o High risk node negatif (SBRIII, RH-, LVI, Her3+..) o Trastuzumab: Her 2 neu +++: HR +: endocrine therapy (pre vs post-menopausal) Indications : Consensus conferences • NCCN 2010 • St Gallen 2009 • St Paul de vence Goldhirsch, Ann Oncol 2009 Primary systemic Therapy 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 Primary systemic therapy: anthracyclines NSABP B-18 , N: 1,523 Wolmark NSABP B18 , JNCI 2001 NSABP B18 update ( 2007) Tumor response Overall Survival Nodal response Disease Free Survival NSABP B18 update ( 2007) DFS and pCR OS and pCR OS and PFS benefit correlated to pCR Wolmark, NCI Meeting March 2007 Taxanes: neo-adjuvant setting • Slide Aberdeen trial Aberdeen, TAX 301 Taxanes: neo-adjuvant setting Pathologic Complete Responses % pCR CVAP x 4 --> 34 Doc x 4 16 CVAP x 8 0 10 20 30 40 Aberdeen, TAX 301 Taxanes: neo-adjuvant setting Pathologic Complete Responses Disease Free Survival Overall Survival 1.0 Follow Up medio: 104 Settimane ( Range 13 - 187) % Libere da Malattia Risposta iniziale Randomizzate a Docetaxel p=0.022 Risposta iniziale Randomizzate a CVAP Survival probability docetaxel .9 Docetaxel DFS and OS CVAP .8 Log Rank Test Nessuna Risposta iniziale Trattate tutte con Docetaxel Tempo (settimane) p=0.05 .7 0 10 20 30 40 time (months) 50 Smith, JCO 2002 Hutcheon, 3rd EBCC 2002 60 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 . For whom? • Inoperable breast cancer: o Inflammatory breast cancer. o Locally advanced breast cancer (T4Nx, TxN2-3) • Operable breast cancer: o Conservative surgery METASTATIC SETTING METASTATIC SETTING • Goals of therapy in MBC: – Improve survival – Delay time to disease progression – Palliate symptoms SCHEDULES Monochemotherapy : Doxorubicin Epirubicin Liposomal Doxorubicin Paclitaxel Docetaxel Gemcitabine Vinorelbine Capecitabine Cisplatine Carboplatin • Targeted therapy •Trastuzumab •Lapatinib •Bevacizumab Monochemotherapy: Fumoleau IGR 2006 Targeted therapy 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 Polychemotherapy versus monochemotherapy: Meta-analysis Fossati JCO 1998 Polychemotherapy = sequentiel monochemotherapy ECOG 1193, Sledge 2003 SCHEDULES in Her2 neu positive disease Trastuzumab + Docetaxel Trastuzumab + Paclitaxel Trastuzumab + Vinorelbine Trastuzumab + Capécitabine Lapatinib + Capécitabine Trastuzumab in Her2 neu positive disease prognosis Trastuzumab in Her2 positive disease = Her 2- 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 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 Treatment criteria choice Prognostic factors Favorable Unfavorable PS Good poor Sites of disease Bone, soft, tissue Viscera N°sites disease Oligo Multiple HR status Positive Negative Her-2/Neu Negative Positive Disease free interval >2 years < 2 years Prior adjuvant therapy NO Yes Prior therapy MBC NO YES Beslija, Ann oncol 2007 In summary Her2+ Agressive Non agressive Her2Agressive Non agressive Hormono RH+ Trastuzumab Trastuzumab + + CT Hormono PolyCT RH- Trastuzumab + CT PolyCT Trastuzumab +/- CT Sequentiel MonoCT, PolyCT? Conclusion Many therapeutic options real survival improvement Area of targeted therapy and molecular profiling: right drug to the right patient Morrocco: recommendations in accordance with literature Morrocan chemotherapy guide Chimiothérapie adjuvante (60% des patients): Pour les patientes Her 2-neu - : 3cycles de FEC (Epirubicine 100mg/m2, 5 Fluorouracile 500mg/m2, cyclophosphamide 500mg/m2) + 3 cycles de docétaxel 100mg/m2 Pour les patientes Her 2-neu + (20% des cas): 3cycles de FEC (Epirubicine 100mg/m2, 5 Fluorouracile 500mg/m2, cyclophosphamide 500mg/m2) + 3 cycles de docétaxel 100mg/m2 + Trastuzumab 8mg/Kg puis 6mg/Kg (tous les 21 jours), pendant une année Chimiothérapie de première ligne métastatique (40% des patients): Moyens multiples: chimiothérapie, hormonothérapie, thérapeutiques ciblées Monochimiothérapie versus polychimiothérapie ? Indication dépend de plusieurs facteurs : Age, co-morbidités (OMS), vécu et préférence du patient Niveau d’agressivité de la tumeur : volume tumoral, nombre de sites métastatiques, présence d’envahissement viscéral, cinétique tumorale, intervalle libre de rechute. Profil biologique de la tumeur : RH et Her 2 +++ Expositions aux thérapeutiques antérieures (adjuvant ou néo-adjuvant) Difficile d’élaborer un seul protocole Chimiothérapie de première ligne métastatique (40% des patients): On distingue les patientes HER 2 +++ (20% des patientes): Patientes ayant déjà reçu taxanes : Trastuzumab 8mg/Kg puis 6mg/Kg (tous les 21 jours) + vinorelbine 25mg/m2 j1j8 (tous les 21 jours) Patientes n'ayant pas reçu de taxanes: Trastuzumab 8mg/Kg puis 6mg/Kg + docetaxel 100mg/m2 J1 (tous les 21 jours) Chimiothérapie de première ligne métastatique (40% des patients): Pour les patientes Her2-: Patientes n’ayant reçu ni taxanes ni anthracyclines: Si Monochimiothérapie : Doxorubicine, Docetaxel Si polychimiothérapie : AT : Doxorubicine + Docetaxel Ou séquentiel programmé : 4 FEC + 4 Docetaxel Patientes n'ayant pas reçu de taxanes (pré-traitées par anthracyclines) : Si Monochimiothérapie : Docetaxel Si polychimiothérapie : Docetaxel + capécitabine Patientes ayant déjà reçu anthracyclines et taxanes: Si Monochimiothérapie : Vinorelbine ou Capécitabine Si polychimiothérapie : Capécitabine + Vinorelbine