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 Breast cancer is the most common malignancy in women, accounting for 32% of all female cancers. Breast cancer also is responsible for 15% of cancer deaths in women, making it the number-two cause of cancer death. According to Moroccan regional registry, An estimated ...... new breast cancer cases was diagnosed in the year ..... Major advances in all aspects of breast cancer research have been made over the past years, ranging from cancer prevention to the management of patients with advanced disease. Inroads have been made in the identification of active and safe combination regimes in the adjuvant setting and advanced disease both using traditional cytotoxic chemotherapy, targeted drugs and endocrine therapy. Those advances allowed survival improvement.

Peto Meta analysis Peto et al, SABCS 2007 REDUCTION OF DEATHS: screening and treatment progress Peto et al, SABCS 2007

INO Recruitement: 1985 - 2006 

Breast cancer treatment Loco-regional: Surgery Radiotherapy Systemic: Chemotherapy Endocrine therapy Targeted therapy Breast cancer treatment is multimodal; it combines: loco-regional treatment : surgery and radiotherapy and systemic treatment: chemotherapy, endocrine therapy, targeted therapy.

Personalize Medicine: Right Drug to the Right Patient

Concept evolution Chan ging Portraits claudin low Lum A Lum B Basal Her2 claudin low 7

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 10-y gain 5.1% (SE 1.6) Lorank 2p < 0.00001 Control 36.4% 40 CMF 31.3% Anthr. 31.0% 30 CMF 32.2% 20.5 19.9 20 Anthr. 27.0% 2008 Lancet * 96 trials 20,000 patients 15.3 % + SE 17.8 Taxane 25.9% 16.5 10 12.8 Years Years Years 5 10 5 10 5 10 Peto et al, SABCS 2007

Role of taxanes: Docetaxel Meta-analysis: Trials Study Nodes No. Pts Regimen F/U (yr) GEICAM 9805 N0 1060 TAC vs FAC 5 ECOG 2197 N0/ N+ ≤3 1893/989 AT vs AC USO 9735 N0/N+ 487/529 TC vs AC 7 UK TACT 835/3327 FEC-T vs FEC/E-CMF RAPP-01 N0/N+ ≤3 627 FinHer N+ (89%) 1010 T-FEC vs V-FEC BCIRG001 N+ 1491 4.5 TAXIT 216 972 E-T-CMF vs E-CMF PACS01 1999 FEC-T vs FEC BIG2-98, TAX315 2887 A-T (AT)-CMF vs A(C)-CMF WSG/AGO N+ ≤3 1837 EC-T vs FEC HORG 756 T-EC vs FEC Study selection criteria Randomized trials of adjuvant chemotherapy including at least 100 patients At least one treatment arm with docetaxel-based regimen compared to a non-taxane regimen Either node-positive or node-negative breast cancer Data extraction Data extracted from publications/ posters and/or presentations In addition, all authors were contacted to obtain more information when required 20,698 Patients Laporte S, et al. SABCS 2009.. 17

Docetaxel Meta-Analysis: DFS and OS According to Nodal Status 20,698 Patients 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. 18

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. Duration : 1 year. HER2 over expressing tumor. Duration : 1 year.

Trastuzumab trials

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

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

Indications Prognostic factors Predictive factors

T N M First « generation » factors « 3d generation » factors:   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

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)

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 Nodal response Overall Survival Disease Free Survival

NSABP B18 update ( 2007) OS and PFS benefit correlated to pCR 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

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

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

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: Operable breast cancer: Inflammatory breast cancer. Locally advanced breast cancer (T4Nx, TxN2-3) Operable breast cancer: Conservative surgery

METASTATIC SETTING

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

SCHEDULES Monochemotherapy : Doxorubicin Epirubicin Trastuzumab 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 Ixabepilone + Capécitabine Bevacizumab + Paclitaxel Etoposide + Cisplatine Gemcitabine + Cisplatine Gemcitabine + Oxaliplatine Paclitaxel + Carboplatine

Polychemotherapy versus monochemotherapy: Meta-analysis polycjhimio>monochimio 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: Menopausel 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 Disease free interval >2 years < 2 years Prior adjuvant therapy NO Yes Prior therapy MBC YES Beslija, Ann oncol 2007

In summary Her2+ Her2- RH+ RH- Agressive Non agressive Non agressive Trastuzumab + CT Trastuzumab + Hormono PolyCT RH- +/- 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): + Trastuzumab 8mg/Kg puis 6mg/Kg (tous les 21 jours), pendant une année

Difficile d’élaborer un seul protocole 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