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Presentation on theme: "MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER"— Presentation transcript:

EMRA against cancer 1st Forum “NGOs and cancer: Challenges and opportunities” Marrakech, June 2010

2 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.

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

4 INO Recruitement:  

5 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.

6 Personalize Medicine: Right Drug to the Right Patient

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

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


12 Adjuvant chemotherapy Goals
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 Paclitaxel

15 Adjuvant Treatment and Survival Improvement Over Past 40 Years

16 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 < 10-y gain 4.3% (SE 1.0) Lorank 2p < 10-y gain 5.1% (SE 1.6) Lorank 2p < 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

17 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 17

18 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

19 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

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. Duration : 1 year.
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 Endocrine therapy 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 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

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) 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

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

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

36 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

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


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

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

45 Polychemotherapy versus monochemotherapy: Meta-analysis
polycjhimio>monochimio 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 disease prognosis
Trastuzumab in Her2 positive disease = Her 2-

49 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

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

51 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

52 In summary Her2+ Her2- RH+ RH- Agressive Non agressive Non agressive
Trastuzumab + CT Trastuzumab + Hormono PolyCT RH- +/- CT Sequentiel MonoCT, PolyCT?

53 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

54 Morrocan chemotherapy guide


56 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

57 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

58 Chimiothérapie de première ligne métastatique (40% des patients):
On distingue les patientes HER (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)

59 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


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