1. MODELS OF SYSTEMIC TREATMENT IN BREAST CANCER
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

11. ADJUVANT SETTING

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

39. METASTATIC SETTING

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