MODELS OF SYSTEMIC MODELS OF SYSTEMIC TREATMENT IN BREAST CANCERTREATMENT IN BREAST CANCER

EMRA against cancer 1EMRA against cancer 1stst Forum Forum

““NGOs and cancer: Challenges and opportunitiesNGOs and cancer: Challenges and opportunities””

Marrakech, 18 - 19 June 2010Marrakech, 18 - 19 June 2010

IntroductionIntroduction• Breast cancer: most common malignancy in Breast cancer: most common malignancy in

women .women .

• Advances Advances in clinical and translationnel in clinical and translationnel researchresearch..

• Systemic treatment: chemotherapy, targeted Systemic treatment: chemotherapy, targeted therapy, endocrine therapytherapy, endocrine therapy

Survival improvementSurvival improvement

Peto Meta analysisPeto Meta analysis

Peto et al, SABCS 2007

INO Recruitement: 1985 - 2006 INO Recruitement: 1985 - 2006 

0

200

400

600

800

1000

1200

Sein Col Poumon Colo-rectum Cavum

Breast cancer treatmentBreast cancer treatment

Loco-regional:Loco-regional:

SurgerySurgery

RadiotherapyRadiotherapy

Systemic:Systemic:ChemotherapyChemotherapyEndocrine therapyEndocrine therapyTargeted therapyTargeted therapy

Personalize Medicine: Personalize Medicine: Right Drug to the Right PatientRight Drug to the Right Patient

Lum A Lum B Basal Her2

claudin low

Chan ging PortraitsConcept evolutionConcept evolution

Biology as the Framework for Biology as the Framework for ProgressProgress

Pathology

Clinical Characteristics

Biology

Treatment improvementTreatment improvement

Indications of systemic Indications of systemic treatmenttreatment

Adjuvant setting

Primary systemic therapy

Palliative chemotherapy

ADJUVANT SETTINGADJUVANT SETTING

Adjuvant chemotherapyAdjuvant chemotherapyGoalsGoals

Post operative Post operative

Against micrometastasic spread Against micrometastasic spread

Aim : Improve survivalAim : Improve survival

Adjuvant chemotherapy:Adjuvant chemotherapy:

Active drugsActive drugs

• Methotrexate Methotrexate • 5 FU5 FU• CyclophosphamideCyclophosphamide• AnthracyclinesAnthracyclines• Taxanes (paclitaxel, docetaxel)Taxanes (paclitaxel, docetaxel)

Adjuvant chemotherapy:Adjuvant chemotherapy:

RegimensRegimens

6 FAC 6 FAC 6 FEC 6 FEC 4 AC 60 4 AC 60 4 TC4 TC3 FEC+ 3 Docetaxel 3 FEC+ 3 Docetaxel 4AC 60 + 12 Paclitaxel4AC 60 + 12 Paclitaxel

Adjuvant Treatment and Survival Adjuvant Treatment and Survival Improvement Over Past 40 YearsImprovement Over Past 40 Years

Peto et al, SABCS 2007

Taxanes > anthra > CMF > No chemotherapy

10

0 5 10 0 5 10 0 5 10

50

0

40

30

20

Breast cancer mortality

Anthr.31.0%

Taxane25.9%

%+ SE

10-y gain 5.1% (SE 1.6)Lorank 2p < 0.00001

15.3

12.8

Years

10-y gain 4.3% (SE 1.0)Lorank 2p < 0.00003

10-y gain 4.3% (SE 1.0)Lorank 2p < 0.00001

YearsYears

CMF31.3%

Anthr.27.0%

Control36.4%

CMF32.2%

20.5

17.8

19.9

16.5

Peto metanalysis EBCTCG up date 2007

Role of taxanes:Role of taxanes:Docetaxel Meta-analysis: TrialsDocetaxel Meta-analysis: Trials

StudyStudy NodesNodes No. PtsNo. Pts RegimenRegimen F/U (yr)F/U (yr)

GEICAM 9805GEICAM 9805 N0N0 10601060 TAC vs FACTAC vs FAC 55

ECOG 2197ECOG 2197 N0/ N+ ≤3N0/ N+ ≤3 1893/9891893/989 AT vs ACAT vs AC 5 5

USO 9735USO 9735 N0/N+N0/N+ 487/529487/529 TC vs ACTC vs AC 7 7

UK TACTUK TACT N0/N+N0/N+ 835/3327835/3327 FEC-T vs FEC/E-CMFFEC-T vs FEC/E-CMF 55

RAPP-01RAPP-01 N0/N+ ≤3N0/N+ ≤3 627627 AT vs ACAT vs AC 55

FinHerFinHer N+ (89%)N+ (89%) 10101010 T-FEC vs V-FECT-FEC vs V-FEC 55

BCIRG001BCIRG001 N+N+ 14911491 TAC vs FACTAC vs FAC 4.54.5

TAXIT 216TAXIT 216 N+N+ 972972 E-T-CMF vs E-CMFE-T-CMF vs E-CMF 55

PACS01PACS01 N+N+ 19991999 FEC-T vs FECFEC-T vs FEC 55

BIG2-98, TAX315BIG2-98, TAX315 N+N+ 28872887 A-T (AT)-CMF vs A(C)-CMFA-T (AT)-CMF vs A(C)-CMF 55

WSG/AGOWSG/AGO N+ ≤3N+ ≤3 18371837 EC-T vs FECEC-T vs FEC 55

HORG HORG N+N+ 756756 T-EC vs FECT-EC vs FEC 55

20,698 Patients Laporte S, et al. SABCS 2009..

Docetaxel Meta-Analysis: DFS and OS Docetaxel Meta-Analysis: DFS and OS According to Nodal StatusAccording 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 Worldwide Overview: Chemotherapy vs no chemotherapy, by age &ER, ratio of recurrence chemotherapy, by age &ER, ratio of recurrence

rates in years 0-4rates in years 0-4

AgeAge ER-poorER-poor ER+ER+

<50<50 0.57 (0.07)0.57 (0.07) 0.51 (0.06)0.51 (0.06)

50-5950-59 0.65 (0.07)0.65 (0.07) 0.75 (0.05)0.75 (0.05)

60-6960-69 0.78 ( 0.08)0.78 ( 0.08) 0.81 (0.05)0.81 (0.05)

Peto et al, SABCS 2007

In summaryIn summary

• Adjuvant chemotherapy:Adjuvant chemotherapy: Survival benefit in node Survival benefit in node positive and negative breast cancerpositive and negative breast cancer

• Anthracyclines based regimen.Anthracyclines based regimen.

• Anthracyclines + TaxanesAnthracyclines + Taxanes• Node positifNode positif• High risk node negatif (SBRIII, RH-, LVI, Her3+..)High risk node negatif (SBRIII, RH-, LVI, Her3+..)

Targeted therapyTargeted therapy

Trastuzumab.Trastuzumab.

HER2 over expressing tumor.HER2 over expressing tumor.

Duration : 1 year.Duration : 1 year.

Trastuzumab trialsTrastuzumab trials

Cancerous cell

RH

H

Adrenal glandbreast

Fat

TAMOXIFEN

CASTRATION

Aromatase inhibitors

FULVESTRANT

Ovary

Hypophyse

LHRH

Hypothalamus

FSH LH

Antagonist

Rôle des sécrétions hormonales dans la prolifération tumorale et site d’action des Tt anti hormonauxEndocrine therapy

Endocrine therapy: in summaryEndocrine therapy: in summary

RH: positive (≥1%)RH: positive (≥1%)

Premenopausal women : TamoxifenPremenopausal women : Tamoxifen

Post menopausal women: Aromatase Post menopausal women: Aromatase inhibitorsinhibitors

5 years 5 years

IndicationsIndications

Prognostic factorsPrognostic factors

Predictive factorsPredictive factors

TNM

  First «First « generation » factorsgeneration » factorsAgeAgeGrade Grade Histological typeHistological typeRE/RP, HER2RE/RP, HER2Vascular invasionVascular invasion

« 2d generation » factors« 2d generation » factors

•Proliferation indexProliferation index• UPA, PAI-1UPA, PAI-1• MicrometastasisMicrometastasis•Alpha II Topoisomerase Alpha II Topoisomerase

« 3d generation » factors:« 3d generation » factors:

Multigenic signatures:Multigenic signatures:Oncotype DxOncotype DxMammaprintMammaprintGenomic gradeGenomic grade

Indications: adjuvant chemotherapyIndications: adjuvant chemotherapy

Anthracycline regimens: all patients

Anthracyclines + TaxanesAnthracyclines + Taxaneso Node positifNode positifo High risk node negatif (SBRIII, RH-, LVI, Her3+..)High risk node negatif (SBRIII, RH-, LVI, Her3+..)

o

Trastuzumab: Her 2 neu +++:

HR +: endocrine therapy (pre vs post-menopausal)

Indications : Consensus conferencesIndications : Consensus conferences• NCCN 2010NCCN 2010

• St Gallen 2009St Gallen 2009

• St Paul de vence St Paul de vence

Goldhirsch, Ann Oncol 2009

Primary systemic TherapyPrimary systemic Therapy

Primary systemic Therapy:Primary systemic Therapy:GoalsGoals

• Induction therapy, preoperative systemic therapy, neo-adjuvant Induction therapy, preoperative systemic therapy, neo-adjuvant chemotherapy.chemotherapy.

• Down staging Down staging

• Breast-conservative surgeryBreast-conservative surgery

• Treat early micro metastasesTreat early micro metastases

• Study of predictive factorsStudy of predictive factors

• Assess chemo sensitivityAssess 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)

DFS and pCR

OS and pCR

Wolmark, NCI Meeting March 2007

OS and PFS benefit correlated to pCR

Taxanes: neo-adjuvant settingTaxanes: neo-adjuvant setting

• Slide Aberdeen trial Slide Aberdeen trial

Aberdeen, TAX 301

% pCR

0 10 20 30 40

CVAP x 8

CVAP x 4 - - >

Doc x 4 3434

1616

Aberdeen, TAX 301

Taxanes: neo-adjuvant settingTaxanes: neo-adjuvant settingPathologic Complete Responses

% L

iber

e da

Mal

attia

Tempo (settimane)

Risposta iniziale Randomizzate a Docetaxel

Nessuna Risposta iniziale Trattate tutte con Docetaxel

Follow Up medio: 104 Settimane( Range 13 - 187)

Risposta iniziale Randomizzate a CVAP

p=0.022

time (months)6050403020100

Surv

ival pro

babili

ty

1.0

.9

.8

.7

docetaxel

CVAP

p=0.05

Log Rank Test

Disease Free SurvivalDisease Free Survival Overall SurvivalOverall Survival

Docetaxel DFS and OSSmith, JCO 2002

Hutcheon, 3rd EBCC 2002

Taxanes: neo-adjuvant settingTaxanes: neo-adjuvant settingPathologic Complete Responses

SCHEDULESSCHEDULES

• Sequentiel anthracyclines and Taxanes.Sequentiel anthracyclines and Taxanes.

• Increase rate of pCR / successful breast conservation Increase rate of pCR / successful breast conservation surgery / node negative patients by 50%.surgery / node negative patients by 50%.

• Trastuzumab is indicated for Trastuzumab is indicated for Her 2-neu +++ Her 2-neu +++ patients, to patients, to be continued in adjuvant settingbe continued in adjuvant setting . .

For whom?For whom?

• Inoperable breast cancer:Inoperable breast cancer:

o Inflammatory breast cancer. Inflammatory breast cancer. o Locally advanced breast cancer (T4Nx, TxN2-3)Locally advanced breast cancer (T4Nx, TxN2-3)

• Operable breast cancer:Operable breast cancer:

o Conservative surgeryConservative surgery

METASTATIC SETTINGMETASTATIC SETTING

METASTATIC SETTINGMETASTATIC SETTING

• Goals of therapy in MBC:Goals of therapy in MBC:

– Improve survivalImprove survival

– Delay time to disease progressionDelay time to disease progression

– Palliate symptomsPalliate symptoms

SCHEDULESSCHEDULES

Monochemotherapy :Monochemotherapy :

Doxorubicin Doxorubicin Epirubicin Epirubicin Liposomal DoxorubicinLiposomal DoxorubicinPaclitaxel Paclitaxel Docetaxel Docetaxel Gemcitabine Gemcitabine Vinorelbine Vinorelbine Capecitabine Capecitabine Cisplatine Cisplatine CarboplatinCarboplatin

• Targeted therapyTargeted therapy

•TrastuzumabTrastuzumab

•LapatinibLapatinib

•BevacizumabBevacizumab

Monochemotherapy:

Fumoleau IGR 2006

Targeted therapy

SCHEDULESSCHEDULES• Polychemotherapy  (Her2 neu -):Polychemotherapy  (Her2 neu -):

• FAC FAC • FEC FEC • AC 60 AC 60 • ATAT• APAP• Docetaxel + capécitabine Docetaxel + capécitabine • Paclitaxel + gemcitabine Paclitaxel + gemcitabine • Docetaxel + gemcitabine Docetaxel + gemcitabine • Capecitabine + Vinorelbine Capecitabine + Vinorelbine • Capecitabine + Vinorelbine Capecitabine + Vinorelbine • Ixabepilone + Capécitabine Ixabepilone + Capécitabine • Bevacizumab + Paclitaxel Bevacizumab + Paclitaxel • Etoposide + Cisplatine Etoposide + Cisplatine • Gemcitabine + Cisplatine Gemcitabine + Cisplatine • Gemcitabine + Oxaliplatine Gemcitabine + Oxaliplatine • Paclitaxel + CarboplatinePaclitaxel + Carboplatine

Fossati JCO 1998

Polychemotherapy versus monochemotherapy: Meta-analysis

Polychemotherapy = sequentiel monochemotherapy

ECOG 1193, Sledge 2003

SCHEDULES in Her2 neu positive diseaseSCHEDULES in Her2 neu positive disease

Trastuzumab + Docetaxel Trastuzumab + Docetaxel Trastuzumab + Paclitaxel Trastuzumab + Paclitaxel Trastuzumab + VinorelbineTrastuzumab + VinorelbineTrastuzumab + Capécitabine Trastuzumab + Capécitabine Lapatinib + CapécitabineLapatinib + Capécitabine

Trastuzumab in Her2 neu positive diseaseTrastuzumab in Her2 neu positive diseaseprognosisprognosis

Trastuzumab in Her2 positive disease = Her 2-Trastuzumab in Her2 positive disease = Her 2-

Endocrine therapyEndocrine therapy Premenopausel women:Premenopausel women:

Tamoxifene + castration Tamoxifene + castration Adjuvant Tamoxifene : no standard, recommendation : ovarien Adjuvant Tamoxifene : no standard, recommendation : ovarien

ablation± AIablation± AI

Menopausel women: Menopausel women: Not pretreated by AI:Not pretreated by AI:

Standard : 3d generation AI (anastrozole, létrozole)Standard : 3d generation AI (anastrozole, létrozole) Exemestane Exemestane Option : fulvestrant Option : fulvestrant

Pretreated by non stéroïdiens AIPretreated by non stéroïdiens AI No standardNo standard Option : Fulvestrant, Exemestane, TamoxifeneOption : Fulvestrant, Exemestane, Tamoxifene

INDICATIONSINDICATIONS

According to :According to :

Hormonal statusHormonal status

Her2 statusHer2 status

Disease agressiveness: Disease agressiveness:

Agressive diseaseAgressive disease  : symptomatic disease, multiple metastatic  : symptomatic disease, multiple metastatic sites, visceral metastases, high tumor burden, relapse interval< sites, visceral metastases, high tumor burden, relapse interval< 2years2years

Non agressiveNon agressive disease : asymptomatic, relapse interval > disease : asymptomatic, relapse interval > 2years (5years ?), low tumor burden, few metastatic sites, slow 2years (5years ?), low tumor burden, few metastatic sites, slow evolutive diseaseevolutive disease

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

Treatment criteria choice

In summaryIn summary

Her2+Her2+ Her2-Her2-

Agressive Agressive Non agressiveNon agressive AgressiveAgressive Non Non agressiveagressive

RH+RH+ TrastuzumabTrastuzumab+ CT+ CT

Trastuzumab + Trastuzumab + HormonoHormono PolyCTPolyCT HormonoHormono

RH-RH-TrastuzumabTrastuzumab

+ CT+ CT TrastuzumabTrastuzumab +/- CT+/- CT

PolyCTPolyCT Sequentiel Sequentiel MonoCTMonoCT, , PolyCTPolyCT??

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 cibléesMonochimiothérapie versus polychimiothérapie ?Indication dépend de plusieurs facteurs :

Age, co-morbidités (OMS), vécu et préférence du patientNiveau 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 + DocetaxelOu 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