Approches du cancer du sein avec focalisation sur le traitement

Approches du cancer du sein avec
focalisation sur le traitement
Ahmad Awada, MD, PhD
Head of Medical Oncology Clinic
Institut Jules Bordet
Université Libre de Bruxelles (U.L.B.)
Brussels, Belgium
02/2016
Approches du cancer du sein
• Prévention
• Dépistage
• Diagnostic
• Traitements
• Suivi
Toutes les femmes
Femmes à risque (génétique)
Maladie précoce  guérison
Maladie métastatique
(situation palliative)
Traitement du cancer du sein au stade
précoce = Traitement multidisciplinaire
Chirurgie
Chimiothérapie
Radiothérapie
Hormonothérapie
Immunothérapie
Chirurgie : Evolution de plus en plus
minimaliste
Mastectomie
Evidement axillaire
Tumorectomie
+
radiothérapie
Technique du ganglion
sentinelle
- Pas de lymphœdème
- Pas d’impotence
fonctionnelle
Radiothérapie : Réduction de plus en plus dans la
durée de traitement avec meilleur ciblage
Radiothérapie ( 6 semaines)
Radiothérapie
hypofractionnée
(3 semaines)
* Tumeurs bien sélectionnées
Mobetron
(1 seule séance*)
The current treatment landscape for
early breast cancer: Towards treatment
individualization
Systemic treatment of early breast cancer
- Chemotherapy and hormone therapies are
important therapeutic components
- Which patients? Which tumors? Adjuvant
chemotherapy and endocrine therapy?
- Latest advances in the (neo)adjuvant settings
(TNBC; Luminal diseases (HR+) ; HER2+)
- Perspectives
CLINICAL CASE
A 61-year-old postmenopausal woman seeks
medical oncology opinion 2 weeks after
conservative surgery for a 3cm invasive
ductal cancer of the left breast. Two positive
axillary lymph nodes.
• ER 7/8 PR 3/8 – grade 2 – Ki67 is 20% and
HER2 is negative
• LVEF is 60%
• Breast radiotherapy is mandatory (at the end of
chemotherapy)
CLINICAL CASE
Your adjuvant chemotherapy recommendation is
1. CMF x 6 cycles or AC x4
2. TC x 4
3. Anthracycline-based chemotherapy x6 (eg, FEC x 6)
4. Anthracycline plus taxane-based chemotherapy (eg,
FEC  taxane or TAC x 6)
5. Dose-dense ECx4  taxane (docetaxel x 4 or paclitaxel
wx12)
Of note: each chemotherapy option is followed by endocrine therapy.
CLINICAL CASE
Your recommendation as adjuvant endocrine
therapy is:
1. An aromatase inhibitor upfront (5 y)
2. Tamoxifen alone (5 y)
3. Tamoxifen alone (10 y)
4. Sequential therapy: tamoxifen
AI (5 y)
Adjuvant therapy of breast cancer:
which patients? Which tumors? Which biology?
ER
Patients
Characteristics
•
•
Age
Comorbidities
(organs dysfunction)
PR
T size
N status
Metastases
HER2
Ki67
Gene profiling?
TILs?
TREATMENT
BURDEN
TUMOR
BURDEN
Host tolerance to chemotherapy
Here resides the decision to
“escalate”/“de-escalate” the
chemotherapy
TUMOR
BIOLOGY
Here are the targets!
 Targeted therapies (endocrine and
HER2 therapies)
Overview of the most important adjuvant
chemotherapy studies in early breast cancer
Addition of capecitabine,
gemcitabine, bevacizumab
not beneficial
Doc-C
AC
<
AC->Pac(qw) or
Doc(3w)
<
=
<
<
=
CMF
<
AC->Pac(3w)
CAF/FAC
<
=
DocAC
=
ddA/EC>Pac(2w)
<
6 cycles
4 cycles
CEF/FEC
8 cycles
5-FU: No benefit in nodes + (Cognetti et al)
<
FEC->Doc
Wildiers H, …, Awada A, Belg J Med Oncol. 2014
SELECTION OF ADJUVANT ENDOCRINE THERAPY
FOR POSTMENOPAUSAL PATIENTS ACCORDING TO ENDOCRINE
RESPONSIVENESS AND TUMOR RISK
Hormone receptors
expression
Absent
Low
T
U
M
O
R
R
I
S
K
C
H
E
M
O
T
H
E
R
A
P
Y
Intermediate
AI switch
High
TAM
AI
Upfront
TAM alone
Switch
AI
TAM
AI upfront
ADD CHEMOTHERAPY
FOR HIGH-RISK PATIENTS
High
Premenopausal patients: Tamoxifen ± GnRH analogs or AI + GnRH analogs according to the tumor risk and side effects.
*Luminal A disease
SELECTION OF ADJUVANT CHEMOTHERAPY REGIMENS :
ACCORDING TO ENDOCRINE-RESPONSIVENESS AND TUMOR RISK
Hormone receptors
expression
Absent
A+T
Low
Tumor
risk
Intermediate
Intermediate
TC
A+T
High
Endocrine
therapy
Anthracyclines (A)
+
taxane (T)
High
ADD Endocrine therapy
A+T: sequencially or in combination (including dose-dense)
A(C) CMF (contraindication to taxane)
TC: of great interest in pts at risk of cardiac failure
Chemotherapy regimens used in pivotal studies for HER2+ breast
cancer: significant positive outcome mainly when trastuzumab
combined with taxane
Trastuzumab
(T) use
Study
Control arm
Trastuzumab arm
BCIRG 006
4xAC->4xDoc
4xAC->4xDoc+T
6xDocCarboT (TCH)*
NSABP B-31
4xAC->4xPac(3w) or
12xPac(qw)
4xAC->4xPac(3w) or 12xPac(qw)
+T
HERA
Chemotherapy
Chemo->T1y
Chemo->T2y
PACS-04
6xFEC or 6xEDoc
6xFEC or 6xEDoc->T1y
NCCTG
N9831
4xAC->12xPac(qw)
4xAC->12xPac(qw)+T1y
4xAC->12xPac(qw)->T1y
Concurrent
Sequential
Concurrent
versus
sequential
*of great interest in pts at risk of cardiac failure
T = trastuzumab; y = years; Carbo = carboplatin
Wildiers H, … Awada A, Belg J Med Oncol. 2014
Therapy de-escalation: for whom?
Phase II Adjuvant Paclitaxel and
Trastuzumab
Eligibility
• HER2+ primary
breast cancer
• Node negative
• Tumor measuring
up to 3 cm in
greatest
dimension
Paclitaxel
80 mg/m2 weekly
x 12 wks
+
Trastuzumab
4 mg/Kg weekly
x 12 wks
Trastuzumab
6 mg/kg every 3wks
X 40 wks
406 patients recruited; Follow-Up 4 years:
- 3-year survival free from invasive disease 98.7%
- Only 2 cases of distant metastasis
- No cases of breast-cancer-related deaths
Tolaney SM, NEJM (2015)
Small HER2-positive BC outcome without
anthracyclines
Tolaney SM, NEJM (2015)
4. Neoadjuvant setting: An attractive approach for clinical practice and
for translational research
Biopsy
Ki67
Gene profiling
Tumor sequencing
PET/CT
Standard preoperative
therapy
Standard preoperative
therapy
+ new agent
Surgery
Molecular
Markers; PET/CT
• “Real-time” evaluation of primary tumor response
• Postoperative therapy adapted based on the induction efficacy (investigational)
• Caveat: Difference in biology of micrometastasis versus primary tumor?!
Selection of important neoadjuvant randomized trials incorporating
taxanes
Author (n)
Control arm
Experimental arm
Outcome
NSABP-B27
(n = 2411)
4xAC->S
4xAC->S->4xDoc
4xAC->4xDoc->S
pCR ↗ with Doc
DFS =
OS =
Aberdeen
(n = 162)
PR/CR after 4xCVAP:
4xCVAP
PR/CR after 4xCVAP:
4xDoc
pCR ↗
DFS ↗
OS ↗
4xADoc
pCR =
DFS =
OS =
4xAPac
pCR ↗
DFS ↗
OS ↗
Anthracycline based +
taxane
pCR ↗ with sequential,
but not concomitant
taxane
DFS =
ACCOG
(n = 363)
Dieras
(n = 200)
Metaanalysis
(n = 2455);
7 trials
6xAC
4xAC->
Anthracycline based
S = surgery; pCR = pathological complete response rate (in breast and axilla); PR = partial response; CR = complete response
Wildiers H, … Awada A, Belg J Med Oncol. 2014
Les essais en néoadjuvant pour les tumeurs HER-2
positives: le taux de pCR est meilleur dans la
population RH négative
 Taux de pCR en fonction du statut des RH dans la population HER2 positive.
(chimiothérapie systémique associée aux traitements anti-HER2)
pCR globale
pCR – RH positifs
pCR – RH
négatifs
NeoSphere
46%
26%
63%
NeoALTTO
51%
42%
61%
CALGB 40601
51%
42%
77%
NSABP B41
62%
56%
73%
TRYPHAENA
55-64%
46-50%
65-84%
Etude
Les essais en néoadjuvant: il existe une population pouvant
bénéficier d’un traitement anti-HER2 sans chimiothérapie
associée uniquement
 Taux de pCR en fonction du statut des RH dans la population HER2 positive
(absence de chimiothérapie systémique associée aux traitements anti-HER2)
Etude
Type de
traitement
Durée de
traitement
pCR – RH
positifs
pCR – RH
négatifs
NeoSphere
trastuzumab +
pertuzumab
16 sem
6%
29%
TBCRC006
trastuzumab +
lapatinib
12 sem
21%
36%
12 sem
9%
20%
TBCRC 023
trastuzumab +
lapatinib
24 sem
33%
18%
12 sem
41%
NA
ADAPT
Harbeck N. et al., SABCS 2015, S5-03
T-DM1
GEPARSIXTO :
résultat principal = réponse histologique
• Le carboplatine augmente la réponse complète histologique
dans les cancers du sein triple-négatifs
Treatment without
carboplatin
Treatment with
carboplatin
(n=293)
(n=295)
No
185
(63,1%)
166
(56,3%)
Yes
108
(36,9%; 31,3-42,4)
129
(43,7%; 38,1-49,4)
ypT0ypN0
p-value
0-107
Subgroup
Number
of patients
Odds ratio
Overall
588
1,33 (0,956-1,85)
315
1,94 (1,24-3,04)
(95%CI)
Test for
interaction
Subtype
TNBC
0,015
HER2 positive
273
0,841 (0,511-1,39)
Von Minckwitz et al., SABCS 2015, S2-04
Von Minckwitz G et al., Asco 2015, updated date; E. Hahnen in prep
Advanced Breast Cancer: are there
new treatments on the horizon?
ADVANCED LUMINAL DISEASE (HR+) :
THERAPEUTIC ALGORITHM AND
PERSPECTIVES
Luminal Diseases: Therapeutic Armamentarium in 2016
Clinical practice and advanced clinical research
- Tamoxifen
- NSAI (HER2-) [letrozole ± palbociclib*, anastrozole]
- NSAI (HER2+) [+ trastuzumab or lapatinib]
- Fulvestrant (500 mg) ± palbociclib* (CDK4/6 inhibitor)
- Exemestane ± everolimus (m-TOR inhibitor)
- Fulvestrant ± Buparlisib* (ct DNA PIK3CA mutant group)??
PD
- Chemotherapy
*Investigational compound.
Several CDK4/ inhibitors are under active clinical investigation
Proposed Therapeutic Algorithm for Luminal Subtype after ASCO
2015 (A. Awada)
Postmenopausal ER+ MBC
Prior Endocrine
Therapy as
Adjuvant Rx only
No
“De novo”
MBC with no
prior AI/Tam
NSAI*
Fulvestrant
TAM
Prior Endocrine
Therapy for MBC
Yes
ER+
HER2+
ER+
HER2–
AI + Anti-HER2
Chemo + (dual) Anti-HER2
MBC: PD following
first-line
TAM
MBC: PD during NSAI
Fulvestrant +
palbociclib * *
or
exemestane +
everolimus
PD
NSAI*
Adj: relapse on or within
12 months of completing NSAI
Adj: Relapse >12 months of
completing NSAI
*Inclusion of CDK4/6 inhibitors in the first line setting depends on ongoing phase
3 trials
NSAI: Letrozole or anastrozole according to the previous NSAI.
**Investigational product
ESR1 Y537S mutation is undetectable in primary
and metastatic disease before endocrine therapy
SABCS 2015
KEYNOTE-028 : pembrolizumab et cancer du sein RE+/HER2• Design
Patients
• ER+/HER2• Localement avancé
ou métastatique
• Échec ou non
candidat à des
traitements
standards
• PS=0/1
• > 1 lésion mesurable
• PD-L1+ (> 1% ces
cellules tumorales
ou stroma positif)
Réponse complète ou
partielle ou maladie
stable
Traitement pour 24 mois
ou jusqu’à progression
ou intolérance
Progression
confirmée ou toxicité
inacceptable
Stop
pembrolizumab
Pembrolizumab
10 mg/kg IV q2w
Evaluation
de la réponse*
• 261 inclus - 248 analysés – 48 positifs pour PD-L1 - 25 traités
*Evaluation de la réponse : toutes les 8 semaines pour les 6 premiers mois ; puis
toutes les 12 semaines
Critère de jugement principal : taux de réponse globale (RECIST v1.1) et sécurité
Critères de jugement secondaires : PFS, OS, durée de réponse
Rugo HS et al., SABCS 2013, S5-07
KEYNOTE-028 : pembrolizumab et cancer du sein RE+/HER2• Activité anti-tumorale (RECIST 1.1)
n (%)
95% CI
Taux de réponse global
3 (12,0)
2,5 – 31,2
Réponse complète
0 (0,0)
0,0 – 13,7
3 (12,0)
4 (16,0)
5 (20,0)
15 (60,0)
3 (12,0)
2,5 – 31,2
4,5 – 36,1
6,8 – 40,7
38,7 – 78,9
2,5 – 31,2
Les réponses sont peu
fréquentes mais semblent
durables !
Change from baseline, %
Réponse partielle
Maladie stable
Bénéfice clinique
Maladie progressive
NE
Responder
Nonresponder
New bone
lesion
New liver
lesion
Temps, semaine
Rugo HS et al., SABCS 2013, S5-07
ADVANCED HER-2 DISEASE :
THERAPEUTIC ALGORITHM AND
PERSPECTIVES
HER2 POSITIF ADVANCED BREAST CANCER:
TOWARDS A CURE?!
HER2
OVEREXPRESSION
HER2
AMPLIFICATION
ER
Gene
expression
A SEPARATE DISEASE
ENTITY!
=
IHC
FISH
NEW TREATMENT
APPROACHES
Trastuzumab
in combination
with cytotoxics or
hormonal agents
Lapatinib,
trastuzumab-DM1,
pertuzumab
BasalHER2
Normal
Basal-like
Subgroup Subgroup breast
Dual HER2
inhibition +
cytotoxics
What’s next?
(neratinib?
HER-2-TDB?)*
Phase III CLEOPATRA Trial: Docetaxel + Trastuzumab
± Pertuzumab in HER2-Positive First-Line MBC
n = 406
Patients with
HER2-positive
first-line MBC
Pertuzumab + trastuzumab
PD
Docetaxel
≥6 cycles recommended
1:1
central confirmation
Placebo + trastuzumab
PD
(N = 808)
n = 402
Docetaxel
≥6 cycles recommended
Primary endpoint: Independently assessed PFS
Secondary endpoints included Overall Survival; PFS by investigator assessment; Safety
Pertuzumab/Placebo: 840 mg loading dose, 420 mg q3w maintenance
Swain SM, et al. ESMO-ECCO 2014. Abstract 350O.
Patients on Pertuzumab plus Trastuzumab and Docetaxel
Lived 15.7 Months Longer!!
100
Ptz + T + D
90
Pla + T + D
80
OS (%)
70
60
50
40
30
HR 0.68
95% CI = 0.56, 0.84
P = .0002
20
10
40.8
months
Δ 15.7
months
56.5
months
0
0
10
20
30
40
50
60
70
Time (months)
n at risk
Ptz + T + D
402
371
318
268
226
104
28
1
Pla + T + D
406
350
289
230
179
91
23
0
Swain SM, et al. ESMO-ECCO 2014. Abstract 350O.
HER2 Therapy for Patients Resistant to Trastuzumab:
T-DM1, A Targeted Chemotherapy!
HER2
T-DM1
Emtansine
release
P
Inhibition of
microtubule
polymerisation
P
P
Lysosome
Internalisation
SYD 985:
Another
antibody drug
conjugate
targeting HER2 (Van Herpen
et al., ECC
2015)
Nucleus
LoRusso PM, et al. Clin Cancer Res. 2011;17(20):6437-6447
EMILIA Study: OS Was Significantly Improved
with T-DM1 Treatment
Median (months)
No. of events
Cap + Lap
25.1
182
T-DM1
30.9
149
Stratified HR = 0.682 (95% CI, 0.55, 0.85); P = .0006
Efficacy stopping boundary P = .0037 or HR = 0.727
1.0
85.2%
Proportion Surviving
0.8
78.4%
64.7%
0.6
51.8%
0.4
0.2
0.0
0
2
No. at risk:
Cap + Lap 496 471
T-DM1 495 485
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
110
136
86
111
63
86
45
62
27
38
17
28
7
13
4
5
Time (months)
453
474
435
457
403
439
368
418
297
349
240
293
204
242
159
197
133
164
Verma S, et al. ESMO 2012; Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.
Preclinical HER2-TDB: A promising
agent targeting resistant HER-2+ BC
= IgG1 bispecific
TDB mechanism of action: T cell
activation and profileration
TNBC/Basal-Like Diseases
Paclitaxel/FAC Neoadjuvant Response by PAM50 Subtype:
A Significant PCR (50%–65%) in a Subgroup of Patients
Poor Outcome of a “Triple-Negative“ Breast Cancer
Subgroup
ER–
PgR–
HER2–
Ki67 80%
HER1+++
"Triple
Negative"
Progressive disease in spite of
•
•
•
•
•
FEC x 6
Weekly paclitaxel
Kinesin inhibitor
Capecitabine
Radiotherapy
Angiogenic and
inflammatory pattern of the
local recurrence!!!
Heterogeneity of TNBC: An Opportunity for
New Agents?!
– Basal-like 1 and 2 – DNA damage response genes (Platinum, PARP
inhibitors)
– Immunomodulatory (checkpoint inhibitors)
– Mesenchymal and mesenchymal/stem cell – PI3K/mTOR pathway
– LAR – androgen receptor signaling (Enzalutamide)
TNT Trial: Patients with BRCA1 or BRCA2 Mutation
Experience Significantly Greater Objective Response with
Carboplatin than Docetaxel
Andrew Tutt, et al. SABCS 2014.
(AR
)
Enzalutamide in TN, Androgen-Receptor–Positive
Breast Cancer
Clinical Benefit in Evaluable and ITT Populations
Traina T, et al. ASCO 2015. Abstract 1003.
Redundant Mechanisms of DNA Repair May Offer a
Therapeutic Opportunity in Basal-Like BRCA1-/- Breast
and Ovarian Cancers
Olaparib, a PARP Inhibitor, Demonstrated Significant
Efficacy in BRCA-Mutated Tumours
Several PARPi are
under clinical
investigation
including in the
adjuvant setting
BRCA-mutant breast cancer
Tutt A, et al. Lancet. 2010;376(9737):235-244; Audeh MW, et al. Lancet.
2010;376(9737):245-251.
Eribulin Mesylate
•A pharmaceutically optimised, synthetic analogue of the marine
sponge halichondrin B
Halichondria
okadai
Probability of Survival
EMBRACE Study: Eribulin vs TPC in Heavily
Pretreated Patients – Overall Survival
TPC, treatment of physician choice.
Cortes J, et al. Lancet. 2011;377:914-923.
Merci
Thank you