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Update on neoadjuvant treatment of breast cancer
Update on neoadjuvant treatment of breast cancer
«IS PATHOLOGIC COMPLETE RESPONSE STILL A
GOOD SURROGATE OF SURVIVAL ? »
Complete histological response varies according to tumoral type
Luminal A (N=572) Luminal B (HER2-) (N=211) (N=281)
Luminal B (HER2+) HER2+ (non-luminal) (N=178)
Triple-negative N=362)
40
35
30
25
20
15
10
5
0
pCR (%)
Untch M, et al J Clin Oncol. 2010, Apr 20;28(12):2024-31
Prognostic impact of pathologic complete response (pCR) on disease-free survival
(DFS) in 4,193 patients according to breast cancer intrinsic subtype.
von Minckwitz G et al. JCO 2012;30:1796-1804
with luminal A– luminal B, HER2 neg luminal B, HER2 pos
luminal B, HER2 neg TN
HER2-positive (nonluminal
pCR rate after neoadjuvant chemotherapy is associated with better outcome
only for patients with: HER2-positive/hormone receptor negative or triple-negative and some more aggressive HER2-negative/hormone receptor positive tumours.
Update HER2+++ breast cancers What’s new ?
Unresolved questions
• Noah study (and other phase II studies) have shown that Traztuzumab should be added to chemotherapy in neoadjuvant setting
• Questions :
– Traztuzumab and Anthracyclins combination ?
– Precocity of Traztuzumab use ?
Trastuzumab and anthracyclin
• Joint use of anthracyclin and Trastuzumab in neoadjuvant studies in HER2+++ patients, acceptable toxicity …
• This combination is doubtfull as for its innocuousness
• Retrospective analysis of 583 patients who received anthracyclins and Traztuzumab (3 neoadjuvant trials)
– Cardiac toxicity rate (linear variable )
– Increase cardiac toxicity (OR = 1,95, 95% CI 1,16-3,29)
– 44 cardiac events in the group with T vs 28 in the group without T
Bozovic-Spasojevic ILancet Oncol. 2011 Mar;12(3):209-11
What is the optimal time for Traztuzumab initiation ?
• There are no direct data answering to this question as there are no studies comparing Traztuzumab in neoadjuvant vs adjuvant setting (except Remagus study….)
• In metastatic setting, arguments in favor of an early use (1)
• In adjuvant setting (NCCTG) in favor of an early use
With a 6 years follow up DFS (2)
– AC-P (12 weeks) = 71,9 %
– AC-P (12 weeks then )-T = 80,1 %
– AC-PT (concommitant) = 84,2 %
(1) Marty et al, J clin oncol, 2005, (23) (2) Perez EA J Clin Oncol. 2011, 29(34):4491-7.
HR : 0,69 [0,57-0,85], p = 0,0005
HR : 0,75 [0,60-1 ,11], p = 0,02
The interest of double blockage ?
Lapatinib in neoadjuvant
Tyrosine Kinase inhibitor of EGFR and HER2
Efficacy in metastatic breast cancers HER2 +++ combined with capecitabine or to Traztuzumab
Geyer CE N Engl J Med. 2007 Apr 5;356(14):1487. Blackwell KL, et al: J Clin Oncol. 2012 Jul 20;30(21):2585-92.
HER2 signaling pathway
• Anti HER2 treatment are monoclonal antibodies against extracellular portion (traztuzumab) and small molecules which inhibit tyrosin kinase (lapatinib).
Ras
Raf
Erk
Rsk
PI3K
TORC1
Rheb
PIP3
Tuberin
PTEN
TORC2 MEK
Akt PDK1
HER2/HER3 Trastuzumab
Lapatinib
Baselga J et al. SABCS 2010
Two randomised trials
Stratification : • S ≤ 5 cm vs. S > 5 cm •RE ou RP + vs. RE & RP – • n 0-1 vs. n ≥ 2 •Surgery or not •Conservative or no
Breast cancer HER2+, T > 2 cm (no inflammatory ) FEVG > 50 % n = 450
34 week
52 semaines de traitement anti-HER2
lapatinib
trastuzumab
lapatinib
trastuzumab
F E C X 3
R ANDOM I S A T ION
lapatinib
trastuzumab
lapatinib
trastuzumab
paclitaxel
paclitaxel
paclitaxel
+ 12 week 6 sem
Neo-ALTTO
Baselga J et al. Lancet. 2012 Feb 18;379(9816):633-40.
surgery
Neo-ALTTO Efficacy – pCR et tpCR
L : lapatinib; T : trastuzumab; L+T : lapatinib plus trastuzumab
pCR : pathologic complete response
p = 0.13
p = 0.001
L T L + T
46.9 %
27.6 % 20.0 %
n = 150* n = 145* n = 145*
tpCR pCR
L T L + T
51.3 %
29.5 % 24.7 %
n = 154 n = 149 n = 152
p = 0.0001
p = 0.34
Loco regional pCR
Baselga J et al. Lancet. 2012 Feb 18;379(9816):633-40.
Neo-ALTTO Efficacy– % of conservative surgery and % N-
L : lapatinib; T : trastuzumab; L+T : lapatinib plus trastuzumab
p = 0.14
p = 0.03
L T L + T
69.0 % 56.6 %
48.0 %
n = 150* n = 143* n = 147*
Negative lymph nodes status Conservative surgery
L T L + T
41.4 % 38.9 % 42.9 %
n = 154 n = 149 n = 152
p > 0.5 p > 0.5
Baselga J et al. Lancet. 2012 Feb 18;379(9816):633-40.
GeparQuinto-HER2+
C : Cyclophosphamide 600 mg/m² Doc : Docetaxel 100 mg/m²
E : Epirubicine 90 mg/m² L : 1000-1250 mg/j p.o.
T : Trastuzumab 6 (8) mg/kg (cycles de 3 semaines)
* + G-CSF
Doc
R Doc*
EC
EC
Trastuzumab (T)
Lapatinib (L)
T 6 months
T 12 months
Untch M et al. Lancet Oncol. 2012 Feb;13(2):135-44
620 Pts 309 ECTH, 311
ECTL
GeparQuinto
pCR (non invasive / no invasive carcinoma in breast and lymph nodes by central review )
EC-Doc + T EC-Doc + L
0,0%
5,0%
10,0%
15,0%
20,0%
25,0%
30,0%
35,0%
40,0%
45,0%
50,0%
p < 0.03
Untch M et al. Lancet Oncol. 2012 Feb;13(2):135-44
GeparQuinto pCR according to subgroups (pre dfined and stratified
39 %
28 %26 %
16 %
31 %
20 %
31 % 30 %
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
EC-Doc + H EC-Doc + L EC-Doc + H EC-Doc + L EC-Doc + H EC-Doc + L EC-Doc + H EC-Doc + L
Negative RE/RP
T1-3 and N0-2
Positive RE/RP
T4 or N3
Untch M et al. Lancet Oncol. 2012 Feb;13(2):135-44
R
AC - wP + T
AC -wP + L
AC- wP + T + L
Operable HER 2 +++
breast cancer
529 ptes
Trastuzumab for one year
T = trastuzumab ; L = lapatinib ; wP = paclitaxel hebdomadaire
ASCO® 2012 - D’après Robidoux A et al., LBA506 actualisé
NSABP B-41 : lapatinib evaluation in neoadjuvant treatment in HER2 +++ breast cancer (1)
• Criteria : pCR, cardiac events , progresssion free survival, overall survival
• Pricipal criteria – pCR rate in the breast (non statistically significant )
• Secondary criteria – pCR rate in the breast and lymph nodes : limit for significativity
wP = paclitaxel hebdomadaire
Taux de réponse histologique
p = 0,78
p = 0,056
49,4 47,4
60,2
0
20
40
60
80
100
AC wP + T (n = 176)
AC wP + L (n = 171)
AC wP + T + L (n = 117)
ASCO® 2012 - D’après Robidoux A et al., LBA506 actualisé
NSABP B-41 : lapatinib evaluation in neoadjuvant treatment in HER2 +++ breast cancer (2)
Pertuzumab :inhibits HER2 dimerisation Monoclonal anti body against a different target of HER2-
HER3
Pertuzumab is a humanised monoclonal antibody , first of a new class : HER2 dimerisation inhibitor
With the inhibition of HER2 dimerisation, pertuzumab inhibits HER 2 signaling patways spark off proliferation and survival of cellular cells .
Pertuzumab prevent HER2-3 formation
Franklin et al. Cancer Cell 2004;5:317-328
Augus et al. Cancer Cell 2002;2:127-137
NeoSphere Design of the study
THP (n = 107) docetaxel + trastuzumab +
pertuzumab
HP (n = 107) trastuzumab + pertuzumab
TP (n = 96) docetaxel + pertuzumab
docetaxel /3 w x 4 →FEC /3 w x 3
trastuzumab /3 w cycles 5–17
FEC /3 w x 3 trastuzumab /3 w
cycles 5–17
FEC /3 w x 3 trastuzumab /3 w
cycles 5–17
FEC /3 w x 3 trastuzumab /3 sem
cycles 5–21
Schéma : /3 weeks x 4
TH (n = 107) docetaxel + trastuzumab
HER2 +++ breast cancers operable > 2cm or locally advanced or inflammatory (n = 417)
CS, cancer du sein; FEC, 5-fluorouracile, épirubicine et cyclophosphamide *Localement avancé = T2–3, N2–3, M0 ou T4a–c, tout N, M0; opérable = T2–3, N0–1, M0; inflammatoire = T4d, tout N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel Gianni L, Lancet Oncol. 2012 Jan;13(1):25-32.
surg
ery
H, trastuzumab; P, pertuzumab; T, docetaxel
NeoSphere pCR (ITT)
p = 0.0141 50
40
30
20
10
0 TH THP HP TP
p = 0.003
29.0
45.8
16.8
24.0
p = 0.0198
Gianni L et al. SABCS 2010
Conclusion
These data show that combining anti hER2 +++ therapies and transduction pathways inhibitors
could bypass resistance mecanisms and improve patients outcome without too much toxicity but
a cost ………………..
Biomarkers which predict who benefit to the addition of pertuzumab to Traztuzumab
• In the cleopatra study there are no blood predictive markers nor tissue markers
J. Baselga et al., SABCS 2012, S5-1
Bevacizumab in neoadjuvant treatment for breast cancer
Interest in triple negative cancers ?
Biology of triple negative breast cancers identification of potential targets
• Triple negative breast cancers come from myoepithelial cells
CK5-6, EGFR (1)
• Kinase Dysregulation
– Loss of PTEN (2)
– Activation of Akt pathway
– Amplification of FGF2, VEGFA, AR
1) Jones et al , 2004 2) Andre 2009 3) Turner et al, 2009 4) Linderholm et al , Ann Oncol, 20,
2009,
• TN breast cancer high level of intracellular VEGF TN could have a higher sensitivity, to angiogenic inhibitors
Bevacizumab added to neoadjuvant chemotherapy for
breast cancer
Harry D Bear;M.D; Ph D
New england journal of médicine ; Janvier 2012
Design of the study
EC
EC
EC
E: Epirubicine 60 mg/m toutes les 3 semaines C: Cyclophosphamide: 600 mg/m toutes les 3 semaines
X: Capecitabine 825 mg/m2 de J1 à J14
GEM:Gencitabine 1000 mg/m2 J1J8
BEV: Bevacizumab 15mg/m2
T: Docetaxel 100 mg/m2 dans le groupe 1 et 75mg/m2 groupe 2 et 3
EC EC EC
EC EC EC
EC EC EC
Biopsy for biomarkers
Operable breast cancers T2 T3 HER2 neg N: 1206 (2007-2010)
R
SUR
GER
Y
Bevacizumab: pCR rate in the breast
0 T-AC
10
20
30
40
50
60
70
TG-AC
TX-AC
T-AC TG-AC
TX-AC
p = 0,10
p = 0,75
Without Bevacizumab With bevacizumab
23,5 % 27,6%
33,7 %
36,1 % 35,8%
31,6 %
p = 0,009
Bevacizumab: pCR rate in the breast and lymph nodes
Bevacizumab addition do not significatively
increase pCR rate in breast and lymph nodes
(P=0,08)
Bevacizumab: pCR rate in breast and lymph nodes
Bevacizumab addition statistically increase pCR rate in breast and lymph nodes in RH+ tumors (p=0,03)
0
Without Bevacizumab
With Bevacizumab
11,1 % 10
20
30
40
50
60
pC
R, %
+ IC
95
%
70
16,8%
p = 0,03
Bevacizumab: pCR rate in the breast and lymph nodes in patients with RH+ tumors
EC
EC+ Bev
Her 2 –
(group 1)
T
T+ Bev Réponse
No response (clinical and/or ultrasound)
>switch Taxol hebdo + Everolimus
E: Epirubicine 90 mg/m2 C: Cyclophosphamide: 600 mg/m2
T:Docetaxel 100mg/m2 BEV: Bevacizumab 15mg/kg
T: Docetaxel 100 mg/m2
Design of the study, 1948 patients
(group 2)
R
pCR
18,4 %
14,9 %
P = 0,04
Sub groups analysis
pCR in TN (663 pts) :
39,3% vs 27,9%, p = 0,0033
pCR in RH +
7,8% vs 7,8%, (p=1,00)
Interaction test negative NS (p = 0.07)
Comparison of the two studies
• pCR increase in the entire population low….
• pCR increase in TN tumors not found in NSABP study.
• BUT
– Smaller population (490 ptes)
– Inflammatory and T4 tumors in the Geparquinto not in the NSABP trial
– Anthracyclins given before in the Geparquinto
– Docetaxel dosage superior in the Geparquinto during 2 cycles
– Beva given for 2 cycles with antracyclins
– Only patients with objective response in the gepar received the Beva
Translational studies could targeted the patients who will answer « maybe » to Bevazusimab
Conclusion
• The neoadjuvant setting gives the unique opportunity to get insights in breast cancer biology
• It allows:
– to evaluate new therapies
– to find predictive factors for better individualization of the treatment.
