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Circulating Tumor Cells (CTC) and pathological Complete Response (pCR) are strong independent prognostic factors
in Inflammatory Breast Cancer (IBC) in a pooled analysis of two multicentre phase II trials
(BEVERLY 1 & 2) of neoadjuvant chemotherapy combined with bevacizumab
Jean-Yves Pierga, François-Clément Bidard, Aurélie Autret, Thierry Petit, Fabrice André, Florence Dalenc, Christelle Levy, Jean-Marc Ferrero, Gilles Romieu, Jacques Bonneterre, Florence Lerebours, Thomas Bachelot, Pierre Kerbrat, Emmanuelle
Charafe-Jaufret, Jérôme Lemonnier, Patrice ViensInstitut Curie, Paris and Université Paris Descartes; Institut Paoli Calmettes, Marseille,Paul Strauss Cancer Center and University of Strasbourg; Gustave
Roussy, Villejuif, Institut Claudius Regaud, Toulouse, Centre François Baclesse, Caen,
Centre Antoine Lacassagne, Nice, Institut du Cancer de Montpellier, Montpellier; Centre Oscar Lambret, Lille,
Centre Léon Bérard, Lyon, Centre Eugene Marquis, Rennes; R&D UNICANCER, Paris, Institut Paoli Calmettes, Marseille, France
Introduction• Inflammatory breast cancer (IBC) is a highly aggressive form of locally
advanced breast cancer – Representing up to 5% of breast cancers1
– Characterized by high vascularity and increased microvessel density
• The 5-year survival is # 40% 1,2
• Bevacizumab, targeting VEGF, significantly improves progression-free survival and response rate in patients with advanced breast cancer but not overall survival3
• In neoadjuvant setting of non-IBC, bevacizumab increases tumor response rate4,5
1. Dawood S. Expert Rev Anticancer Ther 2010. 2. Cristofanilli M, et al. Cancer 2007 3. Miles D. Ann Oncol 2013 4. Bear HD NEJM 2012 5. von Minckwitz G NEJM 2012
Circulating tumor cells
Comen, E. et al. Nat. Rev. Clin. Oncol. 8, 369–377 (2011)
• CTC count is an independent prognostic factor in early breast cancer1–3 - In the REMAGUS 02 study in patients receiving neoadjuvant chemotherapy,
20–25% of patients had ≥1 CTC/7.5 mL3
- A similar rate (22%) was reported in the GeparQuattro trial4- Higher incidence of 35% to 54% of CTC has been reported in non metastatic
IBC 5,6. - We have recently reported that CTC detection is an independent prognostic factor
in 52 primary HER2+ IBC7
• The potential of Circulating Endothelial Cells (CEC) to predict the efficacy of anti-angiogenic therapy remains debated
1. Rack BK, et al. JNCI 2014 . 2. Bidard FC, et al. Ann Oncol 2010;21:729–33. 3. Pierga JY, et al. Clin Cancer Res 2008;14:7004–10. 4. Riethdorf S, et al. Clin Cancer Res 2010;16:2634–45. 5. Pierga, Lancet Oncol 2012. 6. Mego M Breast Cancer Res. 2015;17(1):2.7. Pierga J.Y Clin Cancer Res 2015;
Introduction
• The BEVERLY 1 & 2 studies were evaluating bevacizumab in combination with chemotherapy in neoadjuvant setting in patients with HER2-negative and HER2-positive IBC (T4d), respectively.
BEVERLY 2 HER2-positive IBCBEVERLY 1 HER2-negative IBC
• An ancillary study was evaluating circulating tumor cells (CTCs) and circulating endothelial cells (CECs) as candidate biomarkers
• We present a pooled analysis of these two prospective trials.
Introduction
1 2 3 4 5 6 7 8 Radiotherapy (6 weeks)
FEC x 4 cycles5FU
EpirubicinCyclophosphamide
Docetaxel x 4 cycles
Surgery Endocrine therapy if ER+
Trastuzumab (52 weeks)
CTC CEC inclusion
CTC CEC cycle 5
CTC CEC pre-surgery
CTC CEC post-surgery
BEVERLY 2 treatment schedule (N= 52 HER2+ IBC)
Bevacizumab (24 weeks) Bevacizumab (28 weeks)
1 2 3 4 5 6 7 8 Radiotherapy (6 weeks)
FEC x 4 cycles Docetaxel x 4 cycles
Surgery Endocrine therapy if ER+
CTC CEC inclusion
CTC CEC cycle 5
CTC CEC pre-surgery
CTC CEC post-surgery
BEVERLY 1 treatment schedule (N= 100 HER2- IBC)
Bevacizumab (24 weeks) Bevacizumab (28 weeks)
Trastuzumab (52 weeks)
Methods
• CTC and CEC were detected in 7.5 ml and 4 ml of blood respectively
• CellSearch® system– CTC detection : EpCAM+ immunoselection
followed by cytokeratin, CD45 and HER2 staining
– CEC detection : CD146+ immunoselection followed by CD105 and CD34
staining
HER2 Cytokeratin
Example of CTC detection
• HER2 CTC staining and correlation with primary tumor status in BEVERLY studies has been performed
Objectives• To describe CTC and CEC counts at baseline and during treatment
• To correlate CTC and CEC counts with pathological response.
• To evaluate the prognostic value of CTC and CEC counts and changes on disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS)
Endpoints:- CTC and CEC counts at the five specified timepoints- Pathological response rate (Sataloff TA, NA/NB)- DFS, RFS, and OS at 3 years (current analysis) and 5 years
Patients characteristics (n=152 patients, all T4d M0) Value
Median age, years (range)
ECOG performance status, N (%)01
Lymph node involvement, N (%)N0N1N2N3
Histology: no special type (ductal)
Tumor grade, N (%)IIIIII
Receptors, N(%) ER positive HER2 positive Triple negative subtype
49 [21-75]
135 (93%)10 (7%)
40 (26%)78 (51%)17 (11%)9 (6%)
140 (93%)
4 (3%)53 (35%)87 (57%)
61 (40%)52 (34%)55 (36%)
Results: Baseline CTC and CEC counts
• From October 2008 to September 2010, 152 patients were included
• 137 were evaluable for both CTC and CEC at baseline
• At baseline, 55 patients had ≥ 1 detectable CTC (39%)– Median CTC count for positive cases was 4, range [1-559]
• CECs were detected in all patients except one• Median CEC count was 15, range [0-696]
• No correlation was observed between baseline CTC and CEC counts
Changes in CTC count during neoadjuvant therapy
CTCs /7.5 mL
-20
0
20
40
60
80
100
120
140
160
Num
ber o
f CTC
CTC before C1 CTC before C5 CTC before surg CTC after surg
After 4 cycles of chemotherapy, a dramatic drop of CTC to a rate of 9% was observed (p<0.0001) .
Changes in CEC count during therapy
CEC/4 ml
1
10
100
1000
10000
Num
ber o
f CEC
(log
)
CEC before C1 CEC before C5 CEC before surg CEC after surgery CEC at 1 year
p<0.001
Significant increase during docetaxel + bevacizumab
Surgery
Correlation for HER2 status between CTC and primary tumor
Each case with HER2 discrepancy had a low CTC count ( < 5 CTC/7.5ml) and/or less than 25% of discordant CTC
1. Ligthart & Bidard, et al. Ann Oncol 2013
HER2 negative primary
HER2 positive primary
Results: correlation with pCR
• pCR rate was 40% (95% CI 31-48% ) after central review (Sataloff TA, NA/NB)
• At multivariate analysis higher pCR rates was associated with– Hormone Receptors negative status HR=3.36 [1.33, 8.49] p=0.01– HER2 positive status HR=6.90 [2.83, 16.7]
p<0.0001– cN0 status at baseline HR=2.77 [1.09, 7.02]
p=0.03
• No correlation between pCR and CTC or CEC levels and changes
Results: Univariate analysis for survival• Median follow-up was 43 months.
Disease-Free Survival Overall Survivalp (log rank) HR [95%CI] p (log rank) HR [95%CI]
Age : > 50 years 0.11 0.7 [0.4-1.1] 0.62 0.9 [0.4-1.6]
cN status : cN1, N2, N3 0.02 2.2 [1.1-4.2] 0.03 2.7 [1.1-6.9]
Tumor grade: III 0.90 1.0 [0.6-1.7] 0.37 1.3 [0.7-2.6]
Hormone R. Status: no expression 0.003 2.2 [1.2-3.7] <0.001 3.3 [1.5-6.6]
HER2 status: positive 0.35 1.3 [0.7-2.3] 0.51 1.3 [0.6-2.8]
Triple Negative 0.11 1.5 [0.9-2.4] 0.02 2.1 [1.1-3.8]
pCR (central review): No <0.001 3.3 [1.6-6.5] 0.009 3.7 [1.3-10]
CTC at inclusion: ≥1CTC <0.001 2.8 [1.6-4.7] <0.001 4.3 [2.1-8.7]
CEC at inclusion: <20CEC 0.13 1.5 [0.9-2.7] 0.1 1.8 [0.9-3.6]
Disease Free Survival (ITT)
CTC=0 at C1 n=54CTC ≥ 1 at C1 n=55
CTC=0 at C1 n=85
HR=2.80, 95%CI[1.65-4.76]
3-year DFS: 70% vs. 39%
Overall Survival (ITT)
HR=4.28, 95% CI[2.10-8.74]
3-year OS : 92% vs 56%
CTC=0 at C1 n=85
CTC ≥ 1 at C1 n=55
Multivariate analysis for Disease-Free Survival (ITT)
p (Cox model) HR [95%CI]
cN status : cN1, N2, N3 0.09 2.1 [0.9-4.9]
Triple Negative 0.01 2.5 [1.2-5.3]
pCR (central review): No 0.003 3.2 [1.5-6.8]
CTC at inclusion: ≥1CTC 0.004 2.6 [1.4-4.8]
Multivariate analysis for Overall Survival (ITT)
p (Cox model) HR [95%CI]
cN status : cN1, N2, N3 0.12 2.7 [0.8-10]
Triple Negative 0.04 2.9 [1.1-7.9]
pCR (central review): No 0.03 3.3 [1.1-9.7]
CTC at inclusion: ≥1CTC 0.008 3.1 [1.3-7.2]
Early dissemination and tumor response
• pCR reflects tumor sensitivity to treatment and is correlated with improved overall survival 1
• However not all patients with pCR are cured
• CTCs reflect early tumoral dissemination
• Could CTC detection identify pCR patients still at risk of relapse?
1Cortazar P et al, Lancet 2014
Disease-Free Survival (ITT)According to CTC at baseline & pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,133 had centrally reviewed pCR137 evaluable for CTC
Disease-Free Survival (ITT)According to CTC at baseline & pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,133 had centrally reviewed pCR137 evaluable for CTC
3-year DFS (87%)
3-year DFS (30%)
Overall survival (ITT)According to CTC at baseline and pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,133 had centrally reviewed pCR
Overall survival (ITT)According to CTC at baseline and pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,133 had centrally reviewed pCR
3-year OS (93%)
3-year OS (53%)
Conclusions
• This is the largest prospective study evaluating CTC with a standardized method in non-metastatic IBC.
• We observed a high CTC detection rate of 39% at baseline, with a strong and independent prognostic value for DFS and OS.
• Combination of pCR after neoadjuvant treatment, with CTC at baseline, isolates a subgroup of IBC (25%) with excellent survival.
• CTC count should be part of IBC stratification in prospective trials.
Perspectives
• Proposal of post-neoadjuvant immune-therapy in patients
with absence of pCR and/or presence of CTC at baseline
IMENEO expected data, as of June 2015
• An International MEta-analysis on individual data
in non-metastatic breast cancer (IBC and non-
IBC) treated by NEOadjuvant therapy has been
initiated (IMENEO study)
AcknowledgmentsPatient
Beverly1 Sponsored by UNICANCERBeverly2 Sponsored by Roche
With the financial support of The Ligue Nationale Contre le Cancer RocheChugai Pharma
Technical supportCirculating Tumor Biomarker lab, SIRIC, Institut Curie
21 French participating centersGustave Roussy, Villejuif, FranceCentre Paul Strauss, Strasbourg, FranceInstitut Claudius Regaud, Toulouse, FranceInstitut Curie, Paris, FranceCentre François Baclesse, Caen, FranceCentre Val d'Aurelle, Montpellier, FranceCentre Oscar Lambret, Lille, FranceCentre Antoine Lacassagne, Nice, FranceCentre Eugene Marquis, Rennes, FranceCentre Jean Perrin, Clermont Ferrand, FranceCentre Léon Bérard, Lyon, FranceCentre Paul Papin Center, Angers, FranceInstitut Curie, Saint Cloud, France Institut Jean Godinot, Reims, FranceCentre Alexis Vautrin, Nancy, FranceCentre Catherine de Sienne, Nantes, FranceClinique Armoricaine, Saint Brieuc, FranceInstitut de Cancérologie de l’Ouest, Nantes, FranceHôpital Civil, Strasbourg, FranceInstitut Bergonié, Bordeaux, FranceInstitut Paoli Calmettes, Marseille, France