São Paulo
29/03/2019
Current Practice: Early TNBC Carlos H Barrios MD
POTENTIAL CONFLICTS OF INTEREST 2019
• Clinical Research: AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp Dohme (MSD), Novartis, Pfizer, PharmaMar, Roche/Genentech.
• Academic Research Projects: CPO, PUCRS, LACOG, GBECAM, INCA-Brazil.
• Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai.
• No financial conflicts to declare.
Carlos H. Barrios, MD [email protected]
Conflict of Interest Statement
This presentation reflects my personal opinion, and not that of my employer or the sponsor of this activity. Its main objective is to stimulate independent scientific discussion and does not intend to promote a specific product or indication. The information presented may be different from the local/regional label of some of the medications. Please refer to your local label for further clarification.
Carlos H. Barrios, MD [email protected]
What Is TNBC?
• “Triple negative” - ER negative, PgR negative, HER2 negative
• TNBC accounts for 10% to 17% of all breast carcinomas
• Heterogeneous group of diseases, in general, with significantly more aggressive behavior than other molecular subtypes
• Majority are Grade 3 tumors
• Histologically, most frequently high-grade invasive ductal carcinomas of no special type
Boyle P. Ann Oncol. 2012;23(suppl 6):vi7-vi12.
Anders CK, et al. Clin Breast Cancer. 2009;9(suppl 2):S73-S81.
Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844
Luminal Epithelial Cells
Low molecular wt CK 7, 8, 18 and 19
Mucin, BCL2, Hormone Receptors
Basal Cells (Myoepithelial cells)
High molecular wt CK 5, 6, 14 and 17
SMA, Calponina, p63, P-caderin
Perou C, et al. Nature 460:747-752, 2000
Triple Negative
Basal
~75% of TNBC have
Basal gene expression
Pal & Mortimer. Maturitas 2009; Gluz et al. Ann Oncol 2009;
Ander & Carey. Oncology 2008. Young et al. BMC Cancer 2009
Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018
Triple-Negative vs. Basal-Like: Definitions
• ER- / PR- / HER2- • ~15% of all breast carcinomas • Poorly differentiated • Express CK 5/6, 17, EGFR (+)
• BRCA1-2 mutated tumors
•~5% of Breast Cancer
• 50% BRCA-1 carriers are basal-like
• Basal but not triple negative
• Definition by gene expression
• Includes some if not most of BRCA1 mutated tumors
• 15-40% are ER+, PR+ or HER2+
• Triple negative but not basal
• Definition by IHC
• Includes other histologies (medullar, adenoid cystic)
• 10-30% can also include “claudin-low,” a subtype notable for high expression of stem cell markers
• 90% of TNBC do not have BRCA mutations
BRCA 1-2
Prat A, et al. The Oncologist 2013
TNBC: Classifications
Basallike (BL)
TNBC
Mesenchymallike (ML)
TNBC Immune-associated
(IM) TNBC
Luminal/apocrine (LA) TNBC
HER2-enriched (HER2e)
TNBC
Immune signature
BL2
Cell cycle DNA damage
Basallike cytokeratine
Growth signaling (EGF, IGF)
Low proliferation
AR pathway
IM
Claudin- Low
BL1
M
Normal BL
LA/LB
HER2e
LAR
PI3K mutations
EMT signature: cell motility
growth factor signaling (TFG6, Notch,
Wnt/β-catenin, Hedgehog)
Angiogenesis
MSL
Lehmann’s classification
PAM50/claudin-low classification
Le Du F. Oncotarget. 2015;6:12890-12908.
This work is licensed under a Creative Commons Attribution 3.0 Unported License.
Evolution of Treatment Strategies for EBC
ADJUVANT THERAPY
Adapted from: Bonadonna, NEJM, 2006; EBCTCG, Lancet, 2011; Bonilla, JNCI, 2010; Martin, ASCO 2010; Slamon, NEJM 2011; Tolaney, NEJM 2015.
1 3 5 7 9 11 13 15 y
% D
ise
ase
Fre
e S
urv
iva
l
100%
50%
0%
26%
Surgery
32%
CMF
35%
Antra
62%
TAC
67%
DD
75%
Trastuz
93%
APT
A significant proportion of patients are cured by Surgery. We have not been able to single them out!
Patient selection (HER2 or clinical characteristics) has lead to dramatic improvements in outcomes
Adjuvant Approach to EBC
Patient Selection Issues in Early TNBC
• TNM classification
• Histology
• Gene expression profiles
• Platinum in the treatment of Early TNBC
• BRCA 1/2 mutated vs. non mutated
• Basal vs. Non-Basal
• Tumor Infiltrating Lymphocytes
• Neo-Adjuvant response (pCR) vs. non-response (non-pCR)
• Residual disease after neo-adjuvant therapy
Prat A, et al. The Oncologist 2013
How should we define the disease?
79.6%
89.5%
Log-rank p-value: 0.007 100
90
80
70
60
50
1 0 3 4 5 6 7 2 8 9 10
84.9%
Log-rank p-value: 0.286
88.0%
100
90
80
70
60
50
1 0 3 4 5 6 7 2 8 9 10
OS
Pro
bab
ilit
y
Basal (EGFR and/or CK5/6 positive)
Time (Years)
Subgroup Analysis of OS (ITT)
OS
Pro
bab
ilit
y
Non-basal (EGFR and CK5/6 negative)
Time (Years)
Cape. 329
307
286
263
256
249
238
200
139
63 21
Obs. 318
301
284
268
259
242
223
179
123
64 25
Number of patients at risk
Cape. 119 110 107 104 98 98 86 67 31 8 3
Obs. 110 106 91 82 80 76 73 53 22 9 3
Number of patients at risk
p-value interaction test: 0.0052
Group Events
Capecitabine 13
Observation 27
Group Events
Capecitabine 58
Observation 46 HR: 1.23
(95% CI: 0.84, 1.82) HR: 0.42
(95% CI: 0.21, 0.81)
Evolution of Treatment Strategies for EBC
ADJUVANT THERAPY
NEO-ADJUVANT THERAPY
TNBC: Responsiveness to Neoadjuvant Conventional Chemotherapy
• TNBC is responsive to conventional NAC with good outcome similar to other subtypes
• < pCR = poorer outcome
Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
1 Yrs After Surgery
2 3 4 5 6 7
Pro
bab
ilit
y o
f B
ein
g A
live
pCR/non-TNBC pCR/TNBC RD/non-TNBC RD/TNBC
98%
94% P = .24
88%
68%
P = .0001
Cortazar P, et al. Lancet.2014;384(9938):164-172.
pCR and long-term outcome in TNBC:
The CTNeoBC pooled analysis
Symmans WF, et al. J Clin Oncol. 2017;35(10):1049-1060
Recurrence in TNBC correlates with volume of
residual disease
RCB-0 (pCR) 35%
RCB-1 16%
RCB-2 33%
RCB-3 17%
Evolution of Treatment Strategies for EBC
NEO-ADJUVANT THERAPY
POST NEO-ADJUVANT
THERAPY
CREATE-X: DFS and OS Full Analysis Set
Masuda N, et al. N Engl J Med 2017;376:2147-59. DOI: 10.1056/NEJMoa1612645
Medium Follow up of 3.6 years
Outcome Capecitabine
(n = 440) Observation
(n = 445) HR
(95% CI) P Value
5-yr DFS 74.1% 67.6% 0.70 (0.53-0.92) 0.01
5-yr OS 89.2% 83.6% 0.59 (0.39-0.90) 0.01
CREATE-X: DFS and OS in TNBC
Masuda N, et al. N Engl J Med 2017;376:2147-59. DOI: 10.1056/NEJMoa1612645
Medium Follow up of 3.6 years
Outcome Capecitabine
(n = 440) Observation
(n = 445) HR
(95% CI)
5-yr DFS 69.8% 56.1% 0.58 (0.39-0.87)
5-yr OS 78.8% 70.3% 0.52 (0.30-0.90)
Evolution of Treatment Strategies for EBC
ADJUVANT THERAPY
NEO-ADJUVANT THERAPY
NEO-ADJUVANT THERAPY
POST NEO-ADJUVANT
THERAPY
Unlikely to evolve unless in very well characterized patient subgroups.
It is becoming almost UNETHICAL to treat intermediate and high risk HER2 + and TNBC patients with surgery and adjuvant therapy. Almost mandatory for high risk patients Will need EFS endpoint to change clinical practice Most powerful strategy to select patients and explore new treatments
Personal Treatment Algorithm
“Low Risk” TNBC (TNM and histology based definition)
cT <1cm - clin N0
SURGERY
Discussion on ADJUVANT THERAPY
RT, CT
Not yet ready to apply the CIBOMA Trial findings of discriminating basal vs. non-basal patients to
recommend Capecitabine to these patients
Personal Treatment Algorithm
“Intermediate/high Risk” TNBC (TNM and histology based definition)
cT >1cm - clin N0
Neo-Adjuvant Therapy
Capecitabine for 6 months
cT any - clin N+
pCR non-pCR
Clinical Trials addressing patient selection issues
and EFS endpoints should also be considered in the
discussion with each patient
SURGERY
TAKE HOME MESSAGES
• We should never forget where we are coming from…
• The cure of EBC with adjuvant therapy has been achieved (since the early 70’) based on the concept of treating patients with estimations of risk and offering treatment to a large number of patients that we know do not need any treatment.
• Therapy individualization remains an important and worth-pursuing goal but is an imperfect exercise.
• Still today, most treatment decisions in this area are based in our ability of practicing the “art of medicine” and defining the balance of the potential benefits and harms for each individual patient.
Subgroup Analysis of DFS (ITT)
Hazard Ratio No. of events HR (95% CI)
Subgroup Overall Menopausal Status Premenopausal Postmenopausal Phenotype Basal Non-basal Chemotherapy Neoadjuvant Adjuvant Type of CT Taxanes No taxanes N0 vs. N+ N0 N+ Region Spain Latin America
Subgroup n=876 (100%) 276 (32) 600 (68) 628 (72) 248 (28) 164 (19) 705 (80) 285 (33) 591 (67) 444 (51) 420 (49) 532 (61) 344 (39)
Capecit. 105 24 81 84 21 29 74 33 72 34 70 60 45
Observ.
120 35 85 86 34 24 96 36 84 52 67 75 45
0.819 (0.630-1.065) 0.686 (0.408-1.153) 0.867 (0.639-1.176) 0.942 (0.697-1.272) 0.530 (0.307-0.913) 1.006 (0.586-1.727) 0.747 (0.552-1.012) 0.884 (0.551-1.418) 0.798 (0.583-1.093) 0.685 (0.445-1.057) 0.878 (0.628-1.228) 0.750 (0.534-1.053) 0.934 (0.618-1.413)
0.4 0.6 0.8 1 1.2 1.6 2 <-Capecitabine Observation->
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