Download TNBC: Current Challenge and Perspectives

TNBC: Current Challenge and Perspectives
Henry L Gomez MD, PhD
What Is a Triple-Negative
Breast Cancer (TNBC)?
• “Triple negative”: ER negative, PgR
negative, HER2 negative
– Depending on thresholds used to define ER and PgR
positivity and methods for HER2 testing
• TNBC accounts for 10% to 17% of all breast
carcinomas
• Significantly more aggressive than other
molecular subtype tumors
• Majority grade 3 tumors
• Most frequently high grade invasive ductal
carcinomas of no special type
Reis-Filho JS, et al. Histopathology. 2008;52:108-118.
Triple-negative breast cancer: Range of histology.
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
©2011 by AlphaMed Press
Sobrevida Global a 10 años
Peruvian Patients
Carolina Breast Cancer Study
76.6%
67.1%
66.3%
59.8%
Her2/neu
Luminal A
Luminal B
BCL
p < 0.0001
Source: Cruz et al. INEN
Source:: Carey et al. JAMA 2006; 295(21):2492Source
295(21):2492-2502
Distribución del Perfil
Molecular de acuerdo a IHQ
Breast cancer
subtypes
Peruvian
patients *
Southern
Switzerland **
The Caroline
Breast Cancer Study ***
2000 - 2002
2003 – 2007
1993 – 1996
Luminal A
49.3%
73.2%
54.8%
Luminal B
13.2%
13.8%
16.6%
Basal cell like
21.3%
7.4%
21.5%
Her2/neu
16.2%
5.6%
7.1%
Period of interest
*, Gomez et al. Clin Breast Can Res in press
**, Spitale et al. Annals of Oncology 20: 628-635, 2008
***, Carey et al. JAMA 2006; 295(21):2492-2502
Clinical Characteristic
of Metastatic TNBC
– Higher risk
– Early timing
– Sites differ from
luminal:
• CNS 46% of time
0.30
Other (290 of 1421)
Triple negative (61 of 180)
0.25
HR
• No consistent
association with
nodal status or stage
• Relapse pattern
0.35
0.20
0.15
0.10
0.05
0
0
2
1
3 4 5 6 7 8
Yrs After First Surgery
9
10
n
Bone, %
Soft Tissue, %
Viscera, %
TNBC
79
13
13
74
ER+
123
39
7
54
HER2+
78
7
12
81
Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281. Lin NU, et al. Cancer. 2008;113:2638-2645.
Characteristics and Features
of TNBC Phenotype
• Weak relationship between tumor size and nodal
status
• Rapid rise in risk of recurrence following diagnosis
• Peak risk of recurrence at 1-3 yrs
• Distant recurrence rarely preceded by local recurrence
• Local recurrence not predictive of distant recurrence
• Increased mortality rate first 5 yrs
• Majority of deaths occurs within first 5 yrs
• Rapid progression from distant recurrence to death
Dent R, et al. Clin Cancer Res. 2007;13:4429-4434.
NCCN Guideline–Recommended
Chemotherapy Regimens for MBC
•
•
Preferred single agents
– Anthracyclines (doxorubicin, pegylated
liposomal doxorubicin)
– Antimetabolites
(capecitabine, gemcitabine)
– Microtubule inhibitors
(eribulin, vinorelbine)
– Taxanes (paclitaxel)
•
Panel: little compelling evidence that
combination chemotherapy is superior
to sequential single agents for patients
where immediate response is not
necessary (ie, visceral crises)
Chemotherapy combinations
– AC (doxorubicin/ cyclophosphamide)
– EC (epirubicin/cyclophosphamide
– GT (gemcitabine/paclitaxel)
– CMF (cyclophosphamide/
methotrexate/fluorouracil)
– FAC (fluorouracil/epirubicin/
cyclophosphamide)
– FEC (fluorouracil/doxorubicin/
cyclophosphamide)
– Paclitaxel/bevacizumab
NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2013.
Antracyclines for triplenegative breast cancer
Trial
Phase/no.
TNBC pts
Setting
Regimen
Outcome in triple-negative
breast cancer
Anthracycline vs CMF
23% reduction in risk of relapse (p=.11)
Di Leo (2008)
meta-analysis
III
n=157
Adjuvant
Bidard (2008)
II
n=120
Neoadjuvant
CEF x 4-6
Pathological COMPLETE RESPONSE =
17%
Gluz (2008)
III
n=66
Neoadjuvant
DD EC or CMF vs HD
EC-Ecthiotepa
5 yr event-free survival with HD 71% vs
26% with DD
Abbreviations: C, cyclophosphamide; DD, dose dense; E, epirubicin; F, 5-fluorouracil; HD hogh dose; M, methotrexate
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
TNBC Patients are Characterized by
Receptor Negativity and Poor
Prognosis
PFS/TTP with chemotherapy regimens1-7*
Paclitaxel 175, 210 or 250 mg/m2 q3w1
2,8
n=44†
Paclitaxel 90 mg/m2 qw
for 3 weeks of a 4-week cycle2
n=110†
Paclitaxel 90 mg/m2 qw3
n=28†
Cisplatin 75 mg/m2 q3w4
n=58†
Xeloda 2,000 mg/m2 days 1-14 q3w5
n=50†
Xeloda 2,000 mg/m2 days 1-21 q4w6
n=33†
Gemcitabine 1,000 mg/m2 + carboplatin
AUC2 days 1 + 8 q3w7
n=62†
0
5,3
3,7
1,5
4 months
4,2
2,5
3,6
2
4
6
PFS/TTP (months)
8
10
12
1. Harris, et al. Breast Cancer Res 2006; 2. O’Shaughnessy, et al. Cancer Res 2009; 3. Awada, et al. Ann Oncol 2010; 4. Baselga, et al. Cancer Res 2010;
5. Robert, et al. J Clin Oncol 2011; 6. Roché, et al. Ann Oncol 2010;7. O’Shaughnessy, et al. N Engl J Med 2011
C9344 disease-free survival for paclitaxel by ER and HER-2 status.
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
©2011 by AlphaMed Press
Adjuvant anthracycline plus taxane for triple-negative breast cancer.
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
Sequential taxane and anthracycline-containing
neoadjuvant regimens: The sequential order impact
Thiery-Vuillemin et al. The Breast 2011
Neoadjuvant doxorubicin vs
docetaxel in TNBC
Antitumor activity in intrinsic subtypes
Martin et al. ASCO 2010
Differential Response of TNBC to Docetaxel and
Carboplatin-Based Neoadjuvant Treatment
Chang et al. Cancer 2010
pCR of the primary tumor in three types of breast cancer
Ixabepilone for triplenegative breast cancer
Trial
Phase/
Setting
Regimen
Pivot (2009)
III
n=187
Metastatic
breast cancer
resistant to
anthracycline
or taxane
Ixabepilone + cape vs
cape alone
Improved overall response rate (27% vs
9%) and progressio-free survival [4.1 vs
2.1 mo(s)]
Baselga (2009)
II
n=161
Neoadjuvant
Ixabepilone
Pathological complete response = 26%
Abbreviations: Cape, capecitabine
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
Outcome in triple-negative breast
cancer
What About Platinums?
Good preclinical rationale, particularly in BRCA-associated
Clinical data:
Trial
Population
Results
Control arm BALI-1 (CDDP)
Sporadic TNBC
10% RR
Control arm phase III iniparib (gem/carbo)
Sporadic TNBC
30% RR
TBCRC 001 (cetuximab/carbo)
Sporadic TNBC
17% RR
BRCA1+
86% pCR
Sporadic TNBC
15% pCR
14-pt trials neoadj CDDP (Byrski + Silver)
24-pt trial neoadjuvant CDDP (Silver)
Clinical role of platinums less clear: promising in BRCA+
CALGB 40603 and other trials designed to clarify
Baselga J, et al. Ann Oncol. 2010;21(Suppl 8). Abstract 274O. O’Shaughnessy J, et al. J Clin Oncol.
2011;29(Suppl). Abstract 1007. Carey L, et al. 2008;26(Suppl). Abstract 1009. Byrski T, et al. J Clin Oncol.
2010;28:375-379. Silver DP, et al. J Clin Oncol. 2010;28:1145-1153.
Bevacizumab for triplenegative breast cancer
Trial/arm
Median PFS [mo(s)]
in TNBC subset
E2100
Paclitaxel (n=110)
Paclitaxel + bevacizumab (n=122)
5.3
10.6
AVADO
Docetaxel + placebo (n=52)
Docetaxel + bevacizumab 15 mg/kg (n=58)
5.4
8.2
RIBBON-1
Taxane/anthracycline + placebo (n=46)
Taxane/anthracycline + bevacizumab (n=96)
Capecitabine + placebo (n=50)
capecitabine + bevacizumab (n=87)
6.2
6.5
4.2
6.1
ATHENA
Taxane-based regimen + bevacizumab (n=577)
7.2
Current Treatment for TNBC
Many patients treated with adjuvant
anthracycline, taxane, and cyclophosphamide
PFS ≤ 4 mos with chemotherapy for metastatic disease[1]
Ixabepilone with differential response in TNBC?[2]
Eribulin with differential response in TNBC?[3]
Bevacizumab/paclitaxel improves PFS vs paclitaxel alone[4] as well as
bevacizumab/ixabepilone or bevacizumab/nab-paclitaxel;[5] may
show differential benefit in TNBC?
• Addition of cetuximab to platinum adds little? (17% RR)[6]
•
•
•
•
1. Kassam F, et al. Clin Breast Cancer. 2009; 9:29-33. 2. Perez EA, et al. Breast Cancer Res Treat. 2010;121:261-271.
3. Kaufman PA, et al. SABCS 2012. Abstract S6-6. 4. Miller K, et al. N Engl J Med. 2007; 357:2666. 5. Rugo HS, et al.
ASCO 2012. Abstract CRA1002. 6. Carey LA, et al. J Clin Oncol. 2012;30:2615-2623.
Neoadjuvant
Conventional
Chemotherapy
•
•
TNBC often responsive to conventional NAC with good outcome similar to other subtypes
< pCR = poorer outcome
Probability of Being Alive
1.0
98%
94%
P = .24
0.9
88%
0.8
P = .0001
0.7
68%
0.6
0.5
0.4
pCR/non-TNBC
pCR/TNBC
RD/non-TNBC
RD/TNBC
1
2
3
4
5
Yrs After Surgery
Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281.
6
7
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec. 4-8, 2012
Hypothesis
Clinically silent
micro-metastasis
Residual disease
Primary Tumor Bulk
=
SURGERY
CHEMO
Recurrence
This presentation is the intellectual property of the authors/presenters. Contact them at [email protected] for
permission to reprint and/or distribute
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec. 4-8, 2012
Approach
114 clinically-defined TNBC
patients with RD after NAC
Median
Age
48
Stage
Immunohistochemistry
Ki67, ER, PR, HER2, AR
112/114
Nanostring digital
expression analysis
450 genes
89/114
Next generation sequencing
182 oncogenes and
tumor suppressors
81/114
Taxane
Menopause
Node status
IIa
IIb
IIIa
IIIb
IIIc
NA
Yes
No
NA
Pre
Post
NA
Pos
Neg
NA
Min
24
Max
78
N
3
5
13
77
10
3
55
53
3
55
53
3
70
37
4
%
3%
5%
12%
69%
9%
3%
50%
48%
3%
50%
48%
3%
63%
33%
4%
This presentation is the intellectual property of the authors/presenters. Contact them at [email protected] for
permission to reprint and/or distribute
Figure 1: Ki67 varies by molecular subtype
A) The molecular subtype was determined from 89/104 TNBC samples using the PAM50 genes as assayed by
Nanostring. Basal-like: n=57 (64%); Her2: n=18 (20%); LumA: n=5 (5.6%); LumB: n= 5 (5.6%); Normal ;n=4
(4.5%). B) Post-NAC Ki67 varied significantly by molecular subtype, ANOVA p=0.0001.
A
B
Distribution of the intrinsic molecular and pathology-based subtypes within triple-negative
and basal-like tumors.Abbreviations: HR, hormone receptor; TNBC, triple-negative breast
cancer.
©2013 by AlphaMed Press
Prat A et al. The Oncologist 2013;18:123-133
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec. 4-8, 2012
Ki67 in post-NAC TNBC does not
predict survival
40
17
20
5
5 4
H Ba
er sa
2- len lik
Lu rich e
m ed
Lu ina
l
N min A
or a
m lB
al
-li
ke
0
80
60
40
20
0
100
100
Ki67 > 15%
Ki67 < 15%
80
60
40
20
Percent surviving
60
ANOVA
P=0.0001
Percent relapse-free
% Samples
57
100
H Ba
er sa
2- len lik
Lu rich e
m ed
Lu ina
l
N min A
or a
m lB
al
-li
ke
80
Ki67 score after NAC (%)
• Ki67 was scored by IHC in the residual disease
• At least 500 tumor cells were counted in each case
• A cutoff of 15% was used based on previously published literature
Ki67 > 15%
Ki67 < 15%
80
60
40
20
P=0.42
P=0.84
0
0
0
2
4
6
8 10
Time (years)
0
2
4
6
8 10
Time (years)
This presentation is the intellectual property of the authors/presenters. Contact them at [email protected] for
permission to reprint and/or distribute
Number of samples with aberrations
Clinically targetable pathways in TNBC
40
TSC1
AKT3
20
CDNK2A
CCND3
PIK3R1 BRCA2
ATM
NF1
BRCA1
PIK3CA
PI3K/mTOR
PI3K/mTOR
inhibitors
AURKA
CCNE1
PTEN
10
0
~90% of all patients had
an aberration in at least
one of these pathways
AKT2
AKT1
RAPTOR
RICTOR
30
RB1
DNA Repair
DNA-repair
targeting
agents
MET
CCND2
CRAF
BRAF
KRAS
Ras/MAPK
RAF/MEK
inhibitors
FGFR4
CCND1
CDK6
IGF1R
CDK4
Cell Cycle
Cell cycle/mitotic
spindle inhibitors
FGFR1
KIT
FGFR2
EGFR
GFRs
Targeted RTK
inhibitors
This presentation is the intellectual property of the authors/presenters. Contact them at [email protected] for
permission to reprint and/or distribute
Heterogeneities in the nomenclature
and classification of triple-negative
breast cancer
Metzger-Filho O et al. JCO 2012;30:1879-1887
©2012 by American Society of Clinical Oncology
Conventional Cancer Treatment
Diagnosis
Treatment
Stage, Grade,
IHC
Chemo, Radio,
Surgery
31
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