Download Microarrays or `microawrys`?

Novedades en los tipos histológicos
receptores de estrógenos negativos
JS Reis-Filho, MD, PhD, FRCPath
Department of Pathology
Human Oncology and Pathogenesis Program
Conflicts of Interest
• I have no financial relationships to disclose
• I will not discuss off label use and/ or
investigational use in my presentation
Summary
• Breast cancer molecular classification
• The spectrum of ER-negative breast cancers
• Pathological features and histological subtypes
• Molecular subtypes of ER-negative disease
• Prognostic signatures
• Genetics of ER-negative breast cancers
Breast cancer molecular
classification
ER+ and ER- breast cancers: distinct diseases
Adapted from Van ‘t Veer et al, Nature 415, 2002
Breast Cancer Molecular Taxonomy
‘Intrinsic’ Subtypes
ER-ve
ER+ve
The spectrum of ER-negative
cancers
ER-negative breast cancers
• More aggressive clinical
behaviour
• Two main groups
– ER-negative/ HER2-positive
– Triple-negative breast cancer
Cheang et al. Clin Cancer Res 2008
Pathological Features and
Histological Subtypes
ER-negative breast cancer
Histopathological features
• Grade III (>90%)
• Lymphocytic infiltrate (32%)
• Pushing borders (8%)
• High mitotic rate (>19/10HPF)
• Central/ comedo necrosis (33%)
• Squamous metaplasia (6%)
• Spindle metaplasia (3%)
• Tumour giant cells (32%)
Putti et al. Mod Pathol 2005; Fulford et al, Histopathology 2006; Livasy et al, Mod Pathol, 2006; Turner et al, Oncogene, 2007; Kreike
et al. Breast Cancer Res, 2007
Special histological types of breast cancer:
Immunohistochemical profiles
Mucinous
Neuroendocrine
Micropapillary
Papillary
Medullary
Metaplastic
Secretory
Adenoid cystic
Apocrine
Pleomorphic lobular
Acinic
Reis-Filho et al., Histopathology 2006; Rakha E, Reis-Filho JS, Ellis IO. JCO, 2008; Lae et al. Mod Pathol 2008;
Weigelt et al., J Pathol 2008; Weigelt et al., Breast Cancer Res Treat 2009; Weigelt et al. Nat Rev Clin Oncol 2009
Special histological types of ER-negative disease
Low grade tumours
Secretory carcinoma
High grade tumours
Medullary breast cancer
Metaplastic breast cancer
t(12;15) ETV6-NTRK3
Adenoid cystic carcinoma
Grade 3 – IDC-NST
Apocrine Carcinoma
t(6;9) MYB-NFIB
Reis-Filho et al., Histopathology 2006; Rakha et al. JCO, 2008; Weigelt et al., J Pathol 2008; Weigelt et al.,
Breast Cancer Res Treat 2009; Weigelt et al. Nat Rev Clin Oncol 2009 ; Wetterskog et al. J Pathol 2012
Take Home Messages
• ER negative breast cancers
– Grade II/III
– Constellation of morphological features
• Special histological types
– High-grade: metaplastic, ‘medullary’, apocrine
– Low-grade: adenoid cystic, secretory, acinic
Molecular subtypes of ERnegative disease
Breast Cancer Molecular Taxonomy
‘Intrinsic’ Subtypes
ER-ve
ER+ve
PAM50 subtypes vs ER, PR and HER2 expression
Not all ER-negative/HER2-positive are HER2-enriched
N= 797 patients with ER, PR, HER2 and Ki-67 data available
Luminal Luminal HER2-E Basal- NormalA
B
like
like
ER+ or PR+/HER2-/Ki67<14
230
130
55
3
19
ER+ or PR+/HER2-/Ki67>14
32
80
20
8
6
ER-/PR-/HER2-
3
10
29
55
2
ER- and PR-/HER2+
0
7
31
3
0
ER+ or PR+/HER2+
4
30
37
0
3
76% of ER-negative/HER2-positive are HER2-Enriched
Bastien et al. BMC Med Genomics 2012
PAM50 subtypes vs ER, PR and HER2 expression
Not all TN are Basal-Like
Not all Basal-like are TN
N= 797 patients with ER, PR, HER2 and Ki-67 data available
Luminal Luminal HER2-E Basal- NormalA
B
like
like
ER+ or PR+/HER2-/Ki67<14
230
130
55
3
19
ER+ or PR+/HER2-/Ki67>14
32
80
20
8
6
ER-/PR-/HER2-
3
10
29
55
2
ER- and PR-/HER2+
0
7
31
3
0
ER+ or PR+/HER2+
4
30
37
0
3
56% of Triple-Negative breast cancers are PAM50 Basal-Like
79% of PAM50 Basal-like are Triple-Negative breast cancers
Bastien et al. BMC Med Genomics 2012
TN is not a synonym for basal-like phenotype!
TN
(IHC/FISH)
Basal-like
(microarrays)
HER2 +
(<5%)
Luminal
AR
Claudin
Low
Other
subtypes
70-80%
ER low
PgR low
HER2 –
Basal +
‘Intrinsic’ subtyping revisited:
Claudin-low tumours
luminal
claudin-low
basal
Prat et al, Breast Cancer Res 2010
Claudin-low breast cancers are enriched for
tumours with a TN phenotype
Claudin-low
Basal-like
UNC
NKI
MDACC
UNC
NKI
MDACC
37
21
18
73
42
15
ER+
12%
33%
22%
11%
19%
0%
PR+
23%
-
22%
6%
-
13%
HER2+
22%
-
6%
9%
-
13%
TN
71%
-
61%
80%
-
73%
Grade 3
77%
38%
61%
88%
86%
93%
Patients
Prat et al, Breast Cancer Res 2010
Molecular apocrine breast cancers are
often of TN phenotype
Guedj et al. Oncogene 2012
TNBC subtypes
BL1: Basal-like 1
BL2: Basal-like 2
IM: Immunomodulatory
M: Mesenchymal-like
MSL: Mesenchymal Stem-like
LAR: Luminal AR
Lehmann et al, JCI 2011
Different types of TNBC respond to
different therapies in preclinical models
Basal-like
Mesenchymal-like
Luminal AR
Lehmann et al, JCI 2011
Cisplatin
NVP-BEZ235
Bicalutamide
Comparison of classifications:
PAM50 vs 6 subtypes of TNBC
Lehmann & Pietenpol. J Pathol 2014
PAM50 and 6 subtypes:
heterogeneous groups
Lehmann & Pietenpol. J Pathol 2014
Prognostic signatures
Prognostic signatures
• First generation prognostic signatures
• No discriminatory power in ER-negative tumours
Reis-Filho & Puztai. Lancet 2011; Sotiriou et al. JNCI 2006
Good prognosis classifier for
ER-negative cancers
Seven-gene immune response module
overexpressing immune response module
underexpressing immune response module
Teschendorff et al, Breast Cancer Res 2008
Immune response related signatures are
prognostic in ER-negative cancers....
... but the good prognosis group still
has a high number of events
“Lymphocyte-predominant” ER-negative/ HER2-negative
breast cancers have a significantly better outcome
Intra-tumour lymphocytes Stromal lymphocytes
ER-negative/ HER2-negative DFS
No lymphocytes
ER-negative/ HER2-negative OS
Loi et al. J Clin Oncol 2013
Take home messages
• ER-negative breast cancers
– Multiple molecular subtypes
– Potential framework for precision medicine
• First generation prognostic signatures
– Of no use for ER-negative breast cancer patients
• all poor prognosis
• Inflammatory response
– Prognostic in ER-negative cancers (in particular TNBCs)
– Gene signatures - minimal clinical utility
– Lymphocytic counting and profiling - potential clinical use
Genetics of ER-negative breast
cancers
ER status and highly recurrent
driver mutations
ER positive
ER negative
• Highly recurrent drivers: TP53 and PIK3CA
• Vast number of genes rarely mutated
Stephens et al. Nature 2012
Conclusions
• ER-negative breast cancers
– Heterogeneous group of tumours
– As a group
• More aggressive clinical behaviour
– Subtypes
• ER-negative/ HER2-postive: anti-HER2 therapy
• TNBCs:
– heterogeneous with multiple subtypes
– Luminal AR tumours are fundamentally different
– Low grade histological types driven by fusion genes
– Genetic profiling
• Limited number of highly recurrently mutated genes
Proliferation
HER2 ER signalling
ER-positive and ER-negative breast cancer
subtypes are fundamentally different
Hu et al. BMC Genomics 2006