Patología Molecular Del Cáncer De Mama
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Patología molecular del carcinoma de mama
José PalaciosServicio de Anatomía PatológicaHHUU Virgen del Rocío, Sevilla
Xàtiva, 12 de enero de 2009
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CK8, 18, 19
Cadherina-E
CK5/6, 14, 17
P-Cadherin
Actin
vimentin
Luminal epithelial
Myoepithelial
(Basal)
CELLULAR TYPES IN MAMMARY GLAND
Basal epithelialmarkers
Mesenchymal markers
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CK5/6
CK14
CK17
P-CADHERIN
p63
S100
CD10
CD44
VIMENTIN
CAV1
OSTEONECTIN
SMA
CALPONIN
H-CALDESMON
CALPONINp63
MYOEPITHELIAL MARKERS
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Limiting dilution transplantations studies
Retroviral-tagged mammary implants
Prospective isolation of putative stem cells using cell surface markers
IDENTIFICATION OF MAMMARY STEM CELLS
Multipotent epithelial cells (“stem cells”) with the ability to generate the entire
functional mammary epithelium
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Visvader and Lindeman, Cancer Res 2006
MODEL OF THE EPITHELIAL CELL HIERARCHY IN THE MOUSE MAMMARY GLAND.
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AEP/ADH/LG-DCIS
ALH/LCIS
+8q+17q-17pP53HER2MYC
-16q +11q
CCND1E-CD (-)
BREAST CANCER PROGRESION MODEL
Invasive Lobular Carcinoma
Low Grade (invasive ductal G1,
tubular, cribiforme...)
High grade (invasive ductal G3, apocrine,
medullary metaplastic...)
HG-CDIS
Breast epithelium
TDLU
CCC
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Perou et al., Nature 2000
MOLECULAR CLASSIFICATION OF BREAST CANCER
c Luminal, ER+ (A and B)
d ERBB2e Basalf Normal
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LUMINAL (ER+) PHENOTYPES
Invasive ductal carcinoma (grade 1-2/3)
Invasive lobular carcinoma
Tubular carcinoma
Invasive cribiforme carcinoma
Mucinous carcinoma
LUMINAL A/B PHENOTYPES
GRADE 1-2/3
ER LEVELS
PROLIFERATION MARKERS
HER2 EXPRESSION
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•Invasive breast carcinoma composed by non-cohesive cells individually dispersed or arranged in single-file linear pattern in a fibrous stroma.
LOBULAR BREAST CANCER
INCREASING INCIDENCE (HRT?)
HIGHER AGE AT DIAGNOSIS
HIGHER SIZE AT DIAGNOSIS
DIFFUSE GROWTH PATERN
LOWER SENSITIVITY OF MAMMOGRAPHY TO DETECT ILC
HIGHER RATE OF FAILURE AFTER BCT?
METASTATIC PATTERN
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Lobular carcinomas completely lack E-cadherin expression
Lobular carcinoma in situ
Infiltrating lobular carcinoma
Invasive Ductal carcinoma
Absence of E-cadherin >80% Reduced E-cadherin: 50%
Gamallo et al; Am J Pathol 1993
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C-terminal
• CDH1 is a tumor and invasion suppressor gene
16q22.1
The E-cadherin/catenin adhesion complex
-catenin
CBD
JMD
E-CADHERIN
actin
p120
-catenin
Protein Mw Gene location
E-cadherin 120 kDa 16q22.1 -catenin 102 kDa 5q31 -catenin 92 kDa 3p21 -catenin 83 kDa 17q21 p120ctn 120 kDa 11q11
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N
IS
IF
D16S398
Wt N T IF IS
E-CADHERIN INACTIVATION IS THE HALLMARK OF LN
E-CD E-CD
Sarrió et al; Int J Cancer 2004
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D16S265
CDH1CDH1
D16S496
D16S398
D16S3057
D16S752
16q2
2.1
T
N
D16S496
-126 -21 +81 +144+1
M U M U M U M U M U M U M U M U
14 15 16 17 24 25 38 H2O
CDH1
Mechanisms of CDH1 inactivation in lobular tumors
CDH1 LOH (60-80%)
CDH1 promoter hypermethylation (40-60%)
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6 6 Wt6 6 Wt
Exon 13Exon 13
Wt 5 5Wt 5 5
Exon 10Exon 10
Wt 19 19Wt 19 19
Exon 2Exon 2
1712 G > C
Wt 52 52Wt 52 52
Exon 11Exon 11
• CDH1 mutations (20-40%).
CCNN
SIGSIG PREPRE CaCa2+ 2+ binding domain TMTM CP CP
60-70% produced truncated proteins.
Mechanisms of CDH1 inactivation in lobular tumors
Sarrió et al, Int J Cancer 2003
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HDGC is caused by germline mutation of CDH1.
The lifetime risk of developing gastric cancer by age 80 is 65%-80%.
Female CDH1 mutation carriers are at increased risk for developing lobular breast cancer.
Penetrance studies have shown that female CDH1 germline mutation carriers have an additional risk of breast cancer, particularly lobular breast cancer, in about 39% of patients.
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Some families have been misclassified as breast cancer families due to clustering of breast cancer cases.
This suggests that families with negative test results for BRCA1/2 in whom the proband has lobular breast cancer should be reevaluated for HDGC and screened for CDH1 mutations.
BREAST CANCER IN HDGC PATIENTS
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Perou et al., Nature 2000
MOLECULAR CLASSIFICATION OF BREAST CANCER
c Luminal, ER+ (A and B)
d ERBB2e Basalf Normal
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BREAST CANCER AND THE BASAL-LIKE PHENOTYPE
Palacios et al; Am J Pathol 1995 Tsuda et al; Am J Surg Pathol 2000
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ER/HER2-negative,
CK5- and/or EGFR-positive
Nielsen et al., Clin Cancer Res 2004
BASAL-LIKE PHENOTYPE
VIMENTIN, P-CADHERIN, EGFR, CK5/6, FASCIN
p63, CD10, OSTEONECTIN, SMA, CALPONIN, H-CALDESMON
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BASAL-LIKE PHENOTYPE (ER/HER2-negative, CK5- and/or EGFR-positive)
Rodríguez-Pinilla el al., Clin Cancer Res 2006
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Medullary carcinoma
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IBCMF IDCG3 P
ERPositiveNegative
2/35 (5.7%)33/35 (94.3%)
24/39 (61.5%)15/39 (38.5%)
<0.001
HER2PositiveNegative
0/35 (0.0%)35/35 (100.0%)
9/38 (23.7%)29/38 (76.3%)
0.002
Ck5/6PositiveNegative
21/35 (60.0%)14/35 (40.0%)
7/39 (17.9%)32/39 (82.1%)
<0.001
EGFRPositiveNegative
9/35 (25.7%)26/35 (74.3%)
9/37 (24.3%)28/37 (75.7%)
0.553
Ck19PositiveNegative
13/35 (37.1%)22/35 (62.9%)
26/38 (68.4%)12/38 (31.6%)
0.007
P-CadherinPositiveNegative
14/35 (40.0%)21/35 (60.0%)
3/38 (7.9%)35/38 (92.1%)
0.001
Basal-like phenotypePositiveNegative
22/35 (62.9%)13/35 (37.1%)
7/37 (18.9%)30/37 (81.1%)
<0.001
Differences between invasive breast carcinomas with medullary features (IBCMF) and grade 3 invasive ductal carcinoma of no
special type (IDCG3).
Rodríguez-Pinilla el al., Am J Surg Pathol 2007
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Medullary carcinoma Metaplastic carcinomaPoorly differentiated carcinoma with central
acellular zones
MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL HETEROGENEITY OF BREAST CARCINOMAS WITH BASAL-LIKE PHENOTYPE
VIMENTIN, P-CADHERIN, EGFR, CK5/6, FASCIN
p63, CD10, OSTEONECTIN, SMA, CALPONIN, H-CALDESMON
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SOX2 EXPRESSION IN BREAST CANCER
SOX2 Ki67
CK5/6VIMENTIN
SOX2 (-) SOX2 (+) P
Rodríguez-Pinilla et al., Mod Pathol 2007
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Perou et al., Nature 2000
MOLECULAR CLASSIFICATION OF BREAST CANCER
c Luminal, ER+ (A and B)
d ERBB2e Basalf Normal
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HER2 EXPRESSION IN BREAST CANCER
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BASAL+ HER2+ BASAL/HER2-
RE (-) 95% 60% 20%
RP (-) 93% 58% 37%
GRADO 3 98% 55% 32%
CK5 57% 10% 6%
CK8 50% 98% 95%
P53 (>30%) 55% 42% 16%
Ki67 (>15%) 72% 46% 32%
EGFR (+) 35% 10% 5%
DIFERENCIAS ENTRE TUMORES CON FENOTIPO BASAL+ Y HER2+
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Laakso et al., Clin Cancer Res 2006
HER2 EXPRESSION IN BREAST CANCER
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Oncogene 2005
Apocrine histology
Non-basal ER-negative
AR-positive
HER2-positive (50%)
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Natrajan et al, 2008
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Natrajan et al, 2008
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n HER2 (+)
Anderson (2003) 20 16 (80%)
Fu (2001) 14 14 (100%)
Schelfhout (2000) 30 26 (85%)
Meissner (1990) 23 23 (100%)
ENFERMEDAD DE PAGET y HER2/neu
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HER2/neu Y CARCINOMA INFLAMATORIO
HER2 (+)
CDI-NOS 15-20%
CLA 30%
CI 35-55%
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DSS in non-treated patients
Basal-like tumors (n=12)
Non Basal-like tumors (n=95)
Log Rank P=0.001
Survival Time (Months)
% S
urv
iva
l
DSS in CMF-treated
Survival Time (Months)
Log Rank P=0.633
% S
urv
iva
lBasal-like tumors (n=13)
Non Basal-like tumors (n=85)
ER/HER2-negative, CK5- and/or EGFR-positive
BASAL-LIKE PHENOTYPE AND CMF RESPONSE IN BREAST CANCER
Rodríguez-Pinilla el al., Clin Cancer Res 2006
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Breast cancer Ovarian cancer Male BC
BRCA1 65% 40% -
BRCA2 45% 11% 8%
BCLC Meeting. Madrid, June 2003
BRCA1/2: 30% BRCA (-): 70%
Hereditary breast cancer
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Histological type and grade
BRCA BRCA2 Sporadic
IDC 74% 71% 69%
Medullary features 18% 3% 3%
Grade 3 66% 41% 36%
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Immunohistochemical markers
BRCA1 BRCA2 Sporadic
ER+ 20% 66% 65%
PR+ 20% 49% 66%
PRER
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Probability of carrying a BRCA1 mutation by age, ER status and grade
(Lakhani et al, J Clin Oncol 2002)
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Immunohistochemical markers
BRCA1 BRCA2 Sporadic
Ki67 high 56% 21% 22%
Cyclin D1 30% 56% 79%
Cyclin E 47% 35% 27%
P53+ 45% 27% 12%
HER2+ 0-7% 0-6% 18%
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HER2 amplification
BRCA1 BRCA2 Sporadic
(n=14) (n=10) (n=54)
HER2 (FISH) 0 0 22%
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Morpholgical and immunohistochemical features of BRCA1 and BRCA2 breast carcinomas
GRADE ER PR BCL2 Ki67 p53 HER2
BRCA1 3 - - - ++ ++ -
BRCA2 2/3 + + + + - -
Ki67 p53BCL2PRER
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Sorlie et al. Proc Natl Acad Sci U S A. 2003
BASAL PHENOTYPE IN BRCA1 BREAST CARCINOMAS
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BRCA1 BRCA2 Sporadic
Cytokeratin 5/6 46% 9% 8.5%
Vimentin 80% 15% 23%
Fascin 84% 17% 25%
Laminin 75% 7% 39%
Caveolin 1 22% 0 4.2%
Cytokeratin 5/6
BASAL CELL MARKERS
Palacios et al, J Nat Cancer Inst 2004Rodríguez-Pinilla et al, Clin Cancer Res 206; Breat Cancer Res and Treat 2006; J Clin Pathol 2007
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BRCA1/2: 30% BRCA (-): 70%
Hereditary breast cancer
GRADE ER PR BCL2 Ki67 p53 HER2
BRCA1 3 - - - ++ ++ -
BRCA2 2/3 + + + + - -
BRCA(-) 1/2 + + + - - +/-
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Dontu et al., 2004
BASAL PHENOTYPE
BASAL AND LUMINAL
MARKERS
LUMINAL PHENOTYPE
LUMINAL MARKERS
ONLY
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HER2
PIK3CA
RAS
-16q
CDH1
IDC-G1/2
MUCINOUS
CRIBIFORME
TUBULAR
LOBULAR
METAPLASTIC
MEDULLARY
IDC-G3
IDC-G2/3
APOCRINE
BRCA1
EGFR
P53
MYC
SMA
VIMENTIN
C-KIT
EGFR
P-CADHERIN
CK5/6
CK8/18/19
HER2
AR
CK8/18/19
ER
PR
GATA3
CK8/18/19
BASAL
BASOLUMINAL
HER2
APOCRINE
LUMINAL B
LUMINAL A
LPER-
LPER+
Luminal cells
Luminal Progenitors
Common Progenitor
Stem Cell
ER-
ER-