BIOMARKERS.
Roberto Bordonaro
Struttura Complessa di Oncologia Medica
ARNAS Garibaldi
Catania
BIOMARKERS.
- The management of breast cancer, both in
early and in advanced stages, had become a
“receptor-driven therapy”.
- Main breast cancer determinants have both
prognostic and predictive role, such as ER,
PgR and Her2.
- They also reflect the moment when the cell
develops the tumor phenotype.
image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug;15(8):842-4 (2009)
Her2+ve tumours
Her2+ve / ER
and/or PgR+ve
ER and/or PgR+ve
image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug;15(8):842-4 (2009)
Her2+ve tumours
Her2+ve / ER
and/or PgR+ve
ER and/or PgR+ve
image by Katie Vicari, from Prat and Perou, Nature Medicine, Aug;15(8):842-4 (2009)
BIOMARKERS.
• Triple-negative breast cancer are a heterogenous
subgroup of tumours.
• The 75 per cent of them shown a “Basal-like
signature” (more than a half express TP53mutations, some are BRCA1-mut carriers).
• They have high proliferative rate and a poor
prognosis (in terms of poor relapse-free and/or
overall survival).
Claudin-low Subtype
HER2
1. 5-10% of all tumors
2. typically TNBC
3. low expression of
cell-cell junction proteins
4. lymphocyte infiltrates
5. stem cell + EMT features
Basal
Luminal
Proliferation
Claudin 3
Claudin 4
Claudin 7
E-Cadherin
Claudin-low Subtype
HER2
1. 5-10% of all tumors
2. typically TNBC
3. low expression of
cell-cell junction proteins
4. lymphocyte infiltrates
5. stem cell + EMT features
Basal
Luminal
Proliferation
Claudin 3
Claudin 4
Claudin 7
E-Cadherin
Phenotypic and Molecular Characterization of the Claudin-low Intrinsic Subtype of Breast Cancer,
Prat et al., Breast Cancer Res. 2010 Sep 2;12(5):R68. (PMID: 20813035)



●
●
HER2
CRYAB
ID4
EGFR/HER1
c-KIT
Keratin 5
Keratin 17
P-Cadherin
Luminal
Proliferation

Basal-like phenotype
(75% of TNBC cancers; 10-20%
of BC);
>50% TP53-mutated;
high proliferative rate (RB loss)
DNA-recombination defects
related to BRCA1-mutations.



●
●
HER2
CRYAB
ID4
EGFR/HER1
c-KIT
Keratin 5
Keratin 17
P-Cadherin
Luminal
Proliferation

Basal-like phenotype
(75% of TNBC cancers; 10-20%
of BC);
>50% TP53-mutated;
high proliferative rate (RB loss)
DNA-recombination defects
related to BRCA1-mutations.
Deconstructing the Molecular Portraits of Breast Cancer,
Prat and Perou, Molecular Oncology, Nov 24, 2010
(PMID: 21147047)
BRCA1- Associated Breast Cancer
• One defective gene copy
carried in a germ cell
• 5-10% of breast cancers
• 50-90% lifetime risk of
disease
• Shared characteristics with
sporadic basal-like breast
cancer: “BRCA-ness”
•
•
•
•
•
•
•
•
•
•
•
•
“BRCAness”
High grade
ER- and HER2-negative
C-myc amplified
Medullary
Pushing margins
DCIS less common
Lymphocytic infiltrate
TP53 mutations
Basal phenotype
EGFR expression
X-chromosome inactivation
pattern
• Sensitivity to DNA damage
BRCA1 Is Key to Repairing DNA
Damage
Several DNA damage response pathways exist:
• Homologous recombination (HR)
– DEPENDS ON BRCA1
• Base excision repair (BER)
– DEPENDS ON PARP
• Nucleotide excision repair (NER)
• Mismatch repair (MMR)
Platinum-sensitivity of BRCA1mut – TNBCs
Trial
Byrski
Silver
Characteristics
Regimen
n°
pRC
BRCA1+mut
carriers
Not-platinum-based
90
14 (16%)
BRCA1+mut
carriers
CDDP 75mg/m2 x4
12
10 (83%)
sporadics TNBCs
(not BRCA1+mut
carriers)
CDDP 75mg/m2 x4
26
4 (15%)
2
2 (100%)
51
8 (16%)
BRCA1mut carriers
Ryan
•
•
sporadics TNBCs
(not BRCA1+mut
carriers)
“
“
CDDP 75mg/m2 x4 +
bevacizumab 15 mg/kg
q3wk x3
Neo-adjuvant setting:
– Retrospective trials suggest platinum-based regimens activity;
– Data from prospective trials on TNBCs are controversial;
Metastatics TNBCs:
– control arm in BALI-1 study with DDP alone – 10% RR
Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010
Good platinum response (p =)
Young age
.001
low BRCA1 mRNA expression
.03
BRCA1 promoter methylation
.04
p53 mutation
.01
gene expression profile of E2F3 activation
.03
Interesting biological analysis; small series (28), only two BRCA1 mutation carriers
enrolled.
Biomarkers.
• Are there any biological characteristic
expressed by triple-negative tumours that may
influence the therapeutic choice?
A compact VEGF signature associated with distant metastases and
poor outcomes, Hu et al. BMC Medicine 2009, doi:10.1186/1741-7015-7-9
FOS/JUN
Fibroblast
CXCL12
Immune
Cell
13-gene
VEGFsignature
A compact VEGF signature associated with distant metastases and
poor outcomes, Hu et al. BMC Medicine 2009, doi:10.1186/1741-7015-7-9
FOS/JUN
Fibroblast
CXCL12
Immune
Cell
13-gene
VEGFsignature
Expression
Hypoxia-related Features and
Basal-like Tumors
VEGF
13-gene VEGF-signature
• Antiangiogenic approaches work in TNBC at least as well as other
subtype, possibly more.
Hu, BMC Medicine 2009
A compact VEGF signature associated with distant metastases and
poor outcomes, Hu et al. BMC Medicine 2009, doi:10.1186/1741-7015-7-9
Identification of a clinically relevant gene signature
in triple negative and basal like breast cancer. Rody et
al. SABCS 2010 Oral Presentation.
slide courtesy of Lajos Pusztai (MDACC)
679 consecutive Bc patients; among them, 87 (13%) where ER, PgR and
Her2-ve.
TN patients had significantly higher VEGF activiity:
mValue = 8.2 pg/μg (versus 2.7 pg/μg in non-TN ones; p <.001)
62% of TN-patients had a VEGF acitivity above the median value,
respect to the 47% of ER and/or PgR and/or Her2+ve ones. (p = 0.036).
TN status seems do not correlate with other clinical prognostic factors such as
Tumour size (p = 0.07), nodal status (p =0.1), histological grade (p = 0.17)
type of relapse (p = 0.82), age (p = 0.18).
Her2 overexpression was associated with high levels of VEGF (p <.001).
dDFS
RFS
OS
BCCS
Linderholm, Ann Oncol 2009
Outcome
parameters
Univariate
Multivariate
RFS
H.r.
significance (p)
H.r.
significance (p)
TNBC
1.8
0.0023
1.7
0.078
VEGF
1.6
0.0057
1.3
0.1663
TNBC
1.6
0.087
1.3
0.4099
VEGF
1.7
0.0166
1.4
0.2136
TNBC
1.8
0.0048
1.5
0.1672
VEGF
1.6
0.0021
1.3
0.1353
TNBC
2.2
0.0039
1.6
0.2621
VEGF
2.0
0.0044
1.5
0.0921
dDFS
OS
BCSS
Linderholm, Ann Oncol 2009
Biomarkers.
• But, which chemoterapeutic agents shown
activity and/or efficacy when administered to
triple-negative breast cancer?
Pathologic Response to
Anthracycline/Taxane by Subtype
369 patients from 3 neoadjuvant datasets
Modified PAM50
Overall pCR rate = 22% (82/369)
Residual dz
pCR
47 (58%)
34 (42%)
Claudin-low
29 (67%)
14 (33%)
HER2-enriched
31 (63%)
18 (37%)
LumA
110 (98%)
2 (2%)
LumB
56 (85%)
10 (15%)
Normal-like
13 (76%)
4 (24%)
Classification
Basal-like
Courtesy C. Perou
Majority of TNBC
Chemotherapy Advances Benefit
Triple Negative
ER Negative
ER Positive
HER2 NEG
paclitaxel
paclitaxel
No paclitaxel
• Anthracycline
added to CMF
No paclitaxel
paclitaxel
paclitaxel
HER2 POS
• Docetaxel –
Same findings
(ECOG/Geicam)
No paclitaxel
(CALGB 9344: AC + Paclitaxel)
Hayes, NEJM 2008; Perez, BCRT 2010; Di Leo, SABCS 2008
No paclitaxel
Anthracycline versus Non-Anthracycline
MA.5 Revisited
CEF
Biologic
# 5 Year #
Subtype
OS
Luminal A
62 93%
Luminal NOS
36 94%
Luminal B
67 71%
Luminal B
21 71%
HeR2+/ER20 55%
Basal by IHC
35 51%
TNBC Non-Basal 9 65%
CMF
5 Year p
OS
71
26
65
27
23
35
20
90%
85%
71%
44%
30%
71%
63%
<0.001
<0.0001
Intriguing, although retrospective and small
Cheang M et al, ASCO 2009
Responsiveness to Conventional
Chemotherapy
Basal-like /
triple negative:
Often responsive
If pCR achieved =
good outcome!
Nonresponse =
poor outcome
Predicting Markers of Clinical Benefit
• VEGF genotypes associated
with improved OS in E2100.
• Higher levels of circulating
endothelial cells at baseline
have consistently correlated
with prolonged clinical benefit
and in one study improved
TTP
Dahlberg SE, et al. J Clin Oncol. 2010;28:949-954
Biomarkers.
• AVF2119: 462 patients with MBC randomized
to receive Capecitabine alone or capecitabine
plus Bevacizumab.
• Among them, for 223 patients tissue samples
were collected and tested with:
• a) in situ hybridization (VEGF-A, VEGF-B,
Thrombospondin-2, Flt4)
• b) HIC (VEGF-C, PDGF-C, Neuropilin-1, Delta-like-ligand4/DLL4, BV8, p53 and Timidine Phosphorilase).
Jubb, Clin Cancer Res, 2011
A = low endothelial Delta-like ligand-4 expression
B = high endothelial Delta-like ligand-4 expression.
Clinical trials assessing in-situ biomarkers
in relation to the efficacy of bevacizumab
R. Danesi
Il ruolo dell'angiogenesi
35
Biomarkers.
Conclusions:
1) The absence of a target seems define a target in itself.
2) For a high percentage of triple-negative tumours we may
hypotize an angiogenesis addiction.
3) Anti-VEGf agents seem work well in all the subtypes of triplenegative tumours.
BIOMARKERS.
Roberto Bordonaro
Struttura Complessa di Oncologia Medica
ARNAS Garibaldi
Catania
Thanks for your kindly attention…