Transcript HER2

Highlights in the Management of Breast Cancer
Roma, 10 Maggio 2013
Molecular tools
for decision making
in adjuvant therapy
Enrico Ricevuto & Valentina Cocciolone
Oncologia Medica
Ospedale San Salvatore
Università degli Studi di L’Aquila
Adjuvant Breast Cancer Treatment
Key issues

Patients selection according to biomarkers

Selection of appropriate treatment
2
Adjuvant Breast Cancer Treatment
Molecular Tools for decision-making

Biomarkers
 ER/PR
 HER2

Topoisomerase II
BRCA1/BRCA2
 KI67
Multi-Genes expression profiles (GEPs)
Circulating Tumoral Cells (CTCs)



3
BC Prevalence according to ER/PR and HER2
ER/PR
Total
+++
Negative
Negative
35-40
15-20
15-20
Positive
60-65
10-15
50-55
100
30
70
HER2
Total
4
Hormone receptor status: prognostic potential
• Patients with ER-positive/PgR-positive and ER-positive/PgRnegative BC had significantly better prognoses than patients with
ER-negative/PgR-negative disease.
• Patients with ER-positive/PgR-negative tumors tended to have
slightly worse disease-free and overall survival than patients
with ER-positive/PgR-positive tumors, but the differences did not
achieve statistical significance (P .05)
Bordou et al. J Clin Oncol 2003; 21:1973-1979
5
Hormone receptor status: predictive potential
• multivariate analyses confirmed that
both ER and PgR are independent
significant predictors of DFS and OS
among patients who received adjuvant
endocrine therapy;
• the reduction in RR of recurrence was
53% for ER-positive/PgR-positive
patients and 25% for ER-positive/PgRnegative patients (P .0001);
• patients whose tumors are positive for
both receptors have the greatest
reduction of RR of death compared with
patients whose tumors are ER-negative
and PgR-negative.
Bordou et al. J Clin Oncol 2003; 21:1973-1979
6
Her2 status: prognostic potential
Pritchard et al. N Engl J Med 2006;354:2103-11
7
Her2 status: predictive potential
Pritchard et al. N Engl J Med 2006;354:2103-11
8
BC Prevalence according to ER/PR and HER2
ER/PR
Total
+++
Negative
Negative
35-40
15-20
15-20
Positive
60-65
10-15
50-55
100
30
70
HER2
Total
9
Topoisomerase II and responsiveness to
adjuvant Anthracyclines
amplified or deleted TOPO2A
CEF
normal TOPO2A
CMF
CEF
CMF
O’Malley et al. J Natl Cancer Inst 2009;101:644-650
10
Topoisomerase II and responsiveness to
adjuvant Anthracyclines
amplified or deleted TOPO2A
CEF
CMF
normal TOPO2A
CMF
CEF
O’Malley et al. J Natl Cancer Inst 2009;101:644-650
11
Topoisomerase II and responsiveness to
adjuvant Anthracyclines
Adjusted test for interaction:


TOPO2A
HR 0.53 for RFS (p 0.09)
HR 0.38 for OS (p 0.02)


HER2
HR 0.40 for RFS (p 0.008)
HR 0.44 for OS (p 0.02)
O’Malley et al. J Natl Cancer Inst 2009;101:644-650
12
Topoisomerase II and responsiveness to
adjuvant Anthracyclines
Slamon et al. N Engl J Med 2011;365-1273-83
13
BRCA1-ness in TNBC
ER/PR
Total
+++
Negative
Negative
35-40
15-20
BRCA1+ 11%
“BRCA1-ness”>50%
Positive
60-65
10-15
50-55
100
30
70
HER2
Total
14
BRCA1, BRCA2 predisposition carriers
Breast Cancer prognosis
BRCA1+
Pts
Risk recurrence (CI)
p
Risk death (CI)
p
BRCA2+
Non carriers
93
71
1550
1.19 (.74-1.89) 1.63 (1.02-2.60)
.47
.04
1.43 (.91-2.23) 1.81 (1.15-2.86)
.12
.01
Goodwin et al, JCO’12: 30; 19-26
15
Ki67: prognostic role in EBC
Despite some
limitations, this
meta-analysis
supports the
prognostic role of
Ki-67 in early
BC, by showing a
significant
association
between its
expression and
the risk of
recurrence and
death in all
populations
considered and
for both
outcomes, DFS
and OS.
de Azambuja et al. Br J Cancer 2007;96:1504-13
16
Breast Cancer Genomics and Clinical
Classification
Two different gene sets:
first, a set of 476 cDNA
clones previously selected
to reflect intrinsic
properties of the tumors
and, second, a gene set
that highly correlated with
patient outcome.
Sørlie et al. Proc Natl Acad Sci USA 2001;98:10869-74
17
Gene expression profiling predicts clinical
outcome of breast cancer
Panel A shows the pattern of expression of the 70 marker genes in
a series of 295 consecutive patients with breast carcinomas. Each
row represents the prognostic profile of the 70 marker genes for
one tumor, and each column represents the relative level of
expression of one gene. The tumors are numbered from 1 to 295
on the y axis, and the genes are numbered from 1 to 70 on the x
axis. Red indicates a high level of expression of messenger RNA
(mRNA) in the tumor, as compared with the reference level of
mRNA, and green indicates a low level of expression. The dotted
line is the determined threshold between a good-prognosis
signature and a poor-prognosis signature.
Panel B shows the time in years to distant metastases as a first
event for those in whom this occurred, and the total duration of
follow-up for all other patients.
Panel C shows the lymph-node status (blue marks indicate lymphnode–positive disease, and white lymph-node–negative disease),
the number of patients with distant metastases as a first event
(blue marks), and the number of patients who died (blue marks).
Van de Vijver et al. N Engl J Med 2002;347:1999-2009
18
Gene-expression signature is a predictor of
survival in breast cancer
ASSOCIATION BETWEEN CLINICAL
CHARACTERISTICS
AND THE PROGNOSIS SIGNATURE:
the prognosis profile was significantly
associated with:
- the histologic grade of the tumor (P<0.001);
- the estrogen-receptor status (P<0.001);
-age (P<0.001)
but not with:
- the diameter of the tumor;
- the extent of vascular invasion;
- the number of positive lymph nodes
- treatment
Van de Vijver et al. N Engl J Med 2002;347:1999-2009
19
Gene-expression signature is a predictor of
DFS and OS in breast cancer
Among the overall population:
HR for distant metastases as a first
event was 5.1
(95% confidence interval, 2.9 to 9.0;
P<0.001);
HR for overall survival was 8.6
(95 %confidence interval, 4 to 19;
P<0.001).
Van de Vijver et al. N Engl J Med 2002;347:1999-2009
20
Comparison with St. Gallen criteria and NIH
Consensus Criteria
The St. Gallen and NIH criteria classify patients as at low risk or high risk on the basis of various histologic
and clinical characteristics.
This comparison shows that the prognosis profile assigned many more patients with lymph-node–negative
disease to the low-risk (good-prognosis signature) group than did the traditional methods (40 percent, as
compared with 15 percent according to the St. Gallen criteria and 7 percent according to the NIH criteria).
Van de Vijver et al. N Engl J Med 2002;347:1999-2009
21
Histologic grade
Simpson et al. J Clin Oncol 2000; 18:2059-2069
22
Molecular basis of histologic grade
Most genes are
overexpressed in grade 3
tumors (high expression is
RED) and have functions
that have been previously
associated with cell cycle
progression and
proliferation.
Sotiriou et al. J Natl Cancer Inst 2006; 98:262-272
23
Molecular basis of histologic grade
Sotiriou et al. J Natl Cancer Inst 2006; 98:262-272
24
Oncotype DX
21 Gene Recurrence Score (RS) Assay For ER-positive patients
Category
RS (0 – 100)
Low risk
RS < 18
Intermediate
risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
N
117
Events
13
47
18
25
Paik S, et al. Breast Cancer Res Treat 88 (S1):A24, 2004
Validation in tamoxifen-treated patients with nodenegative, ER–positive breast cancer (NSABP-B14)
Paik et al. N Engl J Med 2004;351:2817-26
26
Validation in tamoxifen-treated patients with
node-negative, ER–positive breast cancer
Paik et al. N Engl J Med 2004;351:2817-26
27
Validation in tamoxifen-treated patients with
node-negative, ER–positive breast cancer
Percentage of patients on
tamoxifen with larger N0 tumors
free of recurrence at 10 years
varies by Recurrence Score in
NSABP B14
Percentage of patients on
tamoxifen with moderately/poorly
differentiated tumors free of
recurrence at 10 years varies by
Recurrence Score in NSABP B14
Paik et al. N Engl J Med 2004;351:2817-26
28
Validation in tamoxifen-treated patients with
node-positive, ER–positive breast cancer
Prognostic disease-free survival and overall survival analyses by Recurrence Score
group in patients treated with TAMOXIFEN ALONE
Albain et al. Lancet Oncol 2010; 11:55–65
29
Dowsett et al. J Clin Oncol 2010; 28:1829-1834
30
Many patients live normal life expectancy
free of breast cancer recurrence after
surgical treatment alone
1.3% of recurrences
occurred after 20 years
(3.7% of the 20-year
survivors)
Albain KS. Presented at SABCS 2012
31
10-Year Survival Rate by axillary node status
for patients treated with radical mastectomy
Study
1-3+ Nodes
4+ Nodes
Valagussa, 1978
50%
24%
Haagensen, 1986
63%
27%
Fisher B, 1975
38%
13%
Ferguson, 1982
52%
27%
Albain KS. Presented at SABCS 2012
32
Prediction of recurrence in NSABP-B20 (Tam vs
Tam + CMF)
Paik et al. J Clin Oncol 2006; 24:3726-3734
33
NSABP-B20
Paik et al. J Clin Oncol 2006; 24:3726-3734
34
Prediction of anthracycline-based chemotherapy
benefit by RS: DFS
The RS was a strong
predictive factor of CAF
benefit for DFS, but degree
of CAF benefit depended on
the RS:
•NO apparent benefit for scores
<18 (p=0.97; HR=1.02) or 18–
30 (p=0.48; HR=0.72);
•SIGNIFICANT advantage for
CAF-T compared to tamoxifen
alone for patients with RS ≥31
(p=0.033; HR=0.59)
Albain et al. Lancet Oncol 2010; 11:55–65
35
Impact on clinical practice (where available)
Albain et al. The Breast 2009;18: S141–S145
36
Available tests and prospective ongoing clinical
trials
Goncalves and Bose. J Natl Compr Canc Netw 2013;11:174-182
37
Theoretical spectrum of sensitivity to
adjuvant systemic therapy
Hayes D. J Clin Oncol 2012; 30:1264-1267
38
TAILORx trial
Goncalves and Bose. J Natl Compr Canc Netw 2013;11:174-182
39
RxPONDER trial
Goncalves and Bose. J Natl Compr Canc Netw 2013;11:174-182
40
MINDACT trial
Goncalves and Bose. J Natl Compr Canc Netw 2013;11:174-182
41
Adjuvant Breast Cancer Treatment
Key questions

Patients selection according to biomarkers

Selection of appropriate treatment
 no adjuvant treatment
 Chemotherapy
 Hormonal therapy
42
Circulating Tumoral Cells in Adjuvant Therapy
Three typical patterns
of response observed:

Decrease >10x

Marginal Change

Increase >10x
Peripherally
circulating tumor
cells are influenced
by systemic CT
An increase (even
after initial response
to therapy) of 10-fold
or more at the end of
therapy is a strong
predictor of relapse
and a surrogate
marker for the
aggressiveness of the
tumor cells
Pachmann et al. J Clin Oncol 2008; 26:1208-1215
43
Circulating Tumoral Cells in Adjuvant Therapy
Trastuzumab
Tamoxifene
44
Metastatic Tumors
Evolution of medical treatment




Markers
None
Clinical
Monogene
Multigenes
“One fit (unfit) all”
“One fit some”
(>10%)
“One fit few”
(<10%)
“One fit one”
(<1%)
45
Early Breast carcinoma
Evolution of medical treatment




Markers
None
Clinical
Monogene
Multigenes
“One fit (unfit) all”
“One fit some”
(>10%)
“One fit few”
(<10%)
“More fit many” (>30%)
46
47
Renal cell carcinoma
Evolution of medical treatment


Parameters
None
Bio-Clinical
 Patient
 Tumor
 Drugs
“One fit (unfit) all”
“One fit some”
(>10%)
fitness (age, comorbidities)
prognostic risk
prediction (safety/toxicity, efficacy)
48
Renal cell carcinoma
Evolution of medical treatment



Markers
None
“One fit (unfit) all”
Clinical
“One fit some”
(>10%)
Monogene
“One fit few”
(1-10%)
 Other genetic alterations
 Heterogeneity (tumor/metastasis)
49
Tailor therapy for individual
patients Unanswered questions



Are CTCs detected in the peripheral blood
released from existing micrometastases or are
they the source of distant metastases after
“seeding” organ sites?
Are there stem cells capable of “seeding”new
tumor sites in the CTC?
Could theCTCs be used to assess sensitivity of
resistant tumor cells to alternative agents?
50
Adjuvant Breast Cancer Treatment
Key questions

Selection of appropriate treatment
 Chemotherapy




anthracycline-based
taxane-based
+Trastuzumab +Hormonetherapy
A/T-based
Hormonetherapy


SERMs
Aromatase Inhibitors
51
Multi-Gene Predictors in Breast Cancer (1)
Classification
Perou
Grading
Sotiriou
OncotypeDx
Genomic Health
MammaPrint
Agendia
Number of Genes
427/33,000
97
21
70
Indication
Tumor Subtypes
Molecular Grading
Prognosis
Tamox/CMF
Prognosis
Guide to Specific
Therapy
No
No
Yes
CMF
ER/HER2
No
Platform
Stanford/ Affymetrix
Affymetrix
RT-PCR
GE/Agilent
Formalin
Paraffin
In Development
No
Yes
No
FDA Approval
No
No
? Pending
Yes
Commercial
Status
None
None
On the Market
On the Market
52
Breast Cancer Prevalence
according to ER and HER2 status
HER 2
ER/PR
Total
+++
Negative
Negative
35-40
15-20
15-20
Positive
60-65
10-15
50-55
100
30
70
Total
53
Breast Cancer Prevalence
according to ER and HER2 status
HER 2
ER/PR
Total
+++
Negative
Negative
35-40
15-20
15-20
Positive
60-65
10-15
50-55
100
30
70
Total
54
CTCs




Identification and Detection
Semiquantitative determination
Prognostic/Predictive factor
Molecular Characterization
55
CTCs
Detection Methods


Immunofluorescent staining (CellSearch System,
Veridex): FDA approved
 Immunomagnetic separation
 Fluorescent staining
Cristofanilli M et al, NEJM’04
Harris et al, JCO’07: 25; 5287
RT-PCR
Xenidis et al, JCO’06
56
CTCs
Cell Search System (Veridex)
Cut-off
>5 CTCs/7.5 ml blood
Metastatic BC
>1 CTC/7.5 ml blood Early BC
57
58
Pharmaco-Genetics and -Genomics

Pharmaco-genetics
Modulations of activity dependent from genetic
alterations (DNA)

structural

mutations (point- or rearrangements)





constitutive
somatic
Allelic variants (constitutive)
Functional (methylation)
Pharmaco-genomics
Modulations of activity dependent from or inducing
alterations of gene expression (RNA, protein)
59
Breast Cancer Genomics and Clinical
Classification
Gene Expression Profile
Breast Cancer
“Basal-like”
“Triple-negative”
(ER/PR/HER2-negative)
HER2-positive
HER2-postive
(IHC+++/FISHampl)
Luminal A/B/C
ER and/or PR-positive
Sørlie et al. Proc Natl Acad Sci USA 2001;98:10869-74
60
Ki67: predictive role in EBC
There are
not robust
evidence
that Ki67
can serve as
a tool to
identify
patients who
will benefit
from a
specific
chemotherap
y or
endocrine
treatment.
Yerushalmi et al. Lancet Oncol 2010; 11:174–83
61
Gene expression profiling
Unfixed samples of tumor tissue
obtained during surgery are the
starting material for gene-expression
profiling.
The expression levels of a set of
prognostically relevant genes are
determined by DNA-microarray
analysis.
The resulting molecular signatures
allow the patients to be classified into
groups with a poor prognosis or a
good prognosis, thus facilitating
therapeutic decision making.
Van’t Veer et al. J Clin Oncol 2005; 23:1631-1635
62
Gene expression profiling
Red= upregulation
Green =Down-regul
Black = constiutive exp
63
Thus, are there tumors with
favorable prognosis which
don’t benefit from
chemotherapy?
64
•Of 89 assessable patients, 11 (12%)
had a pCR;
•86 genes correlated with pCR
(unadjusted P 0.05);
•pCR was more likely with higher
expression of proliferation-related genes
and immune-related genes, and with
lower expression of ER–related genes;
•The Recurrence Score was positively
associated with the likelihood of pCR (P
0.005), suggesting that the
•patients who are at greatest recurrence
risk are more likely to have
chemotherapy benefit
Gianni et al. J Clin Oncol 2005; 23:7265-7277
65
Chang et al. Breast Cancer Res Treat 2008; 108:233-240
66
Single gene/protein predictors of treatment
tailoring
Bedard et al. The Breast 2009; 18:S25–S30
67
Topoisomerase II and responsiveness to
adjuvant Anthracyclines
68
69
Cancer Genetics and Genomics

Genetics → genetic alterations (DNA)
 structural

mutations (point- or rearrangements)





constitutive
somatic
Allelic variants (constitutive)
Functional (methylation)
Genomics → alterations of gene expression
(RNA, protein)
70
Genomics

Identification of biomarkers
 Response Prediction
 Target identification

Between patients

Within patients
during treatment
between primary and mets
71
Breast cancer
Prognostic/predictive factors



“Simple markers”
 HR
 NG
 Tumor size
 N status
GEP
CTCs
72
Candidate targets and pathways in TNBC
Berrada et al. Ann Oncol 2010; 21(S7): vii30-vii35
73
TNBC paradox
Tang et al. J Translational Medicine 2012, 10(Suppl 1):S4
74
EGFR and pCR in TNBC
Tang et al. J Transl Med 2012, 10(Suppl 1):S4
75
Cancer Genetics and Genomics

Genetics → genetic alterations (DNA)
 structural

mutations (point- or rearrangements)





constitutive
somatic
Allelic variants (constitutive)
Functional (methylation)
Genomics → alterations of gene expression
(RNA, protein)
76
Microtubule-Associated Protein-tau is a bifunctional
predictor of endocrine sensitivity and chemotherapy
resistance in ER-positive BC
Adjuvant tamoxifen
No adjuvant therapy
Neoadjuvant T/FAC
Andrè et al. Clin Cancer Res 2007;13:2061-67
77
Prognostic and predictive value of tau-mRNA
expression
• Higher tau-mRNA expression showed borderline non significant association with better prognosis in
the absence of systemic adjuvant therapy
• Higher tau-mRNA expression was significantly associated with no recurrence (at 5 and10 years, P
=0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for
endocrine therapy
• Tau expression was significantly lower in patients who achieved pCR to paclitaxel/FAC chemotherapy
(P < 0.001)
Andrè et al. Clin Cancer Res 2007;13:2061-67
78
C-Myc alterations and association with benefit
from adjuvant trastuzumab
DFS
(median follow-up, 4.0 y):
MYC:CEP8 ratio ≤ 2.2
↓
HR 0.46 (p 0.001)
MYC:CEP8 ratio > 2.2
↓
HR 0.67 (p 0.33)
interaction p 0.38
MYC copies/nucleus ≤ 5.0
↓
HR 0.52 (p 0.002)
MYC copies/nucleus > 5.0
↓
HR 0.48 (p 0.02)
interaction p 0.94
Perez et al. J Clin Oncol 2011; 29:651-659
79
C-Myc alterations and association with benefit
from adjuvant trastuzumab
MYC:CEP8 ratio < 1.3 with
normal chromosome 8 copy number
↓
HR 0.66 (p 0.28)
MYC:CEP8 ratio ≥ 1.3 or < 1.3 with
polysomy 8
↓
HR 0.44 (p 0.001)
interaction p 0.23
MYC copies/nucleus < 2.5
↓
HR 1.07 (p 0.87)
MYC copies/nucleus ≥ 2.5
↓
HR 0.42 (p 0.001)
interaction p 0.05
Perez et al. J Clin Oncol 2011; 29:651-659
80
How to improve the development of predictive
tools
Fumagalli, J Natl Cancer Inst 2011;
81
Gene-expression signature is a predictor of
DFS and OS in breast cancer
Van de Vijver et al. N Engl J Med 2002;347:1999-2009
82
Molecular basis of histologic grade
Sotiriou et al. J Natl Cancer Inst 2006; 98:262-272
83
Prognostic utility of Recurrence Score compared
to clinicopathologic features
The 21-gene assay was a
more accurate predictor of
relapse than standard
clinical features for
individual patients with HRpositive operable breast
cancer treated with
chemohormonal therapy
and provides information
that is complementary to
features typically used in
anatomic staging,
such as tumor size and
lymph node involvement.
Goldstein et al. J Clin Oncol 2008; 26:4063-4071
84
NSABP-B20
Paik et al. J Clin Oncol 2006; 24:3726-3734
85
Prediction of anthra-based CT benefit by RS: OS
There was no statistically significant
benefit to CAF for the low (p=0.63) or
intermediate (p=0.85) RS groups.
However, there was a significant CAF
benefit in the high RS group (p=0.0271),
which did not vary by age.
Albain et al. Lancet Oncol 2010; 11:55–65
86
Prediction over time
Increasing involvement of axillary lymph nodes was prognostic.
At 10 years, the treatments start diverging at approximately RS=10, though any clinically
significant CAF benefit is not evident until much higher RS.
RS has better short- than long-term prediction: the treatments are equivalent up to approximately
RS=20, but diverge at higher RS values
Albain et al. Lancet Oncol 2010; 11:55–65
87