Genomic Profiling of Tumors and Loco

1
Genomic Profiling of Tumors and
Loco-Regional Recurrence
Terry Mamounas, M.D., M.P.H., F.A.C.S.
Medical Director, Comprehensive Breast Program
UF Health Cancer Center at Orlando Health
Professor of Surgery, University of Central Florida College of Medicine
Clinical Professor of Clinical Sciences,
Florida State University College of Medicine
2
Rationale for Evaluating Genomic Profiling
and Molecular Subtyping for Predicting LRR
• Genomic profiling and molecular subtyping are
useful tools for assessing risk of distant
recurrence in early-stage breast cancer
• Risk of LRR and distant recurrence are tightly
correlated
• Hypothesis: Molecular subtyping would
significantly predict risk of loco-regional
recurrence
3
21-Gene RS and Distant Recurrence
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN
ER
PR
Bcl2
SCUBE2
INVASION
Stromelysin 3
Cathepsin L2
HER2
GRB7
HER2
NSABP B-14
Validation Study:
Node(-)/ER (+)
100%
90%
80%
DRFS
70%
60%
50%
40%
GSTM1
CD68
BAG1
30%
20%
Low Risk (RS <18)
Intermediate Risk (RS 18 - 30)
High Risk (RS  31)
10%
REFERENCE GENES
Beta-actin, GAPDH, RPLPO
GUS, TFRC
0%
0
2
4
6
8
10
12
14
16
Years
Paik S, et al: N Engl J Med, 2005
4
NSABP B-14/B-20:
10-Year LRR Rates by RS Category
P<0.0001
15.8
7.2
30
Rate of LRR %
10
20
30
RS < 18
RS 18-30
RS >31
RS < 18
RS 18-30
RS >31
20
40
Tamoxifen + Chemo (n=424)
P=0.028
7.8
10
40
Tamoxifen (n=895)
2.7
0
2
4
6
8
Time in Years
10
1.6
0
0
4.3
0
2
4
6
8
10
Time in Years
Mamounas EP, et al: J Clin Oncol 2010
NSABP B-28: RS and LRR
• To evaluate the association between the 21-gene RS
and risk of LRR in node (+), ER (+) patients treated
with adjuvant chemo-endocrine therapy
• To evaluate the potential for combining the 21-gene
RS with traditional clinico-pathologic factors in
order to derive an improved algorithm for prediction
of LRR risk
– Identify subgroups of ER-positive patients with 1-3 or 4
or more positive nodes who do/do not need chest wall
and regional nodal XRT after mastectomy or regional
nodal XRT after breast conserving surgery + breast
XRT
Mamounas et al: SSO 2013
N
386
364
315
0.3
0.4
RS Low
RS Intermediate
RS High
LRR Events
16
25
39
0.2
P-value < .001
0.1
12.3%
7.2%
3.3%
0.0
Cumulative Incidence Rate
0.5
RS in B-28: Primary Endpoint:
Cumulative Incidence of LRR by RS Risk Groups
0
2
4
6
8
10
Time in Years
Mamounas et al: SSO 2013
Multivariate Regression Analysis for LRR
Variables
Subdistribution HR
(95% CI)
P-value
RS1
2.86 (1.54, 5.31)
<0.001
AC+P vs. AC
0.83 (0.53, 1.30)
0.42
Age ≥50 vs. <50
0.83 (0.51, 1.33)
0.43
>4 + nodes vs. 1-3
2.08 (1.32, 3.27)
0.002
Mastectomy vs.
Lumpectomy
0.82 (0.52, 1.28)
0.38
Tumor size (cm)2
1.26 (1.04, 1.53)
0.017
1.
2.
Rescaled with a range from 0 to 2.
An upper threshold was imposed at 5cm.
Mamounas et al: SSO 2013
RS in B-28: Secondary Endpoint:
Cumulative Incidence of LRR by RS And Nodal Status
1-3 Positive Nodes
(N=722)
0.5
0.1
7.9%
5.1%
3.2%
0
2
4
6
Years
8
10
0.4
LRR Events
5
13
22
0.3
N
118
115
110
P-value = 0.001
0.2
0.2
P-value = 0.12
RS Low
RS Intermediate
RS High
20.3%
11.6%
0.1
12
17
Cumulative Incidence Rate
249
205
0.3
0.4
RS Low
RS Intermediate
RS High
LRR Events
11
3.5%
0.0
N
268
0.0
Cumulative Incidence Rate
0.5
> 4 Positive Nodes
(N=343)
0
2
4
6
8
10
Years
Mamounas et al: SSO 2013
RS in B-28:
LRR in Patients with Mastectomy
0.5
LRR Events
5
5
7
LRR Events
5
6
18
P-value = 0.006
23.6%
0
2
4
6
Time in Years
8
10
0.1
6.0%
4.1%
2.4%
9.6%
5.5%
0.0
0.1
0.2
0.2
P-value = 0.64
N
75
66
77
RS Low
RS Intermediate
RS High
0.4
N
137
132
117
0.3
0.3
0.4
RS Low
RS Intermediate
RS High
>4 Positive Nodes
(N=218)
0.0
Cumulative Incidence Rate
0.5
1-3 Positive Nodes
(N=386)
0
2
4
6
8
10
Time in Years
Mamounas et al: SSO 2013
RS in B-28:
LRR in Patients with Lumpectomy + Breast XRT
0.5
RS Low
RS Intermediate
RS High
P-value = 0.044
N
43
49
33
LRR Events
0
7
4
0
2
4
6
Time in Years
8
10
0.1
0.1
10.5%
6.2%
3.9%
14.3%
12.8%
0.0
0.2
0.2
P-value = 0.12
0.4
0.4
0.3
LRR Events
6
7
10
0.3
N
131
117
88
RS Low
RS Intermediate
RS High
>4 Positive Nodes
(N=125)
0.0
Cumulative Incidence Rate
0.5
1-3 Positive Nodes
(N=336)
0.0%
0
2
4
6
8
10
Time in Years
Mamounas et al: SSO 2013
RS in B-28: Clinical Implications
• These findings can help with patient selection for
post-mastectomy chest wall and regional nodal
XRT and post lumpectomy regional nodal XRT in
node-positive, ER-positive patients treated with
adjuvant chemo-endocrine therapy
Mamounas et al: SSO 2013
P=0.12
12.0%
5.1%
3.8%
Solin et al: Breast Cancer Res Treat, 2012
14
Cheng et al: J Clin Oncol 2006
Genomic Prediction of LRR After Mastectomy
Unsupervised Analysis:
258 Genes in 62 Patients
Kaplan-Meier LRFS
in the Validation Study
Low-Risk
High-Risk
258 Gene Model
Low-Risk
High-Risk
34 Gene Model
15
Nuyten et al: Br Ca Res 2006
Genomic Prediction of LRR After BCS
Wound Response Signature (GSEA)
Validation Set
Training Set
6%
5%
35%
29%
Nguyen et al: J Clin Oncol 2008
LRR According to BC Subtype After BCS
n=793
16
17
Voduc KD et al: J Clin Oncol 2010
Ten-Year Local Recurrence Free Survival
After Breast Conserving Surgery By Subtype
Voduc KD et al: J Clin Oncol 2010
Ten-Year Local Recurrence Free Survival
After Mastectomy By Subtype
18
19
Kyndi et al: J Clin Oncol 2008
PMRT Benefit According to Tumor Subtype
ER+/HER2-
ER+/HER2+
ER-/HER2-
ER-/HER2+
20
DCIS Score
DCIS Score (0 – 100) evaluated 2 ways:
-
Continuous variable
3 pre-specified risk groups:
• Low < 39
• Intermediate 39 – 54
• High > 55
Solin et al, SABCS 2011
21
DCIS Score: Gene Selection Based on
Published NSABP B-14 RS Results: TAM vs. Placebo
Bcl2
SCUBE2
ER
PR
HER2
GRB7
CTSL2
STMY3
CCNB1
Ki-67
MYBL2
STK15
SURV
GSTM1
CD68
BAG1
0.5
ER Group
HER2 Group
Invasion Genes
Proliferation Genes
Single Genes
1.0
1.5
2.0
2.5
B-14 Tam
N=668
B-14 Placebo N=355
# events=109
# events=94
Paik, NEJM 2004, Supplemental materials
22
Validation of DCIS Score in E5194:
10-Yr Ipsilateral Breast Events (IBE) by Risk Group
Any IBE
Invasive IBE
Solin et al, SABCS 2011
23
DCIS Score:
10-Yr Risk of an Ipsilateral Breast Event (IBE)
Solin et al, SABCS 2011
24
Multivariate Models of Risk for IBE
Hazard Ratio
(95% CI)
P value
Excluding the DCIS Score
Tumor size
Postmenopausal
1.54 (1.14, 2.02)
0.49 (0.27, 0.90)
0.01
0.02
Including the DCIS Score
DCIS Score
Tumor size
Postmenopausal
2.41 (1.15, 4.89)
1.52 (1.11, 2.01)
0.49 (0.27, 0.90)
0.02
0.01
0.02
For study cohort, surgical margins, grade, comedo necrosis, and DCIS pattern,
all p > 0.46. For tamoxifen, p = 0.09.
Solin et al, SABCS 2011
25
Summary
• Genomic profiling predicts risk for LRR in node
(-) and node (+) BC pts treated with endocrine or
chemo-endocrine therapy
• These findings may help tailor the extent or need
for LR XRT, particularly in node-positive patients
• Emerging evidence suggests that ER (+) tumors
may be more sensitive to the effects of XRT than
Triple (-) or HER-2 (+) tumors
• Genomic profiling also predicts risk of in-breast
recurrence in patients with DCIS and can help
with decisions regarding the use of breast XRT

Download Report