Transcript Document

Implicaciones clínicas de los subtipos intrínsecos
de cáncer de mama
Joan Albanell
Servicio de Oncología Médica
The intrinsic breast cancer subtypes
PAM50: intrinsic subtypes and ROR
Studies in Hormone Receptor positive disease
Studies in HER2 positive disease
Studies in Triple Negative disease
Summary
Molecular classification in breast cancer:
The intrinsec subtypes
Sorlie, T et al. PNAS, 2001
Perou, CM et al. Nature, 2000
Perreard, L et al. Breast Cancer Res, 2006
Breast cancer intrinsic subtypes vary in subsets
defined by ER and HER2
Prat, A & Perou, CM. Mol Oncol 2011
IHC-based definition of
Luminal A versus Luminal B tumors
Survival analyses within IHC-LumA tumors
IHC-based definition of Luminal A is
ER+ and/or PR+
HER2Ki67<14%
PR>20%
IHC-based definition of Luminal B is
ER+ and/or PR+ / HER2- / Ki67<14% / PR<20%
or
ER+ and/or PR+ / HER2- / Ki67>14%
or
ER+ and/or PR+ / HER2+
However, these definitions 1) do not fully recapitulate the intrinsic subtypes and 2) are
technically challenging (i.e. precise scoring
of Ki-67 and PgR), and thus the Pathology Community needs to establish scoring
standards and provide controls
Prat et al. J Clin Oncol 2013
The intrinsic breast cancer subtypes
PAM50: intrinsic subtypes and ROR
Studies in Hormone Receptor positive disease
Studies in HER2 positive disease
Studies in Triple Negative disease
Summary
Prosigna test (PAM50)
Extract RNA from
FFPE tumor sample
Run RNA & CodeSet on nCounter
Analysis System
RESEARCH
DIAGNOSTICS
Intrinsic Subtype
Adapted from Aleix Prat
FDA 510(k)
Risk of Relapse (ROR)
PAM50 Using nCounter Classifies Breast Cancer
Into Intrinsic Subtypes
1.
The qRT-PCR assay
consists of 50 genes
2. The subtype classification
accuracy of the 50 genes
by qRT-PCR versus 2000
genes by microarray was
93%
3. The assay works using
RNA from FFPE materials
or fresh frozen tissues.
Parker J Clin Oncol 2009
PAM50 Generates a Risk Of Relapse (ROR) Score
Specific to Each Patient
•
ROR is based on the similarity of the gene expression profile to intrinsic subtypes,
proliferation score (i.e. mean expression prolif-related genes), nodes and tumor
size.
•
ROR ranges from 0 through 100 (ROR) indicating the probability of distant recurrence in a
“training cohort” of patients with tumors representing all subtypes and patients that did not
receive any adjuvant systemic therapy.
PAM50 centroids
Patient
expression
profile
ROR
= aRLumA+
bRLumB+
cRHer2e+ Pearson’s
dRBasal+
correlation to
centroids
eP+
fT
Proliferation score
Tumor size
Parker et al. JCO 2009; Nielsen et al. CCR 2010
The intrinsic breast cancer subtypes
PAM50: intrinsic subtypes and ROR
Studies in Hormone Receptor positive disease
Studies in HER2 positive disease
Studies in Triple Negative disease
Summary
PAM50 (PROSIGNA®) Validation Studies
Tam alone
(N=3116)
ATAC study
Postmenopausal
women with
invasive BC
(N=9366)
Tam + Arimidex
(N = 3125)
TransATAC study
(N=1125 blocks)
Arimidex alone
(N=3125)
Tamoxifen
(N=1849)
ABCSG-8 study
Post-menopausal
women with HR+
BC (N=3714)
Tam
2-years
3 years
Anastrozole
(N=1865)
ABCSG-8 study
(N = 1478 blocks)
Primary Objective: Validate
published observations that
Prosigna/ROR Score provides
additional prognostic information
over and above standard clinical
variables for DRFS at 10 yrs
Primary Analysis: All patients
Secondary Analysis: Nodenegative, node-positive, and
HER2-negative patients
Secondary Objective: Validate
observations that Luminal A and
Luminal B patients have
statistically significantly different
DRFS at 10 yrs1
Findings From the Combined Analysis of >2400 Patient Samples
1.0
1.0
0.9
0.9
0.8
0.8
Low-risk
Intermediate-risk
High-risk
0.7
0.7
0.6
0.6
0
2
10
4
6
DRFS by Risk-Group for Node-positive
Patients (1-3 positive nodes)
1.0
1.0
Percent Without Distance Recurrence
Low Risk
patients
remain Low
Risk over
10yrs
DRFS by Risk-Group for Node-negative
Patients
Percent Without Distance Recurrence
Prosigna
0.9
0.9
0.8
0.8
Low-risk
Intermediate-risk
High-risk
0.7
0.7
0.6
0.6
0
8
2
4
6
10 Follow-Up Time (yrs)
Follow-Up Time (yrs)
8
Risk Group
N (%)
Events
Through 10 Yrs
% Without Recurrence
at 10 yrs [95% CI]
Risk Group
N (%)
Events
Through 10 yrs
% Without Recurrence
at 10 yrs [95% CI]
Low
875 (49%)
31
96%.2 [94.7% - 97.3%]
Low
24 (4%)
2
91.7% [70.6% - 97.8%]
Intermediat
e
551 (31%)
53
89.2% [86.%1 - 91.7%]
Intermediat
e
211 (36%)
18
90.4% [85.2% - 93.9%]
High
360 (20%)
73
77.7% [72.8% - 81.95%]
High
355 (60%)
87
71.8% [66.3% - 76.6%]
Total
1,786
(100%)
157
Total
590
(100%)
107
Source: Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant
recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783-2790: Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer Study Group.
Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478
postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339-345.
Knowledge of Luminal Status May Improve Disease
Management
DRFS by Risk-Group for Node-Negative
Patients
Risk
Group
N (%)
Events
Through 10
yrs
% Without
Recurrence at 10
yrs [95% CI]
DRFS by Risk-Group for Node-Positive
Patients
(1-3 Positive Nodes)
Risk
Group
N (%)
Events
Through 10
yrs
% Without
Recurrence at 10
yrs [95% CI]
Luminal
1254
62
94.6% [93.1% –
Luminal
375
41
87.6% [83.5% –
A
95.8%]
A
90.8%]
Luminal
460
75
81.9% [77.7% –
Luminal
186
52
68.3% [60.4% –
B
85.3%]
B
75.0%]
Total
1,714
137
Total score with
561
93IHC4 for predicting risk of
Source: Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence
Oncotype DX and
distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783-2790: Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer
Study Group. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of
Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339-345.
• Discordance between ROR and
RS groups of 43% at the
individual level
JCO 2013
Prospective study of the impact of the Prosigna® assay on adjuvant
clinical decision-making in an unselected population of women with
ER+, HER2-negative, node-negative breast cancer: a GEICAM study
• TransATAC study
• OncotypeDX RS, PAM50 ROR and IHC4 (Ki67, PgR, ER, HER2 status)
JNCI 2013
San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013
Prediction of late distant
recurrence after 5 years of
endocrine treatment:
A combined analysis of 2137 patients from the ABCSG-8
and transATAC studies using the PAM50 Risk of
Recurrence (ROR) score
Ivana Sestak
Jack Cuzick, Mitch Dowsett, Martin Filipits, Peter Dubsky, J. Wayne Cowens,
Sean Ferree, Carl Schaper, Christian Fesl, Michael Gnant
Centre for Cancer Prevention, Wolfson Institute of Prevention Medicine, Queen Mary University, London, UK
Academic Department of Biochemistry, Royal Marsden Hospital, London, UK
Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria
Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria
NanoString Technologies, Seattle, WA, USA
MyRAQA, Redwood Shores, CA, USA
San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013
Luminal A vs Luminal B
Luminal A (N=1530 (71.6%))
-
-
Luminal B (N=542 (25.4%))
2.89 (2.07- 4.02)
<0.0001
12.9%
Luminal B
10
10
Luminal A
5
5
4.1%
0
0
Distant recurrence (%)
15
P-value
15
HR (95% CI)
5
6
7
8
9
10
Follow-up time [years]
Sestak et al. SABCS 2013 and JCO 2014
San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013
Risk groups – ROR score (N=2137)
15
-
Intermediate (N=538 (25.2%))
3.26 (2.07-5.13)
High (N=416 (19.5%))
6.90 (4.54-10.47)
16.6%
15
8.3%
5
5
10
High
Intermediate
Low
10
2.4%
0
0
Distant recurrence (%)
Low (N=1183 (55.4%))
20
20
HR (95% CI)
5
6
7
8
Follow-up time [years]
9
10
Sestak et al. SABCS 2013
The intrinsic breast cancer subtypes
PAM50: intrinsic subtypes and ROR
Studies in Hormone Receptor positive disease
Studies in HER2 positive disease
Studies in Triple Negative disease
Summary
The HER2-enriched subtype is associated wit higher
responses and improved survival outcomes in
HER2+ breast cancer in the NOAH study
• Chemotherapy:
AT x 3  T x 4  CMF x 3
• 156 (46.7%) pre-treatment
samples were PAM50 profiled.
RESPONSE
pCR Odds Ratio P-value
HER2+
HER2+/HR-
HER2+/HER2-E
No-trastuzumab (n=29) 27.6%
Trastuzumab (n=34)
52.9%
5.1
0.009
2.1
0.352
8.7
0.002
2.4
0.582
HER2+/nonHER2-E
No-trastuzumab (n=22) 18.2%
Subtype
Trastuzumab (n=29)
34.5%
HER2+/HR-/HER2-E
No-trastuzumab (n=28) 25.0%
Trastuzumab (n=27)
63.0%
HER2+/HR-/nonHER2-E
No-trastuzumab (n=9)
11.1%
Trastuzumab (n=16)
31.3%
Note: interaction test between HER2E subtype and treatment
was not statistically significant.
Prat et al. Clin Cancer Res 2014
The intrinsic breast cancer subtypes
PAM50: intrinsic subtypes and ROR
Studies in Hormone Receptor positive disease
Studies in HER2 positive disease
Studies in Triple Negative disease
Summary
Prat et al. BJC 2014
Summary
• The PAM50 assay provides better intrinsic subtype molecular (Luminal A and B,
HER2-enriched and Basal-like) classification than current pathology-based
surrogate definitions.
• PAM50 ROR provides robust prognostic information in ER+/HER2- early breast
cancer and influenced systemic treatment recommendations in a prospective
clinical impact study.
• PAM50 ROR and classification of luminal A vs B tumors may also help to
estimate the risk of late recurrences (> 5 years) in ER+ disease.
• HER2+ disease includes all the intrinsic subtypes (i.e. not just Luminal B and
HER2-enriched). HER2+enriched tumors appear to benefit the most from antiHER2 treatments in combination with chemotherapy in the neoadjuvant setting.
The role of HER2+ subtyping may vary by disease burden (neoadjuvant,
micrometastasis, overt metastasis) and type of regimen.
• Within TNBC, distinguishing Basal-like vs. Other subtypes predicted benefit from
chemotherapy and docetaxel vs. carboplatin benefit.