Relevancia práctica de la clasificación de subtipos intrínsecos en cáncer de mama
Miguel Martín
Instituto de Investigación Sanitaria
Gregorio Marañón
Universidad Complutense
Madrid
The new technologies have changed our
understanding of breast cancer
XIX century 1980s 1990s
morphology/ histology single genes
multiple genes
XXI century
DNA/RNA arrays
SNP analysis
Multiplex PCR
NGS TECHNOLOGY
IHC FISH HE
Molecular portraits of human breast tumors
Perou CM et al, Nature 406:747,2000
The intrinsic subtype classification
doi:10.1038/nature11412
Comprehensive molecular portraits of human breast tumors
The Cancer Genome Atlas Network
Gen Mutado
TP53 187 (37%)
PIK3CA 180 (36%)
GATA3 54 (11%)
MAP3K1 39 (8%)
MLL3 37 (7%)
CDH1 33 (6.5%)
MAP2K4 21 (4%)
RUNX1 18 (3.5%)
PTEN 17 (3.4%)
TBX3 13 (2.5%) Integration of information across 5 platforms confirmed
the existence of 4 main breast cancer classes
The Oncologist 2015;20:474–482
Conclusion
Significant discordance remains between clinical assay-defined subsets and intrinsic subtype.
The Oncologist 2015;20:474–482
Distribution of PAM50 intrinsic subtype across IHC-based biomarkers (N=1396, Both Centrally Determined)
PR
ER
Data from: TAMseries (CCR 2010), GEICAM 9906 (JCO 2013) and GEICAM 2012-09 (CMRO 2015)
N % N % N %
LumA 93 48% 378 53% 267 58%
LumB 100 52% 333 47% 196 42%
0-10% 11-90% 91-100%
N % N % N %
LumA 243 42.1% 347 58% 160 73%
LumB 334 57.9% 249 42% 59 27%
0-10% 11-90% 91-100%
30-40%??
N % N % N % N %
LumA 620 70.1% 112 34% 28 20% 4 10%
LumB 265 29.9% 219 66% 112 80% 36 90%
>30%0-10% 11-20% 21-30%Ki-67
Cortesy: A. Prat
The Oncologist 2013;18:123–133
Conclusions
The standard immunohistochemical panel for breast cancer (ER, PR, and HER2)
does not adequately identify the PAM50 gene expression subtypes.
Bastien et al. BMC Medical Genomics 2012, 5:44
Plataformas Genómicas en Cáncer
de Mama
Oncotype Dx (Genomic Health, 21 genes)
Mammaprint (Agendia, 70 genes)
ProsignaTM (Nanostring, 50 genes-PAM50)
EndoPredict (Sividon, 12 genes)
Map-Quant Dx (Ipsogen, 97 genes)
Breast Cancer Index/Theros (Biotheranostics,
2 genes)
Genomic platforms:potenial clinical
applications in breast cancer
prognostication
prediction of
response to
hormones
prediction of
response to
chemotherapy
Prediction of
response to
specific CT drugs
Prediction of
response to
targeted therapies
Genomic platforms:potenial clinical
applications in breast cancer
prognostication
Oncotype DX® : B-14 Results – Distant
Recurrence
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 2 4 6 8 10 12 14 16
Years
P <0.001
RS <18 n = 338
RS 18-30 n = 149
RS 31 n = 181
Paik et al. N Engl J Med. 2004;351:2817-2826.
Pro
po
rtio
n w
ith
ou
t D
ista
nt
Rec
urr
ence
Riesgo de recurrencia a los 10 años •Bajo riesgo (6.8%) •Riesgo intermedio (14.3%) •Alto riesgo (30.5%)
78 breast tumors
Age < 55 years, Tumor size < 5 cm
Lymph node negative & No adjuvant therapy
No distant metastases
for at least 5 years
Distant metastases
within 5 years
van‘t Veer L et al., Nature, 2002; Van de Vijver M et al; N Engl J Med 347:1999,2002
CLASSIFICATION THRESHOLD
Low Risk Signature
High Risk Signature
Mammaprint
43%
Mammaprint: TRANSBIG Validation
Results
Buyse et al (2006) J Natl Cancer Inst 17;1183-1192
15%
Martin et al., Breast Cancer Res Treat (2016) 156:81–89
EP Score 92% MFS
EPclin Score 100% MFS
ABCSG-8 trial
Genomic platforms:potenial clinical
applications in breast cancer
prognostication
prediction of
response to
hormones
Tamoxifen Benefit and Oncotype DX™
Design
Objective: Determine whether the 21-gene RS assay provides predictive information for patients who were treated with tamoxifen (likelihood of recurrence)
NSABP B-14 Tam Benefit Study in N–, ER+ Patients
Randomized
Placebo-Eligible
Tam-Eligible
Paik et al. ASCO 2004. Abstract #510.
B-14 Benefit of Tamoxifen
By Recurrence Score Risk Category
B-14 Benefit of Tamoxifen
By Recurrence Score Risk Category
Prognostic value of PAM50 and risk of recurrence score in patients
with earlystage breast cancer with long-termfollow-up
Ohnstad et al. Breast Cancer Research (2017) 19:120
Observational Oslo1 study (1995–1998)
Prognostic value of PAM50 and risk of recurrence score in patients
with earlystage breast cancer with long-term follow-up
Ohnstad et al. Breast Cancer Research (2017) 19:120
Genomic platforms:potenial clinical
applications in breast cancer
prognostication
prediction of
response to
hormones
prediction of
response to
chemotherapy
Prognostication and prediction are linked
in ER+/HER2- breast cancer
Chemotherapy Benefit and Oncotype DX®
Randomized
Tam + MF
Tam + CMF
Tam
NSABP B-20
Paik et al. J Clin Oncol. 2006;24:3726-3734.
High Recurrence Score® result correlates with
greater benefit from chemotherapy (NSABP B-20)
Overall, 4.4% absolute benefit from tamoxifen + chemotherapy
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
HIGH RS (>30) INTERMEDIATE RS GROUP
Recurrence Score 18-30
High Recurrence Score® result correlates with
greater benefit from chemotherapy (NSABP B-20)
LOW RS GROUP
Recurrence Score <18
Overall, 4.4% absolute benefit from tamoxifen + chemotherapy
28% absolute benefit
Number of Patients Needed to Treat (NNT) to Avoid a Distant
Recurrence with tamoxifen + CT vs tamoxifen alone (NSABP B-20)
Population
Distant Recurrence Rate with
tamoxifen
Distant Recurrence Rate with
tamoxifen + chemotherapy
All patients 12% 8%
High RS 40% 12%
NNT
22.7
3.6
Pathologic complete response to neoadjuvant
chemotherapy differs by subtype
T-FAC1
(N=82)
AC-T2
(n=107)
Luminal A/B 2/30 (7%) 4/62 (7%)
Normal-like 0/10 (0) NA
HER2+/ER- 9/20 (45%) 4/11 (36%)
Basal-like 10/22 (45%) 9/34 (26%)
P<0.001
1Rouzier R, Clin Cancer Res 2005; 2Carey LA, Clin Cancer Res, 2007
P=0.003
Genomic platforms: potential clinical
applications in breast cancer
prognostication
prediction of
response to
hormones
prediction of
response to
chemotherapy
Prediction of
response to
specific CT drugs
Prediction of
response to
targeted therapies
Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline
Substitution in the NCIC.CTG MA.5 Randomized Trial
Premenopausal N+
(n=710)
CMFx6
CEFx6
Levine MN, et al. J Clin Oncol. 2005;23:5166;.
Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline
Substitution in the NCIC.CTG MA.5 Randomized Trial
Premenopausal N+
(n=710)
CMFx6
CEFx6
Levine MN, et al. J Clin Oncol. 2005;23:5166; Cheang M et al, Clin Cancer Res 18:2402.
44,7%
11,7%
30,9%
12,8%
pCR
RCB-I
RCB-II
RCB-III
Respuesta global (Symmans)
Isabel Echavarría, Tesis Doctoral, UCM 2017
83%
13%
1% 3%
Distribución subtipo intrínseco
Basal
HER2E
LumB
Normal
Respuesta a quimioterapia neoadyuvante con docetaxel+carboplatino
en cáncer de mama triple negativo (n=96)
44,7%
11,7%
30,9%
12,8%
pCR
RCB-I
RCB-II
RCB-III
Respuesta global (Symmans)
Isabel Echavarría, Tesis Doctoral, UCM 2017
83%
13%
1% 3%
Distribución subtipo intrínseco
Basal
HER2E
LumB
Normal
Respuesta a quimioterapia neoadyuvante con docetaxel+carboplatino
en cáncer de mama triple negativo
51,30%
12,50%
10,30%
18,80%
29,50%
37,50%
9,00%
31,30%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Basal No-basal
pCR RCB-I RCB-II RCB-III
p=0,007
Genomic platforms:potenial clinical
applications in breast cancer
prognostication
prediction of
response to
hormones
prediction of
response to
chemotherapy
Prediction of
response to
specific CT drugs
Prediction of
response to
targeted therapies