Biomarcadores en cáncer de mama
La genómica versus el microscopio Federico Rojo Fundación Jiménez Díaz
Adapted from McShane, LM. SABCS 2010
Biomarkers Used in Cancer Management: Questions to be addressed by Cancer Biomarkers
Adapted from Ferte, C. et al. Nat Rev Clin Oncol 2010
State of the art in prognostic and
predictive biomarkers in breast cancer
Old Nottingham series (1977-89)
Recent Nottingham series (1990-2002)
Histological grade and morphological
classification in breast cancer
Weigelt, B et al. J Pathology, 2008
ASCO/CAP and BCWG recommendations
Goldhirsch, A. et al. Ann Oncol 2011
Highlights of the St Gallen Consensus on early
breast cancer 2011: Strategies for subtypes
Clinical utility/validity of IHC/FISH risk
stratifiers for breast cancer
Guiu, S et al. Ann Oncol 2012
Allred, DC. Mod Pathol 2010
Sources of variability in pathology
Specificity of three pharmacodiagnostic
antibodies to HER2
Schrohl, AS et al. Histopathology 2011
4B5 CB11 A450
Programa de Garantía de Calidad de la SEAP R
ece
pto
res d
e e
str
óge
nos
HE
R2
IH
Q
40
12 1215
6
1510
13 1520 22
36
59
6966
76 74
68
57
65,5
59,557
2429
19 19 18
11
22
30
19,5 20,5 21
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10 11
<12
12-16
≥17
Inadecuado (puntuación <12)
Aceptable (puntuación 12-16)
Óptimo (puntuación >16)
Clinical impact of ER and PR missclasification:
BIG 1-98 trial
Viale, G. et al. J Clin Oncol 2007
A new paradigm in breast cancer management
Massive target profiling
Selected commercially available first generation
gene expression signatures in breast cancer
Adapted from Weigelt B et al. J Pathol 2010
Test Sorlie-Perou
classifier PAM50
ARUP
bioclasifier
Sotiriou
molecular
grading
MapQuant ProEx Br Mammostrat eXagenBC Mammaprint Netherlands
signature
Invasiveness
gene
signature
Wound-
response
signature
Theros OncotypeDX
Manufacturer Not
commercialized
Not
commercialized
Not
commercialized Ipsogen Inc Ipsogen Inc
Becton-
Dickinson
Applied
Genomics
eXagen
Diagnostics Agendia
Not
commercialized
OncoMed
Pharma
Not
commercialized Biotheranostics
Genomic
Health
Method Microarray RT-PCR RT-PCR Microarray RT-PCR IHC IHC FISH Microarray Microarray Microarray Microarray RT-PCR RT-PCR
Platform Agilent array NanoString LightCycler
(Roche)
Affymetrix
U133 Applied
Ventana-
Roche - - Agilent array
Affymetrix
U133
Affymetrix
U133 Agilent array Applied Applied
Sample
conditions Fresh frozen FFPE FFPE Fresh frozen FFPE FFPE FFPE FFPE Fresh frozen Fresh frozen Fresh frozen Fresh frozen FFPE FFPE
Number of genes 427 50 55 97 8 5 5 3 70 76 186 442 2 (HOXB13:
IL17R) 21
Indication
All cases of
invasive breast
cancer
All cases of
invasive breast
cancer
ER+, ER-, LN-
All cases of
invasive breast
cancer
All cases of
invasive breast
cancer
LN+, LN- ER+, LN- ER+, ER-, LN- ER+, ER-, LN- ER+, ER-
All cases of
invasive breast
cancer
All cases of
invasive breast
cancer
ER+ ER+, LN-, LN+
Prognostic role Partially Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes
Predictive role No
Partially
(Tamoxifen,
adjuvant CT)
No No No No Yes (Tamoxifen) No No No No No
Partially
(Tamoxifen,
adjuvant CT)
Yes
(Tamoxifen,
adjuvant CMF)
Commercial
status No No No No No Yes Yes Yes Yes No No No Yes Yes
US FDA status No No No No No No Exempt No Yes No No No Exempt Exempt
ASCO or NCCN
guidelines No No No No No No No No No No No No No Yes
Clasification Grading Prognosis
Hornberger, J et al. JNCI 2012
Level of evidence of risk stratifiers for
early breast cancer and type of outcome
Limitations of 1st generation of multigene
predictors: ER and proliferation clusters
Reis-Filho, JS. AACR 2012
Weigelt, B. et al. Breast Can Res 2010
Lee, JK. et al. Clin Cancer Res 2010
Reis-Filho, JS. AACR 2012
Haibe-Kains, B. et al. JNCI 2012
Limitations of 1st generation of multigene
predictors: low concordance
Limitations of 1st generation of multigene
predictors: moderate clinical correlation
Prat, A & Perou, CM. Mol Oncol 2011
Bastien, RRL et al. BMC Med Gen 2012
Guiu, S et al. Ann Oncol 2012
Second generation gene expression
signatures in breast cancer
Fumagalli, D et al. Crit Rev Oncol Hemat, 2012
Loi, S et al. J Clin Oncol 2013
Limitations of 1st generation of multigene
predictors: low performance
Fan, C. et al. BMC Med Genomics 2011
Weigelt, B. et al. Breast Can Res 2010
Hallet, RM. et al. Nature 2012
Gene predictors fail to classify triple negative breast cancer
Limitations of 1st generation of multigene
predictors: poor predictive value in TN
Elloumi, F. et al. BMC Med Genomics 2011
Limitations of 1st generation of multigene
predictors: dilution effect by normal breast
G1 G2
Limitations of 1st generation of multigene
predictors: sequence coverage
CGAN, Nature 2012
Limitations of 1st generation of multigene
predictors: a real signature of alterations?
N=2,000
Curtis, C. et al. Nature 2012
Transcriptomic and genomic architecture reveals
novel subgroups in breast cancer
Transcriptomic and genomic architecture reveals
novel subgroups in breast cancer
Dawson, SJ et al. EMBO J 2013
Mensajes finales
• Capacidad pronóstica y predictiva limitada de los biomarcadores
‘clásicos’: gran impacto de los factores analíticos y pre-analíticos y
necesidad de procedimientos normalizados en el laboratorio
• Evidencia y utilidad clínica reducida de los biomarcadores
basados en técnicas de alto rendimiento
• Necesidad imperiosa de nuevos biomarcadores robustos y
validados, de nuevas tecnologías fiables y de un manejo integrado
de la paciente con cáncer de mama