Biomarcadores en cáncer de mama La genómica versus el microscopio Federico Rojo Fundación Jiménez Díaz

Transcripción

1 Biomarcadores en cáncer de mama La genómica versus el microscopio Federico Rojo Fundación Jiménez Díaz

2 Biomarkers Used in Cancer Management: Questions to be addressed by Cancer Biomarkers Adapted from McShane, LM. SABCS 20

3 State of the art in prognostic and predictive biomarkers in breast cancer Adapted from Ferte, C. et al. Nat Rev Clin Oncol 2010

4 Histological grade and morphological classification in breast cancer Old Nottingham series ( ) Recent Nottingham series ( ) Weigelt, B et al. J Pathology, 2008

5 ASCO/CAP and BCWG recommendations

6 Highlights of the St Gallen Consensus on early breast cancer 2011: Strategies for subtypes Goldhirsch, A. et al. Ann Oncol 2011

7 Clinical utility/validity of IHC/FISH risk stratifiers for breast cancer Guiu, S et al. Ann Oncol 2012

8 Sources of variability in pathology Allred, DC. Mod Pathol 2010

9 Specificity of three pharmacodiagnostic antibodies to HER2 4B5 CB11 A450 Schrohl, AS et al. Histopathology 2011

10 HER2 IHQ Receptores de estrógenos Programa de Garantía de Calidad de la SEAP 57 65,5 59, <12 Inadecuado (puntuación <12) Aceptable (puntuación 12-16) 17 Óptimo (puntuación >16)

11 Clinical impact of ER and PR missclasification: BIG 1-98 trial Viale, G. et al. J Clin Oncol 2007

12 A new paradigm in breast cancer management Massive target profiling

13 Selected commercially available first generation gene expression signatures in breast cancer Test Sorlie-Perou classifier Clasification Grading Prognosis PAM50 ARUP bioclasifier Sotiriou molecular grading MapQuant ProEx Br Mammostrat exagenbc Mammaprint Netherlands signature Invasiveness gene signature Woundresponse 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 (HOXB13: IL17R) 21 Indication All cases of All cases of invasive breast invasive breast ER+, ER-, LNcancer cancer All cases of All cases of invasive breast invasive breast cancer cancer LN+, LN- ER+, LN- ER+, ER-, LN- ER+, ER-, LN- ER+, ER- All cases of All cases of invasive breast invasive breast ER+ cancer cancer 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 Adapted from Weigelt B et al. J Pathol 2010

14 Level of evidence of risk stratifiers for early breast cancer and type of outcome Hornberger, J et al. JNCI 2012

15 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

16 Limitations of 1st generation of multigene predictors: low concordance Reis-Filho, JS. AACR 2012 Haibe-Kains, B. et al. JNCI 2012

17 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

18 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

19 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

20 Limitations of 1st generation of multigene predictors: poor predictive value in TN Gene predictors fail to classify triple negative breast cancer Hallet, RM. et al. Nature 2012

21 Limitations of 1st generation of multigene predictors: dilution effect by normal breast Elloumi, F. et al. BMC Med Genomics 2011

22 Limitations of 1st generation of multigene predictors: sequence coverage G1 G2

23 Limitations of 1st generation of multigene predictors: a real signature of alterations? CGAN, Nature 2012

24 Transcriptomic and genomic architecture reveals novel subgroups in breast cancer N=2,000 Curtis, C. et al. Nature 2012

25 Transcriptomic and genomic architecture reveals novel subgroups in breast cancer Dawson, SJ et al. EMBO J 2013

26 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