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