molecular biologygido.es/images/04_mesa1_biologia_molecular_dra_jantus.pdf · kras mutations:...

Molecular Biology: diagnostic, prognostic and predictive biomarkers

Dra. Eloisa Jantus Lewintre

Laboratorio de Oncología Molecular Fundación para la investigación del Hospital General Universitario de Valencia

Modified from Wistuba et al, Nat Rev Clin Oncol 2011

Biomarkers for LUNG CANCER

BLOOD sample

Locoregional

Mestastatic

SAMPLE/ MATRIX ISSUES

Tissue

TYPE OF BIOMARKER

Diagnostic

Prognostic

Predictive

Diagnosis

Response evaluation

Progression

Blood (Serum/Plasma)

BAL, Sputum

Place of sample ?

How many ?

What methodology should be used ?

Tissue

BAL, Sputum

Place of sample ? How many ?

Fresh/ frozen

HETEROGENEITY

Tissue Fresh/ frozen

Biobank

Types of tumor specimens in lung cancer

TUMOR CELLS ARE NEEDED !!

Biobannk

Cell free DNA

Serum Plasma (EDTA)

Proteins

Metabolites

PLASMA TUMOR

T. Mok

PLASMA C3

TYPE OF BIOMARKER

Diagnostic

Prognostic

Predictive

P. Massion

RISK DIAGNOSTIC

RESPONSE

PROGNOSIS

Ajona, JNCI 2013

Complement system: Innate immunity

• Caucasic • Three discovery studies -> plasma patients with benign and stage IA lung cancer (n=147) • The classifier was validated on an independent set of plasma samples (n = 104) • The classifier proteins are modulated by transcription regulators (NF2L2, AHR, MYC, and FOS) associated with lung cancer, lung inflammation, and oxidative stress networks

Sozzi, G

JCO in press 2013

miRNA signature: 24 miRNAS

(high, intermediate, low)

Blood samples

Diagnostic value: NPV: 99%

Prognostic biomarker and Predictive of response

1000 controls

85 lung cancer

Superior diagnostic performance of LDCT if combined with miRNA tests

TYPE OF BIOMARKER

Diagnostic

Predictive

Prognostic

Ferté, C. et al. Nat. Rev. Clin. Oncol. 7, 367–380 (2010)

Ca de pulmón Biomarkers for LUNG CANCER

KRAS SCC ADC* Others Total p

WT 67 51 16 134

0.002 98.5% 79.7% 88.9% 89.3%

Mutated 1 13 2 16

1.5% 20.3% 11.1% 10.7%

Table 2 . KRAS mutations: correlation with Histology

KRAS Non Smoker

Former Smoker

Current Smoker

Total p

WT 13 54 67 134

0.007 Mutated

6 4 6 16

37.5% 25% 37.5% 100%

Table 3. KRAS mutations: correlation with Smoking Status

KRAS SCC ADC* Others Total p

WT 67 51 16 134

0.002 98.5% 79.7% 88.9% 89.3%

Mutated 1 13 2 16

1.5% 20.3% 11.1% 10.7%

Table 2 . KRAS mutations: correlation with Histology

KRAS Non Smoker

Former Smoker

Current Smoker

Total p

WT 13 54 67 134

0.007 Mutated

6 4 6 16

37.5% 25% 37.5% 100%

Table 3. KRAS mutations: correlation with Smoking Status

TYPE OF BIOMARKER

Diagnostic

Prognostic

Predictive

Ferté, C. et al. Nat. Rev. Clin. Oncol. 7, 367–380 (2010)

Ca de pulmón Biomarkers for LUNG CANCER

De-selection

Li et al, J Clin Oncol 2013

CUALES DEBEN SER

EVALUADOS COMO

BIOMARCADORES

PREDICTIVOS????

•EGFR

•ALK

•KRAS

•HER2

•BRAF

•ROS1

•RET

BRAF Sensitive to Vemurafenib / Dabrafenib/ MEK inh

RET Sensitive to RET kinase inh

mut and amplif

Drilon, 2013

Stahel, 2013

In total, 3 of 91 tumor samples which had no other sign of cancer-causing genetic abnormalities, had fusions involving NTRK1.

NGS, Foundation Medicine

Asian population!!

TYPE OF BIOMARKER

Diagnostic

Prognostic

Predictive What methodology

should be used ?

EGFR mutation testing methodology

Test sensitivity

Mutations detected

Peters et al., 2013 Lung Cancer

ALK fusion variants in NSCLC

RNAseq

Tissue should be priorized for EGFR and ALK testing.

EGFR and ALK results should be available within 2 weeks (10 working days)

•In resection specimens, testing is not recommended in lung cancer that lack morphological or IHC evidence of adenocarcinoma differentiation

•In limited specimens (biopsies, cytology), testing may be performed in SCC or small cell histology + clinical criteria

Lindenman, JTO 2013

BUT…..

MULTIPLEX ANALYSIS (NGS) are more informative ….

Same amount of sample

Biomarkers can be determined in BLOOD

samples

TYPE OF BIOMARKER

Diagnostic

Prognostic

Predictive What we should do after resistance to

targeted therapies?

REBIOPSIES

Consider liquid biopsies!!

P. Giannikopoulos, WCLC 2013

RESISTANCE TO EGFR TKI

P. Giannikopoulos, WCLC 2013

sample sample

AXL overexpression in 2

R. Thomas, WCLC 2013

HGF (circulating levels) in SCLC is prognostic may be predictive?

E. Arriola,2013

Rebiopsies … why?

Squamous cell carcinoma

Squamous cell carcinoma : FGFR

Squamous cell carcinoma: FGFR

Squamous cell carcinoma

Squamous cell carcinoma : HLA-A

BIOMARKERS TESTS

Li T, et al, J Clin Oncol 2013

Biomarkers for LUNG CANCER Take a home message ...

Biomarkers for LUNG CANCER Biomarkers for LUNG CANCER Take a home message ...

3rd and 4th generation sequencing for mutation analysis

Validation of the new methodologies: standardization, CLIA

References laboratories: networks organized by contries

Transcriptomic

miRNAs

Epigenetics

Proteomics and Metabolomics

molecular biologygido.es/images/04_mesa1_biologia_molecular_dra_jantus.pdf · kras mutations:...

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