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
Evo
lve
Locoregional
Mestastatic
Biomarkers for LUNG CANCER
SAMPLE/ MATRIX ISSUES
Tissue
TYPE OF BIOMARKER
WHEN?
Diagnostic
Prognostic
Predictive
Diagnosis
Response evaluation
Progression
CNB
Blood (Serum/Plasma)
BAL, Sputum
Place of sample ?
How many ?
What methodology should be used ?
Biomarkers for LUNG CANCER
SAMPLE/ MATRIX ISSUES
Tissue
CNB
Blood
BAL, Sputum
Place of sample ? How many ?
Fresh/ frozen
FFPE
HETEROGENEITY
Biomarkers for LUNG CANCER
SAMPLE/ MATRIX ISSUES
Tissue Fresh/ frozen
FFPE
Biobank
Biomarkers for LUNG CANCER
Types of tumor specimens in lung cancer
TUMOR CELLS ARE NEEDED !!
Biomarkers for LUNG CANCER
SAMPLE/ MATRIX ISSUES
Blood
Biobannk
Biomarkers for LUNG CANCER
CTCs
Cell free DNA
MA
TRIX
Serum Plasma (EDTA)
Proteins
Metabolites
Biomarkers for LUNG CANCER
PLASMA TUMOR
T. Mok
PLASMA C3
Biomarkers for LUNG CANCER
TYPE OF BIOMARKER
Diagnostic
Prognostic
Predictive
Biomarkers for LUNG CANCER
P. Massion
RISK DIAGNOSTIC
RESPONSE
PROGNOSIS
Ajona, JNCI 2013
Biomarkers for LUNG CANCER
Complement system: Innate immunity
Biomarkers for LUNG CANCER
• 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
Biomarkers for LUNG CANCER
1000 controls
85 lung cancer
Superior diagnostic performance of LDCT if combined with miRNA tests
Biomarkers for LUNG CANCER
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
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
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
81.2
mese
s 23
mese
s
Biomarkers for LUNG CANCER
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
Biomarkers for LUNG CANCER
ADC
Li et al, J Clin Oncol 2013
SCC
Biomarkers for LUNG CANCER
ADC
CUALES DEBEN SER
EVALUADOS COMO
BIOMARCADORES
PREDICTIVOS????
Biomarkers for LUNG CANCER
•EGFR
•ALK
•KRAS
•HER2
•BRAF
•ROS1
•RET
BRAF Sensitive to Vemurafenib / Dabrafenib/ MEK inh
RET Sensitive to RET kinase inh
mut and amplif
Biomarkers for LUNG CANCER
Biomarkers for LUNG CANCER
Drilon, 2013
Stahel, 2013
Biomarkers for LUNG CANCER
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!!
Biomarkers for LUNG CANCER
TYPE OF BIOMARKER
Diagnostic
Prognostic
Predictive What methodology
should be used ?
Biomarkers for LUNG CANCER
EGFR mutation testing methodology
Test sensitivity
Mutations detected
Biomarkers for LUNG CANCER
Peters et al., 2013 Lung Cancer
ALK
ALK fusion variants in NSCLC
Biomarkers for LUNG CANCER
FISH
IHC
RNAseq
Biomarkers for LUNG CANCER
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
Biomarkers for LUNG CANCER
BUT…..
MULTIPLEX ANALYSIS (NGS) are more informative ….
Same amount of sample
Biomarkers can be determined in BLOOD
samples
Biomarkers for LUNG CANCER
Biomarkers for LUNG CANCER
TYPE OF BIOMARKER
Diagnostic
Prognostic
Predictive What we should do after resistance to
targeted therapies?
REBIOPSIES
Biomarkers for LUNG CANCER
Consider liquid biopsies!!
P. Giannikopoulos, WCLC 2013
RESISTANCE TO EGFR TKI
P. Giannikopoulos, WCLC 2013
sample sample
N=16
AXL overexpression in 2
R. Thomas, WCLC 2013
HGF (circulating levels) in SCLC is prognostic may be predictive?
E. Arriola,2013
Biomarkers for LUNG CANCER
Rebiopsies … why?
Biomarkers for LUNG CANCER
Squamous cell carcinoma
Biomarkers for LUNG CANCER
Squamous cell carcinoma : FGFR
Squamous cell carcinoma: FGFR
Biomarkers for LUNG CANCER
Squamous cell carcinoma
Biomarkers for LUNG CANCER
Squamous cell carcinoma : HLA-A
Biomarkers for LUNG CANCER
BIOMARKERS TESTS
Li T, et al, J Clin Oncol 2013
Biomarkers for LUNG CANCER
Li T, et al, J Clin Oncol 2013
Biomarkers for LUNG CANCER
Biomarkers for LUNG CANCER
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
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