„Next generation sequencing“ v onkologii
„Next generation sequencing“ in oncology
Doc. MUDr. Mgr. Marek Mraz, PhD
Associate Professor of Oncology
IHOK FN Brno and CEITEC MU
Current (2015)
~1 days
~$1000
30-50X
Genomic Technology
Breathtaking Progress Unparalleled in Human History
Courtesy of Dr. Kurzrock
REMEMBER THIS!
POOLED Analysis
Meta-analysis
ARMS type R
Rate
(%)
PFS
(Mos)
OS
(Mos)
RR
(%)
PFS
(Mos)
OS
(Mos)
Non-personalized
targeted
4 2.6 8.7 7.5 2.5 8.3
Cytotoxic 12 3.3 9.4 16.1 3.3 9.3
Personalized
targeted
30 6.9 15.9 31.3 6.1 13.7
• Non-personalized targeted arms led to
poorer outcomes than cytotoxics arms
(All P<0.0001, except P=0.048 for OS meta-analysis).
Worst outcome
Best outcome
Meta Analysis of 32,149 Patients
in Phase II Clinical Trials
Schwaederle……Kurzrock, JCO, 2015
Courtesy of Dr. Kurzrock
Checkpoint inhibitors
Harnessing the Immune System
The immune system is the
bringing the fight to the same level
• 4% response rate for low mutational burden
• 26% response rate for intermediate
• 45% response rate for high
• 67% response rate for very high mutational burden
The more mutated the tumor,
the better the response to immunotherapy
Mutanome-Directed Immunotherapy
Bridging
Genomics and Immunotherapy
Courtesy of Dr. Kurzrock
FDA Approves pembrolizumab (anti-PD1)
for solid tumors based on MSI-H
(microsatellite instability high)
May 23, 2017
•Tissue agnostic approval
•Approval based on genomic marker
•Approval based on retrospective data
Courtesy of Dr. Kurzrock
Molecular Tumor Board
• Multidisciplinary discussion of patients
• Molecular profiling (clinical-grade) (N ~ 8000)
• Targeted, tailored treatment recommendations
Courtesy of Dr. Kurzrock
Comprehensive Profiling
Tumor
PREDICT/ IPREDICT Clinical Trial
Comprehensive molecular profiling:
• Next-Generation DNA Sequencing
• Protein analysis
• Immune signature analysis
• Liquid biopsy (cancer DNA detection from blood )
“MATCH” the therapy based on the profiling.
Personalized/Precision Medicine approach.
Courtesy of Dr. Kurzrock
Doing genomics on DNA from a small tube of blood or from urine
No tissue biopsy
Liquid Biopsy Program
~2000 patient samples
Courtesy of Dr. Kurzrock
Drug-Centric Trial (Traditional)
Drug
Regimen
A
Patient 1
Patient 2
Patient 3
Strategy: Find common feature between
patients (e.g. type of cancer or type of molecular
aberration) and place all on same drugs
Courtesy of Dr. Kurzrock
Patient-Centric Trial (N-of-One)
Patient 1
Aberrant A, B, C
Patient 2
Aberrant A, E, F
Strategy: Molecular matching for each patient
with customized therapy combination
Drug A Drug A
Drug F
Drug B
Drug EDrug C
Courtesy of Dr. Kurzrock
READ THIS PAPER
.it is well-written and easy to read:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822744/
THANK YOU
for your attention
Marek Mraz
CEITEC MU and FN Brno
Marek.mraz@email.cz