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New Initiatives
Funding
Infrastructure
Multi-investigator teams
BRAF (melanoma)
BCR-ABL (CML)
EGFR (Lung)
Her2 (Breast, gastric)
Phenotype to Genotype
Exceptional Responders
Complete response lasting at least 6 months
Drug did not go on to FDA approval in that
indication due to insufficient activity
Tissue
Prefer just before drug treatment; otherwise any
prior
50% tumor
FFPE, Frozen, core acceptable
Normal: blood or other
DNA transferred to
sequencing center
RNA & additional
tissue banked
Sequenci
ng
Analysis
Data
submitted
to
database
Screening of Potential ER
Cases
Sites submit data through the CTSUs OPEN
Eligibility Stage
Synopsis:
Response
Treatment
info
Copy of
consent
form
Pathology
reports
Submitted
through
CTSU OPEN
Internal
NCI
review
Case is
not
exceptio
nal
Case is
exceptio
nal
Response
letter to
submittin
g
investigat
or
Request
sample
and data
NCI-MATCH
Umbrella protocol for multiple, single-arm phase II
trials
Each molecular subgroup matched to a targeted agent
NCI-MATCH
Identify mutations/amplifications/translocations
in patient tumor sample - eligibility determination
Assign patient to relevant agent/regimen
Tumor biopsies & sequencing at progression to
illuminate resistance mechanisms
De-identified samples submitted to central labs
Whole-exome sequencing (research purposes) to
detect non-ambiguous germline variants
NCI-MATCH - Eligibility
Solid tumors and lymphomas that have progressed
following at least one line of standard therapy
Exclude histologies from a given arm if already FDA
approved for that indication or lack of efficacy documented
COURS
E
1
Genetic
sequencin
g
Actionabl
e
mutation
detected
Study
agent
Stable
Disease
(SD)1 for
6
months
Drug
holida
y
PD
Study
agent
Stable
diseas
e or
better
2
Complete
or partial
response
(CR+PR)1
Progressiv
e
disease
(PD)1
Continue
on
study
agent
until
progressi
on
Continue
on study
agent until
progressio
n
PD
Check for
Additional
actionabl
e
mutations
3
No
additional
actionable
mutations,
or withdraw
consent
Of
study
NCI-MATCH - Assays
NGS: Ion Torrent PGM with custom Ampliseq
panel of 200-300 actionable genes
Validation in network of CLIA certified labs.
IHC, FISH?
Rule driven treatment assignment
Molecular Diagnosis
Screening
Prognosis
Therapy
Cologuard
A Precision Medicine Diagnostic Method
for Screening for Colon Cancer.
Cologuard
Cologuard
Noninvasive stool-based DNA test
Targets Multiple Markers
Methylated BMP3 & NDRG4
Mutant KRAS
-actin (human DNA)
Hemoglobin
Cologuard
NEJM Screening Study
Cologuard + FIT prior to screening
colonoscopy
Topline Cologuard data
CRC
All
Sensitivity*
92%
Stage I-II
94%
Adv Precancer
All**
42%
>2 cm
66%
HGD
69%
Superiority over
FIT, all categories
*At specificity 90% (subset with normal colonoscopy) **Adv adenoma + serrated polyp >1cm
Molecular Diagnosis
Screening
Prognosis
Therapy
Biomarkers
More robust biomarker
capability
SR: GA, BS
Grant: P50 CA108961
Tumor
UNKNOWN
76%
DNA
Sequencing
ALK
10%
DUSP22
8%
TP63
6%
Overall Survival
ALK
DUSP22
Abnormality
Median Surv.
TP63
UNKNOWN
DUSP22
ALK
16 mos.
23 mos.
92 mos.
176 mos.
p=.0011 (log-rank)
Immediate needs:
UNKNOWN Genetics
TP63
Months from diagnosis
Molecular Diagnosis
Screening
Prognosis
Therapy
HER2+
140 women with
invasive breast
cancer
AC or EC or
FEC
Chemotherapy 1
Paclitaxel (ER+) and
HER2- +/- Carboplatin (triple
negative)
AC or EC or
FEC
Magnetic Resonance
Imaging (MRI)
Molecular Breast
Imaging (MBI)
Tumor biopsy
Tumor biopsy
Genomic sequencing
Genomic sequencing
Blood sample
Blood sample
Surgery
Chemotherapy 2
MRI
MBI
5 year
observation
Tumor tissue
Mouse avatars
(xenografts)
Genomic sequencing
Blood sample
High-risk
invasive breast
cancer
considered for
neoadjuvant
chemotherapy
Paclitaxel +
trastuzumab
+/pertuzumab
Paclitaxel +/carboplatin
AC
cycles
1+2
Tumor
biopsy,
ptDNA and
imaging to
identify nonresponders
Identify
actionable
alterations
Target
identified, drug
available:
Nonresponder
No target or no
drug
Responder
Tumor biopsy
Xenografts
Genomic sequencing
Novel agent
window
study
complete 3rd
and 4th cycle
of AC
S
U
R
G
E
R
Y
Mouse Avatars
Opportunity to test individual or combinations of
drugs51.9%
against human tumors implanted in
41.7%
immunocompromised
mice.
drugs
Valuable for precision-based
27.3%
Questions