I reviewed recent advances, challenges, and opportunities to implement clinical cancer genomics. Case studies of advanced systems, such as Foundation Medicine, MI-ONCOSEQ are introduced for benchmark. A few fundamental limitations to establish personalized oncology are also discussed.
22. in the understanding of tumour heterogeneity; second,
the role of surgery as a therapeutic modality in the era of
targeted therapy; third, the use of personalized therapy
in the perioperative period and, finally, the possibilities
of personalization of surgical procedures according to
lung cancer subtypes.
VATS lobectomy showed that intraoperative blood loss
was significantly reduced in the VATS group compared
with open lobectomy in nine studies; however, no differ-
ence was observed in five studies and the values were not
reported in seven studies.12
Hospital stay was also signifi-
cantly shorter in VATS group in five studies. Park et al.,13
Heterogeneity in patients
with adenocarcinoma
of the lung according
to driver oncogenes
Heterogeneity within
patients with
EGFR mutation
Heterogeneity in
resistance mechanisms
in one patient
HER2
3%
EGFR
~40% in Asians
~15% in Caucasians
ALK
~5%
KRAS
~15% in Asians
~30% in Caucasians
RET
~1%
ROS1
~1%
BRAF
~1%
PIK3CA
~1%
NRAS
~1%
MET
<5%
Others?
Exon 19del
~50%
L858R
~40%
Sensitive
Inherent resistance
CRKL
~3%
BIM
20–40%
IκB
~30%
Inherent T790M
~2% by sequencing
~30% by sensitive
method
Further
heterogeneity
EGFR-TKI
Drug X
T790M
MET
a cb
T790M
Heterogeneity in patients
with adenocarcinoma
of the lung according
to driver oncogenes
Heterogeneity within
patients with
EGFR mutation
Heterogeneity
resistance mecha
in one patien
HER2
3%
EGFR
~40% in Asians
~15% in Caucasians
ALK
~5%
KRAS
~15% in Asians
~30% in Caucasians
RET
~1%
ROS1
~1%
BRAF
~1%
PIK3CA
~1%
NRAS
~1%
MET
<5%
Others?
Exon 19del
~50%
L858R
~40%
Sensitive
Inherent resistance
CRKL
~3%
BIM
20–40%
IκB
~30%
Inherent T790M
~2% by sequencing
~30% by sensitive
method
Further
heterogeneity
EGFR-TKI
Drug
T790M
ME
a cb
T790M
Figure 1 | Various classes of tumour heterogeneity in adenocarcinoma of the lung. a | Heterogeneity in patients with
adenocarcinoma of the lung according to driver oncogenes that are crucial for selecting targeted drugs for treatment.2,76
Number of people reflects approximate incidence.2,76
b | Heterogeneity in patients with EGFR mutations, resulting in
MitsudomiT, Suda K,YatabeY. Nat Rev Clin Oncol. 2013 Apr;10(4):235-44.
Heterogeneity in Lung Adenocarcinoma
24. Although the number of actionable alterations in any individual cancer patient’s sample
was low (average, 1.57), a wide variety of alter- ations was observed across all samples,
with 1,579 unique alterations reported.
Actionable Genomic Alterations Were Identified in a Large Number of Genes
assay, highlighting the broad applicability of the approach.
Given that matched normal specimens are not routinely collected
in clinical practice, reporting focused on known sites of somatic
mutation39, truncations or homozygous deletions of known tumor
suppressor genes40, as well as known amplifications of oncogenes
and gene fusions in genes known to be rearranged in solid tumors.
Alterations were reported in 174/189 (92%) of tested genes, with an
surprising to observe that current clinical testing paradigms compris-
ing only mutation hotspots10,11,43 capture less than one-third of total
actionable results (Fig. 6c).
The therapeutic implications of the long tail were particularly notable
for proven targets of therapy, as exemplified by ERBB2. Although ERBB2
is currently clinically validated only as an amplified or overexpressed
drug target in breast and gastro-esophageal cancer, we observed ERBB2
ab
Head & neck 4%
Soft tissue, 6%
Unknown, 9%
Gene amplification, 33%
Sub/indel, 8%
Gene deletion, 8%
Mutation hotspots,
31%
Lung, 18%
Rearrangement, 3%
Truncation, 17%
Breast, 14%
Colon, 7%Pancreas, 5%
Ovary, 5%
Skin, 3%
Liver, 3%
Uterus, 3%
Others, 26%
Patientsamples(%)
c
40
45
35
30
25
20
15
10
5
0
TP53KR
AS
APCM
C
L1
R
B
1
N
F1
B
R
C
A2
AU
R
KAN
KX2_1
KIT
ESR
1
IG
F1R
R
ET
TSC
2
M
SH
6
ALK
EW
SR
1
PD
G
FR
A
R
U
N
X1
VH
L
FG
FR
2
M
AP2K4
TET2
C
C
N
D
2
M
ET
C
D
K6
N
F2
C
C
N
D
3
FG
FR
3
PIK3R
1
AKT1
B
AP1
R
PTO
R
C
D
H
1
ID
H
1
AKT2
SM
AR
C
A4
SO
X2
KD
M
6A
D
N
M
T3A
N
O
TC
H
1
N
R
AS
LR
P1B
R
IC
TO
R
B
R
C
A1
C
TN
N
B
1
ATM
FB
XW
7
C
C
N
E1
PTPR
D
STK11
SM
AD
4
B
R
AF
C
D
K4
FG
FR
1
ER
B
B
2
M
D
M
2
EG
FR
C
C
N
D
1
AR
ID
1A
PTEN
C
D
KN
2B
PIK3C
AM
YC
C
D
KN
2A
amples(%)
d
30
25
20
15
e Lung (17)
Unknown (2)
Stomach (1)
Pancreas (1)
Ovary (1)
Bladder (1)
Duodenum (1)ERBB2
Furin-Like TM Tyrosine_KinaseFurin-Like
R678Q(4) L755S(4)
D769Y(3)
V842I(4)
Receptor_L Receptor_L
Colon (2)
Uterus (4)
Breast (8)
ollected
somatic
n tumor
cogenes
tumors.
with an
ing only mutation hotspots10,11,43 capture less than one-third of total
actionable results (Fig. 6c).
The therapeutic implications of the long tail were particularly notable
for proven targets of therapy, as exemplified by ERBB2. Although ERBB2
is currently clinically validated only as an amplified or overexpressed
drug target in breast and gastro-esophageal cancer, we observed ERBB2
nknown, 9%
Gene amplification, 33%
Sub/indel, 8%
Gene deletion, 8%
Mutation hotspots,
31%
18%
Rearrangement, 3%
Truncation, 17%
Breast, 14%
%
c
AU
R
KAN
KX2_1
KIT
ESR
1
IG
F1R
R
ET
TSC
2
M
SH
6
ALK
EW
SR
1
PD
G
FR
A
R
U
N
X1
VH
L
FG
FR
2
M
AP2K4
TET2
C
C
N
D
2
M
ET
C
D
K6
N
F2
C
C
N
D
3
FG
FR
3
PIK3R
1
AKT1
B
AP1
R
PTO
R
C
D
H
1
ID
H
1
AKT2
SM
AR
C
A4
SO
X2
KD
M
6A
D
N
M
T3A
N
O
TC
H
1
N
R
AS
LR
P1B
R
IC
TO
R
R
C
A1
1
Lung (17)
Unknown (2)
Stomach (1)
Pancreas (1)
Ovary (1)
Bladder (1)
Duodenum (1)
Furin-Like TM Tyrosine_Kinase
R678Q(4) L755S(4)
D769Y(3)
P780_Y781insGSP(4)
V842I(4)
Receptor_L
Colon (2)
Uterus (4)
Breast (8)
Nat Biotechnol. 2013 Nov;31(11):1023-31.
25. The Long Tail
Comprehensive genomic profiling through WGS is necessary
vs.Targeted Seq, SNP chips, Hotspot Panels, Single gene tests…
32. • 암환자의 FFPE 시료를 이용, 315 개의 암 관련 ‘actionable gene’ 변이를 한 번에 분석
• 이를 기반으로, 환자의 유전자 변이를 표적으로 하는 치료제 정보를 의사에게 제공
• Broad Institute 에서 spin-off , GoogleVentures와 빌게이츠 투자
• 2012년에 서비스를 시작, 2013년 9월에 나스닥 IPO
• 분석 가격: $5,800
• 2014년 3사 분기: 6,428 회 분석 (149% 성장), 2014년 22,000-25,000 회 분석 예상
http://www.foundationmedicine.com/
34. 315 cancer related genes
& introns from 28 genes often rearranged or altered in cancer
Current as of
August 4, 2014
th high accuracy. The test simultaneously sequences
anged or altered in cancer to a typical median depth of
ter than 500X. Each covered read represents a unique
tions that occur at low frequencies due to tumor
w tumor purity and small tissue samples. FoundationOne
s of genomic alterations, including base substitutions,
letions (indels), copy number alterations (CNAs) and
using a small, routine FFPE sample (including core or
rovided in an interpretive report, both in hard copy and
4
ation is found in any one of the genes on the current
ort will identify the gene and alteration and will provide an
on the front page of the report are found to have one or
evant alterations. All other genes are not found to have
vant alterations. In some cases, pertinent negatives
the front of the report; these are genes that have no
ancer, EGFR in lung cancer). The complete list of genes
ppears in the “Current Gene List” table to the right, in the
ation is detected in one of the genes included on
in the report so that they may be acted upon in the
clinical evidence emerge.
of the estimated tumor DNA.
One Includes Genes That Are Commonly
n All Solid Tumors
l classes of actionable alterations, including those in
One report often reveals alterations that may lead to
ent options for physicians and their patients to consider.
*As measured from the date the Foundation Medicine laboratory receives a sample that meets requirements.
Current Gene List4
clinical literature.
CURRENT GENE LIST
FANCC GATA3 MITF STAT4
GATA4 JAK3 PDGFRA RET STK11
CIC FANCE GATA6 JUN MPL RICTOR SUFU
AKT1 FANCF
GID4
(C17orf39)
KAT6A
(MYST3)
MRE11A PDK1 RNF43 SYK
CRKL FANCG GLI1 KDM5A ROS1 TAF1
AKT3 FANCL GNA11 KDM5C PIK3CA RPTOR
ALK CSF1R FAS GNA13 KDM6A MTOR RUNX1 TERC
AMER1 C11orf30
(EMSY)
CTCF FAT1 GNAQ KDR PIK3CG RUNX1T1
TERT
(promoter only)
APC CARD11 CTNNA1 GNAS KEAP1 MYC PIK3R1
AR FGF10 KEL
MYCL
(MYCL1)
ARAF CUL3 FGF14 KIT MYCN TNFAIP3
ARFRP1 CCND1 CYLD FGF19 GRM3 TNFRSF14
ARID1A DAXX (MLL) NF1 POLD1 TOP1
CCND3 FGF3
(MLL3)
POLE
CCNE1 DICER1 FGF4 TP53
ASXL1 DNMT3A FGF6 KRAS PRDM1 TSC1
ATM CD79A DOT1L FGFR1 LMO1 SMAD3
ATR EGFR PRKAR1A SMAD4
ATRX CDC73 EP300 FGFR3 LYN PRKCI SMARCA4
AURKA FGFR4 LZTR1 PRKDC VEGFA
NPM1 SMO
AXIN1 CDK4 FLCN IGF1R NRAS SNCAIP
AXL CDK6 FLT1 NSD1 PTEN SOCS1
FLT3 NTRK1 PTPN11 SOX10 XPO1
CDKN1A FLT4 IKZF1 MAP3K1 QKI
IL7R MCL1 NTRK3 RAC1 SOX9
ERG FOXP1 NUP93 RAD50 SPEN ZNF703
ERRFI1 MDM4 PAK3 RAD51 SPOP
ESR1 RAF1 SPTA1
IRF4 SRC
FAM46C GATA1 MEN1 PAX5 RARA
FANCA JAK1 MET STAT3
SELECT REARRANGEMENTS
ALK ETV4 FGFR1 KIT MYC RARA
EGFR ETV5 PDGFRA RET
ETV1 ETV6 FGFR3 NTRK1 RAF1 ROS1
1
and established the performance
-
ndationOne. This updated version of FoundationOne met these performance
-
35. e anatomic
Increasingly,
c alterations,
ns, cancer
pes of
us drivers
equences
an depth of
s a unique
mor
undationOne
stitutions,
Technical Information
Base
Substitutions1 Indels1
Copy Number
Alterations1 Rearrangements
Sensitivity
>99%
MAF 5%
>97%
MAF 10%
>95%
CN 8 or 0
30% tumor nuclei
2
>99% for ALK fusion3
20% tumor nuclei
>99% >99% >99% >99%
(each covered read is of a unique DNA
fragment to enable detection of alterations
at low frequency)
5001
14 day average*
*As measured from the date the Foundation Medicine laboratory receives a sample that meets requirements.
Technical Information
and Test Overview
Current Gene List4
Technical Information of FoundationOne
36. Number of Samples 441
Number of failed samples 4% (16)
Number of samples analyzed 96% (425)
Number of samples analyzed with at
least one actionable alteration
77% (325)
Number of samples analyzed with
at least one actionable alteration not
detectable by hotspot tests1
59% (251)
Number of alterations per analyzed
sample
2.74 (range 0-9)
Number of actionable alterations per
analyzed sample
1.40 (range 0-5)
Actionability for Cancer Samples
• At least one actionable alteration was found from 77% of samples.
• On average,1.4 actionable alterations was found from one sample.
37. Lung Breast Colorectal
Number of
samples
82 70 44
Number of failed
samples
5% (4) 4% (3) 0% (0)
Number of
samples analyzed
95% (78) 86% (67) 100% (44)
Samples with
at least one
actionable
alteration
86% (67) 85% (57) 86% (38)
Alterations per
sample
2.7 (range
0-6)
2.9 (range
0-7)
3.8 (range
1-7)
Actionable
alterations per
sample
1.6 (range
0-5)
1.6 (range
0-4)
1.5 (range
0-3)
Actionability for Lung, Colon, and Breast Cancers was High
The three major tumor subtypes, lung, breast, and colorectal, accounted for 196 out of the 441 samples (44%).
The percentage of samples with at least one actionable alteration was 86%, 85%, and 86% respectively.
38. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 1 of 11
Date of Birth 09 August 1948 Client ASAN Medical Center Specimen Received 04 February 2013
Gender Male Ordering Physician Kim, Kyu-pyo Specimen Site Lymph Node
FMI Case # TRF007878 Additional Recipient C. Anthony Blau Date of Collection 04 January 2013
Medical Record # Not Given FMI Client # 200535 Specimen Type Slide
Specimen ID S-13-132 A Pathologist Sejin Jang
ABOUT THE TEST:
FoundationOne™ is a next-generation sequencing (NGS) based assay which identifies genomic alterations within hundreds of cancer-related genes.
PATIENT RESULTS TUMOR TYPE: SOFT TISSUE SARCOMA (NOS)
7 genomic alterations Genomic Alterations Identified†
NF2 W74*
CCND2 amplification
KRAS G13D, amplification
TP53 R282W
FGF23 amplification
FGF6 amplification
3 therapies associated with potential clinical benefit
0 therapies associated with lack of response
6 clinical trials
†
For a complete list of the genes assayed, please refer to the Appendix
THERAPEUTIC IMPLICATIONS
Genomic Alterations
Detected
FDA Approved Therapies
(in patient’s tumor type)
FDA Approved Therapies
(in another tumor type)
Potential Clinical Trials
NF2
W74*
None Everolimus
Lapatinib
Temsirolimus
Yes, see clinical trials
section
CCND2
amplification
None None Yes, see clinical trials
section
KRAS
G13D, amplification
None None Yes, see clinical trials
section
TP53
R282W
None None None
FGF23
amplification
None None None
FGF6
amplification
None None None
Note: Genomic alterations detected may be associated with activity of certain FDA approved drugs; however, the agents listed in this report may have
varied clinical evidence in the patient’s tumor type. Neither the therapeutic agents nor the trials identified are ranked in order of potential or predicted
efficacy for this patient, nor are they ranked in order of level of evidence for this patient’s tumor type.
Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 2 of 11
GENOMIC ALTERATIONS
GENE
ALTERATION
INTERPRETATION
NF2
W74*
Merlin, encoded by NF2, functions by coordinating signaling of receptor tyrosine kinases (RTKs) such as
the epidermal growth factor receptor (Egfr) with cell contact (Curto and McClatchey, 2008; 17971776).
The inactivation of Merlin in cancer disrupts this mechanism and leads to unrestrained RTK signaling
despite cell contact (Curto and McClatchey, 2008; 17971776). NF2 W74* results in the premature
termination of the 595 amino acid merlin protein, truncating the majority of the protein, and is therefore
predicted to be inactivating. Loss of NF2 has not been reported in a collection of 207 sarcoma samples
reported in the cBio Cancer Genomics Portal (cbioportal.org, Feb 2013). However, loss of heterozygosity
for chromosome 22q (where the NF2 gene resides) has been reported in 6/10 epithelioid sarcomas
(Quezado et al., 1998; 9635681). Additionally, NF2 mutations have been reported in 41% (271/669) of all
soft tissue tumors analyzed in the COSMIC database (COSMIC, Dec 2012). The majority of those
analyzed were schwannoma, which had an NF2 mutation rate of 43% (COSMIC, Dec 2012). At present
there are no approved therapies that directly target NF2 loss. However, preclinical studies in models of
NF2 loss have suggested that the TKI lapatinib and mTOR inhibitors may be a relevant approach
(Ammoun et al., 2010; 20511180, López-Lago et al., 2009; 19451229, James et al., 2009; 19451225).
Lapatinib and the mTOR inhibitors everolimus and temsirolimus have received FDA approval in other
cancer types and are under clinical investigation in solid tumors. Clinical studies of lapatinib in NF2
patients with progressive vestibular schwannoma reported efficacy (Karajannis et al., 2012; 22844108).
CCND2
amplification
CCND2 encodes the protein cyclin D2, which binds and regulates the cyclin-dependent kinases that
control cell cycle progression, and is a downstream target of cancer signaling pathways including
hedgehog and PI-3-kinase (Katoh and Katoh, 2009; 19860666, White et al., 2006; 16301994). CCND2
amplification has been reported in 2.4% of sarcomas (The cBio Cancer Genomics Portal,
http://www.cbioportal.org/, Feb 2013) (Höglund et al., 1996; 8547659). CCND2 alterations have not been
reported in soft tissue sarcomas in the literature (PubMed, Feb 2013). Overexpression of Cyclin D2 has
been reported in several types of sarcomas, including endometrial stromal sarcoma and
rhabdomyosarcoma (Davidson et al., 2013; 23178314, Li et al., 2012; 22330340). Loss of expression of
Cyclin D2 in stage III NSCLC, but not stage II or IV, has been associated with decreased recurrence free
survival (Ko et al., 2012; 22534667). CCND2 expression has been associated with decreased metastasis
in one study of 13 metastatic and 18 non-metastatic neuroendocrine tumors (Lee et al., 2012; 22485171).
There are no approved therapies that specifically target CCND2 amplification; however, several
preclinical studies suggest that cyclin D2 may associate with Cdk4 in cancer cells, and that Cyclin D2-
overexpressing cells may be sensitive to Cdk4/6 inhibitors (Decker et al., 2002; 11896535, Cole et al.,
2010; 20736363). Clinical trials of Cdk4/6 inhibitors are currently underway in multiple tumor types.
KRAS
G13D,
amplification
The KRAS gene is one of the most commonly mutated genes in human malignancies (Farber et al., 2011;
22016105, Feldmann et al., 2007; 17520196, Han et al., 2011; 22011285). Activating mutations in RAS
genes can cause uncontrolled cell proliferation and tumor formation (Pylayeva-Gupta et al., 2011;
21993244, Kahn et al., 1987; 3310850). The G13D mutation lies within the first "G box" domain of the
KRAS protein, one of several conserved regions (Colicelli, 2004; 15367757). Disruption of this region
creates a protein that is defective for GTP hydrolysis and therefore constitutively active. KRAS alterations
have been reported variously from 0-44% in soft tissue sarcoma (COSMIC, The cBio Cancer Genomics
Portal, http://www.cbioportal.org, Feb 2013), perhaps dependent on country of origin (Yoo et al., 1999;
10463479, Yoo and Robinson, 1999; 10391564, Barretina et al., 2010; 20601955, Jin et al., 2010;
20150643). KRAS amplification has been reported in 4/207 (2%) soft tissue sarcomas in the Sarcoma
Genome Project dataset (The cBio Cancer Genomics Portal, http://www.cbioportal.org, Feb 2013).
Constitutive activation of KRAS leads to activation of the RAF/MEK/ERK pathway, leading to
tumorigenesis (Pylayeva-Gupta et al., 2011; 21993244). Therefore, tumors with activating mutations in
KRAS may be sensitive to inhibitors of this pathway. Both the KRAS-targeting reovirus Reolysin and
specific MEK inhibitors are under investigation for tumors bearing KRAS mutations. Activating mutations
in KRAS have been associated with resistance to Egfr inhibitors in colorectal carcinoma; however, this
relationship has not been a significant subject of study in soft tissue sarcoma (Lièvre et al., 2006;
16618717, De Roock et al., 2011; 21163703).
Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 4 of 11
THERAPIES
There are no therapies FDA approved in this patient's tumor type that are specific to the reported genomic alterations.
ADDITIONAL THERAPIES – FDA APPROVED IN OTHER TUMOR TYPES
THERAPY RATIONALE
Everolimus
Everolimus is an orally available mTOR inhibitor that has been approved for use in renal cell carcinoma,
pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with TSC, and
hormone receptor positive, HER2 negative advanced breast cancer. Preclinical data suggests that NF2
loss may be associated with sensitivity to rapamycin, which is similar in mechanism of action to
everolimus (Lopez-Lago et al., 2009; 19451229, James et al., 2009; 19451225). Everolimus is currently
being tested in clinical trials in several tumor types. A Phase 1 trial of everolimus and figitumumab, an
IGF-1R inhibitor, in sarcomas and other solid tumors showed that the combination was safe and well-
tolerated, with a partial response in 1/18 patients and stable disease in 15/18 patients (Quek et al., 2011;
21177764).
Lapatinib
Lapatinib is a dual tyrosine kinase inhibitor, targeting both Egfr and Her2 (Erbb2). It has been approved
for use in metastatic breast cancer. Mutation of NF2 may lead to Egfr and/or Erbb2 activation; lapatinib
inhibits Egfr and Erbb2 and has shown preclinical activity in NF2 deficient vestibular schwannoma
(Ammoun et al., 2010; 20511180). Lapatinib is currently in clinical trials in multiple solid tumor types.
Temsirolimus
Temsirolimus is an intravenous mTOR inhibitor that has been approved for use in advanced renal cell
carcinoma. Preclinical data suggests that NF2 loss may be associated with sensitivity to rapamycin,
which is similar in mechanism of action to temsirolimus (Lopez-Lago et al., 2009; 19451229, James et al.,
2009; 19451225). Temsirolimus is currently being tested in clinical trials in several tumor types. A Phase
2 trial of temsirolimus as single agent in soft tissue sarcoma reported limited efficacy and moderate
toxicity, with a partial response exhibited in 2 of 40 evaluable patients (Okuno et al., 2011; 21287536). A
Phase 1 trial of temsirolimus combined with liposomal doxorubicin in recurrent and refractory bone and
soft tissue sarcoma patients reported that the combination treatment is safe and demonstrates sufficient
preliminary efficacy to pursue the Phase 2 portion of the study (Thornton et al., 2013; 23382028).
Genomic alterations detected may be associated with activity of certain FDA approved drugs, however the agents listed in this report may have little or
no evidence in the patient’s tumor type
Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 5 of 11
CLINICAL TRIALS TO CONSIDER
IMPORTANT: While every effort is made to ensure the accuracy of the information contained below, the information available in the
public domain is continuously updated and should be investigated by the physician or research staff. This is not meant to be a
complete list of available trials. In order to conduct a more thorough search, please go to www.clinicaltrials.gov and use the search
terms provided below. For more information about a specific clinical trial, type the NCT ID of the trial indicated below into the search
bar.
GENE RATIONALE FOR POTENTIAL CLINICAL TRIALS
NF2
W74*
Mutation or loss of NF2 results in the dysregulation of RTK and mTOR signaling. Therefore, RTK or mTOR
inhibitors may be relevant for patients with NF2 mutations.
A search of the trial website clinicaltrials.gov, using terms such as “NF2”, "lapatinib", "mTOR" and/or "solid
tumor" retrieves more than 10 trials that may be relevant for this patient's tumor.
Examples of these trials are shown below.
TITLE PHASE TARGETS LOCATIONS NCT ID
An Open-label, Multi-center Phase I Dose-
finding Study of RAD001 (Everolimus, Afinitor®)
in Combination With BEZ235 in Patients With
Advanced Solid Tumors
Phase 1 MTOR, PI3K Missouri, Auckland (New
Zealand), Barcelona (Spain),
Bordeaux Cedex (France),
Montpellier Cedex 5 (France),
Newcastle Upon Tyne (United
Kingdom), Seoul (Korea,
Republic of), Verona (Italy),
Wilrijk (Belgium)
NCT01482156
A Phase I Study of the HER1, HER2 Dual
Kinase Inhibitor, Lapatinib Plus the
Proteosomal Inhibitor Bortezomib in Patients
With Advanced Malignancies
Phase 1 EGFR,
Her2/neu,
proteasome
District of Columbia NCT01497626
39. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 1 of 11
Date of Birth 09 August 1948 Client ASAN Medical Center Specimen Received 04 February 2013
Gender Male Ordering Physician Kim, Kyu-pyo Specimen Site Lymph Node
FMI Case # TRF007878 Additional Recipient C. Anthony Blau Date of Collection 04 January 2013
Medical Record # Not Given FMI Client # 200535 Specimen Type Slide
Specimen ID S-13-132 A Pathologist Sejin Jang
ABOUT THE TEST:
FoundationOne™ is a next-generation sequencing (NGS) based assay which identifies genomic alterations within hundreds of cancer-related genes.
PATIENT RESULTS TUMOR TYPE: SOFT TISSUE SARCOMA (NOS)
7 genomic alterations Genomic Alterations Identified†
NF2 W74*
CCND2 amplification
KRAS G13D, amplification
TP53 R282W
FGF23 amplification
FGF6 amplification
3 therapies associated with potential clinical benefit
0 therapies associated with lack of response
6 clinical trials
†
For a complete list of the genes assayed, please refer to the Appendix
THERAPEUTIC IMPLICATIONS
Genomic Alterations
Detected
FDA Approved Therapies
(in patient’s tumor type)
FDA Approved Therapies
(in another tumor type)
Potential Clinical Trials
NF2
W74*
None Everolimus
Lapatinib
Temsirolimus
Yes, see clinical trials
section
CCND2
amplification
None None Yes, see clinical trials
section
KRAS
G13D, amplification
None None Yes, see clinical trials
section
TP53
R282W
None None None
FGF23
amplification
None None None
FGF6
amplification
None None None
Note: Genomic alterations detected may be associated with activity of certain FDA approved drugs; however, the agents listed in this report may have
varied clinical evidence in the patient’s tumor type. Neither the therapeutic agents nor the trials identified are ranked in order of potential or predicted
efficacy for this patient, nor are they ranked in order of level of evidence for this patient’s tumor type.
40. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 2 of 11
GENOMIC ALTERATIONS
GENE
ALTERATION
INTERPRETATION
NF2
W74*
Merlin, encoded by NF2, functions by coordinating signaling of receptor tyrosine kinases (RTKs) such as
the epidermal growth factor receptor (Egfr) with cell contact (Curto and McClatchey, 2008; 17971776).
The inactivation of Merlin in cancer disrupts this mechanism and leads to unrestrained RTK signaling
despite cell contact (Curto and McClatchey, 2008; 17971776). NF2 W74* results in the premature
termination of the 595 amino acid merlin protein, truncating the majority of the protein, and is therefore
predicted to be inactivating. Loss of NF2 has not been reported in a collection of 207 sarcoma samples
reported in the cBio Cancer Genomics Portal (cbioportal.org, Feb 2013). However, loss of heterozygosity
for chromosome 22q (where the NF2 gene resides) has been reported in 6/10 epithelioid sarcomas
(Quezado et al., 1998; 9635681). Additionally, NF2 mutations have been reported in 41% (271/669) of all
soft tissue tumors analyzed in the COSMIC database (COSMIC, Dec 2012). The majority of those
analyzed were schwannoma, which had an NF2 mutation rate of 43% (COSMIC, Dec 2012). At present
there are no approved therapies that directly target NF2 loss. However, preclinical studies in models of
NF2 loss have suggested that the TKI lapatinib and mTOR inhibitors may be a relevant approach
(Ammoun et al., 2010; 20511180, López-Lago et al., 2009; 19451229, James et al., 2009; 19451225).
Lapatinib and the mTOR inhibitors everolimus and temsirolimus have received FDA approval in other
cancer types and are under clinical investigation in solid tumors. Clinical studies of lapatinib in NF2
patients with progressive vestibular schwannoma reported efficacy (Karajannis et al., 2012; 22844108).
CCND2
amplification
CCND2 encodes the protein cyclin D2, which binds and regulates the cyclin-dependent kinases that
control cell cycle progression, and is a downstream target of cancer signaling pathways including
hedgehog and PI-3-kinase (Katoh and Katoh, 2009; 19860666, White et al., 2006; 16301994). CCND2
amplification has been reported in 2.4% of sarcomas (The cBio Cancer Genomics Portal,
http://www.cbioportal.org/, Feb 2013) (Höglund et al., 1996; 8547659). CCND2 alterations have not been
reported in soft tissue sarcomas in the literature (PubMed, Feb 2013). Overexpression of Cyclin D2 has
been reported in several types of sarcomas, including endometrial stromal sarcoma and
rhabdomyosarcoma (Davidson et al., 2013; 23178314, Li et al., 2012; 22330340). Loss of expression of
Cyclin D2 in stage III NSCLC, but not stage II or IV, has been associated with decreased recurrence free
survival (Ko et al., 2012; 22534667). CCND2 expression has been associated with decreased metastasis
in one study of 13 metastatic and 18 non-metastatic neuroendocrine tumors (Lee et al., 2012; 22485171).
There are no approved therapies that specifically target CCND2 amplification; however, several
preclinical studies suggest that cyclin D2 may associate with Cdk4 in cancer cells, and that Cyclin D2-
overexpressing cells may be sensitive to Cdk4/6 inhibitors (Decker et al., 2002; 11896535, Cole et al.,
2010; 20736363). Clinical trials of Cdk4/6 inhibitors are currently underway in multiple tumor types.
KRAS
G13D,
amplification
The KRAS gene is one of the most commonly mutated genes in human malignancies (Farber et al., 2011;
22016105, Feldmann et al., 2007; 17520196, Han et al., 2011; 22011285). Activating mutations in RAS
genes can cause uncontrolled cell proliferation and tumor formation (Pylayeva-Gupta et al., 2011;
21993244, Kahn et al., 1987; 3310850). The G13D mutation lies within the first "G box" domain of the
KRAS protein, one of several conserved regions (Colicelli, 2004; 15367757). Disruption of this region
creates a protein that is defective for GTP hydrolysis and therefore constitutively active. KRAS alterations
have been reported variously from 0-44% in soft tissue sarcoma (COSMIC, The cBio Cancer Genomics
Portal, http://www.cbioportal.org, Feb 2013), perhaps dependent on country of origin (Yoo et al., 1999;
10463479, Yoo and Robinson, 1999; 10391564, Barretina et al., 2010; 20601955, Jin et al., 2010;
20150643). KRAS amplification has been reported in 4/207 (2%) soft tissue sarcomas in the Sarcoma
Genome Project dataset (The cBio Cancer Genomics Portal, http://www.cbioportal.org, Feb 2013).
Constitutive activation of KRAS leads to activation of the RAF/MEK/ERK pathway, leading to
tumorigenesis (Pylayeva-Gupta et al., 2011; 21993244). Therefore, tumors with activating mutations in
KRAS may be sensitive to inhibitors of this pathway. Both the KRAS-targeting reovirus Reolysin and
specific MEK inhibitors are under investigation for tumors bearing KRAS mutations. Activating mutations
in KRAS have been associated with resistance to Egfr inhibitors in colorectal carcinoma; however, this
relationship has not been a significant subject of study in soft tissue sarcoma (Lièvre et al., 2006;
16618717, De Roock et al., 2011; 21163703).
41. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
GENOMIC ALTERATIONS
GENE
ALTERATION
INTERPRETATION
NF2
W74*
Merlin, encoded by NF2, functions by coordinating signaling of receptor tyrosine kinases (RTKs) such as
the epidermal growth factor receptor (Egfr) with cell contact (Curto and McClatchey, 2008; 17971776).
The inactivation of Merlin in cancer disrupts this mechanism and leads to unrestrained RTK signaling
despite cell contact (Curto and McClatchey, 2008; 17971776). NF2 W74* results in the premature
termination of the 595 amino acid merlin protein, truncating the majority of the protein, and is therefore
predicted to be inactivating. Loss of NF2 has not been reported in a collection of 207 sarcoma samples
reported in the cBio Cancer Genomics Portal (cbioportal.org, Feb 2013). However, loss of heterozygosity
for chromosome 22q (where the NF2 gene resides) has been reported in 6/10 epithelioid sarcomas
(Quezado et al., 1998; 9635681). Additionally, NF2 mutations have been reported in 41% (271/669) of all
soft tissue tumors analyzed in the COSMIC database (COSMIC, Dec 2012). The majority of those
analyzed were schwannoma, which had an NF2 mutation rate of 43% (COSMIC, Dec 2012). At present
there are no approved therapies that directly target NF2 loss. However, preclinical studies in models of
NF2 loss have suggested that the TKI lapatinib and mTOR inhibitors may be a relevant approach
(Ammoun et al., 2010; 20511180, López-Lago et al., 2009; 19451229, James et al., 2009; 19451225).
Lapatinib and the mTOR inhibitors everolimus and temsirolimus have received FDA approval in other
cancer types and are under clinical investigation in solid tumors. Clinical studies of lapatinib in NF2
patients with progressive vestibular schwannoma reported efficacy (Karajannis et al., 2012; 22844108).
CCND2
amplification
CCND2 encodes the protein cyclin D2, which binds and regulates the cyclin-dependent kinases that
control cell cycle progression, and is a downstream target of cancer signaling pathways including
hedgehog and PI-3-kinase (Katoh and Katoh, 2009; 19860666, White et al., 2006; 16301994). CCND2
amplification has been reported in 2.4% of sarcomas (The cBio Cancer Genomics Portal,
http://www.cbioportal.org/, Feb 2013) (Höglund et al., 1996; 8547659). CCND2 alterations have not been
reported in soft tissue sarcomas in the literature (PubMed, Feb 2013). Overexpression of Cyclin D2 has
been reported in several types of sarcomas, including endometrial stromal sarcoma and
rhabdomyosarcoma (Davidson et al., 2013; 23178314, Li et al., 2012; 22330340). Loss of expression of
Cyclin D2 in stage III NSCLC, but not stage II or IV, has been associated with decreased recurrence free
survival (Ko et al., 2012; 22534667). CCND2 expression has been associated with decreased metastasis
in one study of 13 metastatic and 18 non-metastatic neuroendocrine tumors (Lee et al., 2012; 22485171).
There are no approved therapies that specifically target CCND2 amplification; however, several
preclinical studies suggest that cyclin D2 may associate with Cdk4 in cancer cells, and that Cyclin D2-
overexpressing cells may be sensitive to Cdk4/6 inhibitors (Decker et al., 2002; 11896535, Cole et al.,
2010; 20736363). Clinical trials of Cdk4/6 inhibitors are currently underway in multiple tumor types.
The KRAS gene is one of the most commonly mutated genes in human malignancies (Farber et al., 2011;
• 유전자(단백질)의 기능 및 암 발병에서 메커니즘 소개
• NF2 유전자에서 나오는 Merlin은 EGFR과 같은 RTKs를 조절하는 기능을 가짐
• Merlin의 비활성화는 이런 메커니즘을 망가뜨려, RTKs 신호를 조절하지 못하게 됨
• 유전 변이가 단백질/메커니즘에 어떠한 영향을 미치는지 설명
• NF2 의 W74*는 Merlin의 premature termination을 통해 단백질의 비활성화를 야기함
• 유전 변이가 해당 암종에 대해 DB/논문에 어떻게 보고 되어 있는지 설명
• cBio Cancer Genomics Portal: 207개의 sarcoma 샘플에는 NF2 loss 데이터는 없음
• Quezado et al.: Epithelial sarcoma 에서 NF2가 위치한 염색체의 loss of heterozygosity 가 보고된 바 있음
• COSMIC: NF2의 변이(W74* ?)가 41%의 soft tissue tumor 에서 보고된 바 있으며, 샘플의 대부분은 schwannoma
• 유전 변이에 효과가 있는 약물 (승인/임상)에 대한 간략한 소개
• NF2 loss 변이를 직접 표적으로 하는 승인 받은 약은 없음
• 전임상 결과에 따르면 TKI lapatinib과 mTOR 저해제가 효과 있을 수도 있음
• Lapatinib과 mTOR 저해제는 다른 암종에 대해서 승인 받았으며, solid tumor에 대하여 임상 중임
• Lapatinib은 NF2 변이 vestibular schwannoma 환자에 대한 임상에서 효능을 보임
42. NF2
W74*
despite cell contact (Curto and McClatchey, 2008; 17971776). NF2 W74* results in the premature
termination of the 595 amino acid merlin protein, truncating the majority of the protein, and is therefore
predicted to be inactivating. Loss of NF2 has not been reported in a collection of 207 sarcoma samples
reported in the cBio Cancer Genomics Portal (cbioportal.org, Feb 2013). However, loss of heterozygosity
for chromosome 22q (where the NF2 gene resides) has been reported in 6/10 epithelioid sarcomas
(Quezado et al., 1998; 9635681). Additionally, NF2 mutations have been reported in 41% (271/669) of all
soft tissue tumors analyzed in the COSMIC database (COSMIC, Dec 2012). The majority of those
analyzed were schwannoma, which had an NF2 mutation rate of 43% (COSMIC, Dec 2012). At present
there are no approved therapies that directly target NF2 loss. However, preclinical studies in models of
NF2 loss have suggested that the TKI lapatinib and mTOR inhibitors may be a relevant approach
(Ammoun et al., 2010; 20511180, López-Lago et al., 2009; 19451229, James et al., 2009; 19451225).
Lapatinib and the mTOR inhibitors everolimus and temsirolimus have received FDA approval in other
cancer types and are under clinical investigation in solid tumors. Clinical studies of lapatinib in NF2
patients with progressive vestibular schwannoma reported efficacy (Karajannis et al., 2012; 22844108).
CCND2
amplification
CCND2 encodes the protein cyclin D2, which binds and regulates the cyclin-dependent kinases that
control cell cycle progression, and is a downstream target of cancer signaling pathways including
hedgehog and PI-3-kinase (Katoh and Katoh, 2009; 19860666, White et al., 2006; 16301994). CCND2
amplification has been reported in 2.4% of sarcomas (The cBio Cancer Genomics Portal,
http://www.cbioportal.org/, Feb 2013) (Höglund et al., 1996; 8547659). CCND2 alterations have not been
reported in soft tissue sarcomas in the literature (PubMed, Feb 2013). Overexpression of Cyclin D2 has
been reported in several types of sarcomas, including endometrial stromal sarcoma and
rhabdomyosarcoma (Davidson et al., 2013; 23178314, Li et al., 2012; 22330340). Loss of expression of
Cyclin D2 in stage III NSCLC, but not stage II or IV, has been associated with decreased recurrence free
survival (Ko et al., 2012; 22534667). CCND2 expression has been associated with decreased metastasis
in one study of 13 metastatic and 18 non-metastatic neuroendocrine tumors (Lee et al., 2012; 22485171).
There are no approved therapies that specifically target CCND2 amplification; however, several
preclinical studies suggest that cyclin D2 may associate with Cdk4 in cancer cells, and that Cyclin D2-
overexpressing cells may be sensitive to Cdk4/6 inhibitors (Decker et al., 2002; 11896535, Cole et al.,
2010; 20736363). Clinical trials of Cdk4/6 inhibitors are currently underway in multiple tumor types.
KRAS
G13D,
amplification
The KRAS gene is one of the most commonly mutated genes in human malignancies (Farber et al., 2011;
22016105, Feldmann et al., 2007; 17520196, Han et al., 2011; 22011285). Activating mutations in RAS
genes can cause uncontrolled cell proliferation and tumor formation (Pylayeva-Gupta et al., 2011;
21993244, Kahn et al., 1987; 3310850). The G13D mutation lies within the first "G box" domain of the
KRAS protein, one of several conserved regions (Colicelli, 2004; 15367757). Disruption of this region
creates a protein that is defective for GTP hydrolysis and therefore constitutively active. KRAS alterations
have been reported variously from 0-44% in soft tissue sarcoma (COSMIC, The cBio Cancer Genomics
Portal, http://www.cbioportal.org, Feb 2013), perhaps dependent on country of origin (Yoo et al., 1999;
10463479, Yoo and Robinson, 1999; 10391564, Barretina et al., 2010; 20601955, Jin et al., 2010;
20150643). KRAS amplification has been reported in 4/207 (2%) soft tissue sarcomas in the Sarcoma
Genome Project dataset (The cBio Cancer Genomics Portal, http://www.cbioportal.org, Feb 2013).
Constitutive activation of KRAS leads to activation of the RAF/MEK/ERK pathway, leading to
tumorigenesis (Pylayeva-Gupta et al., 2011; 21993244). Therefore, tumors with activating mutations in
KRAS may be sensitive to inhibitors of this pathway. Both the KRAS-targeting reovirus Reolysin and
specific MEK inhibitors are under investigation for tumors bearing KRAS mutations. Activating mutations
in KRAS have been associated with resistance to Egfr inhibitors in colorectal carcinoma; however, this
relationship has not been a significant subject of study in soft tissue sarcoma (Lièvre et al., 2006;
• 유전자(단백질)의 기능 및 암 발병에서 메커니즘 소개
• CCND2는 cell cycle 조절 단백질인 cyclin-dependent kinase을 조절하는 cyclin D2를 발현
• PI-3-kinase의 cancer signaling pathway 의 downstream target 임 (레퍼런스)
• 유전 변이가 해당 암종에 대해 DB/논문에 어떻게 보고 되어 있는지 설명
• cBio Cancer Genomics Portal: sarcomas의 2.4%에서 CCND2 amplification이 보고 됨
• 논문
• CCND2 변이가 sarcomas와 관련하여 논문에서 보고된 바 없음
• Cyclin D2의 과발현은 몇가지 종류의 sarcomas에 대하여 보고된 바 있음 (레퍼런스)
• 유전 변이가 단백질/메커니즘에 어떠한 영향을 미치는지 설명
• Cyclin D2의 발현저하는 NSCLC stage III에서 생존률을 떨어뜨림 (레퍼런스)
• CCND2의 발현은 13 metastatic & 18 non-metastatic neuroendocrine tumors의 전이성 저하에
• 유전 변이에 효과가 있는 약물 (승인/임상)에 대한 간략한 소개
• CCND2 amplification을 타겟으로 하는 승인 받은 약물은 없음
• 몇몇 preclinical study가 cyclin D2가 CDK4와 관련이 있고, CDK4/6 저해제에 효과가 있을 수도 있음
• CDK4/6 저해제는 몇몇 암종에 대하여 임상 시험이 진행 중임
43. • 유전자(단백질)의 기능 및 암 발병에서 메커니즘 소개
• ARID1A는 SWI/SNF chromatin remodeling complex의 단백질을 encoding 함
• ARID1A 는 tumor suppressor 로 생각되며, 이 유전자의 deletion이나 비활성화는 종양 형성을 유발
• 유전 변이가 단백질/메커니즘에 어떠한 영향을 미치는지 설명
• ARID1A Q633* 는 단백질의 premature truncation을 유도하며, PPI에 중요한 LXXLL motifs의 loss유도
• 따라서, 이 유전변이는 단백질의 비활성화를 유도할 것으로 예측됨 (레퍼런스)
• 유전 변이가 해당 암종에 대해 DB/논문에 어떻게 보고 되어 있는지 설명
• COSMIC:ARID1A 변이가 6%의 폐암에서 보고 됨 (6% lung adenocarcinoma, 7% lung squamous cell carcinoma)
• 유전 변이에 효과가 있는 약물 (승인/임상)에 대한 간략한 소개
• Preclinical Data에 의하면 ARID1A는 tumor suppressor 의 기능을 한다는 것을 뒷받침
• 몇몇 암종에서는 ARID1A의 발현 감소가 세포독성치료의 저항성과 관련이 있음 (레퍼런스)
• 현재,ARID1A의 loss를 표적으로 하는 표적치료제는 없음
44. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 4 of 11
THERAPIES
There are no therapies FDA approved in this patient's tumor type that are specific to the reported genomic alterations.
ADDITIONAL THERAPIES – FDA APPROVED IN OTHER TUMOR TYPES
THERAPY RATIONALE
Everolimus
Everolimus is an orally available mTOR inhibitor that has been approved for use in renal cell carcinoma,
pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with TSC, and
hormone receptor positive, HER2 negative advanced breast cancer. Preclinical data suggests that NF2
loss may be associated with sensitivity to rapamycin, which is similar in mechanism of action to
everolimus (Lopez-Lago et al., 2009; 19451229, James et al., 2009; 19451225). Everolimus is currently
being tested in clinical trials in several tumor types. A Phase 1 trial of everolimus and figitumumab, an
IGF-1R inhibitor, in sarcomas and other solid tumors showed that the combination was safe and well-
tolerated, with a partial response in 1/18 patients and stable disease in 15/18 patients (Quek et al., 2011;
21177764).
Lapatinib
Lapatinib is a dual tyrosine kinase inhibitor, targeting both Egfr and Her2 (Erbb2). It has been approved
for use in metastatic breast cancer. Mutation of NF2 may lead to Egfr and/or Erbb2 activation; lapatinib
inhibits Egfr and Erbb2 and has shown preclinical activity in NF2 deficient vestibular schwannoma
(Ammoun et al., 2010; 20511180). Lapatinib is currently in clinical trials in multiple solid tumor types.
Temsirolimus
Temsirolimus is an intravenous mTOR inhibitor that has been approved for use in advanced renal cell
carcinoma. Preclinical data suggests that NF2 loss may be associated with sensitivity to rapamycin,
which is similar in mechanism of action to temsirolimus (Lopez-Lago et al., 2009; 19451229, James et al.,
2009; 19451225). Temsirolimus is currently being tested in clinical trials in several tumor types. A Phase
2 trial of temsirolimus as single agent in soft tissue sarcoma reported limited efficacy and moderate
toxicity, with a partial response exhibited in 2 of 40 evaluable patients (Okuno et al., 2011; 21287536). A
Phase 1 trial of temsirolimus combined with liposomal doxorubicin in recurrent and refractory bone and
soft tissue sarcoma patients reported that the combination treatment is safe and demonstrates sufficient
preliminary efficacy to pursue the Phase 2 portion of the study (Thornton et al., 2013; 23382028).
Genomic alterations detected may be associated with activity of certain FDA approved drugs, however the agents listed in this report may have little or
no evidence in the patient’s tumor type
45. • 약의 유형 및 표적 소개
• Erlotinib 은 저분자 화합물 (small molecule) 약으로
• EGFR의 타이로신 활성효소 억제제 (tyrosine kinase inhibitor)임
• 약의 FDA 승인 적응증
• NSCLC (비세포성 폐암) 및 췌장암에 승인 되었음
• 해당 유전 변이에 대한 약의 효과 설명
• EGFR 활성화 유전변이가 있는 환자들에게서, erlotinib 의 투여는 암의 진행 속도를 늦추는 효과를 나타냄 (ref)
• (폐암에 대한) 약의 임상 시험 과정 및 결과
• NSCLC에 대한 erlotinib의 승인은 무작위 임상 3상에서 표준항암치료에 비해 생존기간(OS)의 연장에 근거하였음 (ref)
• 몇번의 무작위 임상 3상에서 EGFR 양성 환자들에 대하여, 무진행 생존률(PFS)이 표준치료에 비해 유의미하게 연장됨 (ref)
• 해당 유전 변이의 약에 대한 저항성 설명
• 다른 EGFR 활성화 변이와는 달리, 어떤 exon 20 변이는 (전)임상 시험에서 EGFR 타이로신 활성효소 억제제에 대한 저항성을 보였다.
• Exon 20 insertion 변이의 경우 어떤 환자들에게서는 EGFR 저해제를 투여했을 경우 질병이 더 진행되지 않았다.
46. • (폐암에 대한) 약의 임상 시험 과정 및 결과
• 처음 임상시험에서는 무작위 NSCLC 환자에 대하여 위약 대비 생존율에 대한 유의미한 효과를 보이지 못하여, 임상 실패
• 하지만, 추우에 EGFR 변이 환자들에게 항암요법과 병용투여하였을 경우 생존율에 유의미한 차이를 보인 결과 (승인 받음)
47. Patient Name
Lee, Cheol
Report Date
26 February 2013
Soft tissue
sarcoma (NOS)
THERAPIES
There are no therapies FDA approved in this patient's tumor type that are specific to the reported genomic alterations.
ADDITIONAL THERAPIES – FDA APPROVED IN OTHER TUMOR TYPES
THERAPY RATIONALE
Everolimus
Everolimus is an orally available mTOR inhibitor that has been approved for use in renal cell carcinoma,
pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with TSC, and
hormone receptor positive, HER2 negative advanced breast cancer. Preclinical data suggests that NF2
loss may be associated with sensitivity to rapamycin, which is similar in mechanism of action to
everolimus (Lopez-Lago et al., 2009; 19451229, James et al., 2009; 19451225). Everolimus is currently
being tested in clinical trials in several tumor types. A Phase 1 trial of everolimus and figitumumab, an
IGF-1R inhibitor, in sarcomas and other solid tumors showed that the combination was safe and well-
tolerated, with a partial response in 1/18 patients and stable disease in 15/18 patients (Quek et al., 2011;
21177764).
Lapatinib
Lapatinib is a dual tyrosine kinase inhibitor, targeting both Egfr and Her2 (Erbb2). It has been approved
for use in metastatic breast cancer. Mutation of NF2 may lead to Egfr and/or Erbb2 activation; lapatinib
inhibits Egfr and Erbb2 and has shown preclinical activity in NF2 deficient vestibular schwannoma
(Ammoun et al., 2010; 20511180). Lapatinib is currently in clinical trials in multiple solid tumor types.
Temsirolimus
Temsirolimus is an intravenous mTOR inhibitor that has been approved for use in advanced renal cell
carcinoma. Preclinical data suggests that NF2 loss may be associated with sensitivity to rapamycin,
which is similar in mechanism of action to temsirolimus (Lopez-Lago et al., 2009; 19451229, James et al.,
2009; 19451225). Temsirolimus is currently being tested in clinical trials in several tumor types. A Phase
2 trial of temsirolimus as single agent in soft tissue sarcoma reported limited efficacy and moderate
toxicity, with a partial response exhibited in 2 of 40 evaluable patients (Okuno et al., 2011; 21287536). A
Phase 1 trial of temsirolimus combined with liposomal doxorubicin in recurrent and refractory bone and
soft tissue sarcoma patients reported that the combination treatment is safe and demonstrates sufficient
preliminary efficacy to pursue the Phase 2 portion of the study (Thornton et al., 2013; 23382028).
Genomic alterations detected may be associated with activity of certain FDA approved drugs, however the agents listed in this report may have little or
no evidence in the patient’s tumor type
• 약의 유형 및 표적 소개
• Everolimus는 경구 투여 가능한 mTOR 저해제이다.
• 약의 FDA 승인 적응증
• 신장암, 췌장암, HER2 음성 유방암 등에 승인 받음
• 해당 유전 변이에 대한 약의 효과 설명
• 전임상시험 데이터는 NF2 loss 변이는 everolimus와 유사한 메커니즘을 가진 rapamycin에 반응한다는 결과를 보여준다
• (폐암에 대한) 약의 임상 시험 과정 및 결과
• Everolimus는 현재 여러 암종에 대해서 임상 시험 중에 있다.
• Everolimus 와 IGF-1 수용체 저해제인 figitumumab를 병용투여했을 경우 총 18명의 환자 중,
• 1명은 부분적으로 암이 줄어들었고, 5명은 안정하게 유지되었다. (ref)
48. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
Electronically Signed by Jeffrey S. Ross M.D., Medical Director | CLIA Number: 22D2027531 | 26 February 2013
Foundation Medicine, Inc., One Kendall Square Ste B3501, Cambridge MA | 1.888.988.3639 page 5 of 11
CLINICAL TRIALS TO CONSIDER
IMPORTANT: While every effort is made to ensure the accuracy of the information contained below, the information available in the
public domain is continuously updated and should be investigated by the physician or research staff. This is not meant to be a
complete list of available trials. In order to conduct a more thorough search, please go to www.clinicaltrials.gov and use the search
terms provided below. For more information about a specific clinical trial, type the NCT ID of the trial indicated below into the search
bar.
GENE RATIONALE FOR POTENTIAL CLINICAL TRIALS
NF2
W74*
Mutation or loss of NF2 results in the dysregulation of RTK and mTOR signaling. Therefore, RTK or mTOR
inhibitors may be relevant for patients with NF2 mutations.
A search of the trial website clinicaltrials.gov, using terms such as “NF2”, "lapatinib", "mTOR" and/or "solid
tumor" retrieves more than 10 trials that may be relevant for this patient's tumor.
Examples of these trials are shown below.
TITLE PHASE TARGETS LOCATIONS NCT ID
An Open-label, Multi-center Phase I Dose-
finding Study of RAD001 (Everolimus, Afinitor®)
in Combination With BEZ235 in Patients With
Advanced Solid Tumors
Phase 1 MTOR, PI3K Missouri, Auckland (New
Zealand), Barcelona (Spain),
Bordeaux Cedex (France),
Montpellier Cedex 5 (France),
Newcastle Upon Tyne (United
Kingdom), Seoul (Korea,
Republic of), Verona (Italy),
Wilrijk (Belgium)
NCT01482156
A Phase I Study of the HER1, HER2 Dual
Kinase Inhibitor, Lapatinib Plus the
Proteosomal Inhibitor Bortezomib in Patients
With Advanced Malignancies
Phase 1 EGFR,
Her2/neu,
proteasome
District of Columbia NCT01497626
49. CLINICAL TRIALS TO CONSIDER
IMPORTANT: While every effort is made to ensure the accuracy of the information contained below, the information available in the
public domain is continuously updated and should be investigated by the physician or research staff. This is not meant to be a
complete list of available trials. In order to conduct a more thorough search, please go to www.clinicaltrials.gov and use the search
terms provided below. For more information about a specific clinical trial, type the NCT ID of the trial indicated below into the search
bar.
GENE RATIONALE FOR POTENTIAL CLINICAL TRIALS
NF2
W74*
Mutation or loss of NF2 results in the dysregulation of RTK and mTOR signaling. Therefore, RTK or mTOR
inhibitors may be relevant for patients with NF2 mutations.
A search of the trial website clinicaltrials.gov, using terms such as “NF2”, "lapatinib", "mTOR" and/or "solid
tumor" retrieves more than 10 trials that may be relevant for this patient's tumor.
Examples of these trials are shown below.
TITLE PHASE TARGETS LOCATIONS NCT ID
An Open-label, Multi-center Phase I Dose-
finding Study of RAD001 (Everolimus, Afinitor®)
in Combination With BEZ235 in Patients With
Advanced Solid Tumors
Phase 1 MTOR, PI3K Missouri, Auckland (New
Zealand), Barcelona (Spain),
Bordeaux Cedex (France),
Montpellier Cedex 5 (France),
Newcastle Upon Tyne (United
Kingdom), Seoul (Korea,
Republic of), Verona (Italy),
Wilrijk (Belgium)
NCT01482156
A Phase I Study of the HER1, HER2 Dual
Kinase Inhibitor, Lapatinib Plus the
Proteosomal Inhibitor Bortezomib in Patients
With Advanced Malignancies
Phase 1 EGFR,
Her2/neu,
proteasome
District of Columbia NCT01497626
• 이 임상시험들이 권장되는 이유
• NF2 유전자 변이나 loss는 RTK 와 mTOR 신호전달을 활성화시킨다.
• 그러므로 RTK, 혹은 mTOR 저해제가 NF2 변이 환자들에게 적용될 수 있다.
• Clinicaltrial.gov 는 NF2, lapatinib, mTOR와 solid tumor 등의 키워드에 대하여 10개가 넘는 임상시험을 보여준다.
50. Patient Name
Lee, Cheol
Report Date
26 February 2013
Diagnosis
Soft tissue
sarcoma (NOS)
CLINICAL TRIALS TO CONSIDER (CONT.)
GENE RATIONALE FOR POTENTIAL CLINICAL TRIALS
KRAS
G13D, amplification
Activating mutations in KRAS may result in activation of downstream pathways, including the MAPK
pathway. Therefore, inhibitors of MAPK pathway components, including the protein MEK, may be of use in a
tumor with a KRAS activating mutation. Additionally, the engineered reovirus Reolysin is under investigation
in clinical trials for its ability to specifically target cells bearing activated KRAS.
A search of the trial website clinicaltrials.gov, using terms such as "KRAS", "MEK", "sarcoma", and/or "solid
tumor", retrieves more than 10 trials that may be relevant for this patient’s tumor.
Examples of these trials are shown below.
TITLE PHASE TARGETS LOCATIONS NCT ID
A Phase Ib, Open-Label, Dose-Escalation
Study Evaluating the Safety, Tolerability and
Pharmacokinetics of GDC-0973 in Combination
With GDC-0941 When Administered in Patients
With Locally Advanced or Metastatic Solid
Tumors
Phase 1 MEK, PI3K Massachusetts, Michigan,
Tennessee
NCT00996892
A Phase Ib, Open-label, Multi-center, Dose-
escalation and Expansion Study of an Orally
Administered Combination of BEZ235 Plus
MEK162 in Adult Patients With Selected
Advanced Solid Tumors
Phase 1 MEK, MTOR,
PI3K
Massachusetts, Texas,
Wisconsin, Ontario (Canada),
Barcelona (Spain), Cologne
(Germany), Essen (Germany),
Victoria (Australia), Villejuif
(France)
NCT01337765
• 이 임상시험들이 권장되는 이유
• KRAS의 활성화 변이는 MAPK pathway 등의 downstream pathway를 활성화시킨다.
• 그러므로 MEK를 포함한 MAPK pathway 의 구성요소들을 저해하는 약은 KRAS 활성화 변이에 대해 사용될 수 있다.
• 또한, 임상시험 중인 reovirus Reolysin 은 활성화된 KRAS 를 가지고 있는 세포만을 저해하는 기능으로 연구되고 있다.
• Clinialtrial.gov 에는 KRAS, MEK, sarcoma, solid tumor 등으로 10개가 넘는 임상시험을 찾을 수 있다.
52. Wed Nov 5, 2014
“Google will soon start covering the cost
of Foundation Medicine's DNA tests for
employees and their family-members
suffering from cancer, as part of its
health benefits portfolio.”
53. Oct 16, 2014
“Priority Health has begun coverage
of Foundation Medicine's genomic
profiling services for cancer, making
the health plan the first in the
country to provide such coverage”
55. vs.
Steve Jobs
Apple CEO
Pancreatic Cancer
Dead
Dr. Lukas Wartman
Geneticist,Washington Univ.
Acute Lymphoblastic Leukemia
Survived
Found Nothing Actionable
from Genome
Found Something Actionable
from Genome
56. • He developed Acute Lymphoblastic Leukemia, which he studied himself.
• Recurred, 5 years after the bone-marrow transplant
• Whole genome sequencing +Transcriptome analysis
• Overexpression of FLT3 was found (FLT3: cell growth, proliferation)
• Sutent (sunitinib), which was approved for Kidney cancer, inhibits FLT3
• ALL was successfully treated by Sutent, the Kidney cancer drug.
Dr. Lukas Wartman
http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?pagewanted=all&_r=0
57. ‹›
• June, 2010: 53 y.o. female diagnosed with metastatic
inflammatory breast cancer (IBC) involving liver and bone
• Initial therapies: docetaxel, carboplatin and trastuzumab –
achieved some improvement
• Disease progression within 12 months
• April - November, 2011: Numerous additional drug
regimens attempted
• November, 2011: Rapid progression of disease
24
Case Presentation 2: FMI vs ‘Limited’ Testing
Foundation Medicine,“Next Generation Sequencing in the Clinic - The First 2200+ Cases Lessons Learned”
58. ‹›
FoundationOne® Report – Profiling the Genome
25
Foundation Medicine,“Next Generation Sequencing in the Clinic - The First 2200+ Cases Lessons Learned”
59. ‹›“Common” Mutation Identified
• EGFR Exon 21 L858R point mutation identified
– Associated with unprecedented sensitivity to EGFR-TKIs
such as gefitinib (Iressa) and erlotinib (Tarceva)
• Present in 10% of lung adenocarcinomas
• NOT reported with reproducible frequency in other
tumor types → NO clinical testing done
• Broad based, highly sensitive NGS test
(FoundationOne) identifies a transforming lesion in
this advanced IBC
26
Foundation Medicine,“Next Generation Sequencing in the Clinic - The First 2200+ Cases Lessons Learned”
61. ‹›
Left Supraclavicular Lesion: PET-CT
Sept, 2012 Nov, 2012
Response Assessment After Starting Erlotinib
27
Foundation Medicine,“Next Generation Sequencing in the Clinic - The First 2200+ Cases Lessons Learned”
63. Genomics
WGS, WES
Transcriptomics
RNA-Seq
Epigenomics
Bisulfite-Seq
ChIP-Seq
Smallindels
point mutation
Copy number
variation
Structural
variation
Differential
expression
Gene fusion
Alternative
splicing
RNA editing
Methylation
Histone
modification
Transcription
Factor binding
Functional effect
of mutation
Network and
pathway analysis
Integrative analysis
Furtherunderstandingofcancerandclinicalapplications
Technologies Data Analysis Integration and interpretationPatient
Figure 1 The workflow of integrating omics data in cancer research and clinical application. NGS technologies detect the genomic,
transcriptomic and epigenomic alternations including mutations, copy number variations, structural variants, differentially expressed genes, fusion
Shyr and Liu Biological Procedures Online 2013, 15:4 Page 2 of 11
http://www.biologicalproceduresonline.com/content/15/1/4
The workflow of integrating omics data
in cancer research and clinical application
Shyr D, Liu Q. Biol Proced Online. 2013 Feb 13;15(1):4.
64. C A N C E R
Personalized Oncology Through Integrative
High-Throughput Sequencing: A Pilot Study
Sameek Roychowdhury,1,2
* Matthew K. Iyer,1,3
* Dan R. Robinson,1,4
* Robert J. Lonigro,1,3
Yi-Mi Wu,1,4
Xuhong Cao,1,4,5
Shanker Kalyana-Sundaram,1,4,6
Lee Sam,1,3
O. Alejandro Balbin,1,3
Michael J. Quist,1,4
Terrence Barrette,1,4
Jessica Everett,7
Javed Siddiqui,1,4
Lakshmi P. Kunju,1,4
Nora Navone,8
John C. Araujo,8
Patricia Troncoso,8
Christopher J. Logothetis,8
Jeffrey W. Innis,9
David C. Smith,2,10
Christopher D. Lao,2,10
Scott Y. Kim,11
J. Scott Roberts,11,12
Stephen B. Gruber,2,10
Kenneth J. Pienta,1,2,10,13
Moshe Talpaz,2,10
Arul M. Chinnaiyan1,3,4,5,13†
Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies cur-
rently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying
high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who
were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted
whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to
identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach,
we detected several classes of cancer mutations including structural rearrangements, copy number alterations,
point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated
on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human
prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review
the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we
identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression
of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic
point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8
amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogen-
activated or extracellular signal–regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors,
respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive,
individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.
INTRODUCTION
The management of patients with cancer is well suited to a personal-
ized approach, as reinforced by recent genomic studies that reveal a
disease composed of numerous heterogeneous mutations. Although
hallmark mutations such as inactivation of TP53 or activation of
BRAF occur frequently, they often appear in concert with a host of
uncommon oncogenic events. Further, expanding catalogs of cancer
mutations dispel the notion that cancer mutations are tissue-specific
(1–7). For example, activating BRAF mutations have
in more than 50% of cutaneous melanoma and papilla
cinoma, and the mutant proteins are potential tar
inhibitors (8, 9). However, BRAF mutations also occur
quency (5 to 20%) in multiple myeloma, lung cancer
cinoma, and testicular cancer (10, 11). Moreover, a lo
fraction of major targetable kinases—including PIK3C
dermal growth factor receptor), and ERBB2—may
R E S E A R C H A R T I C L E
Michigan Oncology Sequencing Project (MI-ONCOSEQ)
Roychowdhury S et al. Sci Transl Med. 2011 Nov 30;3(111):111ra121
65. Sequencing
Buccal swab
or
Blood
Sequencing Tumor
Board
Disclosure of
Results
Genetic
Counselor
Analysis 1) Actionable Results?
2) Incidental Results?
Informed
Consent
Tumor
Biopsy
Genetic
Counseling
MI-ONCOSEQ:
The Michigan Oncology Sequencing Center
Precision Medicine
Tumor Board
Clinically RelevantTimeframe
FromTissue Biopsy to Sequencing Results
Day 0 Day 27-30