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Rafael Rosell,
Cancer Research Laboratory, Dr. Rosell
Germans Trias i Pujol Research Institute and Hospital
Badalona, Barcelona, España
Predicting post-operative recurrence of NSCLC
In partnership with
Chairpersons: Luis Léon & Jorge García Scientific Organizer: Rafael López López
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Each metastasis is a disease on its own (Angelova et al Cell 2018)
What to do in the clinical practice? • Bespoke Oncoprint
-Acquired SETD2 mutations to cisplatin -Acquired KEAP mutations to EGFR TKI
• Clearance of lung cancer- NKG2D-activating receptor on NK cells
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• Low frequency of early resected NSCLC
• Limited efficacy of adjuvant therapies Chemotherapy
Promotes metastasis via MENAINV
Promotes HIF1α, CD47
EGFR TKIs Promotes STAT3, SRC, FAK and YAP1 Promotes ALDH+ cancer cells
ICB
Lack of effect in tumor re-population cells o IDO-kynurenine-AhR metabolic circuitry o Natural killers expressing NKG2D, NKP46
• Bespoke Oncoprint
KRAS wtLKB1 -> ICB EGFR -> combinatory therapy BRAF - > combinatory therapy Driver fusions - > combinatory therapy Others (without LKB1 or KEAP mutations) - > ICB + CDK4/6 inhibitors ICB + chemotherapy? Avoid, if possible
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All lung cancer patients are at risk for recurrence following complete surgical resections. Risk increases with stage. The most frequent & concerning form of recurrence after complete resection is metastasis. Therapies to prevent recurrence must address the threat of metastasis. Cisplatin-based chemotherapy administered either before or after surgery improves survival. Cisplatin-based chemotherapy administered before surgery does not enhance resectability or permit lesser resections. Radiation combined with cisplatin-based chemotherapy does not likely enhance resection rates or survival beyond chemotherapy alone and adds toxicity. Radiation combined with cisplatin-based chemotherapy may provide benefits based on stage and the location of the tumor. Immune checkpoint blockade and oncogene-targeted drugs are appropriate for investigation as neoadjuvant therapies because of their established efficacy and safety in the metastatic setting, and preliminary signals of activity in earlier stages. Perioperative collection and storage of blood, high resolution CT and PET/CT images, and digital pathologic images are important for studying emerging technologies using artificial intelligence
Blumenthal et al JTO 2018, Rockville Consensus Meeting, March, 2018
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See also“..Major changes on eighth edition cancer staging..” Rami-Porta, Asamura, Travis and Rusch, CA Cancer J Clin 2017
Navani et al, on behalf of the NSCLC collaborative Group CHEST 2018
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Provisos and limitations of adjuvant therapies
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Rosell and Karachaliou EbioMedicine 2018
Chemotherapy can promote metastasis
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C. Codony-Servat Oncotarget 2017
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Pennell et al (Sequist) JCO 2018 Zhong et al (Wu) Lancet Oncology 2018
Adjuvant erlotinib in EGFR mutant NSCLC Adjuvant/CTONG1104
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Somatic mutations in lung adenocarcinoma: Co-mutation plot
The Cancer Genome Atlas Research Network, Nature 2014
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Park et al FASEB 2018 EGFR TKI resistance mediated by KEAP1 mutations
Zebrafish (Danio rerio) injected with HCC827GRKU cells labeled with the flourescent cell tracker CM-Dil
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Bespoke Oncoprint in plasma DNA of early resected NSCLC
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Nature thanks S. Lippman, R. Rosell and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Abbosh et al Nature 2017
Bespoke multiplex-PCR panels were synthesized for each patient targeting clonal and sub-clonal SNVs
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Chaudhuri et al (Diehn) Cancer Discov 2017
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ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months. 53% of patients had ctDNA mutation profiles linked with favorable response to TKIs or ICB.
Chaudhuri et al (Diehn) Cancer Discov 2017
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Lam et al (Heymach) WCLC, Toronto, 2018
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20
32
18
25
7
30
4
47
94
94
53
7
79
0
85
2
12
12
13
04
13
67
15
84
17
01
18
50
20
54 20
61
21
64
21
85
22
50
22
72
22
72
0 500 1000 1500 2000
Nonsense
Synonymous
Missense
Frameshift
ARID1A = 2285 aa
ARID domainaa 1016-1124
HIC1 binding domainaa 1355-1424
GR binding domainaa 1635-2285
Karachaliou, Bracht, Rosell, J Thor Oncol, Dec, 2018
0
1
2
3
4
5
6
7
8
NCI-H460 A549 Hs746T NCI-H596
Rel
ativ
e A
RID
1A
mR
NA
ex
pre
ssio
n
KRAS-mutated cell lines
MET exon 14-mutated cell lines
**
0,0
0,5
1,0
1,5
1 2
Co
mb
inat
ion
Ind
ex
1.5
1.0
0.5
0.0
AZD6738+ Tepotinib Selumetinib
NCI-H460Hs746T
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Oncoprint in Squamous cell carcinoma of the lung
Lack of studies in plasma DNA
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Teixeira et al Nat Med 2019
Lung carcinoma in situ (CIS) lesions precursor to LSCC
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Circos diagram comparing CIS genomic profiles with TCGA LSCC data
Teixeira et al Nat Med 2019
TP53, CDKN2A, SOX2 and AKT2 FAT1, KMT2D, KEAP1, EGFR and NOTCH1
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LSCC
Dotto and Rustgi Cancer Cell 2016
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Li et al..Baselga, Cancer Cell 2018
Genomic alterations causing YAP activation leads to CDK6-mediated resistance. FAT1 deletion and truncated mutations – PFS of 2.4 months in patients receiving CDK4/6i.
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Cristescu et al Science 2018
KEYNOTE Clinical data sets, Merck
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Predicting immunotherapy response
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Niemeijer et al Nat Comm 2018 Tumor PDL1 expression < 1%. Heterogeneous tracer uptake in the tumor with 89Zr-nivolumab PET
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Mayo de las Casa et al (Molina-Vila) Trans Cancer Res 2019
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Mayo de las Casa et al (Molina-Vila) Trans Cancer Res 2019
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Conclusions
Provisos in early stage NSCLC • TNM is relevant • Adjuvant chemotherapy could be noxious
SETD2 mutations MENAINV
• Adjuvant single EGFR TKI Enrichment of cancer stem cells Cancer cell rewiring
• Adjuvant immunotherapy: NKG2D and other receptors on NK cells is promising
Monitoring plasma DNA warranted, according to bespoke Oncoprint
• NGS and Nanostring
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BACK UP
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Patchwork plots from each donor in a 1-cm square area of normal esophageal epithelium from each donor. A number of samples from the donor were selected to amount to 1cm2 of tissue.
Martincorena et al Science 2019
Rustgi and Serag NEJM 2014
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Pennell et al (Sequist) JCO 2018
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Kadi et al (Hassan) Cancer Res 2018
Activation-induced cytidine deaminase (AICDA) generates T790M mutations
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Martin et al, Nat Comm 2018
Thousand-and-one amino acid kinase (TAOK)
(Han et al Oncogene 2018)
See also: Lin et al Carcinogenesis 2018
KD of PKCι increases YAP binding to AMOT (Justilien et al, Oncogene 2017)
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Abbosh et al Nature 2017
Nature thanks S. Lippman, R. Rosell and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Corcoran and Chabner NEJM 2018
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NGS analysis of early stage surgical biopsy samples
EC
(n=50)
CRC
(n=12)
Patient number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19EGFR
KRAS
BRAF
PIK3CA
NRAS
KIT
PDGFRA
ALK
ERBB2
ERBB3
ESR1
RAF1
Patient number
1 2 3 4 5 6 7 8 9 10 11 12EGFR
KRAS
BRAF
PIK3CA
NRAS
KIT
PDGFRA
ALK
ERBB2
ERBB3
ESR1
RAF1
Patient number
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
EGFR
KRAS
BRAF
PIK3CA
NRAS
KIT
PDGFRA
ALK
ERBB2
ERBB3
ESR1
RAF1
NSCLC
(n=19)
KRAS
hotspot mutation
Non hotspot mutation
hotspot and non-hotspot mutations
PIK3CA
hotspot mutation
Non hotspot mutation
hotspot and non-hotspot mutations
Molina-Vila 2019
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Gwinn et al Cancer Cell 2018
SLC7A11 induced by NRF2
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Iyer et al Cell 2018 Liu et al Nat Comm 2017
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Hunger and Mullighan NEJM 2015
Overall survival among children with ALL
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Bases of Bespoke Oncoprint (Abbosh et al Nature 2017) Relapse of ALL. Subclones with acquired mutations confer resistance to chemotherapy (Hunger and Mullighan NEJM 2015).
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Sayar et al Ann Thorac Surg 2004
Perineural invasion in Stage I NSCLC
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Depression related to cancer observational study: DeCa
Protocol Number: Version Number: 1.0
Version Date: 2018-07-09 Principal Investigator
Rafael Rosell MD Institute of Oncology Rosell
Co-Investigators Manuel Fernandez-Bruno
Niki Karachaliou
ELBA
European
Liquid Biopsies
Academy
Patient Health Questionnaire
(PHQ)-9
ADRB2
norepinephrine
ERK
NGFBDNF
PKA
IL6
STAT3
paxillin/FAK
epinephrine
Exosomes released in BLOOD
TRK receptorsNGF
BDNF
PSYCHOLOGICAL DISTRESS
nerve
Blood vessels
axonogenesis
tumor cell
Exosomes released in URINE
300 METASTATIC CANCER PATIENTS
100 EARLY-STAGE CANCER PATIENTS
CON
TRO
LS
Tissueif available
FIRST VISIT
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100 metastatic lung cancer patients
PHQ-9
Bas
elin
e ti
ssu
e
if a
vaila
ble
Baseline, at best response, at the time of progression
At the first visit
NCounter (custom-designed 200 gene panel)
ADRB2, NGF, BDNF, TrkB, FAK, etc
No depression
Mild depression
Moderate depression
Moderately severe depression
Severe depression
High expressors
Moderate expressors
Low expressors
Covariates to be adjusted: smoking, exercise, food, alcohol
sele
ctio
n o
f b
iom
arke
rs
Depression related
Non-depression related
Transfection of Ba/F3 cell lines with the 2 groups of genes
Identification of genes with oncogenic potential/drug testing
(e.g TPX-0005)
Targeted gene expression in zebrafish→ metastasis, migration,
invasion/therapies
In culture
In vivo
24 mo 36 mo
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MSK-IMPACT in 860 LUADs
Jordan…Drilon…Baselga Cancer Discov 2017
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Paired blood, lavages and tumor surgical samples
Molina-Vila 2019
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Hotspot variants detected by PNA Taqman Assay in blood versus pleural or peritoneal lavages
N= 6 Detected
Detected 2 (33.3%)
No detected 4
Detected 1 (16.7%)
No detected 5
Surgery biopsy LC samples
Plasma (cfDNA)
Pleural lavage (cfDNA)
Molina-Vila 2019
N= 19 Detected
Detected 9 (47,4%)
No detected 10
Detected 2 (10,5%)
No detected 17
Peritoneal lavage (cfDNA)
Plasma (cfDNA)
Hotspots in Surgery biopsy EC samples
N=7 Detected
Detected 2 (28.6%)
No detected 5
Detected 1 (14.3%)
No detected 6
Hotspots Surgery biopsy CRC patients
Peritoneal lavage (cfDNA)
Plasma (cfDNA)
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André et al Cell 2018
Shi et al PNAS 2018 Deng et al Science 2015
NKG2D promotes NK activation and tumor rejection (Guerra et al Immunity 2008)