MOLECULAR CLASSIFICATION OF GASTRIC CANCER IN ......MOLECULAR CLASSIFICATION OF GASTRIC CANCER IN...
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MOLECULAR CLASSIFICATION OF GASTRIC CANCER IN THE CLINICSNew Approaches
Rodrigo Dienstmann
Vall d’Hebron Institute of Oncology
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Gastrointestinal cancer molecular biology
Advisory role: RocheBoehringer-IngelheimAstra Zeneca
Speaker’s fee: RocheSymphogenIPSENAmgenServierSanofiMSD
Research support: Merck
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Gastrointestinal cancer molecular biology
Cancer Cell 2018
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Pathological classification of gastric adenocarcinoma
Lauren (1965) 1 WHO (2010) 2
Intestinal
Adenocarcinoma papilar
Adenocarcinoma tubular
Adenocarcinoma mucinous
DiffuseCarcinoma with signet ring cells
Other undifferentiated carcinomas
Indeterminate Carcinoma mixed
Intestinal type• Well-differentiated• Related to gastritis, gastric atrophy,
intestinal metaplasia• More common in in older men, East
Asia, Eastern Europe, Central and South America
• Decreasing incidence
Diffuse type – Poorly cohesive carcinoma• Undifferentiated• Related to pangastritis• More common in younger patients,
male = female• Increasing incidence• “Worse prognosis”
1. Lauren Classification 1965, 2. AJCC TNM 2010, 7th Edition
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Molecular classification of gastric adenocarcinoma
22%
8%
20% 50%
TCGA Nature 2014
TCGA – unsupervised
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Molecular classification of gastric adenocarcinoma
22%
8%
20% 50%
TCGA Nature 2014
TCGA – unsupervised
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Molecular classification of gastric adenocarcinoma
TCGA, Nature 2017
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Molecular classification of gastric adenocarcinoma
Clin Cancer Res 2017
Prognosis in early-stage gastric cancer
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Molecular classification of gastric adenocarcinoma
Nat Med 2015
22%
15%
26% 37%
Asia – semi supervised
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Molecular classification of gastric adenocarcinoma
Nat Med 2015
Prognosis in early-stage gastric cancer
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Molecular classification of gastric adenocarcinoma
Nat Rev Cancer 2016
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ASCO SITC 2017
Immune markers across molecular subtypes
IFN-Gamma Score in gastric cancer
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Molecular classification of gastric adenocarcinoma
HER2, MSI, EBV testing MSI +
EBV +
CIN HER2 ampl
(+)(-)
NGS (TP53, CDH1...)
CIN TP53 mut
no-CIN TP53 wtCDH1 alt
ESMO 2019
8%
22%
20%
15%
35%
4%
7%
18%
41%
30%
Early-stage Metastatic
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Molecular classification of gastric adenocarcinoma
Diffuse (n=26)
n=6 (23%)
n=2 (8%) n=17 (65%)
n=1 (4%)
Intestinal (n=11)
n=4 (36%)
n=4 (36%)
n=1 (9%)
n=2 (18%) CINampl CIN
GS or no-CIN)
VHIO cohort (metastatic)
ESMO 2019
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Poor outcome of MSI in advanced disease
VHIO cohort (metastatic)
ASCO 2018
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Cancer Discov 2018
Poor outcome of MSI in advanced disease
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JAMA Oncol 2018
Poor outcome of MSI with chemo in early-stage
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Nat Med 2018
Predictive markers for immune-checkpoint inhibitors
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Cancer Discov 2018
Predictive markers for immune-checkpoint inhibitors
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Annals Oncol 2019
Predictive markers for immune-checkpoint inhibitors
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Immune markers across molecular subtypes
VHIO cohort (metastatic)
ESMO 2019
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DNA damage repair alterations in advanced disease
VHIO cohort (metastatic)
ESMO 2019
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JAMA Oncol 2019
Predictive markers for immune-checkpoint inhibitors
TMB (MSI), PDL1 expression and hot immune microenvironment (IFN Gamma) explain 80% of responses to immunotherapy across solid tumors
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Cancer Discov 2017
Spatial and temporal molecular heterogeneity
Significant discrepanciesWithin the primary tumorBetween the primary tumor and metastasis
PANGEA Trial (28 pts)32% discordance between primary tumor
and metastasis85% concordance within metastatic lesions
and cfDNA
Potential use of cfDNA as a biomarker
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Cancer Discov 2017
Spatial and temporal molecular heterogeneity
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ASCO 2018
Spatial and temporal molecular heterogeneity
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Annals Oncol 2019
Spatial and temporal molecular heterogeneity
HER2 positive gastric cancer
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Conclusions
• Substantial inter-tumor molecular heterogeneity of gastric cancer
• EBV positive tumors excellent prognosis with standard therapy early-stage disease
• MSI tumors worse prognosis with standard therapy advanced disease
• EBV positive and MSI tumors are highly responsive to checkpoint inhibitors
• Other tumors may also respond to anti-PD1/L1 (highly enriched for TMB high, PDL1 positive and/or IFNG positive signature)
• Predictive value of CIN vs. GS (Mesenchymal) tumors remains to be studied
• Intra-tumor molecular heterogeneity of gastric cancer may have therapeutic implications (HER2 amplification may be lost after trastuzumab)
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Acknowledgements
Josep TaberneroAndres CervantesFatima Carneiro
Maria Alsina