Medicina Personalizada de Precisión en el Abordaje del ......• GEC should be treated by a...
Transcript of Medicina Personalizada de Precisión en el Abordaje del ......• GEC should be treated by a...
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Medicina Personalizada de Precisión
en el Abordaje del Cáncer Gástrico
Dra Desamparados Roda PérezHospital Clínico de ValenciaIncliva, CIBERONC
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• Gastric cancer is an important health problem worldwide being:
• 4th most common cancer
• 3rd cause of cancer death
• The incidence of gastric cancer is decreasing in developedcountries.
• Incidence and mortality remains high in developing countries.
• Males // Females variation 2:1
• Incidence increases with age
Gastric cancer Epidemiology
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Torre LA et al. Global Cancer Statistics 2012. CA Cancer J Clin 2015; 65;87-108
Estimated new cancer cases and deaths worldwide
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• Wide variation of incidence across countries.
• Highest incidence in:
• East Asia: Korea, Japan, Mongolia, China.
• Central and Eastern Europe
• South America
• Lowest incidence in:
• North America
• Northern Europe
• Africa
Gastric cancer Epidemiology
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Gastric cancer Epidemiology
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• Diet:
• High salt and nitrate intake
• Low in vitamins A and C
• Consumption of smoked or cured foods
• Lack of refrigerated foods
• Poor-quality drinking water
• Regional variations reflect differences in availability of freshproducts, dietary patterns and food storage.
Gastric cancer Etiology
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• The majority of GC are associated with infectious agents includingHelicobacter pylori and Epstein-Barr.
• Helicobacter Pylori:
-Most important cause of sporadic distal GC.
-Billions of people are infected only 1% will develop GC.
-This is due to the interplay between H Pylori virulence factors and geneticpolymorphisms ( IL1B-511*T…)
Gastric cancer Etiology II
• Epstein Barr:-Typical lymphoid infiltrate.
-5% of tumors.-men, proximal tumors, better prognosis
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• Occupational exposure to rubber and coal
• Cigarette smoking
• Atrophic gastritis
• Radiation exposure, prior gastric surgery
• Menetrier’s disease.
• Pernicious anemia.
• Obesity
• Aspirin and other NSAIDs ➔ lower risk of GEJ cancer.
• Type A blood
Gastric cancer Etiology III
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• A small minority of GC are associated with germlinemutation in E-Cadherine (CDH1) or mismatch repairgenes (Lynch Syndrome).
• Sporadic mismatch repair-deficient gastric cancers haveepigenetic silencing of MLH1 gene
Gastric cancer Etiology III
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Helicobacter Pylori
• During the chronic inflammationinduced by HP varios factorsinteract to facilitate damagerepair.
• Pts develop gastric atrophyfollowed by metaplasia, that canevolve to dysplasia andadenocarcinoma.
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Cytotoxin associated gene A protein
cagA + vs - is 6: 4.
β-catenin is acumulated in the nucleus, associating hyperproliferation and aberrant differentiation.
NoD1 activation by H. pylori peptidoglycan increases NF-κb, p38 y ERK.
EGFR desregulation
Polk, Gastric Cancer and Beyond 2016
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Helicobacter Pylori
In 1994 the International Investigation Agency concludedthat H Pylori was class I human carcinogen.
Treaments as HP erradication, and general improvents in people diet in last 50 years, has reduced prevalence of
H Pylori infection
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• Adequate surgical resection is the only curative therapeutic optionfor gastric cancer.
• Although most patients are diagnosed with advanced disease.
• GEC should be treated by a multidisciplinary team of:
• Medical Oncologist, Surgeons, Radiologist…
• Locally advaced disease, surgery is implemented with adjuvant,or neoadjuvant therapy.
• In metastatic disease, outcomes are poor with a median survivalof 1 year.
Clinical Management of Gastric Cancer
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OS at 5 years according to TNM
ESMO 2016
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Esmo Guidelines 2017
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Van Cutsem et al, Lancet 2016
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OS advanced GC disease
ESMO 2016
Inmunotherapy ?
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Evolution in GC: a multi step process
Deng 2016
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• The Cancer Genome Atlas project published the molecular classification of Gastric Cancer in 2014.
• They analysed 295 naïve patients.
• 6 plataformas moleculares fueron utilizadas:
• Whole exome sequencing, array-based somatic copy profiling, messenger RNA sequencing, microRNA sequencing and reverse-phase protein array.
• Integrative analysis of multiple genomic and proteomic data from GC tissues revealed four molecular subtypes.
The Cancer Genome Atlas Research Network, Nature 2014;513: 202-209.
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Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
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Normanno et al, Nat Rev Clin
EGFR-RAS-RAF pathway
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Anti-EGFR agents
Normanno et al, Nat Rev Clin
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Lordick et al, Lacet Oncol. 2013; 14: 490-499.
EXPAND TRIAL
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Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
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HER-2 directed therapies
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• HER2 is a driver key gene of carcinogenesis in GEC.
• 7-34% of tumors showing HER2 amplification or
everexpression.
• Some reports suggest HER2 + tumors are associated with
poor outcome and more agressive disease.
• Preclinical data suggested HER2 was an attractive target for
GC
HER-2 directed therapies
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HER-2 directed therapies
IHC 3+ HER2 FISH HER2 positive
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HER-2 directed therapies
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Anti-HER2 therapy significantly prolongued survival in a selected population of pts
Bang et al. Lancet 2010; 376: 687-697.
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ToGA HER2 Results and Trastuzumab Efficacy
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Treatment Algorithm 1st line for GC
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Mark X et al, Science 2013
New strategies blocking HER2 in Gastric Cancer
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Jara et al SEOM
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Cleopratra study: Pertu + Trastu Her2
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HER2-double Targeting in Gastric Cancer
Tabernero J et al. Ann Oncol 2017; 28(Suppl 5): Abstr 6160
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Tabernero J et al. Ann Oncol 2017; 28(Suppl 5): Abstr 6160
HER2-double Targeting in Gastric Cancer
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EMILIA TRIAL: TDM1 2 line breast cancer
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Anti Her2 therapy: 2nd line
Thuss-Patience et al. Lancet 2017;
18: 640-653.
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Thuss-Patience et al. Lancet 2017; 18: 640-653.
Main findings 2nd line chemo for Her2 GC:
• Trastuzumab emtansine is NOT superior to Taxane as 2nd line.
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1. HER2 Focal Expression in GC (Heterogeneity)
Main causes of HER2 resistance
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2. HER 2 evolution in GC
Main causes of HER2 resistance
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Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
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• Vascular endothelial growth factor (VEGF) and VEGF receptor-2 mediated
signalling and angiogenesis seem to have an important role in pathogenesis of
GC.
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• In animal models of GC, anti-VEGFR2 therapy reduced tumor growth and
vascularity.
Jung et al. European Journal of Cancer 2002;38: 1133-1140.
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• First trials usign anti-VEGF agents, were negative.
• Anti-VEGFR2 Ramucirumab therapy was the first biologic therapy to
produce survival benefit in an unselected population of chemo-refractory
GE cancer.
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Fuchs CS et al. Lancet 2014;383: 31-9.
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RAINBOW TRIAL
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Wilke H et al. Lancet 2014; 15: 1224-35.
Main findings 2nd line chemo for GC:
• Ramucirumab (Anti-VEGFR2) in combination with chemotherapy
increases OS as 2nd line.
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Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
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Rationale for PD1/PDL1 inhibition in GC
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KEYNOTE-059
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PDL1 not tested // OS increased 5.26 vs 4.14
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PDL1 +
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PDL1 +
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• 61 pts were included in this phase II trial
• Tissue analysis:• WES to infer TCGA subtype• RNA signature• EBV infection, EBV DNA sequence• Mutational load
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Take home messages
• GC is a heterogenous disease.
• New personalised therapies should be based on molecular
classification of each tumor.
• Immunotherapy could be effective in MSH and EBV GC.