Medicina Personalizada de Precisión
en el Abordaje del Cáncer Gástrico
Dra Desamparados Roda PérezHospital Clínico de ValenciaIncliva, CIBERONC
• 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
Torre LA et al. Global Cancer Statistics 2012. CA Cancer J Clin 2015; 65;87-108
Estimated new cancer cases and deaths worldwide
• 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
Gastric cancer Epidemiology
• 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
• 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
• 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
• 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
Helicobacter Pylori
• During the chronic inflammationinduced by HP varios factorsinteract to facilitate damagerepair.
• Pts develop gastric atrophyfollowed by metaplasia, that canevolve to dysplasia andadenocarcinoma.
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
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
• 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
OS at 5 years according to TNM
ESMO 2016
Esmo Guidelines 2017
Van Cutsem et al, Lancet 2016
OS advanced GC disease
ESMO 2016
Inmunotherapy ?
Evolution in GC: a multi step process
Deng 2016
• 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.
Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
Normanno et al, Nat Rev Clin
EGFR-RAS-RAF pathway
Anti-EGFR agents
Normanno et al, Nat Rev Clin
Lordick et al, Lacet Oncol. 2013; 14: 490-499.
EXPAND TRIAL
Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
HER-2 directed therapies
• 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
HER-2 directed therapies
IHC 3+ HER2 FISH HER2 positive
HER-2 directed therapies
Anti-HER2 therapy significantly prolongued survival in a selected population of pts
Bang et al. Lancet 2010; 376: 687-697.
ToGA HER2 Results and Trastuzumab Efficacy
Treatment Algorithm 1st line for GC
Mark X et al, Science 2013
New strategies blocking HER2 in Gastric Cancer
Jara et al SEOM
Cleopratra study: Pertu + Trastu Her2
HER2-double Targeting in Gastric Cancer
Tabernero J et al. Ann Oncol 2017; 28(Suppl 5): Abstr 6160
Tabernero J et al. Ann Oncol 2017; 28(Suppl 5): Abstr 6160
HER2-double Targeting in Gastric Cancer
EMILIA TRIAL: TDM1 2 line breast cancer
Anti Her2 therapy: 2nd line
Thuss-Patience et al. Lancet 2017;
18: 640-653.
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.
1. HER2 Focal Expression in GC (Heterogeneity)
Main causes of HER2 resistance
2. HER 2 evolution in GC
Main causes of HER2 resistance
Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
• Vascular endothelial growth factor (VEGF) and VEGF receptor-2 mediated
signalling and angiogenesis seem to have an important role in pathogenesis of
GC.
• In animal models of GC, anti-VEGFR2 therapy reduced tumor growth and
vascularity.
Jung et al. European Journal of Cancer 2002;38: 1133-1140.
• 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.
Fuchs CS et al. Lancet 2014;383: 31-9.
RAINBOW TRIAL
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.
Main pathways in GC:
• EGFR pathway.
• HER2 pathway.
• VEGFR therapy.
• Immunotherapy.
Rationale for PD1/PDL1 inhibition in GC
KEYNOTE-059
PDL1 not tested // OS increased 5.26 vs 4.14
PDL1 +
PDL1 +
• 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
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.