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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.