Medicina Personalizada de Precisión en el Abordaje del Cáncer Gástrico. Dra Desamparados Roda Pérez Hospital Clínico de Valencia Incliva, CIBERONC

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1 Medicina Personalizada de Precisión en el Abordaje del Cáncer Gástrico Dra Desamparados Roda Pérez Hospital Clínico de Valencia Incliva, CIBERONC

2 Gastric cancer Epidemiology 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 developed countries. Incidence and mortality remains high in developing countries. Males // Females variation 2:1 Incidence increases with age

3 Estimated new cancer cases and deaths worldwide Torre LA et al. Global Cancer Statistics CA Cancer J Clin 2015; 65;87-108

4 Gastric cancer Epidemiology 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

5 Gastric cancer Epidemiology

6 Gastric cancer Etiology 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 fresh products, dietary patterns and food storage.

7 Gastric cancer Etiology II The majority of GC are associated with infectious agents including Helicobacter 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 genetic polymorphisms ( IL1B-511*T ) Epstein Barr: -Typical lymphoid infiltrate. -5% of tumors. -men, proximal tumors, better prognosis

8 Gastric cancer Etiology III 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

9 Gastric cancer Etiology III A small minority of GC are associated with germline mutation in E-Cadherine (CDH1) or mismatch repair genes (Lynch Syndrome). Sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 gene

10 Helicobacter Pylori During the chronic inflammation induced by HP varios factors interact to facilitate damage repair. Pts develop gastric atrophy followed by metaplasia, that can evolve to dysplasia and adenocarcinoma.

11 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

12 Helicobacter Pylori In 1994 the International Investigation Agency concluded that 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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14 Clinical Management of Gastric Cancer Adequate surgical resection is the only curative therapeutic option for 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 survival of 1 year.

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16 OS at 5 years according to TNM ESMO 2016

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18 Esmo Guidelines 2017

19 Van Cutsem et al, Lancet 2016

20 OS advanced GC disease Inmunotherapy? ESMO 2016

21 Evolution in GC: a multi step process Deng 2016

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23 The Cancer Genome Atlas project published the molecular classification of Gastric Cancer in 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:

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30 Main pathways in GC: EGFR pathway. HER2 pathway. VEGFR therapy. Immunotherapy.

31 EGFR-RAS-RAF pathway Normanno et al, Nat Rev Clin

32 Anti-EGFR agents Normanno et al, Nat Rev Clin

33 EXPAND TRIAL Lordick et al, Lacet Oncol. 2013; 14:

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35 Main pathways in GC: EGFR pathway. HER2 pathway. VEGFR therapy. Immunotherapy.

36 HER-2 directed therapies

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38 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

39 HER-2 directed therapies IHC 3+ HER2 FISH HER2 positive

40 HER-2 directed therapies

41 Anti-HER2 therapy significantly prolongued survival in a selected population of pts Bang et al. Lancet 2010; 376:

42 ToGA HER2 Results and Trastuzumab Efficacy

43 Treatment Algorithm 1st line for GC

44 New strategies blocking HER2 in Gastric Cancer Mark X et al, Science 2013

45 Jara et al SEOM

46 Cleopratra study: Pertu + Trastu Her2

47 HER2-double Targeting in Gastric Cancer Tabernero J et al. Ann Oncol 2017; 28(Suppl 5): Abstr 6160

48 HER2-double Targeting in Gastric Cancer Tabernero J et al. Ann Oncol 2017; 28(Suppl 5): Abstr 6160

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50 EMILIA TRIAL: TDM1 2 line breast cancer

51 Anti Her2 therapy: 2nd line Thuss-Patience et al. Lancet 2017; 18:

52 Main findings 2nd line chemo for Her2 GC: Trastuzumab emtansine is NOT superior to Taxane as 2nd line. Thuss-Patience et al. Lancet 2017; 18:

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54 Main causes of HER2 resistance 1. HER2 Focal Expression in GC (Heterogeneity)

55 Main causes of HER2 resistance 2. HER 2 evolution in GC

56 Main pathways in GC: EGFR pathway. HER2 pathway. VEGFR therapy. Immunotherapy.

57 Vascular endothelial growth factor (VEGF) and VEGF receptor-2 mediated signalling and angiogenesis seem to have an important role in pathogenesis of GC.

58 In animal models of GC, anti-vegfr2 therapy reduced tumor growth and vascularity. Jung et al. European Journal of Cancer 2002;38:

59 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.

60 Fuchs CS et al. Lancet 2014;383: 31-9.

61 RAINBOW TRIAL

62 Main findings 2nd line chemo for GC: Ramucirumab (Anti-VEGFR2) in combination with chemotherapy increases OS as 2nd line. Wilke H et al. Lancet 2014; 15:

63 Main pathways in GC: EGFR pathway. HER2 pathway. VEGFR therapy. Immunotherapy.

64 Rationale for PD1/PDL1 inhibition in GC

65 KEYNOTE-059

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69 PDL1 not tested // OS increased 5.26 vs 4.14

70 PDL1 +

71 PDL1 +

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73 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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76 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.