ESMO Preceptorship Gastrointestinal Tumours Valencia October 2017

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1 ESMO Preceptorship Valencia October 2017 Gastrointestinal Tumours

2 I have no conflicts of interest to declare Fátima Carneiro ESMO Preceptorship Gastrointestinal Tumours Pathology and carcinogenesis

3 Gastrointestinal tumours Multidisciplinary management, standards of care and future perspectives Molecular events and classification in gastric cancer Hereditary gastric cancer Fátima Carneiro IPATIMUP & Medical Faculty/Centro Hospitalar São João Porto, Portugal

4 Host susceptibility Environment Molecular events Gastric carcinoma 1. Molecular features of different types of gastric carcinoma 2. Hereditary gastric carcinoma 3. Conclusions: a tentative, global picture

5 1. Molecular features of different types of gastric carcinoma 2. Hereditary gastric carcinoma 3. Conclusions: a tentative, global picture Sporadic cancer Hereditary cancer Molecular pathology

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7 Classification of gastric cancer WHO 4th Edition, 2010

8 4-1 Gastric carcinoma Gregory Y. Lauwers Fátima Carneiro David Y. Graham Maria-Paula Curado Silvia Franceschi Elizabeth Montgomery Masae Tatematsu Takenori Hattori Papillary Mucinous Tubular Mixed Poorly cohesive Poorly cohesive (signet ring cell) ICD-O Code Adenocarcinoma 8140/3 Papillary adenocarcinoma 8260/3 Tubular adenocarcinoma 8211/3 Mucinous adenocarcinoma 8480/3 Poorly cohesive carcinoma 8490/3 (Signet-ring cell carcinoma and variants) Mixed carcinoma 8255/3 WHO 4th Edition, 2010

9 Classification of gastric cancer Carneiro F, Grabsch H: Pathogenesis of gastric cancer. In: Minimally Invasive Foregut Surgery for Malignancy: Principles and Practice. Steven N Hochwald and Moshim Kukar (eds). Springer 2015, pp ISBN:

10 Tubulo-papillary ca. (WHO) Intestinal carcinoma (Lauren) Poorly cohesive/signet ring ca. (WHO) Diffuse carcinoma (Lauren) HER2 MSI CDH1 gene Elderly patients, mainly males Decreasing incidence everywhere Blood-born metastases Young patients, mainly females Familial/hereditary conditioning Dissemination to the peritoneum

11 E-Cadherin/CDH1 changes Somatic mutations 1 st HIT Mutation (50% - 70%) 2 nd HIT LOH Diffuse carcinoma Promoter methylation

12 Mixed Gastric carcinoma Laser microdissection CDH1 mutations: 83% Diffuse component Intestinal component CDH1 mutations: 17% E-cadherin expression CDH1 mutations E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas Machado J et al: Lab Invest 79: 459, 1999 Carvalho B et al: Cellular Oncology 28:283, 2006

13 HER-2 in gastric carcinoma HER-2 Prognostic factor YES (56%) NO (44%) HER-2 amplification in intestinal-type gastric carcinoma Blood born metastases Poor prognosis David L et al; Mod Pathol 5:384, 1992 Barros-Silva J et al; Br J Cancer 100: 487,2009 ToGA Trial HER-2 overexpression in 22% of advanced gastric cancers; improved survival in patients treated with with trastuzumab ASCO 2009 (LBA 4509)

14 Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer Kanayama K et al; Cancer Sci 107: 536, 2016

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17 Survival of patients MSI in gastric carcinoma Molecular marker of good prognosis in sporadic gastric cancer (caused byhmlh1 promoter hypermethylation) Univariate analysis Multivariate analysis Staging (ptnm) (p< ) Venous invasion (p= 0.004) Histological classification (p=0.08) Microsatellite instability (p=0.04) Seruca R et al. Int J Cancer 64: 32, 1995 Santos N et al. Gastroenterology 110: 38, 1996 Oliveira C et al. Am J Pathol 153: 1211, 1998

18 Mismatch Repair Deficiency (MMRd) (Immunohistochemistry) Microsatellite Instability (MSI) Next Generation Sequencing (NGS) Instability signatures (Fluorescent Multiplex PCR) Instability burden (correlation with overall survival)

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20 New findings? Genes related to RTK/RAS signaling (FGFR2, KRAS, HER2, EGFR and MET) are frequently amplified in gastric carcinoma in a mutually exclusive manner. KRAS amplifications associated with adverse prognosis. Deng N et al, Gut 61:673, 2012

21 Virchows Arch DOI /s y

22 Mesenchymal Proliferative Metabolic CHC (Consensus hierarchical Clustering) & IFS (Iterative feature Selection) Lauren s classification Diffuse (58.2%) Intestinal (73.6 %) Intestinal (53.6 %) Diffuse (40.6%) Sensitive to mtor inhibitors Copy number alt. (CNA) Low CNA High CNA Methylation Hyper methylation Hypo methylation Sensitive to 5-FU TP53 mutations Low High Low Lei Z et al. Gastroenterology 2013 [Epub ahead of print] Pathway activation EMT, TGF-β, VEGF, NFkB, mtor, CSC E2F, MYC, RAS SPEM - (TFF2 expressing metaplasia) Gastric differentiation

23 Intestinal type Gastric type The dawn of phenotypic classification Gastric adenocarcinoma Gastric dysplasia Nogueira AM et al. J Pathol 187: 541, 1999 Nogueira AM et al. Cancer 86: , 1999 Endoh et al. J Pathol 191: 257, 2000 Kushima R et al: Gastric Cancer 9:177, Valente P: gastric Cancer 18: , 2015

24 Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype Japanese classification Oue N et al; Cancer Sci 106:951, 2015

25 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Oue N et al; Cancer Sci 106:951, 2015 Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype

26 Normal gastric mucosa Weeks Superficial gastritis Years Chronic atrophic gastritis Intestinal metaplasia SPEM metaplasia Dysplasia (intestinal phenotype) Dysplasia (gastric phenotype) Adenocarcinoma (intestinal phenotype) Adenocarcinoma (gastric phenotype) Proliferative genotype? Metabolic genotype?

27 The Cancer Genome Atlas (TCGA) project; Nature 2014

28 Asian Cancer Research Group

29 Survival Pattern of recurrence TCGA, Singapore & ACRG cohorts

30 A protein and mrna expression-based classification of gastric cancer EBBER PD-L1 Setia M et al; Modern Pathology 29:772, 2016

31 Am J Surg Pathol 41:106,2017

32 EBV infection (66.7%) Gastric Cancer with Lymphoid Stroma Younger patients Proximal location /gastric stump MSI-H status (16.7%) Better overall survival Expansive growth Lesser venous/ lymphatic invasion Lower ptnm stage Lauren classification: Indeterminate What is new? Tumour immune microenvironment CD8/CD3R significantly associated with EBV infection PD-L1/PD-1 immune inhibitory checkpoint PD-L1 expression (33.3%) restricted to EBV+ and MSI-H GCLS Targeted therapies?

33 EBV infection & immune response The tumour microenvironment

34 Jiang et al; Ann Oncol 2016 [CD3-IM; CD3-TC; CD8-IM; CD45RO-TC (lymphocytes); CD66b (eosinophils)] High-Isgc Low-ISgc

35 PD-L1 in gastric cancer EBV MSI H&E EBBER Gullo I et al; Virchows Arch: suppl, 2016 PD-L1

36 Host susceptibility Environment Molecular events Gastric carcinoma 1. Molecular features of different types of gastric carcinoma 2. Hereditary gastric carcinoma 3. Conclusions: a tentative, global picture

37 Gastric cancer in familial/hereditary cancer syndromes Syndromes Genetic alterations Lynch syndrome (HNPCC) Li-Fraumeni syndrome Peutz-Jeghers syndrome Familial adenomatous polyposis MMR TP53 STK1 APC

38 Precursor lesions Sporadic cancer Hereditary cancer Molecular pathology

39 Gastric cancer Sporadic cancer (90%) Familial cancer (10%) Familial Gastric Cancer (FGC) Familial Intestinal Gastric Cancer (FIGC) Familial Diffuse Gastric Cancer (FDGC) Hereditary cancer (1%)

40 Maori kindred E-cadherin gene (CDH1) *germline mutations Hereditary Diffuse Gastric Cancer (HDGC) Guilford P et al. Nature 392:402,1998 *Gene map locus: 16q22.1 (MIM ID )

41 1998/9 E-cadherin & gastric cancer (sporadic and hereditary) Cleft lip/palate and CDH1 mutations in families with HDGC First Portuguese family with HDGC - Model of development of HDGC - Functional analyses of E-cadherin (CDH1) germline missense mutations - Second hit E-cadherin gene (CDH1) inactivation (promoter methylation) in sporadic diffuse gastric carcinoma - Familial gastric cancer: overview and guidelines for management. (IGCLC) Prophylactic gastrectomies in asymptomatic carriers of germ-line E- cadherin mutations 2010/11/12/13/14/15/16/ Second hit of CDH1 inactivation NMD mrna surveillance downregulates aberrant CDH1 transcripts - E-cadherin repressors in gastric ancer - Novel germline CDH1 mutations - Experimental model in Drosophila Int J Surg Pathol 6: 135, 1998 Histopathology 35: 477, 1999 Lab Invest 79: 459, 1999 J Med Genet 36: 873, 1999 N Engl J Med 344:1904, 2001 Oncogene 20: 1525, 2001 Gastroenterol Clin Biol 25: 931, 2001 Hum Mutat 19:510, 2002 Hum Mol Genet 12: 575, 2003 Hum Mol Genet 12: 3007, 2003 Oncogene 22:5716, 2003 J Pathol 203: 681, 2004 Virchows Arch 446: 18, 2005 Clin Cancer Res 11:5401, 2005 J Med Genet 43:138, 2006 J Mol Med 84:1023, 2006 Hum Mol Genet15:1704, 2006 Hum Mutat 28:203, 2007 J Pathol 211:507, 2007 Oncogene 27: 4255, 2008 J Clin Pathol 61:25, 2008 J Pathol 216:295, 2008 Gastroenterology 136:2137, 2009 J Med Genet 47: 436, 2010 PLoS One 6:e23188,2011 Cell Mol Life Sci, 2011

42 4-3 Hereditary Diffuse Gastric Cancer Fátima Carneiro Amanda Charlton David Huntsman TNM stage Tis T1a Mucos a Muscula ris mucosa Submuc osa A B WHO 4th Edition, 2010 In situ carcinoma Pagetoid spread T1a intramucosal signet-ring cell

43 HEREDITARY Germline mutations Genetic susceptibility (germline alterations)

44 Genetic susceptibility (germline alterations) Missense mutations (In vitro analysis)

45 Even more recently JAMA Oncol. doi: /jamaoncol Published online February 12, 2015.

46 Genetic susceptibility (germline alterations) Other genes; 6% CDH1 deletions; 4% CDH1 methylation; 1% CDH1 mutations; 30% CDH1 negative; 49% Oliveira C et al, Hum Mol Genet, 2009 Pinheiro H et al. Hum Mol Genet, 2010 Currently, ongoing sequencing of the full 100kb CDH1 locus in 90 HDGC patients

47 Oliveira et al; Lancet Oncology Vol 16 February 2015

48 Clinical features Familial gastric cancer: overview and guidelines for management (International Gastric Cancer Linkage Consortium) Caldas C, Carneiro F, Lynch H et al; Eur J Genet 36: 873, 1999

49 Clinical features Caldas C et al; Eur J Genet 36: 873, 1999 Fitzgerald R et ; J Med Genet 47: 436, 2010 Updated guidelines; in preparation, 2014 Familial gastric cancer: overview and guidelines for management (International Gastric Cancer Linkage Consortium) New Zealand Carriers of germline E-cadherin truncating mutations Intensive screening Prophylactic gastrectomy Europe & North America

50 Penetrance The cumulative risk of DGC for CDH1 mutation carriers by age 80 years is reported to be 70% for men and 56% for women Furthermore, the cumulative risk of LBC for women with a CDH1 mutation is estimated to be 42% by 80 years. There is currently no evidence that the risk of other cancer types in individuals with a CDH1 mutation is significantly increased. Van der Post C et al; J Med Genet 52:361,2015

51 Clinical features Clinical criteria for the identification of families with HDGC Criteria for identification of HDGC families were defined by IGCLC in 1999: 1) Two or more documented cases of diffuse gastric cancer in first/second degree relatives, with at least one diagnosed before the age of 50 2) Three or more cases of documented diffuse gastric cancer in first/second degree relatives, independently of age Caldas C, Carneiro F, Lynch H et al: Familial gastric cancer: overview and guidelines for management. J Med Genet 36: 873, 1999 IGCLC criteria for genetic testing were updated in 2010: 1) Idem 2) Idem 3) Diffuse gastric cancer before the age of 40 years without a family history 4) Families with diagnoses of both diffuse gastric cancer and lobular breast cancer, with one case before the age of 50 years Fitzgerald R et al: Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 47: , 2010

52 Van der Post C et al; J Med Genet 52:361,2015

53 Pathology Intramucosal signet-ring cell (diffuse) carcinoma

54 In situ (signet ring cell) carcinoma Pagetoid spread of signet ring cells: Two-layer structure: an inner layer composed of benign mucous cells and an outer layer of signet ring cells. TNM stage Tis T1a Mucos a Muscular is mucosa Submuc osa A B Carneiro F, Charlton A, Huntsman D 4th Edition of WHO book, 2010

55 Oliveira et al; Lancet Oncology Vol 16 February 2015

56 Pathology Hereditary Diffuse Gastric Carcinoma

57 van der Post RS, Gullo I et al; Adv Exp Med Biol 908: , 2016

58 van der Post RS, Gullo I et al; Adv Exp Med Biol 908: , 2016

59 Endoscopic biopsies HDGC Same family Same CDH1 mutation Different phenotypes van der Post RS, Gullo I et al; Adv Exp Med Biol 908: , 2016

60 Indolent phenotype van der Post RS, Gullo I et al; Adv Exp Med Biol 908: , 2016 Aggressive phenotype

61 The GAPPS syndrome (A new hereditary gastric cancer syndrome) Proximal polyposis of the stomach Fundic gland polyps

62 Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS): a new autosomal dominant syndrome. Fundic gland polyps Dysplasia Dysplasia Adenocarcinoma Genetic cause recently identified Worthley et al; Gut 61: , 2012

63 Proximal polyposis of the stomach: Fundic gland polyps (predominant) Hyperplastic (rare) Adenomatous (rare)

64 Dysplasia in fundic gland polyps

65 astric Adenocarcinoma and Proximal Polyposis of the Stomach

66 Diagnostic criteria for GAPPS i) gastric polyps restricted to the body and fundus with no evidence of colorectal or duodenal polyposis; ii) >100 polyps carpeting the proximal stomach in the index case or >30 polyps in a first degree relative of another case; iii) predominantly FGPs, some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma); iv) an autosomal dominant pattern of inheritance. Exclusions include other heritable gastric polyposis syndromes and use of PPIs. In patients on PPIs it is recommended to repeat the endoscopy off therapy.

67 Mutations were excluded in the following genes: APC MUTYH CDH1 SMAD4 BMPR1A STK11 PTEN

68 The genetic defect is now identified The American Journal of Human Genetics (2016),

69 The American Journal of Human Genetics (2016),

70 APC: Genotype Phenotype correlations Pro GAPPS (the stomach is the target) Severe FAP (the colon is the main target) Attenuated FAP (colon & stomach are the targets)

71 Mixed gastric carcinoma Repak R et al:gastrointestinal Endoscopy. doi: /j.gie

72 Hereditary gastric cancer (1 3% of the burden of stomach cancer) Hereditary Diffuse Gastric Cancer HDGC (CDH1,CTNNA1 and other genes) Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) HIGC (APC gene)

73 Thanks for your attention