molecular pathology: upper gi cancer · 2019. 5. 29. · hans prenen 2 revisiting pathology:...

BGDO Digestive Oncology Course 2019 Molecular pathology: upper GI cancerHans Prenen

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Hans Prenen, MD, PhDDepartment of OncologyUniversity Hospital Antwerp

Molecular pathology: upper GI cancer

Moving from pathology

Diffuse type Intestinal type


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Revisiting pathology: clinical perspectives

Bittoni A et al. PLoS One 2013

From pathology to genetics

Tan IB et al. Gastroenterology 2011

• Gene expression profiling for 37 gastric cancer cell lines• Two major intrinsic subtypes identified (171 gene set): Genomic‐Intestinal vs. Genomic‐Diffuse• Concordance between genomic (G‐INT and G‐DIF) and pathological (INT and DIF) findings: 64%


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Ready for clinical application?

Tan IB et al. Gastroenterology 2011

From pathology to genetics: molecular subtypes

Lei Z et al. Gastroenterology 2013

Mesenchymal Proliferative MetabolicDiffuse vs. Intestinal vs. Mixed

58.2% ‐ 29.2% ‐ 11.9% 17.3% ‐ 73.6% ‐9.1%

40.6% ‐ 53.6% ‐5.8%

Pathway activation EMT, TGFβ, VEGF, NF‐κB, mTOR, SHH, CSC

E2F, MYC, and RAS SPEM

Amplified genes ‐ CCNE1, MYC, ERBB2, KRAS

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Methyled CpGs, hyper vs. hypo

84.6% ‐ 15.4% 57.8% ‐ 42.2% 76.1% ‐ 23.9%

TP53mutations low high low


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TCGA: molecular subtypes

Cancer Genome Atlas Research Network. Nature 2014

≈9%

≈22%

≈20%

≈50%

TCGA: limitations

• Limited follow up for the examined patients

limitations in the interpretation of the prognostic role

• No clear distinction of different driver molecular alterations among different subgroups

anticipated limited role in the prediction of benefit from targeted agents

• Subgroups evaluated on resected specimens

different prevalence of subgroups between localized and advanced settings


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• 50% of cases• Mostly in the GEJ• Related with intestinal type and copy number gains of

chr 8q, 17q and 20q• “loss or gain of functions of some key genes (oncogene

or tumorsuppressor)”• Enriched in mutations of TP53 and RTK• Amplifications of cell cycle genese (ex Cyclin E1, …)

Key molecular events: HER2 amplification


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TOGA: trastuzumab in HER2 positive disease

Bang YJ et al. Lancet 2010

TOGA: HER-2 status and clinical parameters

Van Cutsem E et al. Gastric Cancer 2015


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Risk of inadequate selection: failure of lapatinib

LOGiC (first‐line) TyTAN (second‐line)

Hecht JR et al. ASCO Ann Meeting 2013 (LBA 4001)Satoh T et al. J Clin Oncol 2014

Risk of inadequate selection: TyTAN subgroups

Satoh T et al. J Clin Oncol 2014

PFS in HER‐2 3+ by IHC OS in HER‐2 3+ by IHC


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Her-2 status sufficient for all anti-HER-2 agents?

Second-lineGATSBY: paclitaxel vs trastuzumab emtansine, 412 patients

First‐line

JACOB: capecitabine, cisplatin and trastuzumab + / – pertuzumab, 780 patients. PUBLISHED LANCET ONCOLOGY 2018

HELOISE: capecitabine, cisplatin and 2 dose levels of trastuzumab, 400 patients. JCO 2017

FAIL

What if we do not select? Failure of anti-EGFR Abs

Waddell T et al. Lancet Oncol 2013

EXPAND (Cape + Cis +/‐ Cetuximab) REAL‐3 (EOC +/‐ Panitumumab)

Lordick F et al. Lancet Oncol 2013


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Key molecular event: KRAS and BRAF

• KRAS : < 5% og GC• BRAF: 2% (mostly V599M, unknown role)

Key molecular event: FGFR2

• FGFR2 amplification occurs in almost 10% of gastric cancer cases and is associated with higher FGFR2 expression

• Trials ongoing: ex. Dovitinib (TKI258): multitargeting oral TKI with potent inhibitory activity against bFGF receptors 1, 2, 3, VEGF receptors 1, 2, 3, PDGFR and c‐ KIT


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Key molecular event: c-MET

• MET copy number alteration and over‐expression reported in a variable number of gastric cancer cases

no standard methods for assessment

•Good correlation between gene number alteration by ISH and expr. by IHC

IHC 0 IHC 2+ IHC 3+

disomy high polysomy gene amplification

MET: negative prognostic role

Peng Z et al. PLoS One 2014


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MET and resistance to anti-EGFR/HER2

De Silva N et al. Br J Cancer 2015

• Patients with HER2+ esophago-gastric cancer treated for 10 days with lapatinib and then with XELOX + lapatinib. Endoscopic samples were taken for molecular analysis at:

baseline including for ex vivo culture +/- lapatinib to predict in vivo response post-lapatinib monotherapy at surgery

• Significant correlation between the activation of MET with the level of P-Erk and P-PI3K:T-PI3K (total PI3K) ratio MET is likely to be a significant mechanism of lapatinib resistance in vivo

MET and gastric cancer: the end of the beginning?

1Cunningham D et al. ASCO Ann Meeting 2015 (abstr. 4000)2Shah MA et al. ASCO Ann Meeting 2015 (abstr. 4012)

Study Arms (n) RR p PFS (mos)

HR OS (mos) HR

RILOMET‐11 ECX + Placebo 39.2% 5.7 11.5

ECX + Rilotumumab 30% 0.027

5.7 1.30 9.6 1.37

METGastric2 FOLFOX + Placebo 41% 6.8 11.3

FOLFOX + Onartuzumab 46% 0.253

6.7 0.90 11.0 0.82


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Key molecular event: VEGF and VEGFR-2

• VEGF frequently amplified in CIN subtype

1Ohtsu A et al. J Clin Oncol 20112Fuchs CS et al. Lancet 20143Wilke H et al. Lancet Oncol 2014

Study Arms (n) Line RR p PFS (mos)

HR OS (mos)

HR

AVAGAST1 FP + Placebo First 37.4% 5.3 10.1

FP + Bevacizumab 46% 0.031 6.7 0.80 12.1 0.87

REGARD2 Placebo Second 3% 1.3 3.8

Ramucirumab 3% 0.76 2.1 0.483 5.2 0.776

RAINBOW3

Paclitaxel + Placebo Second 16% 2.9 7.4

Paclitaxel + Ramucirumab 28%


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MSI in gastric cancer

• Therapeutic options:• Pembrolizumab: 50% RR• Nivolumab

• MSI-H and EBV positive tumors are mutually exclusive• Dramatic responses seen with pembrolizumab (Nat med 2018)


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PDL1 as a biomarker ??

Phase 3 KEYNOTE-181 Study (NCT02564263)

Presented By Takashi Kojima at 2019 Gastrointestinal Cancer Symposium

Overall Survival (PD-L1 CPS ≥10)



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Overall Survival (SCC)


Overall Survival (ITT)



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KN-181 had 3 co-primary endpoints

Presented By Harry Yoon at 2019 Gastrointestinal Cancer Symposium

What in the genomic stable?

• Claudine 18.2: • Tight junction protein, expressed in several cancers including

GC• Zolbetuximab (anti-Claudine 18.2) is being evaluated in a

phase 3 trial (Spotlight study)


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THANK YOU !

molecular pathology: upper gi cancer · 2019. 5. 29. · hans prenen 2 revisiting pathology:...

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