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Pr. Francoise Galateau SalléMESOPATH-MESOBANK.fr

Department of BiopathologyCancer Center Leon Berard

28 Rue de Laennec, Lyon, France

12th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain & Ireland 2 – 4 July 2019

Molecular Biology of MesotheliomaImplications for diagnosis and management

DisclosureDiagnostic and research institutional supports from French National Institute of Health (SpF) and from French National Institute of Cancer (INCA)

Research support: MSD for Artificial Intelligence

Genotoxic effects: mutagenic and clastogenic

o DNA

o guanine hydroxylation, simple or double strand breaks

o Gene

o mutations

o Chromosome alteration

o structural (deletion, translocation, inversion, duplication, etc..

o numeric changes ( aneuploidy, polyploidie, hyperpolyploidie, exchange of segment between chromosomes….)

Non genotoxic effects

• Men in ~90% with long latency period after asbestos exposure (~ 30 to 40 years)

• multi step process secondary to an accumulation of mutations on several key genes.

• Other etiological causes ( Radiation, inflammation, others fibers…)

Asbestos exposure a model of carcinogenesis for MM Incidence is still increasing in the upcoming years due to the long latency and use in non western countries

InflammationROS +++

Molecular biology and MM: several issuesdiagnostic, prognostic, therapeutic

1° Conventional types

2° WDPM

WHO 2015 9051/3 ICD-O codeMesothelioma• Diffuse• Localized

Other tumors of mesothelial origin9052/1bI ICD-O code

157 Authors

MM rare aggressive tumor < 0.3% of all cancers, very heterogeneous in morphology a great mimickers of many other cancers .A model of EMT

WHO 2015 a classification based on morphology

157 Authors from 29 countries

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Molecular biology and MM: several issuesdiagnostic, prognostic, therapeutic

1° Conventional types

2° WDPM

3° Separation of benign mesothelial proliferation from malignant mesothelioma

WHO 2015 9051/3 ICD-O codeMesothelioma• Diffuse• Localized

By courtesy of A Churg

Other tumors of mesothelial origin9052/1bI ICD-O code

157 Authors from 29 countries

MM rare aggressive tumor < 0.3% of all cancers, very heterogeneous in morphology a great mimickers of many other cancers

In 2015 ONLY Academic Research molecular data

CDKN2A(p16) (homozygous deletion) and promotor Hypermethylation 45-100% Cheng JQ, et al, Cancer Res 1994, TLCR 2017 , GUO et al Cancer Res 2015,De Rienzo et al, 2016, Serra et al J Clin Pathol 2018

Nf2 (homo and heterozygous deletion, nonsense and missense mutation) 50- 60% Sekido et al, Cancer Res 1995, Bianchi et al, Proc Natl Acad Sci U S A 1995, Cheng et al, Genes Chromosomes Cancer 1999, Miyanaga et al, JTO 2015

BAP1 (deletion, mutation, insertion) 20-25 to >65 %Bott, et al. Nat Genet 2011, Yoshikawa et al, Cancer Science 2012, Cheung et al, TLCR 2017 , Testa et al, Nat Genet 2011, Yoshikawa et al, Proc Nat Acad Sci USA 2016Somatic and Germline mutation (5%)

Molecular and genomic abnormalities in MPM in 2015-2017

Bueno et al, Nat Genet 2016, Yap et al, Nature Reviews Cancer, 2017

Molecular abnormalities in MPMA big step for mesothelioma

Hmeljak et al, Cancer Dscovery 2018 Bueno et al, Nat Genet 2016, Yap et al, Nature Reviews Cancer, 2017

Molecular abnormalities in MPM

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Major molecular abnormalities according to histological subtypes

Bueno et al, Nat Genet 2016, Yap et al, Nature Reviews Cancer, 2017

Molecular abnormalities in MPM

n=99 exomes

Ladanyi PPS Dubrovnik June 2019

The most significant mutated genes

Bueno et al, Nat Genet 2016, Yap et al, Nature Reviews Cancer, 2017

Molecular implications for diagnosis

Hmeljak et al, Cancer Dscovery 2018

The BRCA1–associated protein 1 (BAP1) gene, is a TSG located on chromosome 3p21.1.

BAP1 protein is a deubiquitinating enzyme, that suppress tumor through regulation of DNA damage repair, cell cycle, and cellular differentiation.

BAP1 DUB activity is associated with cytoskeleton reorganization & migratory capacity

BAP1 DUB is associated with reduced respiratory capacities through mitochondrial dysfonction

BAP1 DUB is associated with increased intracellular ROS and accumulation of many proteins involved in oxidative stress response

Carbone M, NATURE REVIEWS | Cancer , 2012 , Hebert et al, Oncotarget 2017,

BAP1

Molecular abnormalities implication for diagnosis BAP1 immunohistochemistry

The loss of the BAP1 protein, is detected by IHC (Clone C-4 Santa Cruz)

BAP1 wt is intranuclear Diverse levels of alteration exist at the protein level and loss of expression by post-translational modifications do exist.

BAP1 Tumor Predisposition Syndrome (melanoma, renal cell carcinoma, mesothelioma, basal cell carcinoma & other tumors …) Carbone et al, Testa et alGerminal mutation <5%

BAP1 loss is associated with a better prognosis

MESOPATH data unpublished

Carbone et al Carcinogenesis 2015

Cl C4 Santa Cruz

BAP1 loss in EMM BAP1 retained in SMM

N Median 3 yrs-survival [CI95%] BAP1 loss 318 15 mos 20% [14%; 26%]BAP1 retained 213 9 mos 11% [5%; 17%]

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MS17.01: Pathology

JTO, 2018BAP1 loss was observed in 50% (n=21/42) of the total cases in both components (EM &SM) for 27% of the cases (n=11/41)

BAP1 loss on the sarcomatoid component alone was not observed.

BAP1 loss in the TM group (50%), (n=8) and non-TM group (50%) (n=13) (p=1.00).

BAP1 Cl.C-4)

Molecular assessment in the diagnosis of Biphasic mesothelioma

BAP1 staining for diagnosis & histological subtypes in MM

Can we use BAP1 immunostaining to separate EM from metastatic lung NSCLC: could be helpfulCan we use BAP1 immunostaining for the separation between SM and SC: NO!!!!!

Loss of BAP1 nuclear staining is rare in SMM and more prevalent in EMM

Mesopath cohort series 2015-2018 BAP1 clone C-4,

Righi et al, JTO 2016

Carbone et al Oncotarget 2017

BAP1 staining is low or either absent in NSCLC

Owen et al, Human Pathology (2017) 60, 82–85TMA 133 confirmed casesBAP1 loss (nuclear) 1%

SM

SC

NO!!!

Can we use BAP1 immunostaining for the separation between AMH versus MM:YES !!!

•M 70 yrs Recurrent PE,

•AE (Shypyard was carrying bag of asbestos)

•CT scan minimal pleural effusion without any otherabnormalities

•Surgical biopsy for diagnosis 1 first biopsy

Diagnosis of atypical Mesothelial hyperplasia

2nd Biopsy

5 years later he presented with an invasive EMM

BAP1 loss

Retrospectively we run BAP1

BAP1 staining to differentiate benign AMH from MM

Churg et al, (Arch Pathol Lab Med. 2016;140:318–321; Sheffields, Am J Surg Pathol 2015;39:977–

982 for EMM

Series n=75Benign 0/49Malignant 7/26Sen (95% CI) % 27% (17-31)Spec (95% CI)% 100% (100-100)

BAP1 loss may support a diagnosis of MM together with the clinical context

Can we use BAP1 immunostaining for the separation between AMH versus MMYES !!!

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p16 is located on chromosome 9p21, also called (inhibitor of cyclin-dependent kinase 4a) or p16INK4 and CDKN2A (cyclin-dependent kinases inhibitor 2A)

2nd most important TSG play a role in inhibition of cell growth

P16 expression ( clone E6H4) is a nuclear stainingPositive staining Benign 87% MM 60%Chiosea et al, Mod Pathol 2008; 21:742-7

MTAP (cl. 42-T Santa Cruz, sc-10078)MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion.Chapel et l Mod Pathol 2019

FISH CDKN2A (p16) Cut Off 20% of cells

Cl E6H4)

ZytoLight ® SPEC CDKN2A/CEN 9 Dual Color Probe

Daniel.Pissaloux@lyon.unicancer.fr

HD p18 in MM 40-100%

P16 protein loss and CDKN2A(p16) Homozygous deletion by FISH and MTAP

homozygous deletion

CDKN2A

Homozygous deletion by FISH review from the litterature

FISH Homozygous deletion CDKN2A(p16) 40-100%

Am J Surg Pathol Volume 40, Number 5, May 2016

Can we use FISH p16 for the separation of cellular diffuse pleural fibrosis from SMM and in spindle cell component of biphasic:YES !!!

p16 homozygous deletion by FISH was present in 74 % of the series (n=28/38) and in 80% (n=15) of the TM group (p=NS). .

p16 homozygous deletion by FISH was observed on the EM alone in 18% (n=5/28) in both components in 82% (n=23/28)

P16 HD in the assessment of the spindle cell component of biphasic mesothelioma

Daniel Pissaloux@Lyon.unicancer.fr

HD p16 EM HD p16 SM

Can we use MTAP staining instead of FISH p16 : ongoing studies

• They performed MTAP immunohistochemistry on:• 20 benign mesothelial lesions• 99 malignant mesotheliomas• from five mesothelioma centers in four countries,• each MTAP stain was independently interpreted by four pathologists. • CDKN2A (p16) data were available for a subset cases, Results of the multicentric evaluation was:

Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82).Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77–0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A (p16).

M, 83 yrs oldExposed to asbestosClinical suspicion of Mesothelioma

Diffuse pleural fibrosis-Diffuse pleural thickening benign or malignant

No invasion of the adipose tissue

Daniel.Pissaloux@lyon.unicancer.fr

Can we use FISH p16 for the separation of cellular diffuse pleural fibrosis from SMM:YES !!!

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BAP1, p16 protein expression and FISH HD CDKN2A (p16)

Initial Diagnosis AMHDont’know

Diffuse Pleural fibrosis

AMH morphologicallyReactive

Total

HD CDKN2A (p16) N=3118 (58%)

N=3920 (51%)

N=168 (50%)

N=8646 (53%)

MESOPATH experienceHigh risk asbestos exposed patients > 50yrs presenting recurrent pleural effusion with on the biopsy an AMH or a diffuse pleural fibrosis should be tested for HD p16

MESOPATH Database from a series of 1129 cases collected from 1998-2018 Daniel Pissaloux from the Cancer Centre Leon Berard –unpublished data

Churg et al, Histopathology 2018

No visible tumor, by imaging & thoracoscopy

BAP1 loss and/ or CDKN2A (p16) may support a diagnosis of MM or ‘’in situ ‘’ when no visible tumor are present

Sheffields et al, AMJSP 2015, 39;7:977-82

BAP1 loss+p16 homozygous deletion by FISH allow a diagnosis of MM with a sensitivity of 60% & a specificity of 100%

Can the combination of FISH p16 and BAP1 staining can be used for the separation of AMH from MM and for the diagnosis of in situ MM:YES !!!

Algorithm for AMH

BAP1 loss BAP1 retained

BAP1 loss

BAP1 retained

P16 HD

No p16 HD

Consider the diagnosis of in Situ MM

Close follow uo

Adapted from A. ChurgAJSP 2016

Algorithm for the separation of AMH from MM and for the diagnosis of in situ MM:YES !!!

NF2 gene is located in the chromosomal region 22q12 and encodes the ezrin, radixin and moesin (ERM) family protein MERLIN Mutations are estimated to be 50-60%

By Immunohistochemistry NF2 polyclonal rabbit Sigma-Aldrich loss nuclear staining) LATS1/2 polyclonal rabbit loss nuclear staining) YAP1 /TAZ polyclonal rabbit (nuclear translocation = activated phenotype)

By FISHHemizygous NF2 loss (monosomy or hemizygous deletion)

Yap et al, Nature reviews /Cancer 2017, Sighi et al, Mod Pathol, 207 , Sheffield et al, Archiv Pathol lab Med 2016

NF2 YAP1

NF2 protein and FISH hemizygous deletion

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NF2 LATS1/2 & YAP/TAZ immunostaining to separate benign from malignant proliferations

Sheffields Arch Pathol Lab 2016, Vol 140./p 391

NF2 polyclonal rabbit Sigma-AldrichLATS2 polyclonal rabbit Sigma-AldrichYAP/TAZ polyclonal Cell Signaling Technology

« Since the incidence of NF2 mutations is estimated >50% these results indicate that many MM with mutated NF2 retain NF2 »

2 cases with comprehensive genomic profiling were NF2 positive nuclear

Can we use Nf2 staining LATS1/2 & YAP/TAZ: not yet!!!

Yap et al, Nature Reviews Cancer, 2017

Molecular abnormalities and therapeutic targets for the management of MM

What we learned from the literatureon the role of the microenvironment Observational versus complementary to drug analysis

Alley EW, WCLC Denver 2015 Abs 3011

What we learned from the literature (IHC)Series drug setting N pts IHC assays PDL1 scoring Cut off Correlation Histology Stage Survival

Mansfield et alJTO 2014

Cis platine + pemetrexed 89%Gemcitabine 8%

77/119Surgicalspecimens

PDL -1B7-H1 (clone 5H1-A3)

>TC 1% intensity

0,1,2,3

> 5 % No epithelioid 37.7%Epithelioid 13.2%P<0.0001

Stage III- IV 5 mos vs 14.5 moP<0.0001Multivariatep=.004

Cedres et alPlos 1 2015

Cis platine + pemetrexed 89%Gemcitabine 8%

77/119Surgicalspecimens

PDL-1EIL3N XP cell signaling

CD4 cl BC/156 AbcamCD8 cl 4B11 Novocastra

TC >1% intensity

0,1,2,3%%

>1% 20%No epithelioid 56%Epithelioid43.7%

Stage III- IV 4.8 mos vs 16.3 mosP=0.012

Combaz Lair et alHum Pathol 2016

58/68Biopsies and Surgicalspecimens

PDL1EIL3N XP Cell SignalingSP142 Spring BiosciencesPD1 Nat 105 Abcam

CD3 poly DakoCD8 /144B DakoTLR3 Poly Promokine

TC >1% moderatestrongintensity

>1%

IC0, IC1, IC2, IC3

0,1,2,3

>1%EIL3N No epithelioid 62%

SP142 No epithelioid 38%TILSEIL3N 48%

SP142 19%TILS +TC better correlation withSP142 p=0.0023

Stage III-IV 4 mos vs 13 mosP=0.04

Thapa et alJTO 2017

373 Pts374 TMA

PDL1 Abcam

CD4cell marqueCD8 C8/144B DakoFOXP3

TC >5% onlymembranousLow, HighLow ,High

>5% No epithelioidNo significant correlation with OS But when Strong expression High correlation with OS

Stage I,II,III, IV 9.8 mos vs 13.5 mosP<0.001

MAPS IFCT NivolumabNivo+Ipilimumab

RelapsingMPM afterchemo DCR<30%

125Biopsies and surgical

PDL- 1Cl 28.8 Pharm DX Dako

TC % of cellsIC scoringVentanaIC0,IC1,IC2,IC3

>1% No epithelioid Stage 5 mos vs 14.5 mos

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PDL-1 immunohistochemistryPredictive markers for response to Immunotherapy Lesson from lung cancer and from the mesothelioma seriesNeed for standardization

Ming Tsao JCO vol 12 N°2208-222 Fred Hirsch JTO , 2017 Mansfield, Cedres, Combaz lair et al, Hum Pathol 2016, Lantuejoul et al, JTO 2017

Conclusion Combaz Lair: EIL3N have a better sens and spe than SP142 for PDL1 TC expression

Cedres E1L3N Mansfield B7H1

E1L3N

E1L3N

SP142

SP142

Do we have to look at the TCs or at the ICs

Predictive markers for response to immunotherapy on mesothelioma

Chee et al BJC 2017 Patil et al, JTO 2018

In the epithelioid group, high CD4 (P<0.003), high CD20 (P<0.010), low FOXP3 (P<0.000414), low NP57þ(P<0.038) counts Are predictors of better survival

In the non epithelioid groupHigh CD8, Low FOXP3 (p=0.004) are associated with a worst prognosis

Does histopathological subtypes modulatethe response to immune checkpoints inhibitors in MMPD1/PDL-1 immunohistochemistry

Maio et al, Lancet Oncol, 2017, Scherpereel et al, Lancet Oncol 2019, Metaxas JTO 2018, Disselhorst Lancet Respir Med 2019

Immunotherapy using checkpoints inhibitors targeting PD1/PDL1 or CTLA-4 is not approved in the treatment of MM but therewas trials ongoing:

1. Phase 2b trial DETERMINE using CTLA4 inhibition (564 pts) NO BENEFIT of Tremelimumab in epithelioid (83%)2. MAPS2 in second/third line setting to treatment with nivolumab or nivolumab +ipilimumab randomized (125pts)

1. The primary endpoint DCR at 12weeks was 44% for nivolumab & 50% for nivo+ ipimilumab2. with median PFS of 4.0 and 5.6 mos respectively3. Median OS of 13.6 mos not reached but tendancy to better OS with nivo+ipilimumba for non epithelioid types

3. A real world cohort (93 pts) treated by Pembrozilumab second line as palliative immunotherapy showed better efficacityin non epithelioid(n=73) with a response rate of 24% VS 16% median PFS 5.6 vs 2.8 mos (p=0.02) in epithelioid (n=27)

4. INITIATE trials in recurrent MM reported efficacity with recurent MM We are not yet:

Efficacy of IO is variable depending of histologyNon epithelioid may be associated with a prolonged duration of response

PDL-1 immunohistochemistry Need for standardization and correlation with ongoing trials

Nicholson et al, Euracan IASLC PROPOSALS FOR UPDATING CLASSIFICATION Under submission JTO

All series are in agreement with:1° PDL-1 expression is correlated with non epithelioid histology where there is

few therapeutic options and very poor prognosis2° PDL1 expression is correlated with poor survival ( ~4-5 mos when High PDL1

expression is observed) for comparable series in term of stage of disease

There is a need for harmonization series are difficult to compare due to the1° Lack of uniformity in:

1. Staining procedures ( membranous vs cytoplasmic), 2. Selection of antibodies (E1L3N,SP142, 22C3, 28.8, SP263), 3. Difference probable in staining plateforms, 4. no precision regarding FDA approved reference and LDTs, difference in cut off, evaluation of high versus low expression,

size of sample etc….

2°The results of ongoing trials show # resultsPDL-1s expression show a trends for correlation with OR, or PFS but there are no precision on the selection of Abs, cut off, and staining procedure

3°recommendations PDL1 should be incorporated in reports if undertaken

Mansfield et al

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ALK Mesothelioma

Design88 consecutive ptsM n=39 F n=49Median age 61 range 17-84ALK pos by Immunohistochemistry confirmed by FISH ALK rearrangementIn ALK rearranged cases they characterized the fusion partners using NGSThey compraed with a series of 205 pts with Pleural MM

ResultsALK immunosating in 11/88 (13%) of peritoneal mesothelioma All pleural MM were negativeFISH confirmed ALK rearrangementNGS identified novel fusion partners ATG16L1, STRN, TPMI

Pts with ALK rearrangements were women and younger than peritoneal MM without rearrangement

Molecular abnormalities in other tumor of mesothelial origin WDPM

They performed genomic profiling on a cohort of 10 WDPM mesothelioma of the peritoneum. Theyidentified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, They lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALKBAP1 retained and absence of CDKN2A (p16) homozygous deletiondeletion

BAP1 cl. C-4

Stevers et al, Mod Pathol Jan ,32 (1):88-99 2019

Computational BiologyN Alcala (IARC, postdoc)A Poret (IARC, postdoc)

A Gabriel (IARC, PhD student)E Mathian (IARC, master student)

J Poizat (IARC, master student)A Chabrier (IARC, research assistant)

Biology/BiochemistryL Mangiante (IARC, PhD student)

N Leblay (IARC alumni)S Boyault (CRCL, scientist)

S Tabone-Eglinger (CLB, CRB manager)N Le-Stang (CLB, data manager)

F Damiola (CLB, scientist)

Key collaboratorsL Alexandrov (California Univ, mutation signatures)

OWKIN (Artificial Intelligence)Christophe Caux (immune-related stuff)

Hector Hernandez-Vargas (methylation analyses)S Lantuejoul (MESOPATH)

Synergy Lyon Cancer (data analyses)

Coordinators and key members

L Fernandez-Cuesta(PI)

M Foll(co-PI, data analyses

coordinator)

F Galateau-Salle(Pathology

coordinator)

N Girard JY Blay(Clinical coordinators)

S Boyault(Biorepositorycoordinator)

Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular

interactions

Alcala N#, Mangiante L#, Le-Stang N, Gustafon CE, Boyault S, Damiola F, Alcala K, Brevet M, Thivolet-Bejui F,

Blanc-Fournier C, Le Rochais JP, Planchard G, Rousseau N, Damotte D, Pairon JC, Copin MC, Scherpereel A,

Wasielewski E, Wicquart L, Lacomme S, Vignaud JM, Ancelin G, Girard C, Sagan C, Bonnetaud C, Hofman V,

Hofman P, Mouroux J, Thomas de Montpreville V, Clermont E, Mazieres J, Rouquette I, Begueret I, Blay JY,

Lantuejoul S, Bueno R, Caux C, Girard N, McKay JD, Foll M†, Galateau-Salle F†, Fernandez-Cuesta L†

Under review

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7 3 Tr an scr ip t om es(Hmeijak et al. Can Discov 2018)

21 1 Tr a nscr ip t om es(Bueno et al. Nat Genet 2016)

Tech n ica l va l i dat ion

Study design

Francoise Galateau-Salle

Molecular profile and prognosis better explained by a continuum model

Histopathologicalmodels

Molecularmodels

(i)

(ii)

(iii)

(iv)

(v)

Pred

ictiv

e ac

cura

cy(i

AU

C)

Dis

cret

e(3

-cla

sses

)

Con

tinu

ous

(%

sar

com

atoi

d)

Dis

cret

e(B

ueno

et a

l. 20

16)

Con

tinu

ous

(PC

1 &

PC

2)

Con

tinuo

us(P

C1)

Nicolas Alcala

CD8 PDL1 VEGFR3 VEGFR2 VISTA

VEGFR1

VEGFR3

VEGFC

PDGFRB

CD8APD1

PDL1

CTLA4

TIM3 VISTAVEGFR2

LAG3

EpithelioidDiffuseNOS

VEGFR2+ / VISTA+ Median Survival: 36 months

Inducing Angiogenesis

Avoiding Immune

Destruction

Proportion of TILS

0.0 0.2 0.4 0.6 0.8 1.0

CD8 PDL1 VEGFR3 VEGFR2 VISTA

Cold / Angio+ Median Survival: 10 months

VEGFR1

VEGFR3

VEGFC

PDGFRB

CD8APD1

PDL1

CTLA4

TIM3 VISTAVEGFR2

LAG3

TumourPromoting

Inflammation

Inducing Angiogenesis

Sarcomatoid

Biphasic

Proportion of TILS0.0 0.2 0.4 0.6 0.8 1.0

CD8 PDL1 VEGFR3 VEGFR2 VISTA

Hot / IC+ / Angio+Median Survival: 7 months

EpithelioidSarcomatoid

Biphasic

VEGFR1

VEGFR3

VEGFC

PDGFRB

CD8APD1

PDL1

CTLA4

TIM3 VISTA VEGFR2

LAG3

TumourPromoting

Inflammation

Inducing Angiogenesis

Avoiding Immune

Destruction

Proportion of TILS

0.0 0.2 0.4 0.6 0.8 1.0

Sarcomatoid

6

30

18

Biphasic Epithelioid

Dimension 1 (11%)

Dim

ensi

on 2

(8%

)

Survival (m

onths)

The extrema of this continuum had specific clinically relevant molecular profiles

Lise Mangianteand Nicolas Alcala

Molecular investigation to support classification

Franck TirodeGenetics and epigenetics of sarcomas” Group Leader, Cancer Research Center of Lyon “Rare

Sarcoma Group” Group Leader, Centre Léon Bérard

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SarcomatoidmesotheliomasTransitional

Mesotheliomas

Sarcomatoidcarcinoma

Sarcomatoidcarcinoma

Epithelioid mesothelioma

Molecular investigation to support classification

Conclusion ConclusionEURACAN/IASLC proposals for updating the histologic classification of pleural mesothelioma: towards a more

multidisciplinary approach.

Andrew G Nicholson DMa, Jennifer L. Sauter MDb, Anna Nowak MDc, Hedy Kindler MDd, Ritu Gill MDe,

Martine Remy-Jardin MDf, Sam Armato MDg, Lynnette Fernandez-Cuesta PhDh, Raphael Bueno MDi, Nicolas

Alcala PhDj, Matthieu Foll PhDk, Harvey Pass MDl, Richard Attanoos FRCPathm, Paul Baas MDn, Mary Beth

Beasley MDo, Luka Brcic MDp, Kelly J Butnor MDq, Lucian R.Chirieac MDr, Andrew Churg MDs, Pierre Courtiolt,

Sanja Dacic MDu, Marc De Perrot MDv, Thomas Frauenfelder MDw, Allen Gibbs MDx, Fred R. Hirsch MDy,

Kenzo Hiroshima MDz, Aliya Husain MDaa, Sonja Klebe MDbb, Sylvie Lantuejoul MDcc, Andre Moreira MDdd,

Isabelle Opitz MDee, Maurice Perol MDff, Anja Roden MDgg, Victor Roggli MDhh, Arnaud Scherpereel MDii,

Frank Tirode PhDjj, Henry Tazelaar MDkk, William D Travis MDb, Ming Sound Tsao MDll, Paul van Schil MDmm,

Jean Michel Vignaud MDnn, Birgit Weynand MDoo, Ian Cree PhDpp, Valerie W Rusch MDqq, Nicolas Girard MDrr,

Francoise Galateau-Salle MDss.

Rec. 5) clinically relevant molecular data (PD-L1, BAP1 loss, CDKN2A deletion) should be incorporated into reports, if undertaken, Rec.6) other molecular data should be accrued as part of future trials looking at prognostic indicesRec.14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome.

The Recommendations for molecular abnormalities in MM from the multidisciplinary group are;

Under submission to JTO

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N. Le StangStatistician

Elise & Cyril

Daniel PissalouxSandrine Paindavoine

Sylvie LantuejoulAnnabelle BojElodie FerreyRuth SequeirosFrancesca DamiolaClara Farge Franck Tirode

Leader molecular groupJP Michot &The lab

Thanks