Diagnostische Pathologie van de long in vogelvlucht · 2019. 10. 10. · • bestraling van de long...
Transcript of Diagnostische Pathologie van de long in vogelvlucht · 2019. 10. 10. · • bestraling van de long...
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Pathology UNIVERSITY MEDICAL CENTER GRONINGEN
Diagnostische Pathologie van de long in vogelvlucht
Wim TimensDept. Pathology and Medical Biology, University Medical Center Groningen
“Week van de Pathologie" 27 – 30 maart 2017, Ede
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(potentiële) belangenverstrengeling Zie hieronder
Voor bijeenkomst mogelijk relevante relaties met
bedrijvenBedrijfsnamen
• Adviesraad (niet persoonlijk, vergoeding naar
afdeling)
• Lezing / cursus (niet persoonlijk, vergoeding naar
afdeling)
• Merck Sharp & Dohme, Pfizer,
Roche/Ventana.
• Boehringer Ingelheim, Bristol-Myers
Squibb, Glaxo Smith Kline, Biotest, Chiesi,
Lilly Oncology, Merck Sharp & Dohme,
Novartis, Pfizer, Roche/Ventana
Disclosure belangen spreker
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Pathologie van de long
• Interstitiële longziekten
• Longkanker
• Infecties
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Interstitiële longziektenHistopathologische reactiepatronen bij diffuse alveolair-interstitiële longafwijkingen:
“The alphabet soup”
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Alveolair-interstitiele longafwijkingen
• diffusieweg voor gaswisseling langer
• long stijver, minder compliant
• ventilatie-perfusie wanverhoudingen
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Transbronchiaal biopt:
Beperkte diagnostische mogelijkheden:
• Longtransplantatie
• Sarcoidose e.a. granulomateuze afwijkingen
• Infecties
• Pulmonale Langerhanscel histiocytose
• Eosinofiele pneumonie
• Lymfangioleiomyomatose
• (sommige) maligniteiten
• Churg-Strauss syndroom/vasculitis
http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjB5_i2lu3SAhVFF8AKHcP3AHMQjRwIBw&url=http://www.ramsayhealth.co.uk/treatments/transbronchial-biopsy&bvm=bv.150475504,d.ZGg&psig=AFQjCNE2w7psSWfhtK0W0-T8G2OYwa4nig&ust=1490377245351062http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjB5_i2lu3SAhVFF8AKHcP3AHMQjRwIBw&url=http://www.ramsayhealth.co.uk/treatments/transbronchial-biopsy&bvm=bv.150475504,d.ZGg&psig=AFQjCNE2w7psSWfhtK0W0-T8G2OYwa4nig&ust=1490377245351062
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Open long / VATS biopsie:
Welke?…antwoorden mag je verwachten:
• Identificatie van potentieel behandelbare afwijkingen:
– Infectie
– Alveolaire proteinose
– Extrinsieke allergische alveolitis (hypersensitiviteits pneumonitis)
• Identificatie van eerste manifestatie van systeemziekte:
– Immuundeficientie
– Auto-immuunziekte
• Classificatie van (idiopathische) interstitiele pneumonieën
• Vaatpathologie van de long (pulmonale hypertensie, pulmonale veneuze occlusie)
• Belangrijke prognostische informatie
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Interpretatie longbiopten
• Belangrijkste plaats van afwijkingen:
– luchtruimte
– interstitieel
– gemengd
• Uitbreiding van het proces:
– diffuus
– wisselend in ernst
• indien wisselend bepaling van patroon.
– willekeurig
– specifiek:
• bronchiolair
• lymfbanen volgend
• arterieel
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Cryptogene organiserende pneumonie
(Bronchiolitis obliterans organiserende pneumonie)
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Interstitiële pneumonie
• Bekende oorzaken:
– Infectieus of postinfectieus
– Omgevingsfactoren (inhalants)
– Geneesmiddelen
• Idiopathisch
– Neoplastisch
– Lymfoproliferatief
– Metabool
Acute interstitiele pneumonie (AIP)
Usual interstitiele pneumonie (UIP)
Desquamatieve interstitiele pneumonie (DIP) / Respiratoire bronchiolitis interstitiele pneumonie
(RBILD)
Niet-specifieke interstitiele pneumonie (NSIP)
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Overige vormen idiopathische interstitiele
pneumonie
(doch vaak etiologie wel bekend)
• Reuscel interstitiele pneumonie
(meestal pneumoconiose, geassoc. met zware metalen)
• Granulomateuze interstitiele pneumonie.
• Lymfoide interstitiele pneumonie
(meestal geassoc. met immuundeficienties)
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Desquamatieve interstitiële
pneumonieDesquamatieve interstitiele pneumonie (DIP)
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Desquamatieve
interstitiële pneumonieDesquamatieve
interstitiele
pneumonie (DIP)
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Niet-specifieke interstitiële pneumonieNiet-specifieke interstitiële pneumonie (NSIP)
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Niet-specifieke
interstitiële
pneumonie
Niet-specifieke
interstitiële
pneumonie
(NSIP)
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Niet-specifieke interstitiële
pneumonie,
Fibroserende vorm
F-NSIP
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Waar moet je aan denken bij NSIP-patroon?
• Collageen ziekten
• Geneesmiddelen reacties
• Hypersensitiviteitspneumonie (extrinsieke allergische alveolitis)
• Pneumoconiose
• Chronisch pulmonale veneuze hypertensie (mitraalstenose)
• Allogene beenmergtransplantatie
• Idiopathisch
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Acute interstitiële
pneumonie
Diffuse alveolaire schade (“DAD”)Acute interstitiële pneumonie (AIP)
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Acute interstitiële
pneumonie
diffuse fibroblasten
proliferatie en sporadische
lymfocyten
Diffuse alveolaire
schade (“DAD”)Acute interstitiële
pneumonie (AIP)
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Oorzaken van diffuse alveolaire schade
• inhalatie van toxische gassen of dampen
• inhalatie van anorganische stoffen (pneumoconiosen)
• sommige cytostatica (busulfan, bleomycine)
• bestraling van de long (bestralingspneumonitis)
• sepsis, shock, diffuse intravasale stolling
• beademing met hoge concentraties O2
• aspiratie van de maaginhoud
• narcotica-abusus (hereoïne, methadon)
• ernstige infecties, vooral bij immuundeficiënties
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Pathology UNIVERSITY MEDICAL CENTER GRONINGENSlide courtesy of KO Leslie, MD.
Stadium heterogeniteit in UIPUsual interstitial pneumonie (UIP)
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Usual interstitial pneumonia: fibroblast focus
Usual interstitial pneumonie (UIP):
“Fibroblast focus”
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Interstitiële longziektenMultidisciplinaire aanpak!
Histopathologische diagnose moet tesamen met radiologie, klinische informatie en beloop
worden overwogen
• Histopathologisch onderzoek:
• in veel gevallen gouden standaard; kan belangrijke bijdrage leveren in aanvulling op klinische gegevens
en beeldvormende diagnostiek, relevant voor verdere behandeling en therapie.
• Informatie m.b.t. klinisch beloop en radiologische bevindingen essentieel voor optimale diagnose
• Belang van beeldvormende diagnostiek:
• naast diagnostische bijdrage ook als uitgangspunt voor:
• biopsie van anatomische locatie, representatief voor de afwijking
• locatie alwaar actieve of vroege fase van het ziekteproces
• Tijdstip biopsie is belangrijk:
• indien indicatie dan vroeg in het ziekteproces
• geïndividualiseerde multidisciplinaire besluitvorming
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Longkanker
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What was the past:
• Clinical Relevance:
– SCLC vs NSCLC
– Neuroendocrine tumors
• NSCLC:
– Adenocarcinoma
– Squamous cell carcinoma
– Large cell carcinoma• Large cell neuroendocrine carcinoma
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How defined then:
WHO: definition: morphology by histochemistry (only)
• Squamous cell carcinoma:
– Intercellular bridges
– keratinization
• Adenocarcinoma:
– Glandular morphology
– Mucus production (PAS, Alcian Blue)
• Large cell carcinoma: all NSCLC that do not have above criteria
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Reactive atypia courtesy Dr. Doug Flieder, Cornell University, New York
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Reactive atypia courtesy Dr. Doug Flieder, Cornell University, New York
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Atypical Adenomatous hyperplasia
courtesy Dr. Doug Flieder, Cornell University, New York
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Atypical Adenomatous hyperplasia
courtesy Dr. Doug Flieder, Cornell University, New York
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Bronchiolization of alveolar septa
courtesy Dr. Doug Flieder, Cornell University, New York
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Bronchiolization of alveolar septa
courtesy Dr. Doug Flieder, Cornell University, New York
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Adenocarcinoma in situ
courtesy Dr. Doug Flieder, Cornell University, New York
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Adenocarcinoma in situ
courtesy Dr. Doug Flieder, Cornell University, New York
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Papillary adenocarcinoma
courtesy Dr. Doug Flieder, Cornell University, New York
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Papillary adenocarcinoma
courtesy Dr. Doug Flieder, Cornell University, New York
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Targeted therapy: new demands
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Targeted therapy: new demands
Phenotyping more relevant, because restriction to phenotype:
• Side effects of new drugs
• Driver mutations with therapeutic effects
• Mutations with adverse effects
• But also: easy and accurate identification of patients without
likelihood of relevant mutations
• Expensive diagnostics and therapy:
the right drug in the right patient
http://davidjrodger.files.wordpress.com/2011/12/photography-c2a6-the-end-of-business-old-man-with-a-double-barrel-shotgun-by-danielle-tunstall.jpghttp://davidjrodger.files.wordpress.com/2011/12/photography-c2a6-the-end-of-business-old-man-with-a-double-barrel-shotgun-by-danielle-tunstall.jpg
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How to identify our targetable patient?
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Relevance of lung cancer histotyping
• p53 mutations: frequent in all lung carcinomas
• HER2/neu expression infrequent in AC; rare in SCC
• K-RAS mutations: found in AC, rare in SCC
• EGFR-(tyrosine kinase) inhibitors: Erlotinib and Gefinitib:
do not work in SCC: > 80% SCC are EGFR positive (but in general no relevant EGFR-TK driver
mutations)
• Pemetrexed (anti-folate agent): little effect in SCC
• VEGF-inhibitors (Bevacuzimab): serious side effects in SCC (hemorrhage)
• EML4-ALK translocations (Crizoitinib): associated with signet ring adenocarcinoma
• ……………….
• ……………….
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Diagnostic pathology in lung cancer:What are the challenges?
• Include appropriate molecular pathology
• Include other companion diagnostics (Immunotherapy)
• Fast
• Accurate
• What is possible with cytology (EUS/EBUS) and small biopsies
• Limited costs
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Vraag 1: kan een diagnose grootcelligcarcinoom van de long worden gesteld
op cytologie
1. Nee, nooit
2. Ja, indien gesteund door immunocytologie
3. Ja, indien gesteund door moleculaire diagnostiek
4. Nee, daarvoor heb je een biopt nodig
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What was/is to improve:
• Large cell carcinoma (NSCLC) is a wastebag (and therefore mixed bag!) category:
should be reduced
• “Classic” (so mostly: well-differentiated) squamous cell carcinoma and
adenocarcinoma are not so frequent:
– On morphology often over-interpretation in poorly to moderately differentiated SCC and
AC: too often wrong
Much more relevant role for immunohistochemistry
Criteria phenotyping should be re(de)fined
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J Thor Oncology
2011: 244-285 (41
pages!)
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Rossi et al. Int. J Surg Path 2009
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p63p63
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p63p63
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p63
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TTF1
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Pathology UNIVERSITY MEDICAL CENTER GRONINGENRekhtman, Biannual meeting Pulmonary Pathology Soc. New York, 2011
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Tumour heterogeneityis it a problem?
• Variabele differentiation within one type NSCLC
• Mixed tumours
• Mosaic of mutations: do they exist?
• Small samples (biopsies / cytology):
– Selection bias / representativity
– Risk false negatives
– Risk selective detection in case of mosaic
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Present day diagnostic pathology:
• Phenotyping is not only giving main classifying
diagnosis, but:
• Describe all components and differentiation
• Selecting for MolDiag, not only “percentage” but also
right part of the tumor!
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Extraction of tumour cells
(if necessary, separate tumour cells from non-tumour cells)
Preservation = formalin fixation and
embedding using paraffin
How do we test for a mutation?
Sectioning = confirmation of tumour content
and tissue quality
DNA extraction and purification
Mutation analysis (e.g. sequencing)
Tumour sample collection = histological specimen
http://www.clker.com/clipart-11526.htmlhttp://www.clker.com/clipart-11526.html
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Vraag 2: welk antwoord is beste m.b.t moleculaire diagnostiek
1. Levert beter resultaat bij coloncarcinoom dan bij longcarcinoom, omdat
daar meestal resectiemateriaal ter beschikking is
2. Kan op cytologie als er maar genoeg celmateriaal ter beschikking is
3. NGS op weefsel zal op termijn vervangen kunnen worden door “liquid
biopsy”
4. Moleculaire pathologie geeft meer waarschijnlijkheid op een zinvolle
diagnose dan huidige whole genome sequencing
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Present day diagnostic pathology:
(and in fact also for clinician….)
Realize (and report?) which limitations are relevant for which technique:
• Mutation analysis: percentage of nucleated cells (not volume% !!) in a certain area of
the tissue or cell block: morphology doesn’t help anymore to recognize the tumor
DNA between the normal DNA
• ISH: number of recognizable tumor cells is relevant: cut-off points for counting are
validated on minimum number of “countable” tumor cells: morphology (and IHC?)
help if many normal (often inflammatory) cells present
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Metastases:
• Intrinsic to tumor heterogeneity
• In general prognosis determined by metastatic disease:
• Metastases can acquire organ-specific mutations
Should metastases more often be biopsied (and re-phenotyped!) for molecular diagnosis?
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Sequist et al. : Genotypic and Histological
Evolution of Lung Cancers Acquiring
Resistance to EGFR Inhibitors
Sci Transl Med 2011: 3 (75): 75ra26
Is this really evolution or could
extended sampling have
shown both components early
on…?
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Other targets: Immunotherapy…
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Immune checkpoint blockade
Drake, C. G. et al. (2013) Nat. Rev. Clin. Oncol.
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Mechanisms by Which Cancers Evade Immune Destruction
Excluded infiltrate
CD8
Immunologic ignorance
CD8
…unable to act
PD-L1
T cells present but..
CD8
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Early Data Suggest that Anti-PDL1/PD1 is Active Across a
Wide Range of Tumor Types
Bladder cancerColorectal cancer
Renal cancer
Melanoma
Liver cancer
Lung cancer
Gastric
Breast cancer
Glioblastoma
Pancreatic
Head & neck cancer
Ovarian
Hodgkin lymphoma
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Non-sq.=non-squamous; sq.=squamous
1. Weber et al. Lancet 2015; 2. Robert et al. Lancet 2015; 3. Larkin et al. N Engl J Med 2015; 4. Borghaei et al. N Engl J Med 2015
5. Brahmer et al. N Engl J Med 2015; 6. Antonia et al. ASCO 2015; 7. Motzer et al. J Clin Oncol 2015; 8. Le et al. ASCO GI 2016
9. Kefford et al. ASCO 2014; 10. Garon et al. N Engl J Med 2015; 11. Plimack et al. ASCO 2015; 12. Vansteenkiste et al. ECC 2015
13. Rosenberg et al. Lancet 2016; 14. McDermott et al. J Clin Oncol 2015; 15. Rizvi et al. ASCO 2015; 16. Segal et al. ASCO 2015
17. Gulley et al. ASCO 2015; 18. Apolo et al. ASCO GU 2016; 19. Dirix et al. SABCS 2015; 20. Chung et al. ASCO GI 2016
Response Rate by PD-L1 Status
0
20
40
60
80ITT
PD-L1+
PD-L1-
Nivolumab Pembrolizumab Durvalumab AvelumabAtezolizumab
OR
R (
%)
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Hegde, et al. Clin Cancer Res 2016
The Tumor Immunity Continuum
Pre-existing immunity Excluded infiltrate Immunologically ignorant
Inflamed Non-inflamed
Convert to inflamed phenotype with combinations
CD8 T cells/IFNPD-L1
TILs
Mutational Load
Reactive stroma
Angiogenesis
Respond favorably to
checkpoint inhibition
MDSCs
Proliferating
Tumors/ Low
MHC Class I
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Immune cells
(ICs)
Tumor cells
(TCs)
Tumor and immune cells
(TCs and ICs)
PD-L1 Staining Can Be Observed In Tumor Cells, Immune Cells
or Both
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Vraag 3: Bij diagnostiek t.b.v. immunotherapie:
1. Moet altijd een PD-L1 kleuring worden verricht
2. Zijn alle beschikbare assays geschikt om dit te doen
3. Moet dit op histologie worden verricht
4. Kan het beste de “mutational load” worden bepaald
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Agent Nivolumab Pembrolizumab Durvalumab Atezolizumab
Antibody Dako 28-8 VentanaSP263
Dako 22C3 VentanaSP263
VentanaSP142
Cut-off(s)Tested (NSCLC)
1%, 5% or 10% (TC)
≥ 25% TC
TC ≥ 50% (and 1% any stroma)
≥ 25% TC TC 1%, 5%, 50%IC 1%, 5%, 10%
Analytically validated assays used in clinical studies
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PD-L1 IHC variation
Different PD-L1 clones on consecutive sectionsof one tumor
Scheel et al. Modern Pathol 2016
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Variable expression of PD-L1 within one tumor / within onepatient
Cree et al, Histopathology 2016
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Pardoll. Nat Rev Cancer 2012
Regulation of T Cell Activation:
Balancing Activating and Inhibitory Signals
Inhibitory interactions
APC/tumor APC/tumor
CTLA-4
PD-1
PD-L1
B7.1
BTLA
LAG-3
HVEM
MHC
B7.1
PD-L2
B7.2
Activating interactions
CD137
CD28
OX40
GITR
CD27
CD70
CD137L
GITRL
OX40L
B7.1
TCR
B7.2
MHC
T cell
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Chen & Mellman, Immunity 2013
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Topalian et al. Nature Rev Cancer 2016
Multifactorial biomarkers
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Kerr et a; Histopathology 1998, Johnson et al. Lung Cancer 2000
Kerr, USCAP 2015
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Eur Respir J 2015; 46: 1762–
1772
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Conclusions:
• PD-L1 testing evaluation is encouraging with respect to better and simpler, reliable routine application in pathology
• Since PD-L1 alone is not the optimal biomarker for PD-1 therapies, considerable effort is and should be spent in examining (combination with) others such as tumor-infiltrating immune cells, mutational load, gene signatures
• In the future, it is likely that it will be an optimal combination of biomarkers to be used to determine, with a sufficient degree of certainty, whether a particular patient will benefit from anti-PD-1/PD-L1 therapy and future immune checkpoint blocking drugs to come
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Dank voor uw aandacht
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Pitfalls of using PDL1 immunohistochemistry as a biomarker test for anti-PD1–PDL1 therapy
• Focal programmed cell death 1 ligand 1 (PDL1) expression in some tumoursmay be missed in small biopsy specimens, such as needle biopsies
• PDL1 expression among multiple tumour lesions from individual patients can vary over time and by anatomical site
• PDL1 expression in tumour biopsies collected months or years earlier might not accurately reflect PDL1 status at the time of treatment initiation; therapies given after biopsy but before administration of programmed cell death protein 1 (PD1) pathway blockade (radiation therapy, chemotherapy or kinase inhibitors) may alter PDL1 expression
• PDL1 epitopes detected by some antibodies are potentially unstable with prolonged specimen fixation or inadequate tissue handling before fixation (see NCI guidelines for tissue handling)
• Antibodies used for PDL1 detection have different affinities and specificities
• PDL1 protein expression can be membranous and/or cytoplasmic; however, only membranous PDL1 is functionally relevant, by contacting PD1+ T cells
• PDL1 can be expressed by multiple cell types within the tumourmicroenvironment, which poses challenges for scoring and interpretation
Topalian et al. Nature Rev Cancer 2016
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Topalian et al. Nature Rev Cancer 2016
Multifactorial biomarkers
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Figure 4. Percentage of PD-L1 expression in adenocarcinomas and mutational status of significantly associated genes. The combination of TP53 mutation, KRAS mutation and
STK11 wildtype is associated with the highest percentage of PD-L1 expression in adenocarcinoma tumor cells. Conversely, STK11 mutations in the absence of TP53 and
KRAS mutations are associated with the lowest percentage.
Scheel et al.
Oncoimmunology 2016
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Rizvi et al, Science 2015
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• In two independent cohorts treated with pembroluzimab(n=14 vs 18), higher nonsynonymous mutation burden in tumors was associated with: – improved objective response,
– durable clinical benefit, and
– progression-free survival
• Efficacy also correlated with:– molecular smoking signature,
– higher neoantigen burden, and
– Higher DNA repair pathway mutations;
– -> each factor was also associated with mutation burden.
Rizvi et al, Science 2015