lung cancer diagnosis: role of pathology and genetic ......1. increased pd-l1 expression is...
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ESMO PRECEPTORSHIP ONLung Cancer Diagnosis:
Role of Pathology and Genetic Analysis
Teh-Ying Chou, MD, PhD, MBA
November 20, 2019
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DISCLOSURES
I have nothing to disclose.
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Lung Cancer: Pathological Classification
20041999 2015
Histology
Targeted Therapy
Immunotherapy
Molecular Pathology-based Precision Medicine of Lung Cancer
Precision Medicine
Molecular Biomarkers
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Lung Cancer: Molecular Classification
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Carcinoma (CA)
Non-small Cell CA (NSCC)
Small Cell CA
Squamous Cell CA
Non-squamous Cell NSCC
Large Cell CA
Adenocarcinoma
Other NSCC
Large Cell Neuroendocrine CA
Other Large Cell CA
Typical Carcinoid
Atypical Carcinoid
Neuroendocrine CA
Molecular Analysis
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Lung Cancer: Molecular Diagnostics
EGFRoma, ALKoma…
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Lung adenocarcinoma: Molecular profile
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Tsao et al. J Thorac Oncol. 2016 May;11(5):613-38.
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Recommended biomarker tests for patients
with newly diagnosed NSCLC
� EGFR
� ALK
� ROS1
� BRAF
� PD-L1
� RET
� MET exon 14
� HER2
� KRAS
� NTRK
Am Soc Clin Oncol Educ Book. 2019 Jan;39:531-542.
Minimum necessaryRecommended
(for NGS panels)
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EGFR mutation in lung cancer
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Test mutations in EGFR exon 18-21 with ≧1% prevalence(codons 709, 719, exon 19 del, 768, exon 20 insertions, 790, 858, and 861)
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TechniqueSensitivity
(% t DNA)Mutations identified
Comprehensive detection
of deletions and insertions
PCR/Direct sequencing 25 Known and new Yes
PCR-SSCP
(ss conformation polymorphism)10 Known and new Yes
PCR-RFLP and length analysis 5 Known only No
MALDI-TOF MS-based genotyping 5 Known only No
Real-time PCR based technology
•PNA-LNA PCR clamp 1 Known only No
•Scorpion/Arms 1 Known only No
•TaqMan PCR 10 Known only No
Mutant-enriched PCR 0.2 Known only No
Next generation sequencing 1 Known and new Yes
Modified from Pao et al. Clin Cancer Res 200711
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Mechanisms of acquired resistance to
1st and 2nd generation EGFR-TKIs
Ann Oncol. 2018 Jan 1;29(suppl_1):i10-i19
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EGFR testing at the time of recurrence
Piotrowska Z, et al. Cancer J. 2015
1st biopsy and EGFR testing
2nd biopsy and EGFR testing
3rd biopsy and EGFR testing
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Mechanisms of acquired resistance to first-
line Osimertinib therapy
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Lung adenocarcinoma: Molecular profile
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ALK rearrangement in lung cancer
Chromosome 2
1. Expression of ALK fusion protein
2. Dimerization of ALK
3. Constitutive activation of ALK
Shaw AT at al. Clin Cancer Res. 2011Soda M et al. Nature. 2007
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Testing for ALK rearrangement
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ALK testing by break apart FISH
Thunnissen E. et al. Virchows Arch. 2012
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ALK break apart FISH
ALK (-) ALK (+)
Cheng L. et al. Modern Pathology 2012
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� Normal lung tissue does not express ALK
� ALK fusion (+) lung cancer express ALK fusion protein
ALK Fusion: Immunohistochemistry
Adapted from IASLC Atlas of ALK Testing, 2013
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� Recommended IHC assay: D5F3 or 5A4 clone
� Pooled estimates of IHC relative to FISH
� 97% sensitivity
� 99% specificity
� Discrepant FISH and IHC results
� No consistent pattern of clinical outcome
ALK rearrangement: IHC vs. FISH
Arch Pathol Lab Med.
2018 Mar;142(3):321-346.
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Lung adenocarcinoma: Molecular profile
Kohno et al. Transl Lung Cancer Res. 2015 Apr;4(2):156-64.
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ROS1
• Receptor tyrosine kinase (RTK) of the insulin receptor family,
closely related to ALK
(a) Glycoprotein-rich extracellular domain
(b) Transmembrane domain
(c) Intracellular tyrosine kinase
ROS1 gene: Chromosome 6q22
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Leads to constitutive
kinase activity
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Detection of ROS1 rearrangement
� Fluorescence in-situ hybridization (FISH)
� Reverse transcription polymerase chain reaction (RT-PCR)
� Immunohistochemistry (IHC)
� Next generation sequencing (NGS)
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Detection by FISH
Negative for ROS1
rearrangement
Positive for ROS1
rearrangement
(split signal in
>15% of cells)
3’ 5’
Positive for ROS1
rearrangement
(isolated 3’ signal
in >15% of cells)
Detect known and unknown fusion variants
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� Anti-ROS1 clone D4D6 (Cell Signaling)
� Anti-ROS1 clone SP384 (Ventana)
Detection by IHC
ROS1 FISH (+), IHC (+) ROS1 FISH (-), IHC (-)
Mod Pathol. 2014 May;27(5):711-20
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ROS1 IHC staining pitfalls
Macrophages/Giant cells Reactive pneumocytes
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� Pooled estimates of IHC (≧2+) relative to FISH� 96% sensitivity
� 94% specificity
� Up to 1/3 ROS1 FISH (-) cases show focal or weak ROS1
expression by IHC
ROS1: IHC vs. FISH
Arch Pathol Lab Med. 2018 Mar;142(3):321-346.
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CAP/IASLC/AMP molecular test guideline:
ROS1 testing in lung cancer
� ROS1 IHC may be used as a screening test
� Positive ROS1 IHC results should be confirmed by a
molecular or cytogenetic method
� Each laboratory must validate its own interpretive cutoff
from known positive and negative samples
Arch Pathol Lab Med. 2018 Mar;142(3):321-346.
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ROS1: IHC vs. FISH (VGH-TPE data)
ROS1 IHC
(SP384)
ROS1 FISH/NGS
Negative Positive Total
0 125 0 125
1+ 41 0 41
2+ 5 1 6
3+ 3 6 9
Total 174 7 181
0: H-Score = 0
1+: H-Score = 1~100
2+: H-Score = 101~200
3+: H-Score = 201~300
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ROS1 IHC
No stain or
Weak / Focal stain
Moderate to Strong
Diffuse stain
ROS1 FISH
Negative PositiveNegative
VGH-TPE
approach
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Lung adenocarcinoma: Molecular profile
Kohno et al. Transl Lung Cancer Res. 2015 Apr;4(2):156-64.
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http://www.apmggroup.net/innovation/molecular_testing/Colon_Pathways/colon.html35
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BRAF mutation in lung cancer
By Sholl LM, from BWH/DFCI data (~2500 NSCLC sequenced)
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Dabrafenib plus trametinib in
BRAF-V600E mutant NSCLC (1st line)
Lancet Oncol. 2017 Oct;18(10):1307-1316.
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Characteristics of patients with
BRAF-V600E mutated lung tumors
Lancet Oncol. 2017 Oct;18(10):1307-1316.
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BRAF V600E IHC testing (clone VE1)
BRAF-V600E
mutated
tumor
BRAF
non-V600E
mutated
tumor
Ann Oncol. 2013 Mar;24(3):742-8.
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BRAF V600E IHC testing (clone VE1)
Study Sensitivity Specificity
Ilie et al.
Ann Oncol 2013
90.5%
(19/21)
100%
(19/19)
Sasaki et al.
Lung Cancer 2013
100%
(5/5)
95.2%
(20/21)
Gow et al.
Cancers 2019
96.6%
(28/29)
98.6%
(69/70)
Total94.5%
(52/55)
98.2%
(108/110)
Cancers (Basel). 2019 Jun 21;11(6).
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Recommended biomarker tests for patients
with newly diagnosed NSCLC
� EGFR
� ALK
� ROS1
� BRAF
� PD-L1
� RET
� MET exon 14
� HER2
� KRAS
� NTRK
Am Soc Clin Oncol Educ Book. 2019 Jan;39:531-542.
Minimum necessaryRecommended
(for NGS panels)
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Key elements in biomarker
development for checkpoint inhibition
Nishino M. et al. Nat Rev Clin Oncol. 2017 Nov;14(11):655-668.
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Cells with PD-L1 expression
� Tumor cells
� Immune cells
� Lymphocytes (T cells, B cells)
� Dendritic cells
� Macrophages
� Stromal cells
� Certain types of normal epithelial cells
Analyzed by
Immuno-
histochemistry
(IHC)
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PD-L1 expression in tumor cells (TC)
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PD-L1 expression in immune cells (IC)
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Key points:
1. Increased PD-L1 expression is associated with higher ORR
2. Negative PD-L1 expression does not preclude response
3. ORR in high PD-L1 expression patients still below 50%Cancer Biol Med. 2016 Jun;13(2):157-70
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Confounders in PD-L1 expression IHC testing
� Multiple different assays and cut-off values
� Inter-observer variability
� Heterogeneous expression of PD-L1
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NivolumabPembro-
lizumabAtezolizumab
Durva-
lumabAvelumab
Detection
antibody28-8 22C3 SP142 SP263 73-10
IHC platform Dako Dako Ventana Ventana Dako
Epitope
locationExtra-cellular Extracellular Intracellular
Intra-
cellular
Intra-
cellular
Cell types
evaluatedTC TC TC + IC TC TC
Cut-offs in
clinical trials1, 5, 50%
1%
50% (High)
TC: 1, 5, 50%
IC: 1, 5, 10%25% 1%
FDA
diagnostic
status
Complementary
(Not required)
Companion
(Required)
Complementary
(Not required)
PD-L1 testing: at least 5 different assays
TC: tumor cells; IC: immune cells
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Blueprint project (phase 2):
PD-L1 IHC comparability study
Tsao MS. et al. J Thorac Oncol. 2018 May 22. pii: S1556-0864(18)30626-9.
Tumor staining:
SP142: Lower
73-10: Higher
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Tsao MS. et al. J Thorac Oncol. 2018 May 22. pii: S1556-0864(18)30626-9.
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Tsao MS. et al. J Thorac Oncol. 2018 May 22. pii: S1556-0864(18)30626-9.
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Interobserver variability (for TC scoring)
in Blueprint phase 2
Presented by Tsao MS at WCLC 2017
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Interobserver variability (for IC scoring)
in Blueprint phase 2
Tsao MS. et al. J Thorac Oncol. 2018 May 22. pii: S1556-0864(18)30626-9.
Presented by Tsao MS at WCLC 2017
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Tumor heterogeneity
� Intra-tumoral heterogeneity
� PD-L1 expression is frequently heterogeneous within a tumor
� Sampling error
� Inter-tumoral heterogeneity
� Differences between primary and metastasis?
Fusi A et al. Lancet Oncology 2015; 16(13),1285-1287
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PD-L1 Tumor Heterogeneity
McLaughlin et al, JAMA Oncol., 2016.
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H&E PD-L1 (SP142)
PD-L1 Tumor Heterogeneity
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57PD-L1 (SP142)
PD-L1 TPS > 50%
PD-L1 TPS < 1%
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Discordance of PD-L1 expression between paired
biopsy and resection specimens
Ilie M et al. Ann Oncol. 2016 Jan;27(1):147-53.
Overall concordance rate = 52%
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Primary tumor vs. Metastasis
Concordance: 80.1% (1% cutoff), 90.7% (50% cutoff)
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PD-L1 expression as a biomarker
� Imperfect & Weak predictive power
� Multiple different assays and cut-off values
� 22C3/28-8/SP263 are highly analytically comparable
� Interobserver agreement
� Good for tumor cells, Bad for immune cells
� Challenges
� Heterogeneous expression
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Recommended biomarker tests for patients
with newly diagnosed NSCLC
� EGFR
� ALK
� ROS1
� BRAF
� PD-L1
� RET
� MET exon 14
� HER2
� KRAS
� NTRK
Am Soc Clin Oncol Educ Book. 2019 Jan;39:531-542.
Minimum necessaryRecommended
(for NGS panels)
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Cocco E, Scaltriti M & Drilon A, Nature Reviews Clinical Oncol 201864
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