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Lung Cancer: Guidelines, Biomarkers and You
April 2, 2019
Cynthia A Schandl, MD, PhDMUSC Pathology
Disclosure
• Pathologist Consultant for Inivata, Ltd. (Liquid Biopsy):• No other disclosures
Objectives
• Review Tier 1 / Actionable Mutations in mNSCLC
• Discuss Emerging NSCLC Biomarkers
• Understand the pathologist role
Lung Cancer
• Leading cause of cancer death in the US• ~85% are smoking related• NSCLC: 18% 5-year survival overall
• Most are non-small cell carcinoma (~85%)• 40% Adenocarcinoma• 30% Squamous• 15% Large cell
• Several 1st line targeted therapies depend upon molecular analysis
Odds for Targetable Mutation
20%Never
7%Never
75% of never smokers
15% of smokers
MORE Likely in Never Smoker
ASCO Post 2017. http://ascopost.com/issues/December-25-2017/lung-cancer-in-never-smokers-a-complex-clinical-phenomenon*Sacher AG, et al. Association between younger age and targetable genomic alterations and prognosis in non-small-cell lung cancer. JAMA Oncol 2016; 2(3):313-20.
MORE Likely in Younger Age*
Barlesi F, Mazieres J, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). The Lancet 2016; 387:1415-26.
Staging is still important
Guidelines are currently aimed at advanced / unresectable disease
In lung cancer, most present at Stage III / IV
Low stage-specific survival; (?smoking comorbidities)
Tiers of Clinical Importance
1. Strong clinical significance2. Potential clinical significance3. Unknown clinical significance (“VUS”)(4. Likely benign)
Tier 1 Mutations in NSCLC
• Up to 50% of patients will demonstrate an actionable mutation
• Minimum testing recommendations (sensitivity at least 20% at diagnostic sample and 5% at recurrence / suspected resistance):• CAP: 1. EGFR, 2. ALK, 3. ROS1• NCCN: 4. BRAF, 5. PD-L1
• Additional recommendations (NCCN):METRETERBB2KRASNTRK 1, 2, 3
https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
Practical Progress: 15 sites in NJ and MD
Gutierrez ME, et al. Genomic Profiling of Advanced Non-Small CellLung Cancer in Community Settings: Gaps andOpportunities. Clin Lung Cancer 2017, 18(16), 651-9 .
Variants to Test
1. EGFR2. ALK3. ROS14. BRAF5. PD-L16. NTRK1, 2, 3---------1. KRAS2. MET3. ERBB2
Wenxiao J, et al. Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspectiveActa Pharmaceutica (2018) 8(4): 530-538. https://doi.org/10.1016/j.apsb.2018.04.005
Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival between responders and nonresponders. Exp, experimental; HR, hazard ratio.
Blumenthal GM, et al. Overall Response Rate, Progression-Free Survival, and Overall Survival With Targeted and Standard Therapies in Advanced Non–Small-Cell Lung Cancer: US Food and Drug Administration Trial-Level and Patient-Level Analyses. J Clin Oncol (2015) 33(9): 1008-1014 PMID: 25667291
Testing – what test for what
1. EGFR – insertions / deletions, amplification, SNVs2. ALK – rearrangements, SNVs3. ROS1 – rearrangements, SNVs4. BRAF - SNVs5. PD-L1 – overexpression (IHC)6. NTRK1, 2, 3 - rearrangements---------1. KRAS – SNVs, copy number changes2. MET – SNVs, intronic changes, amplification (7q31.2)3. RET – rearrangements4. ERBB2 – insertions, amplification (17q12)
Lung Access
Samples
Sample
• Tumor – FFPE, Fresh, FNA• DIAGNOSIS• Molecular testing: NGS, FISH, etc
• Plasma• NOT diagnostic• HIGH specificity• Up to 30% false negative rate• NCCN guidelines:
• Patient unfit for invasive sampling• Have tumor diagnosis, but sample insufficient for molecular testing
The small sample - triage
Initial materials: PD-L1 and NGS assay / FISHCut extra unstained if FISH is protocol (avoid re-facing block)Each biopsy in separate cassette / Shallow facing to preserve tissue deeper in block (avoid aggressive initial block facing)
Use your cytology smears (validate these for any in house assay)
Prioritize PD-L1 / consider blood based test for NGS
1. EGFR
• 1. EGFR sensitizing mutations (7-23% Western; 30-50% Asian)• Most are either exon 19 deletion or exon 21 L858R mutation• At Diagnosis – EGFR tyrosine kinase inhibitor (TKI) therapy (e.g. osimertinib)
• First line treatment • Longer progression-free survival • Higher overall response rates
Patient progression on EGFR TKI
• Upon Progression - ?resistance mechanism• 1st / 2nd generation TKIs - ~50% develop EGFR T790M mutation• 3rd generation clinical trial / chemoimmunotherapy / ?
Other mechanisms of acquired resistance (many !!)MET ampERBB2 ampEGFR ampEGFR C797SKRASRET fusionSmall cell transformation
EGFR - What test?
IHC – not recommendedSequencing
SangerNGSMass Array
What about amplifications?What about at recurrence?
Chemoresistance and the chronic disease theory of cancer
2. ALK
• (D) Computed Tomography Scan of This Patient With the EML4-ALK Variant E17; Ins89A20 Before and After Crizotinib Treatment, Showing a Good PR After Second-Line CrizotinibTreatment
Lei Y-Y, et al. Anaplastic Lymphoma Kinase Variants and the Percentage of ALK-Positive Tumor Cells and the Efficacy of Crizotinib in Advanced NSCLC. Clin Lung Cancer(2016) 17(3):223-231.
ALK Rearrangement – What test?
• IHC is OK• FISH is common• Sequencing is possible: DNA / RNA / cDNA sequencing
3. ROS1
• ROS1 rearrangement (1-2%) – IHC screen ONLY (low specificity); FISH confirm• At Diagnosis – crizotinib (70% response rate)
Break-apart FISH probe for ROS1 gene
ROS1 Rearrangement – What test
IHC not recommendedFISH is commonSequencing is possible
4. BRAF
• BRAF V600E (1-2%)• At Diagnosis – combination BRAF and MEK inhibitor therapy
BRAF SNV – What test?
Sequencing:Sanger (20%)NGS (5%)
5. PD-L1
• PD-L1 expression (23-28%)• >50% cells – 1st line treatment (pembrolizumab)
• Note that PD-L1 testing is not needed for other inhibitors (e.g. nivolumab, atezolizumab)
• >1% cells – 2nd line• Harmonization of IHC ??
Wenxiao J, et al. Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspective.Acta Pharmaceutica (2018) 8(4): 530-538. https://doi.org/10.1016/j.apsb.2018.04.005
Figure 5 Hirsch FR, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol (2017) 12(2):208-222.
αPD-L1
Immunooncology predictive markers
PD-L1 IHCMicrosatellite instabilityTumor mutational burdenKRAS / STK11 mutation
“© National Comprehensive Cancer Network, Inc 2011, All Rights Reserved. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN Guidelines®, NCCN COMPENDIUM® and NCCN TEMPLATES® are trademarks owned by the National Comprehensive Cancer Network, Inc.”
NTRK1, 2, 3 Rearrangement
• TRK = tropomyosin receptor kinase• TRK inhibitor
• FDA-approved drug, November 2018, Larotrectinib• Into NCCN guidelines January 2019• 0.23% of NSCLC cases• PAN-CANCER indication
Drilon A, et. Al. Efficacy of LarotrectinibIn TRK Fusion-Positive Cancers in AdultsAnd Children. NEJM (2018) 378(8):731- 739.
Lung adenocarcinoma with SQSTM1-NTRK1 fusion
Kummar, S. & Lassen, U.N. Targ Oncol (2018) 13: 545. https://doi.org/10.1007/s11523-018-0590-1
Why do I care aboutKRAS??
Wenxiao J, et al. Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspectiveActa Pharmaceutica (2018) 8(4): 530-538. https://doi.org/10.1016/j.apsb.2018.04.005
KRAS Plus
KRAS plus STK11 mutations
LKB1 modulates STING (stimulator of interferon genes) expression in KRAS-mutant lung cancer.
Shunsuke Kitajima et al. Cancer Discov 2019;9:34-45
©2019 by American Association for Cancer Research
Note: LKB1 =STK11
Emerging Biomarkers
“© National Comprehensive Cancer Network, Inc 2011, All Rights Reserved. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN Guidelines®, NCCN COMPENDIUM® and NCCN TEMPLATES® are trademarks owned by the National Comprehensive Cancer Network, Inc.”
MET
MET AmplificationCrizotinib: Subcarinal
lymph node
Ou S-H I, et al. Activity of Crizotinib (PF02341066), a Dual Mesenchymal-Epithelial Transition (MET) and Anaplastic Lymphoma Kinase (ALK) Inhibitor, in a Non-small Cell Lung Cancer Patient with De Novo MET Amplification. J Thorac Oncol (2011) 6(5):942-946. https://doi.org/10.1097/JTO.0b013e31821528d3
FISH showing amplification
Computed tomographic scans obtained after 4 weeks of crizotinib treatment in a 73-year-old man with metastatic squamous cell lung cancer and MET exon 14 skipping.
Rebecca S. Heist et al. The Oncologist 2016;21:481-486
©2016 by AlphaMed Press
MET Exon 14 skipping
Summary of clinical characteristics of all patients identified with MET exon 14.
Rebecca S. Heist et al. The Oncologist 2016;21:481-486
©2016 by AlphaMed Press
The genomic position of METex14 alterations.
Garrett M. Frampton et al. Cancer Discovery 2015;5:850-859
©2015 by American Association for Cancer Research
RET Rearrangement
Treatment options: “multi tyrosine kinase inhibitors” (MKIs) with anti-RET activity (i.e. not crizotinib or gefinitib) such as cabozantinib / vandetanib
High toxicity / lower response ratesRET-selective inhibitors – clinical trial (e.g. LOXO-292, BLU-667)
ERBB2
Exon 20 Insertion - sensitive
Amplification - resistance to EGFR TKIs
Microarray results (Illumina I-Scan platform)
ERBB2 (HER2) amplification
TMB – Tumor mutational burden
A rough measure of potential immunotherapy efficacy
“TMB Harmonization Project” – Friends of Cancer Research – www.focr.org
The Future: ?Targeted or Genomic Approach?Copy numbers, SNVs, InDels, structural variants, oh my
Tumor / Normal whole exome sequencing Generated 152,708 candidate mutations Per tumor (on average) by subtraction methodAnd 508 using [VarScan 2] pipeline…
Doboldt DC, et al. Genome Research (2012) 22:568-575. doi/10/1101/gr.129684.111
-Mario Andretti