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Caris Centers of Excellence Virtual Molecular Tumor Board - October 28, 2015 (No Audio)
1. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Virtual Molecular Tumor Board
October 28, 2015
Hosted By: Barbara A. Karmanos Cancer Center
Moderator: Dr. Anthony Shields
Cases:
• HER2+ CRC
• NSCLC, PD-L1+ and HER2 mutation
• Gliosarcoma with NTRK fusion
• Rectal carcinoma with PTEN loss
2. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 1
3. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Clinical History
• Demographics: male approx. 60 years old
• Rectal adenocarcinoma
– Anterior-Poster resection
– pT3 N1c (stage III)
– Adjuvant radiation/capecitabine and CAPOX
chemotherapy
4. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Treatment History
• 2 yr Follow-up:
• CEA 27
• CT: normal
• PET/CT: positive pre-sacral mass, nodes and 3
cm liver lesion - Liver Bx positive.
• Started CAPOX/bevzcizumab
• CT after 3 cycles (pending)
5. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
H&E 20x HER2 IHC 20x
6. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
HER2 Amplified
IHC expression results:
EGFR 1+60%, HER2 3+ 75%, cMET 2+60%, PTEN 1+40% (neg)
7. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
NGS Results
• KRAS, NRAS, and BRAF wildtype
• Mismatch Repair proficient (MSI 0/5 markers).
8. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
HER2 in rectal cancer
• The Cancer Genome Atlas project identified HER2 somatic
mutations and gene amplification in 7% of patients with
colorectal cancer.
• Preclinical xenograft models show these mutations can
contribute to EGFR resistance, and targeting HER2 inhibitors
(trastuzumab, neratinib, or lapatinib) can lead to tumor
regression.
Kavuri et al, Cancer Discovery, 2015
9. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Discussion Points
• Standard chemotherapy options at this point
• Irinotecan and EGFR inhibitors still available
• HER2 amplified by CISH and NGS CNV
• Options: trastuzumab/lapatinib and trastuzumab
emtansine (TDM1) on Match
• EGFR and cMET expression may indicate
resistance mechanisms
10. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 2
11. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Clinical History
• Demographics: male in late thirties
• Relevant medical history:
– Right sided chest pain
– Underwent chest xray and then CT scan
– Large 7 cm right lung mass
– PET scan positive in multiple lymph nodes with a
supraclavicular lymph node
– EBUS showed adenocarcinoma
– Brain MRI negative
12. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Treatment History
• Received chemotherapy+RT.
13. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
H&E 20x PD-L1 20x
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Immune Markers
• PD-L1
2+ in 100% of tumor cells
• PD-1
Positive; 1 per HPF
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PD-1 / PD-L1 Immune Checkpoint
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PD-L1 as Biomarker in Lung
• Nivolumab studies presented at ASCO 2015
• Checkpoint-017
– Squamous NSCLC
– 41% OS improvement with nivolumab versus docetaxel in
the squamous setting
• Checkpoint-051
– Non-squamous NSCLC
– OS benefit with nivolumab was 27% in patients with
nonsquamous NSCLC
– Stronger OS outcomes were observed in PD-L1–positives
– Including 60% reduction in the risk of death for those with
the highest PD-L1 levels.
17. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
PD-L1: Meta-analysis
• Sensitivity analysis of 20 (12 nivolumab, 4 pembrolizumab,
and 4 MPDL3280A) trials where a checkpoint inhibitor was
utilized either as a single agent or in combination
– ORR was found to be slightly higher in PD-L1 positive patients than in
PD-L1 negative patients treated with nivolumab and pembrolizumab,
– with an absolute difference of 16.4% and 19.5%, respectively.
• A significant difference in activity of 22.8% and 8.7% according
to PD-L1 was found for melanoma and NSCLC, respectively.
Carbognin et al, 2015
18. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Carbognin et al, 2015
19. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Carbognin et al, 2015
20. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
HER2 mutated, non-ampified
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Discussion
Role for immunotherapy with PD-L1 expression
Impact of sub-clone with HER2 kinase domain
mutation
22. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 3
23. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
History
•Female in early fifties with one month onset of behavioral changes, L visual
field defects, L sided weakness, and gait disturbance.
•Presented to the ER after a fall with blunt head trauma, L facial droop, and
on-going L sided weakness, and visual complaints.
•No Hx of LOC, seizures, bowel/bladder dysfunction, or neuro problems.
•PE: Complete L homonymous hemianopsia, weak LUE, L facial drooping, L
hemineglect
•CT head and MRI brain: R temporo-parietal and R parieto-occipital mass
lesion w/ extensive edema, and slight midline shift.
•PET scan: Areas of increased uptake w/ necrotic centers in the lesion.
24. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Treatment History
• R temporo-parietal-occipital craniotomy, and tumor
resection
• PBRT: 6000 cGy over 30 fractions
• Chemo: Temozolomide
25. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
Although the tumor appeared predominantly glioblastoma,
and contained extensive areas of necrosis, solid tumor, and
infiltrative tumor, the histologic patterns were
heterogeneous and included areas of proliferating cellular
connective tissue considered consistent with sarcoma. The
tumor was thus classified as gliosarcoma. (H&E, next slide)
26. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
H&E 20x
27. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
28. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
29. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
30. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
31. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Molecular Tumor Summary
• NGS Mutations detected
– PTEN
– TP53
• CNV alterations detected
– CMET amplification
– EGFR amplification
• EGFRvIII mutation detected
• Absence of IDH1 expression and 1p19q
32. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
TRK Fusions in Cancer
Investigational molecule: LOXO-101
“An oncogenic NTRK fusion in a soft
tissue sarcoma patient with
response to thetropomyosin-related
kinase (TRK) inhibitor LOXO-101”
(Doebele et al, 2015)
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Discussion
• Lack of MGMT promoter methylation may explain progression under
temozolomide.
• PTEN: Point mutation and intact protein expression may indicate presence of
dysfunctional PTEN protein.
• Cancer is EGFR driven (shown by EGFR overexpression, gene copy number
increase and EGFRvIII presence), and is a typical fast-growing de novo grade IV
glioma (also supported by lack of IDH1 mutation).
• Potentially targetable genes:
– EGFR (ABT-414, EGFR-targeted antibody-drug conjugate; EGFRvIII-targeted
vaccine)
– cMET-amplification may indicate resistance to EGFR-targeted therapy
– NTRK re-arrangement (LOXO-1010, an NTRK inhibitor may be promising)
34. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 4
35. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Clinical History
• Demographics: male in early forties
• Rectal adenocarcinoma
–Diagnosed with limited liver mets
–KRAS WT
36. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Treatment History
• Treated with FOLFOX/bevacizumab with stable disease
• Treated with FOLFIRI/cetuximab with CEA decline
– partial hepatectomy with extensive necrosis
– low anterior resection
– PET/CT new liver lesions
• Treated with FOLFIRI/cetuximab with CEA decline
– Radiofrequency ablation
– Progressed in liver and FOLFIRI/cetuximab resume followed by partial
hepatectomy
• Further liver progression treated at times with
FOLFIRI/cetuximab, FOLFIRI/panitumumab, and
FOLFOXIRI/panitumumab
• 3 yr post-DX:
– Y-90 radiomebolization and regorafenib
– Biliary drain placed for obstructive jaundice
37. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Genomics History
Previously testing:
MYC, TP 53, and SMAD4 alterations
Testing negative for Lynch syndrome.
KRAS was wildtype.
Biopsy of peritoneal lesion 4 years-post Dx
sent for Match and Caris Molecular
intelligence testing
38. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
H&E 20x PTEN IHC 20x
39. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
40. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
PTEN Loss by IHC
• Clinical Trials Connector
• NCI Match study
41. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
NGS Findings
• TP53 R273C pathogenic mutation
• No other pathogenic mutations on 592 genes
• KRAS, NRAS, HRAS wildtype
42. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
PTEN Pathway
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Discussion Points
• Now without standard therapy available except
trifluridine/tipiracil (TAS-102, Lonsurf)
• Tbili now 3.2 and stent being revised
• PTEN loss on Match and Caris testing, possible new
arm on Match trial
• How and when to do both Match and Caris testing?
44. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Next Molecular Tumor Board:
Thursday, November 19, 2015
5pm ET (4pm CT)
Host: MedStar Franklin Square Medical Center
Leader: Dr. Albert J. Aboulafia