This document summarizes three patient case presentations from a virtual molecular tumor board meeting. It discusses the histories, test results, relevant gene mutations, and potential treatment options for 1) a gastric tumor with FBXW7 and GNAS mutations, 2) a cholangiocarcinoma with a RET mutation, and 3) an EGFR-mutated non-small cell lung cancer. Standard therapies, clinical trial options, and molecular pathways are reviewed for each case.

1. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Today’s VMTB
Presented by Dr Alex Spira, M.D., PhD
Director of the Research Institute and Phase I Program
Virginia Cancer Specialists
Agenda
– Patient 1: gastric antrum tumor with FBXW7 and GNAS mutations
– Patient 2: cholangiocarcinoma with RET mutation
– Patient 3: EGFR-mutated NSCLC
Housekeeping
 Please identify yourself and organization when speaking
 If you are not speaking, please make sure your phone is on mute to
reduce background noise

2. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 1: gastric antrum tumor with
FBXW7 and GNAS mutations

3. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
History
• Early 70’s female presented with:
– abdominal pain, nausea, 20 pound weight loss
• Staging:
– EGD Found to have large gastric antral mass with
diffuse erythema
– CT c/w gastric carcinoma and extensive liver mets
• Received FOLFOX chemotherapy
– PR after two cycles and continuing
– Specimen sent Caris Molecular Intelligence™ profiling
to explore additional treatment options

4. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
H&E 20x

5. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Caris Molecular Intelligence™ Summary
• NGS
– GNAS pathogenic mutation, exon 8, R201H
– FBXW7 pathogenic mutation, exon 9, R465C
– TP53 pathogenic mutation, exon 5, R158H
– TP53 pathogenic mutation, exon 8, R273C
• IHC
– Sensitivities: platinum, taxanes, epirubicin
– Non-sensitive: 5-FU, irinotecan, trastuzumab

6. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
FBXW7
• F-box protein
• Component of ubiquitin ligase complex
• Helps regulate proliferation and growth
• Maintains quiescence of normal and
cancer stem cells
• May be associated with mTOR inhibitor
response (Jardim et al, P One, 2014) (Villaruz and
Socinski, Lung Cancer 2014)
• Alterations implicated in multiple cancers
esp. breast and GI malignancies
(Takeishi et al, British J. of Cancer (2014)

7. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
GNAS Pathway

8. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Clinical Trial Options

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Discussion
• Standard therapies
– Continue FOLFOX?
• Clinical trials
– MEK inhibitor trials?
– mTOR inhibitor?
• Other options?

10. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 2: cholangiocarcinoma
with RET mutation

11. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
History
• Elderly man with h/o Lung transplant on
immunosuppression (prograf, prednisone) for 3 years
• Diagnosis:
– CT scan in follow-up showed mass in liver.
– Biopsy c/w spindle cell tumor. Suspected cholangiocarcinoma.
– Underwent resection c/w the same and single implant.
• First CT scan 2 months later extensive metastatic disease
at the surgical bed, peritoneum.
• Was going to start chemo but rapid progression within
two weeks and pt in hospice

12. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Pathology
H&E 20x

13. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Caris Molecular Intelligence™ Findings

14. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
RET Pathway

15. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Vandetanib
• Approved in 2011 for metastatic
medullary thyroid carcinoma
• Activity against RET, EGFR, VEGFR
• Dosage: 300 mg PO daily
• Side effects: diarrhea, rash, prolonged
QT interval, hypertension, and fatigue
• Limited data on off-label use in GI
malignancies with RET mutations

16. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Patient 3: EGFR-mutated NSCLC

17. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
History
• Woman, late 50’s, presented with headache and MRI
c/w meningioma.
– Preop chest xray shows a lung mass
• Pathology revealed with NSCLC
– Multiple nodes involved.
• Received adjuvant chemotherapy with Cisplatin and
pemetrexed x3 and Radiation to the mediastinum.
– Substantial nausea
• Caris Molecular Intelligence™ profiling ordered given
high chance of relapse.

18. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
EGFR Pathway Results

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EGFR exon 19 deletion

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EGFR Resistance Mechanisms
• EGFR secondary mutations
– T790M ,D761Y, T854A, L747S
• Amplifications
– CMET, HER2, MAPK
• Other mutations
– KRAS, HRAS, NRAS, PIK3CA, BRAF, AXL
• PTEN loss
• Surviving down regulation

21. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
EGFR Resistance Mechanisms
Reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929287/figure/F3/

22. The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Discussion
• Treatment options
– Role for EGFR inhibitors?
• Maintenance versus treat on progression
– Re-test tumor if EGFR resistance develops?

23. Conclusion
The next VMTB will be presented by Dr. Ed Kim
of the Levine Cancer Institute the week of December 14.
Look for an Outlook invitation for the next VMTB
Please direct any questions regarding the VMTB to
cariscentersofexcellence@carisls.com