Caris Centers of Excellence Virtual Molecular Tumor Board - August 12, 2015

Virtual Molecular Tumor Board
Fox Chase Cancer Center
August 12, 2015
Presented by: Wafik El-Deiry, MD, PhD, FACP
Professor, Hematology/Oncology Deputy Cancer Center; Director for
Translational Research; Co-Program Leader, Molecular Therapeutics
Patient 1: Pancreatic neuroendorcine tumor with C-KIT mutation
Patient 2: Rectosigmoid junction cancer with HER2 amplication and PTEN loss
Patient 3: Recurrent Sertoli-Leydig ovarian tumor with multiple cytotoxic biomarker
findings and no NGS mutations
The information contained in these slides is provided for educational purposes only and has been permanently de-identified.

Case 1
Neuroendocrine tumor

Metastatic Neuroendocrine Tumor
• Male in mid-forties presented with nausea and severe RUQ pain.
• Received 4x cycles of Cis-Etoposide
• For two years received 5FU+Streptozocine chemotherapy, PD
• Obtained PR on Phase I trial of Litronesib/LY2523355 kinesin 5 inhibitor.
Eventual PD with rapid growth of the liver mets
• A biopsy with molecular studies was obtained
• Additional alterations: MCL1 amplification, BAP1 splice site 2056+1 C>T
mutation
Perkins J. et al. JNCCN, 2014

Pathology
H & E (previous specimen) H & E (current specimen)

Baseline 3 months on
KIF11 inhibitor
4 months on
imatinib
Perkins J. et al. JNCCN, 2014
Sustained response
for 2 years

Imatinib-resistant clone- Bx#2
TACE => continue on Sunitinib

Litronesib
Bx#1 Bx#2
Imatinib Sunitinib
TACE

initial liver biopsy

Follow-up biopsy

C-KIT variants
Tyr823
(new variant)
Activation Loop
Val560
(original deletion)
Bound inhibitor
(active site)

Secondary C-KIT mutations in exon 17
cause sunitinib resistance
Heinrich et al. JCO, 2008

Molecular Tumor Summary
• Recurrent neuroendocrine tumor with repeat
NGS testing
• Persistance of previously noted C-KIT mutation
exon 11 V560del
• Now with Secondary C-KIT mutation exon 17
Y823D (imatinib-resistant)

Case 2
Metastatic rectal carcinoma

Metastatic rectal adenocarcinoma
• Male in mid-forties presented with mts rectal cancer
• No Fam Hx
• Laparoscopic liver resection
• Rectal surgery after ~4 months of chemotherapy
• For about two years, received FOLFOX-Bev chemotherapy on OPTIMOX-2
schedule. Stopped due to hypersensitivity to Oxaliplatin
• Second line FOLFIRI-Bev, x 1 year
• SIR embolization with Capecitabine until progression
• Caris testing was ordered on the primary rectal tumor specimen

Pathology
H & E (10x) H & E (20x)

Pathology
HER2 IHC (10x) HER2 IHC (20x)

FOLFOX-Bev/SIR+cape
Liver resection
Rectal Sx
FOLFIRI-Bev
Trastuzumab+
MM111+paclitaxel
Progressive liver Ds
Caris test
FOLFIRI-Bev
IRI-Cet
SIR embo
Trastuzumab+
regorafenib
Death

Initial presentation One year later,RFA ablated metastases
5 years later- Portal HTN from
Radiation & multiple embolizations

• NGS reveals no driver mutations (RAS WT)
• HER2 amplified by FISH, over-expressed by IHC
– PTEN loss by IHC suggests lack of anti-HER2 benefit
• Cytotoxic biomarkers (TS and ERCC1 low) indicate
potential benefit with 5-FU and oxaliplatin
– Low expression of TOPO1 suggests lack of irinitocan benefit

Additional references
• HER2 amplification in CRC may be Rx with a combination of trastuzumab plus lapatinib: Siene,
S., S. Marsoni, et al. (2015). “Trastuzumab and lapatinib in HER2-amplified metastatic
colorectal cancer patients (mCRC): The HERACLES trial”. J Clin Oncol. 33 (suppl; abstr 3508).
• ·Meta-analysis on TS/FU-based Rx in advanced CRC: Qiu, L., Zheng, M., et al. (2008).
“Predictive value of thymidylate synthase expression in advanced colorectal cancer patients
receiving fluoropyrimidine-based chemotherapy: evidence from 24 studies”. Int J Cancer.
123:2384-2389.
• ERCC1/oxaliplatin in CRC: Li, P., Y. Fang, et al. (2013). “ERCC1, defective mismatch repair
status as predictive biomarkers of survival for stage III colon cancer patients receiving
oxaliplatin-based adjuvant chemotherapy”. British J Cancer.108:1238-1244.
• PTEN and lack of response to cetuximab: Negri, F.V., A. Ardizzoni, et al. (2010). “PTEN status
in advanced colorectal cancer treated with cetuximab”. British Journal of Cancer. 102:162-64.

Patient 3
Recurrent ovarian stromal tumor

Clinical Summary
Demographics: Female in early twenties
At diagnosis, the patient underwent exploratory laparotomy and right salpingo-
oophorectomy for a 29 cm mass which was ruptured on entry. Stage IC and
received 6 cycles of adjuvant chemotherapy with cisplatin and paclitaxel.
Four years later the patient noted new onset abdominal pain. Imaging revealed a
large supra-vesical complex mass with ascites.
Ex-lap debulking with small bowel resection. Received 6 cycles of dose dense weekly
paclitaxel/q 3wk carboplatin.
One year later, abdominal recurrence on CT scan.
Underwent ex-lap and complete debulking, cholecystectomy
3 cycles of BEP chemotherapy

Pathology
H & E

• No relevant NGS mutations identified
• EGFR IHC positive
• Cytotoxic biomarkers suggest benefit for
taxanes, anthracyclines, camptothecins
– Predicted lack of benefit for gemcitabine

The next VMTB will be presented by Sandy Swain, M.D.,
Medical Director of the Washington Cancer Institute at
MedStar Washington Hospital Center
Date: Monday September 14, 2015
Time: 5pm EST
Look for an invitation coming soon!
Please direct questions regarding the VMTB to
cariscentersofexcellence@carisls.com
30The information contained in these slides is provided for educational purposes only and has been permanently de-identified.

Caris Centers of Excellence Virtual Molecular Tumor Board - August 12, 2015

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Caris Centers of Excellence Virtual Molecular Tumor Board - August 12, 2015