Caris Centers of Excellence Virtual Molecular Tumor Board - Sep 28, 2015 - West Cancer Center

The information contained in these slides is provided for educational purposes only and has been permanently de-identified.
Virtual Molecular Tumor Board
Hosted By: Dr. Lee Schwartzberg
West Cancer Center
September 28, 2015
Cases:
• Unknown primary
• NSCLC with c-KIT mutation
• Breast cancer with BRCA2 mutation
• Renal cell carcinoma with VHL and PTEN mutations
• Concurrent advanced malignancies with VHL and 2 PTEN mutations

Patient 1

History
• 31 year old woman
• Fall: abdominal bloating following SNVD in Spring
• 6 months later: R pleural effusion, large volume ascites,
R ovarian mass.
– Ca 125: 111; Ca19-9: 41,149; CEA 2.
– EGD reported negative.
– No panc mass on CT
• 3 weeks later: TAH/BSO
– Metastatic signet ring cell adenocarcinoma on ovary and in
ascites.
– IHCs: HER2 -, CK7+, GATA3-. Most c/2 upper GI or
pancreatic/biliary origin. MMR proficient
• 3 months later: Started FOLFOX

History continued
• Cancer Type ID: 90% likely ovarian
• Genetics: 25 gene panel negative for germline
mutation except for VUS in PMS2
• 3 months later: Hospitalized and re-evaluation
– EGD showed poorly differentiated signet ring cell
involving stomach and duodenum
– Switched to taxotere/5FU

Pathology
H&E 10x H&E 20x

Molecular Tumor Summary
• NGS findings:
– KRAS exon 3 A59E pathogenic mutation
– GNAS exon 8 R201H pathogenic mutation
• IHC predicted benefit:
– ERCC1 (platinum), TS (5-FU), TUBB3/PGP (taxanes)
– Non-beneficial: topotecan, anthracyclines, BRAF,
temozolomide

Discussion
• Unknown primary
– Treating as GI primary (colon vs. gastric)
– Avoid cetuximab with exon 3 KRAS mutation
– Has received the predicted beneficial drugs for
colon cancer
– Consider clinical trial

Patient 2

History
• 60 year old male
• Presented with LUL mass, mediastinal and hilar adenopathy,
contralateral lung lesion and adrenal metastases.
– MRI head: multiple brain mets. Heavy smoker and hx of colon
cancer 2007
– NSCLC, adenocarcinoma T4N2M1. Molecular testing referred to in
note but not documented
• Received whole brain radiotherapy, and treated with Carbo /
Alimta + Alimta maintenance with systemic and brain
response
• One year later: Brain mixed response, progressive disease in
lungs and LNs.
– Rebiopsied: met adenocarcinoma.
– Tissue sent for Caris Molecular Intelligence tumor profiling.
– Started second line chemo with docetaxel and palliative care

NGS findings:
– CKIT exon 11 W557R pathogenic mutation
– TP53 exon 10 E339X pathogenic mutation
– BRCA1 exon 23, E1829K (VUS)
IHC findings:
– PD-1 positive, PD-L1 negative
– EGFR H-score positive
– TOPO1 (irinotecan benefit)

Discussion
• c-KIT pathogenic mutation
– Consider imatinib, sunitinib, etc?
– Alone or sequenced with platinum doublet
– References:
– 11 of 34 patients with CKIT+ NSCLC responded to
imatinib. (Donnenberg et al. 2012, PLOS One)

Patient 3

History
• Presented to hospital with unrelenting hip pain
– Pathologic fracture, underwent acetabular repair.
Path: mod diff adenocarcinoma, c/w breast
– CT: liver and bone mets
– Ca15.3 235, CEA 2.6
– Mammogram R breast mass
– Began AC + denosumab

Discussion
• Likelihood of representing a germline mutation
• Genetic counseling for BRCA2 mutation
• Use of platinum or PARP inhibitor with BRCA2m
– Olaparib monotherapy in BRCA-mutant breast cancer:
• 8 of 62 (12.9%) patients responded
• (Kaufman et al, JCO. V33: 244-250 , 2015.)

Patient 4

History
• 46 year old man
• Presented with painless hematuria.
– W/u: L renal mass, multiple pulmonary nodules.
• Nephrectomy
– Clear cell Ca, Furhman grade III, 4 cm. Lung bx: met renal
cancer.
– Started sutent-achieved CR systemically by Spring 2013.
• 1 year later: Solitary hemmorhagic cerebellar.
– Treated with gamma knife x 3 over next 15 months.
• 6 month later: Recurrent disease in L sacrum and adjacent
soft tissue.
– Rebiopsy: Metastatic renal clear cell carcinoma
– Tumor sent for Caris Molecular Intelligence Tumor Profiling.
– Began everolimus.

• VHL exon 3 L169P pathogenic mutation
• PTEN exon 1 K13X pathogenic mutation
• PTEN absent by IHC
• PIK3CA wildtype
• IHC findings:
– Predicted benefit for taxanes, capecitabine,
temozolomide, topotecan
– Predicted lack of benefit for platinums (ERCC1)

Role of PTEN

Discussion
• Any likelihood of PTEN of VHL representing
germline mutations
• Availability of PTEN directed therapies:
– mTOR or AKT inhibitors

Patient 5

History
• Squamous cell carcinoma of lung, stage 3B
– Treated with cis/gem, followed by nivolumab
• PET avid lesion noted on right renal hilum
– With retroperitoneal lymph node involvement
– Biopsy of retroperitoneal node suggested
urothelial origin.
– Tissue sent for Caris Molecular Intelligence Tumor
Profiling.

Pathology
PTEN IHC 20x

• NGS findings:
– KRAS exon 3 E36K pathogenic mutation
– VHL exon 3 R200W pathogenic mutation
– PTEN two pathogenic mutations:
• Exon 6 Q171X
• Exon 7 S229X
• IHC findings:
– PD-L1 negative
– PTEN IHC positive
– Predicted benefit: TUBB3(taxanes), TOP2A (doxo)

Role of VHL

Discussion
• Significance of mutations:
– KRAS
– VHL
– Two PTEN point mutations
• With retention of IHC positivity
• Second primary vs distant metastasis?

Caris Centers of Excellence Virtual Molecular Tumor Board - Sep 28, 2015 - West Cancer Center

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Caris Centers of Excellence Virtual Molecular Tumor Board - Sep 28, 2015 - West Cancer Center