Caris Centers of Excellence Virtual Molecular Tumor Board - July 27, 2015

Today's VMTB
Presented by: Dr. Elisabeth Heath
Professor of Oncology,
Karmanos Cancer Center
Cases:
1. NSCLC with EFGR and CTNNB1 mutations
2. Prostate adenocarcinoma
3. Colon adenocarcinoma with KRAS and PIK3CA mutation
4. Jejunal adenocarcinoma with KRAS mutation
Housekeeping:
Please identify yourself and organization when asking / responding to questions
The information contained in these slides is provided for educational purposes only and has been permanently de-identified

Patient 1

Clinical History
• Demographics:
• Relevant medical history:
– Papillary renal cancer, s/p cryoablation, size 1.7
cm right kidney
– Developed sternal and back pain and sought
medical attention
• Symptoms / physical findings:
– Back pain worsening, no weight loss, negative
neurologic deficits
• Caucasian male in mid-sixties

Treatment History
• Diagnosis / pathology: biopsy from right iliac
crest, papillary cancer
• IHC: positive CK7, TTF-1/Napsin A
• IHC: negative PAX 8 and PAX 2
• Diagnosis: metastatic adenocarcinoma of lung
• Staging: diffuse bone mets T, L S spine,
paratracheal/pretrachel lymph nodes, liver lesion,
brain metastasis
• Completed WBRT
• EGFR mutation: exon 21 L861q
• Started Tarceva

Pathology
H & E

Pathology
EGFR TLE3

Molecular Tumor Summary
• EGFR mutation Exon 21 L861Q
• TP53 mutation Exon 8 R273C
• CTNNB1 mutation Exon 3 S37P
• IHC findings:
– Support taxanes, irinotecan, anthracycline benefit

Discussion Points
• Significance of other mutations in Caris Panel

References
Kaiser U, Hofmann J, Schilli M, Wegmann B, Klotz U, Wedel S, Virmani AK, Wollmer E, Branscheid D, Gazdar AF,
Havemann K. Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer. Int J
Cancer. 1996 Jul 29;67(3):357-64
AR expression in NSCLC : around 3% based on internal Caris data.
Nishio M, Ohyanagi F, Horiike A, Ishikawa Y, Satoh Y, Okumura S, Nakagawa K, Nishio K, Horai T. Gefitinib
treatment affects androgen levels in non-small-cell lung cancer patients. Br J Cancer. 2005 May
23;92(10):1877-80. PubMed PMID: 15870715
Gefitinib treatment lowers androgen levels in NSCLC patients. Perhaps gefitinib treatment would have two
effects in this patient: blocking EGFR and reducing tumor growth via AR by lowering androgen levels?
Recchia AG, Musti AM, Lanzino M, Panno ML, Turano E, Zumpano R, Belfiore A, Andò S, Maggiolini M. A cross-
talk between the androgen receptor and the epidermal growth factor receptor leads to p38MAPK-
dependent activation of mTOR and cyclinD1 expression in prostate and lung cancer cells. Int J Biochem
Cell Biol. 2009 Mar;41(3):603-14. doi: 10.1016/j.biocel.2008.07.004.

Patient 2

Clinical History
• Demographics:
– Elevated PSA (7.5) on general check up, and rising on two
subsequent occasions up to low 80's
– Gleason 7, suboptimal brachytherapy, completed EBRT
• Symptoms / physical findings:
– Back pain, nausea, anorexia, 40 lb weight loss
• Caucasian male in early seventies

Treatment History
• Diagnosis / pathology: Bone marrow biopsy: metastatic
prostatic adenocarcinoma, minimal plasma cells
• Staging: diffuse bone mets LS spine, pelvic lymph nodes
• Started abiraterone and prednisone
• PSA 103 decreased to 30 in 3 weeks
• MRI brain showing clivus and skull mets causing pain,
completed xrt

Pathology
AR TLE3

Caris Molecular Intelligence Profile

• TP53: one pathogenic mutation and one VUS
• Androgen receptor IHC positive
• Potential beneficial therapies:
• anti-androgens, taxanes

Discussion Points
• Chemotherapy versus oral agents versus radium 223
• Aggressive disease: send molecular profile when
patient is castrate sensitive metastatic disease
• Check for PIK3CB mutation due to upcoming trial?

References
Based on CHAARTED trial (Sweeney, et al.), ADT + docetaxel.
Based on CMI results of TLE3+ (2+85%) and TUBB3 – (0+100%), he has 2/3 predictive markers in the “favorable” direction. Data
for TLE3 is in breast, data for TUBB3 is in prostate (Ploussard, 2010). It would be interesting to see the impact of PGP
(2+90%) in this patient, in response to treatment.
ADT + Docetaxel : Sweeney C, Carducci MA, Eisenberger MA et al. Chemohormonal therapy versus hormonal therapy for
hormone naive newly metastatic prostate cancer: ECOG-led randomized trial. Ann Oncol 2014; (Suppl 4): Abstr 7560.
ADT + Docetaxel : Sweeney C, Chen Y-H, Carducci MA et al. Impact on overall survival with chemohormonal therapy versus
hormone therapy for hormone-sensitive newly metastatic prostate cancer: an ECOG-led phase III randomized trial. J Clin
Oncol 2014; 32(5s): abstr LBA2.
TUBB3 in prostate : Ploussard, G., et al. 2010 “Class III B-Tubulin Expression Predicts Prostate Tumor Aggressiveness and Patient
Response to Docetaxel-Based Chemotherapy.” Cancer Res 70:9253-9264.
TLE3 : (breast) Kulkarni, S.A., D.T. Ross, et. al. (2009). "TLE3 as a candidate biomarker of response to taxane therapy". Breast
Cancer Research. 11:R17 (doi:10.1186/bcr2241).
PGP (lung) Yeh, J.J., A. Kao, et al. (2003). "Predicting Chemotherapy Response to Paclitaxel-Based Therapy in Advanced Non-
Small-Cell Lung Cancer with P-Glycoprotein Expression." Respiration 70:32-35.
PTEN Loss (0+ 100%) – prognostic feature of prostate cancer (poor prognosis) •Kluth, M., T. Schlomm, T. et al. (2015). “Concurrent
deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer.” Int J Cancer May 22. doi:
10.1002/ijc.29613.
EGFR+, staining is only at 1+85%, not too intense, plus in the face of PTEN loss, unlikely activity with EGFR-mabs.
Consider an ADC-EGFR antibody, at clinical trial phase.

Patient 3

Clinical History
• Demographics: African American in early sixties
• Diagnosis:
– Metastatic KRAS WT colon, disease in liver, LN, and lungs
– Initial Dx 3 years earlier:
• cecal mass stage T3N1b
• Negative for mismatch repair proteins
– Post-op PET/CT- liver mets- biopsy proven mets
• Treatments
1. FOLFOX Avastin
2. 5-FU Avastin
3. FOLFIRI and Vectibix
4. FOLFOX Avastin
5. Stivarga

Pathology
TS TOPO1

• NRAS exon 2 G13D mutation
• PIK3CA mutation E542K
• TP53 mutation R175H
• PD-1 positive IHC
• Potentially beneficial therapies:
• 5-FU, platinums, taxanes, irinotecan

References
NRAS mutated patients should not be treated with cetuximab/panitumumab, based on NCCN guideline which updated molecular
testing to pan-RAS testing based on PRIME trial (Douillard, J-Y, S.D. Patterson, et al. (2013). "Panitumumab–FOLFOX4
Treatment and RAS Mutations in Colorectal Cancer" N. Engl. J. Med. 369;11: 1023-1034)
PIK3CA mutation is frequently found in CRC, however, data has shown that mTor inhibitors are ineffective in CRC irrespective of
PIK3CA mutation status so we don't report out everolimus in CRC cancer type.
a. Janku 2012 Oncotarget shows that PIK3CA is predictive of everolimus in 270 patients in various tumor types, however in
CRC patients, 0 patients responded in either mutated cohort (n=14) or wild type cohort (n=33). (Janku et al. Oncotarget
2012; 3: 1566-1575)
b. Garrido-Laguna 2012 PLoS One showed that in CRC everolimus response rate is independent of PIK3Ca mutation.
c. In a phase II everolimus trial of everolimus in pretreated CRC patients, no PR or CR were achieved in 71 patients and
median PFS and OS were 1.8m and 4.9m. KRAS mutated patients had shorter OS and lower DCR. (Ng 2013, Clin Cancer Res
19(14): 3987-95
d. combination therapy of everolimus with other therapies have been attempted but with limited success (e.g., with
bevacizumab, the efficacy is very limited. (Altomare 2011, The Oncologist, ;16:1131–1137))
There has been data showing that regular use of aspirin after diagnosis was associated with longer survival among patients with
mutated PIK3CA CRC with HR of 0.54, but not in patients with wild type PIK3CA. (Liao 2012, NEJM, "Aspirin Use, Tumor
PIK3CA Mutation, and Colorectal-Cancer Survival", 369;11)
Based on patient's IHC marker status, Low TS, high TOPO1 and low ERCC1, good in-lineage evidence is available to support use of
fluorouracil, irinotecan and oxaliplatin; see example evidence below.
a. Meta-analysis of TS and fluoropyrimidine in CRC: (Qiu, L.X., M.H. Zheng, 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.)
b. FOCUS trial for Topo1 and irinotecan in CRC ( Braun, M.S., M.T. Seymour, et. al. (2008). "Predictive biomarkers of
chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial." J. Clin. Oncol. 26:2690-2698.)
c. ERCC1 and oxaliplatin in CRC (Li 2013, British Journal of Cancer (2013) 108, 1238–1244)

Patient 4

Clinical History
• Demographics:
Caucasian, greater than 50 years of age
– Approximately 3 years ago - partial bowel
obstruction
– Resected jejunal adenocarcinoma stage III
– Adjuvant FOLFOX

Treatment History
• About 3 years ago: presented with abdominal pain
and PET showed peritoneal disease, biopsy +
• Started FOLFIRI, but developed obstruction requiring
resection, lysis of adhesions about one year ago
• Resume FOLFIRI
• CT essentially stable.
• Recently surgery for bowel obstruction due to
omental and mesenteric deposits with colostomy
performed.

• KRAS exon2 G12D mutation
• TP53 Y220S mutation
• Potential benefical therapies:
• 5-FU, taxanes, irinotecan, gemcitabine

Discussion Points
• Standard chemotherapy options at this point
• Role of EGFR inhibitors in small bowel cancer
• Immunotherapy options

The next VMTB will be presented by Wafik El-Diery, M.D., PhD, FACP Deputy
Cancer Center Director for Translational Research and Co-Program Leader in
Developmental Therapeutics at Fox Chase Cancer Center
Date: Wednesday August 12, 2015
Time: 5pm EST
Look for an invitation coming soon!
Please direct questions regarding the VMTB to
cariscentersofexcellence@carisls.com

Caris Centers of Excellence Virtual Molecular Tumor Board - July 27, 2015

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