VMTB: Metastatic Cancer Cases and Molecular Profiling

Today’s VMTB
Presented by Edward Kim, M.D.
Chair, Solid Tumor Oncology at Levine Cancer Institute -
Carolinas Healthcare System
Agenda
Patient 1 – metastatic adenocarcinoma, gallbladder
Patient 2 – metastatic NSCLC
Patient 3 – bladder cancer
Patient 4 – metastatic colorectal cancer
Patient 5 – adenoid cystic carcinoma
Housekeeping
Please identify yourself and organization when asking or
responding to questions
1The information contained in these slides is provided for educational purposes only and has been permanently de-identified

Case 1
The information contained in these slides is provided for educational purposes only and has been permanently de-identified

Clinical History
• Female in mid-40’s, Caucasian, never smoker
• At diagnosis: Presented with pain, CT showed ill-defined mass involving medial
segment of left hepatic lobe adjacent to gallbladder, necrotic lymph
node in portal hepatis indicating concern of primary gallbladder
malignancy with local tumor invasion and small lesions in hepatic lobes
• Metastatic adenocarcinoma of gallbladder, wedge resection of liver lesion
Gemcitabine + cisplatin, 6 cycles with eventual progressive disease
• at 2 months: CT showed marked decrease gallbladder and liver lesions,
CA19-9 = 70
Palliative gemcitabine + cisplatin
• At 3 months: Laparoscopy for tissue for Caris testing, CA 19-9 = 114

Pathology
H & E HER2 IHC
• Liver biopsy: adenocarcinoma of liver, segments 3 & 4A
• Gallbladder: moderately differentiated adenocarcinoma of gallbladder

Molecular Tumor Summary
• HER2 positivity by IHC and amplified by CISH
• TP53 mutation
• Cytotoxic markers suggesting response:
– Gemcitabine
– Taxanes
– Irinotecan
– Anthracyclines

Current Treatment
• At 6 months: Xeloda + herceptin + oxaliplatin, 3rd cycle
CA 19-9 = 509 (5/1/15)
• At 7 months: CA 19-9 decreased (509326)
• At 8 months: Intrahepatic lesions increased, stable lymph node,
abnormal significant bowel wall thickening involving ileum and distal ileum

Discussion Points
• Her2+ and subsequent treatment
• RRM1-
• Gemcitabine may be useful due its inhibition of ribonucleotide
reductase activity
• Progression, what’s next?

Case 2

Clinical History
• Female, early 70’s, Caucasian, NSCLC, never smoker
• PMH: Hypertension, hyperlipidemia, renal insufficiency, asthma
• Initial diagnosis: Presented with musculoskeletal pain in right chest wall with
history of stage IV NSCLC (adenocarcinoma, EGFR L858R+)
• CT: 4.7x3.7cm right hilar poorly differentiated adenocarcinoma, 2.4x1.7cm lower lobe mass
• PET: 3.6x3.9cm high lower lobe mass, multiple bilateral mediastinal hilar lymph nodes, right
pleural effusion, and hepatic metastasis of 1.3x1.4cm
 Started Tarceva  partial response
• At 13 months: Progression, treated with carb/pem 4 cycles
• At 19 months: Maintenance pemetrexed, quickly progressed in lung/liver
• Liver biopsy  EGFR L858R+ and T790M+ poorly differentiated
adenocarcinoma  Began clinical trial AZD9291
• At 29 months: CT showed continued response to AZD9291
• At 32 months: CT showed left hepatic lesion increasing
• Surgical resection of hepatic lesion; sent to Caris

Pathology
H&E EGFR IHC
• At diagnosis: FNA hilar lesion – poorly differentiated adenocarcinoma, ALK-,
EGFR L858R+; lymph nodes showed no carcinoma
• At 2 years: poorly differentiated metastatic adenocarcinoma of liver, EGFR
T790M+, L858R+
• At 2.75 years: metastatic adenocarcinoma, poorly differentiated

Pathology
EGFR L585R specific EGFR deletion-specific

• ATM pathogenic mutation
• CMET amplification
• CMET IHC+
• EGFR pathogenic mutation exon 21, L858R
• EGFR H-score positive
• TP53 pathogenic mutation, exon 5, A159V

Discussion Points
• EGFR L858R+: IHC and prior treatment
• cMET amplification and IHC+: Possible clinical trial?
• What’s next?

Case 3

Clinical History
• Female, Caucasian, in mid-70’s
• PMH: Diabetes without neuropathy, coronary artery disease post bypass graft
• At diagnosis: Microhemoturia, nocturia, urinary frequency and urgency
1st TURBT/cystoscopy , 1.5 cm high-grade papillary urothelial carcinoma
with superficial and angliolymphatic invasion, without muscularis invasion
BCG, one round, difficulty tolerating
• At 4 months:CT, cytourethroscopy/fulgration showed T2 N0 M0 high-grade urothelial
carcinoma of the bladder, nested variant with prominent propria invasion and
muscularis propria invasion
 Recommended neoadjuvant chem followed by radical cystectomy but patient
requested bladder preservation and started Tx w/concurrent 5FU/mitomycin C/
radiation
• At 8 months: Mild increased size of right posterior lateral wall thickness, extension into
right ureter causing marked right hydronephrosis consistent with progression
but not metastasis
• At 10 months: Post-radiation radical cystectomy, extended pelvic lymph node dissection

Pathology
H & E
At diagnosis: Urothelial carcinoma, nested variant, prominent lamina propria and
muscularis propria invasion, indeterminate for lymph-vascular space invasion
At 10 months: High-grade urothelial carcinoma of the bladder, focal nested features,
pathologic state pT3b pN3; metastatic carcinoma involving 1/3 right obturator
pelvic and 1/1 paracaval lymph nodes with extranodal extensions

Caris Molecular Intelligence Profile

• No Pathogenic Mutations on NGS
• IHC findings:
– Suggest benefit with: platinums, taxanes, anti-
androgen, temozolomide
– Suggest lack of benefit with: 5-FU, capecitabine,
irinotecan, anti-HER2, anthracyclines

Discussion Points
• Prior Treatment w/concurrent 5FU/mitomycin C/ radiation
• Patient is:
• AR+: Treatment with anti-androgens?
• ERCC1 -: Treatment with platinums?
• MGMT-: Treatment with temozolomide?
• PGP, TLE3, TUBB3+: Treatment with taxanes?
• PD-1+: Treatment with immunotherapy?
• EGFR +: Cetuximab?
• Clinical trials?
• What’s next?

Case 4

Clinical History
• Female, Caucasian, in her late 60’s, Smoker ~2 packs/day, 60 yrs
• Family history: Father colorectal and prostate cancer
• PMH: Diabetes mellitus w/neuropathy, GERD; sick sinus syndrome w/ pacemaker,
hypertension, hyperlipidemia
• At diagnosis: Patient presented with chronic abdominal pain
• CT: Thickening/irregularities in ascending colon at the hepatic flexure;
• Biopsy: mucinous adenocarcinoma of hepatic flexure
• Right hemicolectomy
• Stage IIIB pT3 pN1 M0 colorectal adenocarcinoma
• Began 5FU, discontinued in at month 4 due to GI side effects; surveillance
• In 6 years: persistent RUQ pain, CT/PET showed 13 x 9 cm right hepatic lobe
• Neo-adjuvant irinotecan/bev, 2 cycles, partial response
• In 4 months: CT showed 12.2 x 8.9 cm prominent lesion right hepatic lobe
• Metastatic – adenocarcinoma, liver
• Right partial hepatic resection,
• Post-resection CT showed 4.8x4.2 cm right hepatic lobe
• Completed 1/ 4 cycles 5FU/leucovorin/irinotecan/bev; side effects required
switching to irinotecan + bev

Pathology
H & E
• Initial diagnosis: 9 cm moderately differentiated, low grade mucinous
adenocarcinoma; metastatic, 2/15 lymph nodes; pathologic stage pT3, pN1 pMX
Resection: Metastatic adenocarcinoma of liver, NRAS/KRAS negative
• Recurrence at 6 years: Right partial hepatic resection, loss of MLH1, PMS2
nuclear positivity, BRAF V600E+

Pathology
PMS2 MLH1

Pathology
BRAF V600E-specific IHC

• Pathogenic Mutations on NGS:
– APC N1455fs, T1556fs
– PTEN K267fs
– BRAF V600E
– VHL P138L
• IHC findings predict benefit for:
– 5-FU / Capecitabine
– Gemcitabine

Discussion Points
• TOPO1 negative: May not respond to irinotecan
• KRAS/NRAS/PIK3CA/PTEN negative: Cetuximab, panitumimab?
• BRAF V600E+: Vemurafenib, dabrafenib?
• TS-: Capecitibaine, fluorouracil, pemetrexed?
• RRM1-: Gemicitabine?
• What’s next?

Case 5

Clinical History
• Female, Caucasian, in her late 60’s
• Initial diagnosis:Treated for unresectable myoepithelial carcinoma
• Chemoradiation (carboplatin + taxol, 7 weeks)
• Total thyroidectomy for papillary carcinoma, 0.6 cm, T1a N0
• In 3 years: CT/PET showed recurrence in left masticator space and abnormal
area in right lobe of liver
• Confirmed with biopsy metastatic head and neck and liver cancer
• Left parotid, skin cheek, mandible, zygoma, maxillary wall resected
• CT showed stable right lobe hepatic lesion and small portal lymph nodes
• Radiation with concomitant cisplatin
• Ablation of liver lesion followed by chemoradiation and resection; found 2.4 cm
metastatic adenoid cystic carcinoma with negative margin
• Reduction of hypodense right hepatic lobe lesion
• Follow-up: No evidence of recurrent disease by PET, FDG activity in right hepatic
lobe suggestive of necrosis; metastatic disease portacaval lymph node

Pathology
H & E ERCC1 IHC
• Initial diagnosis: Salivary gland neoplasm with basaloid features, cKit+
• At 3 years, recurrence: Adenoid cystic carcinoma or parotid, 3.8 cm, with admixed bone
(tissue over left medial zygoma), perineural invasion in pes anserinus of left facial nerve,
adenoid cystic carcinoma of left maxillary mucosa, no lymph node involvement
• 2.4 cm metastatic adenoid cystic carcinoma right hepatic lobe, margin negative

• No mutations detected by NGS
• EGFR IHC+
• Cytotoxic IHC markers predicteding response to:
– Capecitabine, 5-FU
– Gemcitabine
– Taxanes
– Carboplatin
– Temozolomide

Discussion Points
• Previous treatment with platinums, taxol, radiation
• ERCC1-: Treatment with platinums?
• PCP, TLE3, TUBB3-: Treatment with taxanes?
• TS-: Treatment with capecitabine?
• RRM1-: Treatment with gemcitabine?
• EGFR+: Cetuximab trial?
• PD-1+: Immunotherapy trial?

Summary
The next VMTB will be presented by Elisabeth Heath, M.D., of
the Barbara Ann Karmanos Cancer Center
Date: July 27, 2015
Time: 5:00 pm EST
Look for an Outlook invitation in the next week
Please direct any questions regarding the VMTB to
cariscentersofexcellence@carisls.com
52The information contained in these slides is provided for educational purposes only and has been permanently de-identified

References: Case 1
• Javle 2015 “HER2/neu-directed therapy for biliary tract cancer”, J Hemotol
Oncol, 8:58.
– A retrospective analysis of biliary tract cancer patients carrying Her2 aberrations: 8
out of 9 patients showed gene amplification or overexpression, 3 showed SD, 4 PR
and 1 CR. 1 patient carrying mutation had a mixed response.
• Law 2012 “Dramatic response to trastuzumab and paclitaxel in a patient
with human epidermal growth factor receptor 2-positive metastatic
cholangiocarcinoma.” J Clin Oncol. 2012 30(27):e271-3
– A case report of a gallbladder cancer
• Sorscher 2013 “Marked radiographic response of a HER-2-overexpressing
biliary cancer to trastuzumab”, Cancer Management and Research 2014:6
1–3

References: Case 2
• Brugger W, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized,
placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung
cancer. J Clin Oncol. 2011 Nov 1;29(31):4113-20.
• Engelman JA, et al. MET amplification leads to gefitinib resistance in lung cancer by activating
ERBB3 signaling. Science. 2007 May 18;316(5827):1039-43.
– Resistance to gefitinib with cMET amplification
• Douillard JY, et al. Final results from PRIME: randomized phase III study of panitumumab with
FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-
55.
– Cetuximab benefit in high expressing EGFR patients is not limited by concomitant EGFR mutations
• Bhattacharya N et al. Frequent alterations of MCPH1 and ATM are associated with primary
breast carcinoma: clinical and prognostic implications. Ann Surg Oncol. 2013
– ATM-altered patients had poor prognosis when treated with DNA-interacting drugs

References: Case 3
• ASCO GU 2015. Systematic review and meta-analysis on ERCC1 in
urothelial CA: http://meetinglibrary.asco.org/content/141786-159.
• ASCO GU 2015, on androgen deprivation therapy to prevent bladder CA
recurrence: http://meetinglibrary.asco.org/content/141184-159.
• Powles T, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity
in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62.

References: Case 5
• Dahse R, et al. KRAS status and epidermal growth factor
receptor expression as determinants for anti-EGFR therapies in
salivary gland carcinomas. Oral Oncol. 2009. Sep;45(9):826-9.
– supports EGFR and KRAS status as determinant for anti-EGFR
• Popovtzer, et al. BioMed Research International 2015
– TUBB3/PGP for taxanes

VMTB: Metastatic Cancer Cases and Molecular Profiling

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