CAP Molecular Diagnosis of Lung Cancer

List 5 treatment defining molecular transformation, the neoplasm, and the genetic alteration
1. 100% of CML: BRR-ABL > Imatinib, 2. 20% of Lung Adenocarcinoma: EGFR > Erlotinib/Gefitinib, 3. 25% Infiltrative ductal carcinoma of breast HER2>Trastuzumab, 4. 50% of Melanoma, BRAF v600E > PLX4032, 5. 4% of Lung Adenocarcinoma: ALK > Crizotinib

List and describe 5 areas of Genetic characaterization of tumours for personalized medicine
DNA mutations, DNA chromosomal alterations, mRNA and MiRNA profiling, Proteomics, DNA epigenetics

What fraction of Lung adenocarcinomas have no known detactable mutations
42%

What are the three most common molecular alterations of Lung Adenocarcinoma
KRAS 23%, EGFR 15%, TP53 5%

What is the two most common molecular alteration makes patients with EGFR mutations resistant to targetted therapies?
KRAS (primary) and T790M (primary and acquired)

List two EGFR kinase inhibitors.
Gefitinib/Iressa, Erlotinib/Tarceva

What are the three most common cancers associated with KRAS mutations?
Pancreatic 90%, Colon 50%, Lung NSCLC 30%

Why don't KRAS + tumours respond to Anti EGFR therapies?
KRAS is downstream from EGFR, so changing the function of EFGR would not have any effect on mutated KRAS

Explain the cost effectiveness of genetic testing for targetted therapies?
Most molecular tests cost $200-1000, vs one month of targetted therapy $2000-10000/month

What are the three most common cancers associated with BRAF mutations?
Melanoma 70%, Papillary Thyroid Carcinoma 50%, Ovarian serious carcinoma 30%, Colon cancer 10%, Hint Papillary architecture

Beta catenin/CTNNB1 expression is found with which histological pattern of lung adenocarcinoma?
Low grade adenocarcinoma of fetal type, poor px, <40yo, and has glycogen rich glandular formations, may occur in FAP patients

What is the most common ALK rearrangement found in NSCLC?
EML4-ALK (90% of the 13% of lung cancers found to due to ALK fusions)

List some pros and cons of ALK FISH.
Pros: commercial FDA approved probes available, not too expensive, moderately easy to disseminate screening, clinically validated, and failed tests on poorly preserved tissues are not reported as negative. Cons: need fish lab expertise (including pathologist and PhD), can be tricky if genes are close

List some pros and cons of ALK IHC.
Pros: fast, cheap, easy to disseminate screening, Cons: commercial antibodies sub-optimal, poorly preserved tissues (esp bx) may give false negative results due to loss of antigenicity, no internal control

What is a positive count in the ALK-FISH?
Signal split >2 probe diameters