Somatic Mutations (hematology/oncology) Flashcards
Cancer management
-shifted from cytotoxic to chemical.biological agents
Somatic mutation
-found within tumor
Germline mutation
-heritable found within individual
Mutations can be used to identify:
- prognostic markers
- Predictive markers (identify subpopulations most likely to respond to therapy)
Drugs with EGFR somatic markers/target
-GEFitinib
-ERLOtinib
-AFAtinib
-all lung cancer
Drugs w ALK markers targeting receptor tyrosine kinases
-CRIZotinib
-CERitinib
-both lung cancer
Drugs with EFGR and KRAS markers
-cetuxiMAB (also head and neck)
-PanitumuMAB
-coloractal cancer
Lung cancer types
-non-small cell lung cancer
-small cell lung cancer
Non-small cell lung cancer
-85% of lung cancers
-platinum based chemotherapy (first line, resistance reduces survival rate)
-target therapy linked to biomarkers may overcome resistance
EGFR (HER/ErbB) family members:
-EGFR (HER1/ErbB1)
-HER2 (ErbB2)
-HER3 (ErbB3) and HER4 (ErbB4)
EGFR protein tyrosine kinase family
-overexpression is cause of many cancers
-dysregulated and overactive
-expression may indicate different cancer phenotype
Non-small cell lung carcinoma genotype
-EGFR (HER1/ErbB1) mutations
-if mutations: TKI inhibitors may be more effective
-if no mutations: chemo might be better
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EGFR TKI sensitivity
-mutations that inc susceptibility are on exons 18,19,21 in TK domain?
-mutations with resistance to EGFR-TKIs are on exon 20
Common EGFR (Her1/ErbB1) mutations in NSCLC
-deletion in exon 19
-L858R mutation in exon 21
-more common in women, asians, and non-smokers
EGFR protein TKI inhibitors
-oral admin
-GEFitinib (conflicting data/limited use)
-ERLOtinib (most effective w higher EGFR expression)
-AFAtinib (most effective w higher EGFR expression)
GEFTitinib
-fast track approval after phase II trial
-phase IV trial showed no survival benefit overall or in pt w high levels of EFGR
ERLOtinib and AFAtinib
-first line for all metastatic NSCLC w:
-exon 19 deletions
-exon 21 L858R substitution mutations
-often desired to initiate before genotype results are available tho
ERLOtinib drug interactions
-CYP3A4 substrate
-cig smoking dec concentrations
AFAtinib interactions
-P-gb substrate
-P-gb inhibitors inc exposure
-inducers dec exposure (inc by 10mg/day as tolerated)
CetuxiMAB/PanitumuMAB
-mAbs that inhibit growth and survival of tumor cells w overexpressed EGFR
-indicated in colon and neck cancer and also NSCLC
-not all the way effective bc KRAS mutations independent of upstream EGFR signaling
-no beneficial effect in curing KRAS-induced cancers
KRAS missense mutations
-located in exon 2 in codons 12 and 13
-activation of KRAS –> cancer
-40% of colon cancer pt
-no sex differences, more white than asia, more pt who have smoked cigs
Cetuximab/Panitumumab drug labeling
-PGx test on the KRAS gene recommended first
-only pt w EGFR-expressing colon cancer and KRAS mutant negative (wild-type) should receive these drugs
