lecture 21 - somatic mutations Flashcards
(29 cards)
how do malignancies arise?
from the transformation of genetic material from a normal cell
what type of agents are used now a days for cancer management?
chemical and biological agents
in the best it was cytotoxic agents
what are the characteristics of chemical and biological agents?
target a critical gene or pathway
not as a narrow of a TI as cytotoxic agent
gene expression determines proper agent
what are somatic mutations?
variations found within the tumor
what are germline mutations?
heritable variations found within the individual
what can germline/somatic mutations be used to identify?
prognostic markers
predictive markers (used to identify subpopulations of pts most likely to respond to a therapy)
what are characteristics of getitinib and afatinib?
target – EGFR (ERBB1, HER1)
cancer – lung
somatic markers – EGFR
what are the characteristics of erlotinib?
target - EGFR (ERBB1, HER1)
cancer – lung, pancreatic
somatic markers - EGFR
what are the characteristics of crizotinib and ceritinib?
target – receptor tyrosine kinases
cancer – lung
somatic markers – ALK
what are the characteristics of cetuximab?
target – EGFR (ERBB1, HER1)
cancer – colorectal, head and neck
somatic markers – EGFR, KRAS
what are the characteristics of pantiumumab?
target – EGFR (ERBB1, HER1)
cancer – colorectal
somatic markers – EGFR, KRAS
what are the characteristics of lung cancer?
originates from the lining cells of a respiratory tract
75-90% of pts having a hx of smoking
classified into 2 types based on biological characteristics (non-small cell and small cell)
what are the drug targets of NSCLC?
platinum-based chemotherapy (traditional first-line in advanced stage, resistance reduces survival rate)
targeted therapy linked to biomarkers may overcome drug resistance
what gentoypes are members of the EGFR family?
EGFR (HER1/ERBB1)
HER2 (ERBB2)
HER3 (ERBB3) and HER4 (ERBB4)
what are the characteristics of EGFR protein tyrosine kinase family?
overexpression implicated in numerous cancers
dysregulated and constitutively active
expression may indicate an entirely different cancer phenotype
how does an EGFR mutation influence therapy for NSCLC?
if present, TKI inhibitors are more effective
if not, chemotherapy better
what drugs directly impact EGFR?
cetuximab, pantiumuab
afatinib, erlotinib, gefitinib (ORALLY ADMINISTERED)
what exons encode the TK domain?
18-24
what exons have mutations that increase susceptibility to TKI?
18
19 (deletions)
21 (L858R substitutions)
what exons lead to resistance to EGFR-TKIs?
exon 20
how does gefitinib differ from erlotinib and afatinib?
there was no survival benefit in pts who had high levels of EGFR while it predicts E/A response if higher
when should erlotinib and afatinib be used?
first-line with metastatic NSCLC who have EGFR exon 19 deletion or exon 21 substitution
what is the drug-drug interactions of erlotinib?
CYP3A4 substrate
cig smoking decreases plasma conc
what are the drug-drug interactions of afatinib?
p-gp substrate
co-admin of inhibitors increase exposure
co-administ of inducers decreases exposure (so increase by 10 mg per day as tolerated)
