Oncology PGx Flashcards
What type of mutation does cancer usually have?
Somatic usually, germ and somatic second, Germ-line last
5 year survival for Colorectal cancer?
64%
5 year survival for mCRC
14%
What is KRAS?
Proto-oncogene
what happens if KRAS is on?
GTPase state and propagate cell growth and differentiation
What is K-ras?
It can be intercellular as well
When do you give a EGRF inhibitor?
KRAS -
Cant give is positive
What codon is activated in KRAS mutation?
12,13 or 61
What happens when you bind EGFR?
Attaches cell surface and turns off the tumor like environment
Is EGRF therapy given alone?
No always in combo with a chemotherapy
Do we have toxic and dosing data for KRAS positive pt given EGFR?
No
KRAS mutation on what codon for mCRC cant receive what?
Codon 12 and 13 and can’t get EGFR therapy
What do you give if they have KRAS mutation?
Sotorasib NSCLC
What is BCR-ABL?
The fuse of 2 gene (9 and 22) and when fused it shortens one called the Philadelphia chromosome
Effect of BCR-ABL?
Speeds up cell division and block DNA repair
What are the 3 symptoms phase of CML
Chronic - mild or no
Accelerated - symptoms
Blast - severe symptoms
what is first generation TKI and what does it do?
Gleevac (imatinib) - prolongs survival and events
Doesn’t cure and goes back to chronic state
How does CML develop imatinib resistant?
BCR-AML point mutation bc of amplification and over expression
Cause point mutation in ATP binding site
What is IC50?
Lower the better for mutations
What is T315I?
ATP binding site point mutation that is important for drugs
What are the 4 mutations we look for in CML and which ones do we worries about?
P-loop, ATP binding site, Catalytic domain, A-loop
P-loop and ATP binding site most common
When do we test CML pt?
Accelerated or blast phase
When to test when on mediation for CML?
See fails or resistance to imatinib
Same with 2nd gen dasatinib or nilotinib
Which drug do i give with mutation T315I?
3 or 4th gen ( ponatibnib or asciminib)
FDA approve for this mutation
Where are V299L, T315A, and F317L/V and what drug do i give
ATP binding site mutations and i give Nilotinib over dasatinib
Where are Y253H, E255K/V and F359V/Cand what drug do i give
Y and E are P loop and F is a catalytic domain
Give Dasatinib over Nilotinib
What is HER2 or ERBB2?
Givens a worst prognosis and over expressed
How does Trastuzamab work and when do I use
Binds to HER 2 and use only if + for HER 2
What are the 2 test that find HER2?
FISH and Hercept test
6-MP and TPMT what are the alleles?
3A, 3C and 2
What does the Allele changes in TPMT do?
Decrease Allele activities
What type of SNP is TPMT?
Non-Synonymous
How does TPMT cause toxicity?
Usually make 6 - MeMP but since it is decreased you make 6-TGN which is toxic and drive effectively
CPIC guidelines for Homo-TPMT?
Reduce 10 fold 75-10
give 3 times a week
CPIC for hetero-TPMT?
Reduce dose 30-80%
What is FDA recommendation for TPMT testing?
Recommends testing
HOMO- reduce initial dose
HETERO - monitor
What SNP is NUDT15?
Non-synonymous C>T
Loss of function
*2 and *3
What does NUDT15 do?
Converts 6-TGN to less toxic form
Loss of function more cytotoxic effects
CPIC for HOMO-NUDT15?
Does to 10mg
Daily
CPIC for Hetero-NUDT15
30-80% reduction
Impact of TPMT and NUD15 on OS?
NONE
What is Tamoxifen for?
Prodrug too
SERM for ER+ and PR+
What is need for Tamoxifen to worK?
2D6 and Endoxifen
What does 2D6 *10, 17 and 41 do?
Double digits decreased
What does 2D6 *3, 4, 5 and 6 do?
Loss of activity
What does 2D6 *1xn and 2xn do?
Can be a ultra metabolized
Should we test for tamoxifen?
No recommended bc no OS for null but inconsistencies
CPIC for DPYD NM?
No change
CPIC for DPYD IM?
Reduce does based on activity score
1- 50%
1.5 - 25-50%
CPIC for DPYD PM?
Avoid use
Why do we test DPYD and is it worth it?
Yes bc hospiliztion have been related to these toxicities
Rn cost neutral soon cost effective
Not required rn
5-FU
UGT1A1*28 does what?
Reduce enzyme activity for the drug Irotecan
What factors do i consider when dosing Irotecan and why?
UGT1A1*28 and strong CYP3A4 inhibitors bc of the dose reduction provides a safer profile for neutropenia
