pharmacogenomics in oncology

rancher

germline mutation

inherited mutation

* present in egg or sperm

somatic mutation

mutation in tumor only

* cannot be inherited

examples of germline mutations in oncology

* thiopurines and TMPT
* fluoropyrimidines and DPYD
* irinotrcan and UGT1A1
* tamoxifen and CYP2D6

examples of thiopurines

* azathioprine
* 6 mercaptopurine
* thioguanine
* oral agents

what do TPMT polymorphisms result in

decreased TPMT activity

* predisposes patients to severe toxocities like bone marrow suppression

administration of 6 mp to high or normal TPMT metabolizers

initiate normal starting dose

how to administer 6mp to intermediate TPMT metabolizers

start at 30-70% of full dose and wait for steady state

how to administer 6mp to low TPMT metabolizers

reduce daily doses by 90% and admin TID

* wait to reach steady state

examples of fluoropyrimidines

* 5-FU
* capecitabine (prodrug)

what enzyme metabolizes 5-FU

DPD

what do DPD polymorphisms result in

decreased DPD activity

* predisposes patients to:
* bone marrow suppression
* mucositis
* diarrhea

DPD genetic tests have _____

a high false negative rate

metabolite of irinotrcan

SN-38

what does SN-38 cause

acute cholinergic diarrhea

* premedicate with atropine

enzyme that metabolizes irinotecan

UGT1A1

UGT1A1\*28

associated with decreased metabolism of SN-38

* accumulation of SN-38 leads to diarrhea and neutropenia

what is tamoxifen metabolized by

CYP2D6

CYP2D6 poor metabolizes have _______

poorer drug response to tamoxifen

why are tamoxifen studies inconsitenf

* differences in stages of breast cancer
* differences in treatment
* drug interactions
* adherence

is 2D6 testing recommended

no

somatic mutations are ____ __and__ ____ markers

* prognostic
* predictive

prognostic marker

foretells how the patients disease will behave

predictive markers

foretells if a patient will respond to a drug therapy

what do targeted therapies do

block the growth and spread of cancer by interfering with s specific molecules involved in tumor growth

Her2

oncogene that drives cell division

* predictive and prognostic

treatment if Her2 is positive

mab directed at Her2

* trastuzumab
* pertuzumab

kras mutation is ____ and _____

predictive and prognostic

treatment if kras is not mutated/wild type

anti EGFR mab

* cetuximab
* panitumumab

when do you test for kras

check all solid tumors

what does an EGFR mutation result in

activation of tyrosine kinase = constant proliferation of malignant cells

is EGFR predictive or prognostic?

predictive, not prognostic

examples of EGFR (-)

* erlotinib
* gefitinib
* afatinib
* oral

EGFR T790M mutation

single amino acid substitution at position 790 in EGFR from T to M

treatment if patient is EGFR T790M mutation positive

use osimertinib

\-must confirm patient has mutation

who to test for EGFR mutation

all lung cancer patients

\-most will be negative

what does BRAF mutation result in

activation of protein = constant proliferation of malignant cells

when are BRAF mutations present

metastatic melanoma

are BRAF mutations predictive or prognostic?

predictive, not prognostic

examples of BRAF inhibitors

* vemurafenib
* dabrafenib
* oral agents for BRAF mutation positive

who to test for BRAF mutation

all patients

* tells us if some patients are candidates for oral therapy

NTRK fusion

mutation when a piece of the chromosome containing NTRK gene breaks off and joins with a gene on another chromosome

what does NTRK fusion lead to

abnormal proteins

* TRK fusion proteins

NTRK is an _______

oncogenic driver of tumor growth

is NTRK predictive or prognostic?

predictive, not prognostic

treatment for NTRK mutation

larotrectinib

* can be used in any patient with NTRK mutation

what is larotrectinib based on

tumor agnostic therapy based on cancer’s genetic and molecular features without regard to the cancer type or where it started in the body