ONC

Question 1

KRAS for mCRC (metastatic colorectal cancer)

Answer 1

gene that produces K-ras protein, proto-oncogene

K-ras protein is ON/OFF switch
-Activated by EGFR
-Turned on, must be bound to GTP = cell growth/dif (downstream signaling)
-Turned off, in GDP state, does not relay signals to nucleus

No mutation = wild type KRAS

Question 2

KRAS Mutation

Answer 2

KRAS in codon 12, 13, or 61
-always turned on

Question 3

TX of colorectal cancers

Answer 3

Anti-EGFR therapy
-cetuximab and panitumumab

Pts whose tumor has a mutated KRAS, have a low likelihood of responding to anti-EGFR therapy
-ASCO guideline: tumors should be tested for KRAS mutations if they are candidates for EGFR TX
-KRAS mutation codon 12 or 13 = should not receive anti-EGFR tx

Question 4

Alternative TX for KRAS mutations MCRC

Answer 4

Sotorasib

Question 5

BCR-ABL

Answer 5

Fusion gene
-rearrangement of 2 genes from 2 different chromosomes
-ABL1 from CHR9
-BCR from CHR22

Codes for tyrosine kinase
-effect: constitutive tyrosine kinase activity (speeds division, inhibits repair, unregulated division)

Question 6

Chronic Myelogenous Leukemia (CML)

Answer 6

-Slow growing cancer in bone marrow
-Men, older, radiation

○ Chronic - mild or no symptoms
○ Accelerated - symptomatic
○ Blast - symptoms worsen

TX
-TKIs “NIBs”
-Interferon
-Chemo
-Stem cell transplant

~95% of patients with CML will express BCR-ABL

Question 7

Imatinib for CML

Answer 7

Target ATP binding domain of tyrosine kinase
-prolongs overall survival, remission, reduces CML related deaths (not a cure)

Question 8

Imatinib Resistance

Answer 8

Particularly in accelerated and blast phases

Several mechanisms of imatinib resistance
-BCR ABL amp and overexpression
-Cytogenetic abnormalities by the leukemia clone
-Expression of drug resistance proteins
-Most common: point mutations in ATP binding site

Testing for BCR-ABL mutations is recommended for patients in accelerated and blast phase

Question 9

TKI Name and Generation

Answer 9

ID NAP!

Question 10

CML: Mutations Where Nilotinib Is DOC

Answer 10

V299L

T315A

F317L/V/I/C

Question 11

CML: Mutations Where Dasatinib Is DOC

Answer 11

Y253H

E255K/V

F359V/C/I

Question 12

For T315I Mutation in CML

Answer 12

Ponatinib, Asciminib
-also stem cell transplant

Question 13

ERBB2

Answer 13

● Proto-oncogene
● Codes for human epidermal growth factor receptor (HER2)

Question 14

HER2

Answer 14

● Overexpressed in 30% of metastatic breast cancers
● Also ovarian, stomach, and uterine cancers
● Strong association with increased disease recurrence and poor prognosis

*HER2 levels may be inversely related to BMI among premenopausal women

Question 15

Trastuzumab (Herceptin®)

Answer 15

Monoclonal antibody against HER2

Must be tested and positive for HER2 expression before starting
-POS: OK to use
-NEG: do NOT use

Tests
○ Fluorescence in situ hybridization (FISH)
○ Immunohistochemistry (have to be 2+/3+)

Question 16

Trastuzumab plus chemotherapy in HER2-positive breast cancer are associated with:

Answer 16

• ↑ time to disease progression
• longer median survival time
• ↓ risk of death in metastatic breast cancer

Question 17

HER2 testing also required for other agents affecting HER2 used to treat breast and gastric cancer

Answer 17

Ado-trastuzumab, Lapatinib, Pertuzumab