Cancer Pharmacogenomics

Question 1

Genetic Variations

Answer 1

• Differences in DNA sequence between people

- NOT mutations

Question 2

Examples of Genetic Variations

Answer 2

• Insertions (Indels)
• Deletions (Indels)
• Inversions
• Amplifications
• Duplications
• Single Nucleotide Polymorphisms (SNPs)
• Translocations

Question 3

Possible Consequences of Genetic Variations

Answer 3

• Translocations (dysregulated gene expression, chimeric proteins)
• Copy number variants (more copies)
• Non-coding region variants
• Coding Region variants

Question 4

Coding Region SNPs may result in…

Answer 4

• Reduced protein activity compared to common variant
• Increased enzyme activity
• No change in enzyme activity
• Must do functional assay to determine effect

Question 5

Non-coding Region Variants

Answer 5

• Changes in enzyme levels
• Reduced levels of gene expression, decreased activity
• Increased levels of gene expression, increased activity

Question 6

Somatic Mutations

Answer 6

• Neoplasms are heritably altered
• Genetic changes in cancer are mutations (not born variants)
• Mutations can create specific targets for cancer treatment or can make it resistant to treatments

Question 7

EGFR Inhibitors

Answer 7

• EX: Cetuximab and Panitumumab
• Monoclonal antibodies used to treat mCRC
• Bind to extracellular EGFR domain to inhibit downstream signaling
• Only 10-20% benefit from anti-EGFR
• EGFR doesn’t correlate with clinical benefit

Question 8

KRAS

Answer 8

• NRAS, HRAS, and KRAS are 3 family gene members
• KRAS is most frequently found mutated in human cancers
• Belongs to gene family of oncogenes encoding GTP-binding proteins
• Downstream effector of EGFR
• Its pathways controls cell growth, differentiation, and apoptosis

Question 9

KRAS Cancer Mutations

Answer 9

• Functional effect: downstream activation of signaling pathways and confers resistance to inhibition of cell surface receptor tyrosine kinases such as EGFR
• Prevalence: 27-43% of colorectal cancer patients

Question 10

Anti-EGFR Efficacy + KRAS

Answer 10

• Reduces likelihood of responding to anti-EGFR therapy by ~1/3
• Evaluate for KRAS mutations in all mCRC patients before giving anti-EGFR therapy

Question 11

6MP + TPMT

Answer 11

• TPMT inactivates 6 MP

- 6MP is used to treat pediatric leukemias

Question 12

TPMT

Answer 12

• Thiopurine S-methyltransferase
• Deficiency is an autosomal recessive inherited trait
• Polymorphisms in its gene/allele results in low activity
• Less TPMT leads to decreased clearance of active 6MP and increased toxicity (myelosuppression, hepatotoxicity)
• Multiple variants but 3 alleles account for 95% of the deficiencies

Question 13

6MP Clinical Applications

Answer 13

• Efficacy: no loss of efficacy was observed if reduced in patients with low/absent TPMTs
• Toxicity: Severe hematologic toxicity developed in those given standard doses with one of these variants

Question 14

6MP Clinical Relevance

Answer 14

• Dosing/Selection: 80-90% dose reduction in those with variants
• If heterozygous variation, dosing recommendations aren’t as clear
• NUDT15 variants now taken into consideration

Question 15

Irinotecan

Answer 15

• Camptosar
• Class of topoisomerase inhibitors
• Activity against variety of malignancies like colorectal and SCLC
• Binds to topoisomerase I and inhibits the cleavable complex resulting in DNA breaks
• Prodrug that is metabolized to SN-38 (active form) by UGT1A1
• Significant SE like diarrhea, neutropenia, and vascular syndromes

Question 16

UGT1A1 Polymorphism

Answer 16

• UHT1A1*28 is of interest, reduces expression by 40%
• Less UGT1A1 transcription and activity
• Associated with reduced clearance of SN-28 (active/toxic metabolite)
• Associated with mild unconjugated hyper-bilirubinemia (Gilbert’s Syndrome)

Question 17

Tamoxifen

Answer 17

• Gold standard endocrine therapy for ER+/PR+ breast cancer
• SERM
• Approved for a variety of indications like metastatic and adjuvant therapy as well as breast cancer risk reduction
• Endoxifen is metabolite most responsible for in vivo pharmacologic activity

Question 18

CYP2D6 Polymorphisms

Answer 18

• Most polymorphic P250
• Can have a 200x effect on drug metabolism
• Can be associated with decreased, loss, or increased enzyme activity

Question 19

Rasburicase

Answer 19

• Elitek
• Recombinant tetrameric protein originally cloned from Aspergillus flavus
• Clears uric acid from blood to prevent/treat tumor lysis syndrome in those receiving chemo
• Catalyzes enzymatic oxidation of uric acid into an active, more soluble metabolite allantoin with carbon dioxide and hydrogen peroxide byproducts

Question 20

Rasburicase PGx

Answer 20

• Gene/Allele: G6PD A-variant and Mediterranean variant
• Leads to excessive hydrogen peroxide during the conversion
• Those with G6PD deficiency at risk for hemolytic anemia and methemoglobinemia due to excessive hydrogen peroxide
• Puts patient in state of “oxidative stress”

Question 21

DPYD

Answer 21

• Dihydropyrimidine dehydrogenase deficiency
• Protein encoded by this gene is a pyrimidine catabolic enzyme (initial/rate-limiting in this pathway)
• Increases risk of toxicity in cancer patients receiving 5FU chemo when deficient
• Dosing for 5FU depends on the type of DPYD metabolizer the patient is