IE 4: Personalized Medicine in Oncology

What is a mutation?

• A mutation is an alteration in a DNA nucleotide sequence of the genome

  • Can occur in single nucleotides or large segments of DNA

  • Linked to a variety of factors, such as hereditary, exposure to carcinogens, age, etc.

    
    

What is the differences between mutations vs polymorphism?

• Mutation:

  • Very rare (less than 1% of population)

  • Direct cause of disease

• Polymorphism:

  • Widely prevalent

  • Contribute to genetic diversity

Polymorphisms do NOT directly cause a disease but can do what? What is an example of this?

• Can influence therapy

• Ex:

  • Polymorphisms: TPMT/NUDT15 and DPYD

    • Do not contribute to disease pathology of cancer, however, can influence therapy tolerance and efficacy

  • Mutations: CFTR

    • Cystic fibrosis

What are some germline polymorphisms that impact cancer therapy?

• TPMT/NUDT15 and 6MP

• DPD and 5-FU

How does 6-MP and TPMT/NUDT15 affect therapy?

• Acute lymphoblastic leukemia (ALL) treatment: 6-MP

• Polymorphisms of TPMT or NUDT15 with reduced metabolic rate of 6-MP → lead to increased risk of side effects

  • Bone marrow suppression, leukopenia, thrombocytopenia

How does DPD and 5-FU affect therapy?

• DPD is the enzyme involved in 5-FU and capecitabine metabolism and degradation

• DPD deficiency is an autosomal recessive disorder

• Reduced DPD activity leads to reduced metabolism of 5-FU and results in high concentrations of 5-FU in the body

  • Results in severe 5-FU toxicity

Where do germline mutations occur?

• Occur in the germline, tissues that develop sex cells

Germline mutation can be transmitted to what? What happens to when it gets passed on?

• May be transmitted to some or all progeny

  • Mutation will be passed on the next generation if the mutant sex cell participates in fertilization

  • Resulting mutation found in all cells of the offspring

What are germline mutations the cause of?

• Cause of rare diseases

  • Cystic Fibrosis (CFTR gene)

    • Most common mutation is an amino acid deletion, F508

How are germline mutations distinguished from germline polymorphisms?

• They are very rare

• They are the direct cause of disease pathology

What are somatic cells?

• Those that are not gametes

When do somatic mutations occur?

• Random mutations that occur during mitotic cell divisions

Somatic mutations are only found where?

• Only found in tissue where it occurred and resulting cells from mitosis

Somatic mutations are not transmitted where? They are the source of genetic mutations leading to what?

• Not transmitted to progeny (not inherited)

• Source of genetic mutations leading to cancerous growth and treatment resistance

  
  

What is cancer?

• Cancer is a molecular disease that can develop anywhere in the body

• Uncontrollable growth of cells that can invade surrounding tissues or spread to other organs (metastasis)

What are biomarkers? How can they be used?

• Biological molecule found in blood, other body fluids or tissues that is a sign of a normal or abnormal process, or of a condition or disease

• May be used to see how the body responds to a treatment for disease or conditions

• May be used to provide information about prognosis

What do tumor suppressor genes regulate and prevent? What are many involved in? When mutated, what can happen?

• Regulate cell growth and division

• Prevent development of cancer

• Many involved in DNA repair

• When mutated, cells can grow uncontrollably and lead to cancer

What are examples of tumor suppressor genes?

• BRCA

• TP53

BRCA1 and BRCA2 do what? Mutation in either gene does what?

• Produce proteins that help repair damaged DNA

• Mutations in either gene increases the risk of developing breast and ovarian cancer

How many copies in BRCA1 and BRCA2? What is the process when it gets mutated?

• Two copies of each gene – one inherited from each parent

• BRCA1/2 mutation (+) → inactivation of tumor suppressor → uncontrolled cell growth

What can treat the BRCA1 and BRCA2 mutations?

• PARP inhibitors: olaparib, rucaparib, niraparib, talazoparib

What does the TP53 code for? What is it used for?

• Codes for tumor protein 53 inside of the cell nucleus

• A tumor suppressor gene that helps control cell division and cell death

In DNA damage, what does p53 determine? What happens when TP53 has a mutation?

• DNA damage → p53 determines either DNA repair or apoptosis

  • If DNA repaired → p53 activates other genes to help fix damage

  • If apoptosis → p53 prevents cell division and signals apoptosis

• TP53 mutation (+) → lack of cell growth control and apoptosis control for damaged DNA → uncontrolled cell division

Inherited TP53 gene mutations are often found where?

• Inherited TP53 gene mutations often found in Li-Fraumeni syndrome

  • Genetic condition that causes increased risk for developing rare tumors (soft tissue sarcomas, osteosarcomas)

Oncogenes are usually what? How are they activated?

• Oncogenes are usually kinases, growth factors or transcription factors

• Oncogenes are activated by point mutations, amplification, and gene fusions

In oncogenes, what are examples of point mutations and amplifications, gene amplification, and chromosomal translocation?

• Point Mutations and amplification

  • Growth factor receptor network

    • EGFR

    • KRAS

    • BRAF

    • ERBB2 (HER2)

• Gene Amplification

  • ERBB2

• Chromosomal Translocation

  • Philadelphia chromosome (eg; BCR-ABL)

    
    

What does the presence of EGFR protein (EGFR+) only, indicate?

• Presence of EGFR protein (EGFR+) only indicates worse disease prognosis

  • Determined by immunohistochemistry

  • Higher the protein, worse the prognosis

Overexpression of EGFR protein serves as what?

• Overexpression of EGFR protein serves a biomarker for EGFR-targeting monoclonal antibody(Mab):

  • Cetuximab, panitumumab

EGFR+ alone does not predict what?

• EGFR+ alone does not predict therapeutic response to EGFR inhibitors (EGFRI)

  • KRAS mutations leads to EGFRI resistance

  • Not effective if EGFR mutations are present

  • EGFRI tyrosine kinase inhibitors (TKI)

    
    

EGFR mutation occurs in how many with what? The mutation is to the portion of DNA in cells responsible for what?

• Occurs in ~15% of people with lung cancer in the US

• Mutation to the portion of DNA in cells that are responsible for developing EGFR proteins

  • Activate tyrosine kinase (TKI) domain

What are examples of EGFR mutations?

• EGFR mutations:

  • L858R mutation (+) → predictive of treatment benefit from EGFR TKI therapy

    • Erlotinib, gefitinib, lapatinib, afatinib

  • T790M mutation (+) → may lead to resistance of EGFRI

    • Osimertinib-3rd generation EGFR TKI is indicated for EGFR T790M mutation

For the HER2 receptor or ERBB2 gene, amplification shows what? It is over expressed in what patients?

• Poor prognostic factor

• Overexpressed in 15-20% breast cancer patients

What is first line treatment of HER2?

• Trastuzumab (Herceptin)

Where is the KRAS found?

• Found downstream of the EGFR signaling network

Mutations in the KRAS gene is associated with what? Presence of KRAS mutation is mutually exclusive of presence of what?

• Resistance to EGFRI-TKI therapy

• Presence of KRAS mutation is mutually exclusive of presence of EGFR mutation

  
  

If a patient is BRAF V600E mutation positive, what can help benefit?

• Significant long term treatment benefits from BRAF inhibitors

What are the BRAF inhibitors?

• Vemurafenib, trametinib, dabrafenib, encorafenib

The presence of BRAF mutation is exclusive of what?

• Presence of BRAF mutation is exclusive of KRAS mutation

  • Co-mutation for both BRAF and KRAS is extremely rare

The BCR-ABL is an abnormal gene found where? What does it code for/

• Found in chronic myeloid leukemia (CML) cells

• Codes for tyrosine kinase protein for cell growth and reproduction

If a patient is BCR-ABL positive, what happens?

• CML cells grow and divide uncontrollably

What is treatment that targets BCR-ABL?

• Imatinib

• Nilotinib

Higher expression of ERCC1 (DNA repair gene) causes what? What are platinum drugs

• Causes resistance to platinum molecules (and drugs)

• Platinum drugs:

  • Oxaliplatin, cisplatin, carboplatin

  • Triggers cell death by crosslinking of DNA

What should be considered without platinum compounds?

• Alt chemo regimens

What is an inhibitor of Thymidylate Synthase (TS) which causes what?

• fluorodeoxyuridylate (FdUMP) is an inhibitor of TS → DNA damage →
  cell death

  • FdUMP is an active metabolite of 5-FU

High TS levels causes what?

• High TS levels → decreased response to 5-FU and antifolates,
  increased overall mortality, increased risk of recurrence and progression of cancer

  • Antifolates: MTX, pemetrexed

  • With High TS levels, can use alternates in chemo regimen such as paclitaxel (taxane) or etoposide (plant alkaloid)

What is the summary of biomarkers with drugs affected?

Continuation

What is the classification of lung cancer?

• Lung cancer classification:

  • Non-Small Cell Lung Cancer (NSCLC) – 85%

    • Adenocarcinoma, squamous cell carcinoma, large cell carcinoma

  • Small Cell Lung Cancer (SCLC) – 15%

What is the staging of NSCLC?

What is the treatment for NSCLC?