Precision Medicine and Pharmacogenomics

Precision Medicine

• Precision medicine is an individualized, molecular approach to disease diagnosis and treatment.
• It analyzes a patient's genomic, proteomic, gene expression profiles, and other molecular profiles.
• This is used to select precise disease treatments and develop new treatments/drugs.
• Precision medicine classifies patients into subpopulations based on molecular profiles.
• Treatment regimens are then tailored to each group to maximize benefit.

Personalized Medicine

• Personalized medicine is a way to design specific, or even unique, treatments for individual patients.
• Treatments are based on unique molecular profiles.
• Personalized medicine is a part of precision medicine.

Pharmacogenomics

• Pharmacogenomics is the study of how an individual's genetic makeup determines their body's response to drugs.
• It also involves developing and using drugs targeted specifically to a patient's genetic profile.
• The term pharmacogenetics is often used interchangeably with pharmacogenomics.
• However, pharmacogenetics refers to studying sequence variation within specific genes to understand drug responses.

Optimizing Drug Responses

• Variations in dozens of genes affect a person's responses to drugs.
• These gene variants control drug metabolism, interactions of drugs with carriers/receptors, enzymes (that degrade/modify drugs), and proteins (that affect drug storage/excretion)
• Examples of drug metabolism-related genes are the cytochrome P450 family.
• People with certain cytochrome P450 variants metabolize/eliminate drugs slowly, leading to drug accumulation/overdose side effects.
• Others have variants causing drugs to be eliminated quickly, reducing effectiveness.
• CYP2D6 gene encodes debrisoquine hydroxylase, involved in metabolizing approximately 25% of pharmaceuticals(acetaminophen, clozapine, beta blockers, tamoxifen, codeine).
• Approximately 80% of the population are extensive metabolizers for CYP2D6
• Poor metabolizers (10-15%) have alleles reducing enzyme activity, while ultra-rapid metabolizers have duplicated genes.

Optimizing Drug Responses (Specific Genes)

• TPMT enzyme is involved in the metabolism of mercaptopurine, thioguanine, azathioprine. Low TPMT levels lead to toxic side effects from these drugs(used for leukemia/inflammatory conditions).
• HLA-B alleles affect allergic reactions related to different drugs(gout, epilepsy, HIV).
• CYP2C9 gene affects warfarin metabolism, variants may result in overdosing.
• CYP2C19 gene affects metabolism of tricyclic antidepressants, clopidogrel, voriconazole (10-15% drug metabolization).
• SLCO1B1 gene affects simvastatin removal, variants make removal less efficient.

Optimizing Drug Response - Goals

• One primary goal of precision medicine is providing pre-treatment screenings.
• Genomic profiles are tailored to drug/dosage choices.
• Physicians usually conduct single-gene tests when a specific drug is needed or existing treatment isn't working.

Developing Targeted Drugs

• Pharmacogenomics aims to develop drugs targeted to specific patient genetic profiles, mostly in cancer treatment.
• Large-scale sequencing studies show tumor genetic uniqueness.
• This has been used to create drugs targeting cancer cells that express mutant/overexpressed proteins.
• One early success story is the HER-2 gene's use in breast cancer using the drug Herceptin®,
• The HER-2 gene codes for a transmembrane tyrosine kinase receptor protein.
• These receptors are located in normal breast epithelial cells' membranes. They direct signals to the nucleus, leading to gene transcription for cell growth.
• In about 25% of invasive breast cancers, the HER-2 gene is amplified, with the protein being overexpressed on the cell surface.
• Overexpression is linked with greater tumor invasiveness, metastasis, cell proliferation, and poorer prognosis.
• Genentech created a monoclonal antibody (trastuzumab/Herceptin), binding to the HER-2 receptor's extracellular region.
• This inhibits signaling, triggering cell-cycle arrest, and destroying cancer cells.
• Molecular assays (IHC and FISH) determine gene/protein status of breast cancer cells.

Developing Targeted Drugs - Example

• About 40% of colon cancer patients respond to Erbitux(cetuximab) and Vectibix(panitumumab) that bind to EGFR receptors, inhibiting signaling pathways.
• Work requires EGFR presence on cancer cell surfaces and a wild-type K-ras gene.

Precision Oncology

• Precision medicine aims to treat cancer using therapies targeting specific gene mutations/expression defects in tumors.
• It leads to effective remissions and cures.
• Beyond targeted drugs, research focuses on other targeted modalities, including immunotherapies.

Breast Cancer Biomarker Assays

• Assays like Oncotype DX, MammaPrint, and EndoPredict are used to guide adjuvant endocrine and chemotherapy guidance for postmenopausal patients with early-stage, ER+/HER2-ve breast cancer.

Gene Expression Signatures

• Oncotype DX tests determine individual tumor biology based on gene expression of 21 genes. It assesses proliferation, invasion, and HER2 status.
• Other assays like MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index also measure gene expression. Different assays examine different genes, but some reference genes/measures are consistent across these tests.

Oncotype DX - Key Results

• Recurrence Score: A number between 0 and 100, measuring breast cancer gene activity. Used to predict risk of recurrence and determine whether chemotherapy should be used.
• Distant recurrence risk: Percentage showing the risk of cancer returning to another part of the body within a set timeframe depending on whether the patient is node-negative or positive.
• Absolute chemotherapy benefit: Percentage showing the potential benefit from using chemotherapy alongside hormonal treatments to reduce recurrence risk/death.

Recurrence Score Result by Node Status

• Oncotype DX examines recurrence scores to predict treatment for different types of patients with breast cancer depending on their initial node statuses.

Precision Medicine and Rare Genetic Disorders

• Cystic fibrosis, caused by mutations in the CFTR gene, has seen advancements in targeted therapies, notably with the drug IVACAFTOR for patients with common genotypes (F508del) .

Targeted Cancer Immunotherapies

• Therapies leverage the patient's immune system to target cancer cell response.
• Adoptive cell transfer (ACT), one example, removes, selects, amplifies, and reintroduces tumor-infiltrating lymphocytes (TILs) from a patient's tumor to recognize the antigen.
• Immunotherapy with engineered T cells utilizes genetically modified T-cell receptors (TCRs) to recognize cancer antigens.
• Cancer cells may use strategies to suppress T cell responses by repressing T cell activity and altering MHC expressions on their surface. These include checkpoint inhibitors, suppressing tumor-related regulatory T cells, and creating neoantigens