Precision Medicine MD 2024 PDF

Precision medicine Raghda Saad Zaghloul Taleb Assistant Professor of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University  Precision medicine: definition Precision medicine can be defined as an individualized, molecular approach to disease diagnosis and treatme...

Precision medicine Raghda Saad Zaghloul Taleb Assistant Professor of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University  Precision medicine: definition Precision medicine can be defined as an individualized, molecular approach to disease diagnosis and treatment—one that examines a patient’s individual genomic, proteomic, gene expression, and other molecular profiles and applies that information to select precise disease treatments and to develop new treatments and drugs.  Precision medicine: definition Precision medicine classifies patients into subpopulations based on their molecular profiles, and then directs each group into a treatment regimen that will bring about maximum benefit.  Personalized medicine Although often used interchangeably with precision medicine, personalized medicine is defined as a way to design specific, even unique, treatments for each individual, also based on their unique molecular profiles. Personalized medicine can be considered a part of precision medicine.  Pharmacogenomics Pharmacogenomics is the study of how an individual’s genetic makeup determines the body’s response to drugs. It also involves the development and use of drugs that are specifically targeted to a patient’s genetic profile.  Pharmacogenomics The term pharmacogenetics is often used interchangeably with pharmacogenomics but refers to the study of how sequence variation within specific genes affects an individual’s drug responses.  Optimizing drug responses Sequence variations in dozens of genes affect a person’s reactions to drugs. The proteins encoded by these gene variants control many aspects of drug metabolism, such as the interactions of drugs with carriers, cell-surface receptors, and transporters; with enzymes that degrade or modify drugs; and with proteins that affect a drug’s storage or excretion.  Optimizing drug responses Examples of genes that are involved in drug metabolism are members of the cytochrome P450 gene family. People with some cytochrome P450 gene variants metabolize and eliminate drugs slowly, which can lead to accumulations of the drug and overdose side effects. In contrast, other people have variants that cause drugs to be eliminated quickly, leading to reduced effectiveness.  Optimizing drug responses An example is the CYP2D6 gene, which encodes debrisoquine hydroxylase. This enzyme is involved in the metabolism of approximately 25 percent of all pharmaceutical drugs, including acetaminophen, clozapine, beta blockers, tamoxifen, and codeine. There are more than 135 variant alleles of this gene. Some variants reduce the activity of the encoded enzyme, and others can increase it. Approximately 80 percent of people are homozygous or heterozygous for the wild-type CYP2D6 gene and are known as extensive metabolizers. Approximately 10 to 15 percent of people are homozygous for alleles that decrease activity (poor metabolizers), and the remainder of the population have duplicated genes (ultra-rapid metabolizers). Optimizing drug responses  Optimizing drug responses One of the primary goals of precision medicine is to provide screening to patients prior to treatment so that the choice of drug and its dosage can be tailored to the patient’s genomic profile. Normally, physicians order a single-gene test only when a specific drug needs to be prescribed or when a prescribed drug is not performing as expected.  Developing targeted drugs Another goal of pharmacogenomics is to develop drugs that are targeted to the genetic profiles of specific subpopulations of patients. The most advanced applications are in the treatment of cancers. Large-scale sequencing studies show that each tumor is genetically unique. This genomic variability has been exploited to develop new drugs that specifically target cancer cells that may express mutant proteins or overexpress others.  Developing targeted drugs One of the first success stories in precision targeted therapeutics was that of the HER-2 gene and the drug Herceptin® in breast cancer.  Developing targeted drugs The HER-2 gene codes for a transmembrane tyrosine kinase receptor protein. These receptors are located within the cell membranes of normal breast epithelial cells and, when bound to other growth factor receptors and ligands on the cell surface, they send signals to the cell nucleus that result in the transcription of genes whose products stimulate cell growth and division.  Developing targeted drugs In about 25% of invasive breast cancers, the HER-2 gene is amplified and the protein is overexpressed on the cell surface. HER-2 overexpression is associated with increased tumor invasiveness, metastasis, and cell proliferation, as well as a poorer patient prognosis. Based on this knowledge, Genentech Corporation in California developed a monoclonal antibody known as trastuzumab (or Herceptin) that binds to the extracellular region of the HER-2 receptor, inhibiting HER-2 signaling, triggering cell-cycle arrest, and leading to destruction of the cancer cell.  Developing targeted drugs A number of molecular assays have been developed to determine the gene and protein status of breast cancer cells. These include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays.  Developing targeted drugs There are now dozens of drugs that are targeted to the genetic status of the cancer cells. For example, about 40% of colon cancer patients respond tothe drugs Erbitux® (cetuximab) and Vectibix® (panitumumab). These two drugs are monoclonal antibodies that bind to epidermal growth factor receptors (EGFRs) on the surface of cells and inhibit the EGFR signal transduction pathway. To work, cancer cells must express EGFR on their surfaces and must also have a wild- type K-ras gene. The presence of EGFR protein can be assayed using a staining test and observation of cancer cells under a microscope. Mutations in the K-ras gene can be detected using assays based on the PCR method. Developing targeted drugs  Precision oncology One of the promises of precision medicine is to treat cancer patients with therapies that target specific gene mutations and gene expression defects in their tumors, leading to effective remissions and even cures. Beyond the use of targeted drugs, researchers are also making progress in the use of other targeted modalities, including targeted cancer immunotherapies. Breast cancer biomarker assay results to guide adjuvant endocrine and chemotherapy decisions in early-stage breast cancer  Gene expression signatures Gene expression assay The genes Oncotype Dx 21 (16 tumor related, plus 5 control genes) MammaPrint 70 genes Prosigna 58 (50 tumor related, plus 8 control genes) EndoPredict 12 (8 tumor related, plus 4 control genes) Breast Cancer Index 7 genes Oncotype DX Oncotype DX European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) NTRK1,2,3 fusions, RET and FGFR1/2/3 fusions/mutations, BRAFV600E mutations, MSI-H, and tumour mutation burden-high (TMB-H) are designated as tumour-agnostic biomarkers, categorised as level IC. This classification is based on the clinical improvement of patient outcomes in basket trials. ESMO recommends carrying out multigene NGS in patients with advanced cancers in countries where tumour-agnostic targeted therapies are accessible. European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) Genomic alterations according to ESCAT in advanced non-squamous non-small-cell lung cancer (NSCLC) Genomic alterations according to ESCAT in advanced non-squamous non-small-cell lung cancer (NSCLC)  Genomic alterations according to ESCAT in advanced breast cancer (ABC) ESR1 mutations have been upgraded to level IA based on the results of the EMERALD trial. In this randomised, phase III study, elacestrant, an oral selective oestrogen receptor degrader (SERD) demonstrated an improvement in PFS among patients with hormone receptor-positive/HER2- negative ABC, with a greater benefit observed in those with detectable ESR1 mutations. Several data recently reported high performance for tumour NGS in detecting germline BRCA1/2 mutations; however, around 7% of these alterations were not identified. This suggests that patients presenting a high likelihood of harbouring germline BRCA1/2 mutations and a negative tumour NGS should undergo dedicated germline testing. Genomic alterations according to ESCAT in advanced breast cancer (ABC)  Genomic alterations according to ESCAT in advanced breast cancer (ABC) It is recommended to carry out tumour NGS of a tumour (or plasma) sample from a patient with hormone receptor-positive/ HER2-negative ABC as standard of care. The NGS testing should be done after resistance to endocrine therapy to optimise the likelihood of detecting ESR1 mutations. Patients with high likelihood of harbouring germline BRCA1/2 mutations should undergo clinical genetic testing even if these alterations were not detected by tumour NGS.  Genomic alterations according to ESCAT in advanced colorectal cancer (CRC) KRAS G12C mutations have been integrated in advanced CRC since they became level IA. Moreover, hotspot-inactivating missense mutations in the exonuclease domain of the polymerase epsilon (POLE) gene in mismatch repair (MMR)-proficient solid tumors were associated with TMB-H and predict high activity from anti-programmed cell death protein 1 (PD-1) therapy, warranting their classification at level IIB.  Genomic alterations according to ESCAT in advanced colorectal cancer (CRC) ESMO recommends carrying out multigene tumour NGS in daily practice for patients with advanced CRC, if the testing itself does not add extra cost as compared to standard procedures such as immunohistochemistry (IHC), polymerase chain reaction (PCR), or Sanger sequencing.  Targeted cancer immunotherapies These therapies harness the patient’s own immune system to kill tumors. Two of the most promising precision cancer immunotherapies: adoptive cell transfer and engineered T-cell methods. Both adoptive cell transfer and engineered T-cell methods exploit cytotoxic T lymphocytes (CTLs) to recognize specific antigens on the surface of cancer cells, bind to the cells, and destroy them. Immune system T-cells (T-lymphocytes)  Targeted cancer immunotherapies Cancer cells express many proteins that are specific to the tumor and have the capacity to be recognized by the patient’s immune system as nonself antigens. These nonself antigens result from abnormal gene expression and mutations in the coding regions of both cancer driver and passenger genes. For example, 30 percent of human cancers contain mutated ras-family genes (such as K-ras and H-ras), which act as cancer driver genes. Many different point mutations can occur in these genes, each encoding an altered protein that is not found in normal cells. Cancer cells also contain up to hundreds of mutations in passenger genes whose products are not involved in the cancer phenotype, but also encode mutated, and hence nonself, proteins. Collectively, the novel, nonself antigens that are contained within their proteins are known as neoantigens.  Targeted cancer immunotherapies Although T cells are known to associate with tumors and are able to recognize tumor neoantigens, they are often not able to destroy tumor cells. These tumor-associated T cells are also known as tumor-infiltrating lymphocytes (TILs). Targeted cancer immunotherapies Cancers use many different strategies to suppress T- cell responses. These strategies include: 1. The synthesis of molecules that bind to T cells and repress their activity. – Interestingly, some effective new drugs called checkpoint inhibitors help T cells avoid these checkpoint molecules, thereby enhancing the tumor-killing ability of TILs. Targeted cancer immunotherapies 2. Another way that tumors avoid immune system activity is that they are often abnormal in their expression of cell surface MHC molecules, which are essential to stimulate antigen-presenting cells, which in turn are necessary to stimulate T cells to recognize and kill cells that bear nonself antigens. Targeted cancer immunotherapies 3. A third way that tumors avoid immune responses is through the presence of tumor-associated regulatory T cells called T-regs (including suppressor T cells), whose role is to repress the activities of activated T cells. The presence of other tumor- infiltrating cells such as macrophages and monocytes also repress the activities of T cells.  Adoptive cell transfer Adoptive cell transfer (ACT) involves removing TILs from a patient’s tumor, selecting those that specifically recognize tumor antigens, amplifying these specific TILs in vitro, and reintroducing them back into the patient.  Immunotherapy with genetically engineered T-cells The principle behind genetically engineered T-cell therapies is to create recombinant T-cell receptors (TCRs) that specifically recognize antigens on cancer cells. The DNA sequences that encode these engineered TCRs are then introduced in vitro into a patient’s normal, naïve T cells which then express these TCRs on their surfaces. The TCR-transduced T cells are then selected, amplified, and reinfused into the patient.  Immunotherapy with genetically engineered T-cells The synthetic TCR genes encode either TCRs that are structurally similar to natural TCRs or chimeric antigen receptors (CARs) that can directly recognize antigens on the tumor cell without requiring T-cell activation by antigen- presenting cells.  Immunotherapy with genetically engineered T-cells CAR T-cell therapies that have been approved by the FDA: 1. In August 2017, a CAR T-cell therapy called Kymriah™ was approved for treating children with ALL who had relapsed twice or did not respond to earlier treatments. – In clinical trials of these patients, Kymriah treatment produced complete remissions in 83% of patients. 2. In October 2017, the FDA approved a CAR T-cell therapy called Yescarta™ for treating adults with some types of large B-cell lymphomas.  Precision medicine and disease diagnostics The ultimate goal of precision medicine is to apply information from a patient’s full genome to help physicians diagnose disease and select treatments tailored to that particular patient. Not only will this information be gleaned from genome sequencing, but it will also be informed by gene expression information derived from transcriptomic, proteomic, metabolomic, and epigenetic tests. Presently, the most prevalent use of genomic information for disease diagnostics is genetic testing that examines specific disease-related genes and gene variants. Most existing genetic tests detect the presence of mutations in single genes that are known to be linked to a disease.  Precision medicine and disease diagnostics Currently, more than 65,000 genetic tests are available. A comprehensive list of genetic tests can be viewed on the NIH Genetic Testing Registry at www.ncbi.nlm.nih.gov/gtr/.  Precision medicine and rare genetic disorders Cystic fibrosis, an autosomal recessive disease caused by mutations in the CFTR gene, has seen advancements in targeted therapies. For instance, the drug ivacaftor was developed specifically for patients with cystic fibrosis and has shown improvements in pulmonary function, particularly for patients with specific mutations (such as G551D mutation) that affect CFTR channel activity. Combination approaches involving ivacaftor and lumacaftor have been approved, providing further benefits for patients with common genotypes (F508del mutation).