Precision Medicine

Introduction

This module outlines the definition and goals of precision medicine, including pharmacogenomics. It identifies several of the genomic research initiatives targeted to determine markers of disease risk or those markers that may be used to detect, monitor or treat disease. This module also discusses current strategies to use precision medicine both in the clinic and in a direct-to-consumer setting.

What is Precision Medicine?

According to the NIH, “Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person” (NIH Precision Medicine Initiative Cohort Program, 2015). Precision medicine is also called personalized or individualized medicine. Many claim that medicine has always been personalized, as physicians treat individuals. Thus, the terminology “precision medicine” arose to describe this approach. In contrast to a more traditional approach in which strategies are developed for a group or cohort of patients with a common clinical presentation, precision medicine is a tailored approach to predict diagnostic, treatment and prevention strategies for an individual based on his or her genes and genetic modifications of these genes. Drugs designed to target specific characterized mutations can be leveraged for treatment based on the patient’s molecular aberrations.

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Video 1-1: Combination Therapy. Edward S. Kim MD, discusses the advantages of using targeted therapies within the scope of precision medicine.

Pharmacogenomics 

Pharmacogenomics is a component of precision medicine. By combining pharmacology and genomics, pharmacogenomics studies the impact a person’s genomic fingerprint has on how they respond to a particular drug. This approach aims to improve the patient’s drug response and decrease his or her treatment side effects by matching the right drug and drug dosage to an individual based on his or her genetic makeup.

Precision Medicine in the Clinic

Ultimately, precision medicine is meant to be used in prevention and treatment approaches for all health issues. At the present time, however, its day-to-day application in most disease states is relatively limited. Still, in certain areas of medicine, such as cancer care, precision medicine is already routinely put to use.

Elements of precision medicine in use today include:

• Genomic testing (sometimes termed molecular or genetic testing), which seeks to identify changes in chromosomes, genes or proteins related to disease;
• Targeted therapies, which are drug treatments that interfere with specific molecules (molecular targets) involved in a given disease; and
• Genomic markers, which are genetic elements that convey information about an individual (such as risk for disease or likelihood to respond to a particular treatment).

Genomic Testing

Genomic and technological advances have improved the ability to rapidly test biological specimens for mutations of interest, at a substantially decreased cost to the patient. Whereas the first human genome took more than 10 years to complete, commercial companies now offer testing of targetable genes with turnaround times of days to weeks. These tests are typically offered as a panel of targeted genes of interest with gene coverage ranging from analysis of hot spot regions (well-characterized mutational sites within a gene) to full gene sequencing. Protein expression analysis by immunohistochemistry or panels may also be used to monitor samples for molecular aberrations.

Despite the technical advances, genomic testing still yields a significant financial burden for the patient. Currently, few tests are covered or have limited reimbursement by Medicare or private insurance, with costs in the hundreds to thousands of dollars per test for the patient.

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Targeted Therapies

Targeted therapies impact specific molecules that drive a disease, such as cancer molecules that encourage angiogenesis or impact cell growth and tumor progression. Multiple targeted therapies are being developed and approved for cancer treatment. Even with the specificity, targeted therapies may inhibit more than one molecule. The majority of drugs available at this time fall into two different types of drugs:

• Monoclonal antibody: Commercially created antibodies designed to attack specific protein targets on cancer cells, or other implicated cells. Generic names of these drugs end in –mab.
• Small-molecule drugs: Chemicals that target specific molecules or pathways. Generic names of these drugs end in –ib.

Examples of targeted drugs include the following:

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Genomics in the Continuum of Care

Genomic information is used throughout the continuum of care, and now markers for prevention, treatment and survivorship have been identified:

• Risk markers – to help screen patients appropriately
• Prognosis markers – to help know who is at risk of rapid progression, recurrence and outcomes based on his or her genetic makeup, not on the treatment chosen
• Predictive markers – to help guide treatment choices, including toxicity (e.g., pharmacogenomics)
• Response markers – to determine response for a patient to a particular treatment

Markers for response, recurrence and toxicity impact the long-term quality of life for a patient once cancer treatment is completed. As more is learned, patients will receive more optimal treatments, targeted to their tumor, improving response and decreasing side effects by limiting exposure to drugs that are not effective and getting the best dose for them based on their pharmacogenomic profile. Thus, patients will live longer with fewer complications from their treatments (e.g., neuropathies and cardiac toxicity).

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Direct to Consumer Genomic Testing

Health care providers have traditionally managed genomic testing. The provider orders the test from a certified lab, collects and sends the samples and then interprets the test results.

Direct-to-consumer (DTC) genomic testing operates differently. Direct-to-consumer companies market and sell genomic tests directly to the consumer/patient (e.g., via the Internet or television) and provide the consumer with access to his or her genetic information without the involvement of a health care professional.

Direct-to-consumer genomic testing has become a highly accessible and increasingly affordable option for consumers; however, it is under increasing scrutiny by government, scientists and consumers alike owing to lack of regulation. Additional concerns surrounding DTC genomic testing include misleading results and privacy issues.

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Video 1-2: Direct-to-Consumer Genomic Testing. Edward S. Kim MD, weighs the pros and cons of emerging direct-to-consumer genomic testing.

Analysis Process

For DTC genomic testing, a kit is typically sent to the consumer through the mail. The DNA sample is often collected at home by swabbing the inside of the cheek or, if necessary, by visiting a health clinic for a blood draw, depending on the test sample required by the company. The consumer then mails the sample to the company, which performs the genomic testing and reports the results back to the patient. Results may be disclosed by phone, mail or through a web portal maintained by the company. Some companies offer consultation with a genetic counselor or health care provider to discuss the results.

Information Reported Back to the Person

Three federal agencies are involved in regulation of genomic tests: CMS, the FDA and the Federal Trade Commission. The FDA has played a critical role in regulating these genomic tests and sets limits on what is reported back to the consumer.

The FDA has approved companies to report results from validated tests that have gained FDA approval. Companies have been approved to report mutations associated with known inherited diseases, but they have been prohibited from reporting diseases a person may be at risk for in the future. The FDA and others have expressed a variety of concerns regarding DTC genomic testing including companies reporting data on assays/platforms that have not been validated to demonstrate sensitivity and specificity to measure what is being tested, companies misrepresenting their platforms in marketing materials, lack of clinical role for some markers, the risk to patients due to availability of their genetic information and lack of provider support to help consumers understand their results.

Examples

Examples of DNA testing companies include:

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Ongoing Research and Big Data

The Human Genome Project identified the sequence of the human genome and is the foundation of our understanding of how DNA instructions lead to a functioning human. Continued genomic research has sought to build on this foundation, evaluating questions surrounding:

• the function of genes and the elements that regulate them;
• variations in DNA sequences among individuals and their significance;
• protein structures and functions; and
• DNA/protein interactions with each other and the environment

Specifically, several international initiatives have been undertaken to evaluate the genetic profile of patient populations and identify patterns associated with disease risk and therapeutic response. Further research efforts are underway to develop new strategies to use these genomic differences for disease detection and monitoring.

The Cancer Genome Atlas

The Cancer Genome Atlas is a project initiated by the NIH and the National Human Genome Research Institute to sequence specimens from multiple disease sites and learn more about the genomic alterations associated with cancer. This program is coming to a close after analyzing more than 30 types of cancer and specimens from more than 100,000 patients, and creating a database and multidimensional maps for researchers worldwide. More than 1,000 studies and publications from this program have helped to form everyone’s understanding of cancer.

Genome Wide Association Studies

A genome-wide association study (GWAS) is an approach to compare the genomes of people with or without a disease and identify genetic variations called single-nucleotide polymorphisms, or SNPs (pronounced “snips”), which are associated with the disease. A SNP is a nucleotide variation at a single position in the genome within a population typically found at more than 1%. While most SNPs are a normal DNA variation having no negative health effects, some SNPs may influence health factors such as disease risk or drug response. SNPs are distinguished from a mutation in which a disease-causing mutation occurs in less than 1% of the population, typically in the coding or regulatory region of a gene affecting the function of the resulting protein.

GWAS use technologies to evaluate hundreds to millions of SNPs at the same time. As new SNPs or combinations of SNPs are linked with a disease, researchers use these data to identify the genes associated with the disease. These data can also be leveraged to identify markers of disease risk and develop new strategies to detect, monitor or treat the disease.

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Examples of these studies include:

Large-scale genotyping identifies 41 new loci associated with breast cancer risk
Michailidou K, et al. Nat Genetics. 2013;doi:10.1038/ng.2563.

Analysis of a patient population from 9 GWAS including 10,052 breast cancer cases and 12,575 controls of European ancestry was performed. A total of 29,807 SNPs were genotyped with data analysis identifying SNPs at 41 loci, a specific location of a gene, DNA sequence or chromosome that were associated with susceptibility to breast cancer. This study represents one of the largest cancer GWAS and substantially increases the number of identified breast cancer susceptive loci.

Large-scale association analysis in Asians identifies new susceptibility loci for prostate cancer
Wang M, et al. Nat Commun. 2015;doi:10.1038/ncomms9469

A large-scale meta-analysis of two GWAS was performed with a Japanese population consisting of 1,583 prostate cancer cases and 3,386 controls and a Chinese population consisting of 1,417 prostate cancer cases and 1,008 controls. Replication in three independent sample sets was also performed to verify the results. Two loci were identified that indicated susceptibility for prostate cancer, with the loci corresponding to two genes, PPFIBP2 and ESR2. Additional experiments assessed the mRNA levels of these corresponding genes, and confirmed differential expression in prostate tumors compared with paired normal tissues for PPFIBP2 and ESR2.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil of FOLFOX administration

Fernandez-Rozadilla C, et al. Pharmacogenomics J. 2013;doi: 10.1038/tpj.2012.2.
A large-scale meta-analysis of two GWAS was performed with a Japanese population consisting of 1,583 p A GWAS was performed on 221 patients with colorectal cancer treated with 5-fluorouracil (5-FU) either alone or in combination with oxaliplatin (FOLFOX) followed by validation in 791 additional patients. Seven SNPs were identified that were associated with adverse drug reactions.

International HapMap Project

The International HapMap Project is an international scientific effort to identify patterns of human genome variation and determine those that impact health and disease as well as response to drugs or environmental factors. SNPs clustered together on a chromosome are inherited from a single parent as a block, with the pattern of SNPs on a block known as a haplotype. The term haplotype is a combination of the words haploid, or cells with a single set of chromosomes, and genotype, or the genetic composition of an organism. HapMap is a map of these haplotype blocks across broad genomic regions, and presents information on their locations in the genome and their frequency in different populations across the world. HapMap reduces the data complexity by consolidating the SNPs shared within a haplotype allowing genetic variations to be searched indirectly by using a small set of variants that distinguish a haplotype to assess variations in genes, chromosome regions or broader DNA regions. Genomic studies using this data are potentially more efficient for identifying regions of detectable disease-associated markers.

Encyclopedia of DNA Elements Project

Launched by the National Human Genome Research Institute in 2003, the Encyclopedia of DNA Elements (ENCODE) project was designed to expand the information from the Human Genome Project. Whereas the Human Genome Project sequenced the DNA that makes up the human genome, the goal of ENCODE is to identify the functional and regulatory elements in the human genome sequence including proteins and noncoding RNA molecules.

By mapping regions of transcription, transcription factor association, histone modification and chromatin structure, researchers have been able to associate a biological function to approximately 80% of the human genome. These efforts include not only previously characterized protein coding regions but also regions external to protein coding areas considered to be candidate regulatory elements such as noncoding RNAs, alternative splice transcripts and regulatory sequences. The regulatory regions determine if a gene is expressed, activating or repressing cellular signals. Several of these noncoding functional elements have been correlated with disease-associated SNPs, highlighting the strength of these approaches to identify new biological factors associated with disease.

Additional Genomics Research Efforts

In addition to genomic DNA regions, there is substantial evidence that RNA including messenger RNA and noncoding RNA, such as microRNA (miRNA), may also serve as an effective disease diagnostic. Studies have identified changes in RNA expression associated with malignancy and tumor progression, or drug response. Efforts are also underway to develop drugs that target miRNAs and selectively block their activity.

With ongoing technological and bioinformatics improvements, significant advances have been made in the area of disease diagnosis and monitoring in circulating body fluids such as blood, plasma/serum, urine and cerebral spinal fluid. Research efforts highlight the potential to diagnose disease, or monitor for indicators of drug response or disease progression based on the DNA signatures in circulating tumor cells, circulating tumor DNA (or cell-free DNA) or extracellular RNA.

Further clinical efforts have also focused on a variety of variables such as pharmacogenomics studies to match the right drug and therapeutic dose to a patient based on his or her molecular markers. Patient financial burden is also a critical area of interest with efforts focused on how to implement precision medicine in a cost effective strategy.