Precision Medicine: Benefits & Risks

President Obama’s recent announcement of the Precision Medicine Initiative (PMI) brings precision medicine to the forefront of conversations concerning effective and affordable medical treatment options. Precision medicine is an exciting and promising new approach to medical treatment, but as such its benefits and risks must be considered.

Early Precision Medicine: Beatrice’s Story

Early Precision Medicine: Beatrice’s Story

Early Precision Medicine: Beatrice’s Story

Early Precision Medicine:
Beatrice’s Story

Hugh Rienhoff’s daughter, Beatrice, was born in 2003 with noticeably wide spacing between her eyes, and weak muscles. Rienhoff, a trained clinical geneticist and worried father began searching (over many years and multiple doctors) for a diagnosis for Beatrice (1); he coordinated an international team of thirteen members spanning the US, the Republic of Korea, and Canada to research Beatrice’s undefined condition. About ten years into their research the team discovered a de novo mutation in the transforming growth factor β, which none of Beatrice’s family were known to carry. The team used exome sequencing to capture all of the whole protein encoding genes of the genome in order to identify this mutation (2). Rienhoff’s work is perhaps one of the earliest examples of precision medicine in action.

As a result of this discovery, there are currently two broad avenues for continued research of Beatrice’s condition. A mouse model of her genetic mutation offers the opportunity to study the biological mechanism. Additionally, locating other people with the same gene mutation could offer insight into the progression of Beatrice’s condition and what treatments might improve her health. The use of this technology to diagnose Beatrice, and open new avenues of research makes her case an exceptional example of how precision medicine can affect the lives of everyday Americans. As such the White House featured Beatrice’s story, along with five others, as a testament to the importance of precision medicine (3).

Hugh Rienhoff - Beatrice Rienhoff - DNA Sequencing

Hugh Rienhoff prepared his daughter’s DNA for sequencing at home using second-hand equipment (Credit: Leah Fasten, Nature)

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Hugh Rienhoff - Beatrice Rienhoff - DNA Sequencing

Hugh Rienhoff prepared his daughter’s DNA for sequencing at home using second-hand equipment (Credit: Leah Fasten, Nature)

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Hugh Rienhoff - Beatrice Rienhoff - DNA Sequencing

Hugh Rienhoff prepared his daughter’s DNA for sequencing at home using second-hand equipment (Credit: Leah Fasten, Nature)

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Hugh Rienhoff - Beatrice Rienhoff - DNA Sequencing

Hugh Rienhoff prepared his daughter’s DNA for sequencing at home using second-hand equipment (Credit: Leah Fasten, Nature)

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What is precision medicine?

What is precision medicine?

What is precision medicine?

What is precision medicine?

According to a 2011 National Research Council report, precision medicine refers to the tailoring of a medical treatment to individual characteristics of each patient (e.g. genetic, biomarker, phenotypic, or psychosocial characteristics) (4). Research in lung cancer is an example of using precision medicine to identify a genetic subgroup in response to a particular treatment or disease. Patients with anaplastic lymphoma kinase (ALK) rearrangements experienced tumor shrinkage or stabilized disease when receiving crizotinib therapy; patients without ALK rearrangements did not respond to crizotinib treatment (5). In this case, precision medicine informs lung cancer patients without specific genetic rearrangements that the costly and potentially toxic crizotinib therapy is unlikely to improve their condition.

Treating lung cancer with precision medicine

Treating lung cancer with precision medicine

Treating lung cancer with precision medicine

Treating lung cancer with precision medicine
Response to ALK Inhibition

Panel A shows the best response of patients with ALK-positive tumors who were treated with crizotinib, as compared with pretreatment baseline. Numbers along the x axis indicate arbitrarily assigned subject numbers from 1 to 79. The bars indicate the percent change in tumor burden from baseline.

Three study patients are not included in this plot: one patient was clinically assessed as having had a partial response, although the response was primarily in areas of nonmeasurable disease, so the patient was classified as having stable disease; two patients with abrupt clinical deterioration could not be assessed.

Four patients had complete resolution of their target lesions but were classified as having had a partial response on the basis of stability in nontarget lesions. Eight patients had tumor shrinkage of more than 30% but were classified as having stable disease either because confirmatory scans were not available by the data-cutoff point (for five patients) or early restaging was performed at 6 weeks after crizotinib initiation (for three patients). The dashed line indicates a tumor reduction of 30% from baseline, the minimal percent decrease that constitutes a partial response, according to Response Evaluation Criteria in Solid Tumors. Panel B shows the results of CT with coronal reconstruction in a representative patient at baseline (left) and after two cycles of therapy (right). This patient had undergone previous left lower lobectomy.

Precision Medicine Initiative

Precision Medicine Initiative

Precision Medicine Initiative

Precision Medicine Initiative

During his State of the Union Address on January 20, 2015, President Obama announced the Precision Medicine Initiative (PMI) with hopes of accelerating progress toward individualized medical treatments (6). As a part of this initiative the National Institute of Health will build a national, large-scale research participant group program (a cohort program) including at least one million Americans; it is expected to face common challenges such as the navigation of laws and regulations, recruiting a diverse cohort, and the establishment and maintenance of biobanks.

Beginning in 2016, the PMI will be used to study and better understand factors which contribute to individual health and disease in eight specific areas: discovering disease risk factors, how genes affect individual response to drugs, searching for disease biomarkers, the use of mobile health technology to correlate disease outcomes, the clinical impact of loss-of-function or inactivation mutations, developing new disease classifications, clinical trials targeting specific disease-causing gene mutations, and empowering participants.

The Health Nucleus

The Health Nucleus

The Health Nucleus

The Health Nucleus

The Health Nucleus platform is another example of precision medicine’s usefulness in addressing human health and disease. In October of 2015 genome scientist and entrepreneur J. Craig Venter launched Health Nucleus, a genome powered clinical research project within Human Longevity Inc. (7). The platform focuses combining genome sequencing, clinical imaging, computer science, and personal health history to explore new ways to keep people healthy.

Although it is a comprehensive and personalized health platform, Health Nucleus draws concern among the medical community regarding the platforms position to give people meaningful information without confusing or even harming them. The cost of a Health Nucleus check-up is currently about $25,000 and is not covered by health insurance companies.

A randomized, controlled experiment comparing health outcomes of individual patients who receive the service and those who do not could aid in proving the efficacy and general safety of Health Nucleus. Furthermore, a comparison of this kind may change the opinion of the medical community and health insurance providers. Many of the challenges surrounding the Health Nucleus program are related to identifying the benefits and risks of precision medicine in general.

Health Nucleus

Above: Health Nucleus clients will receive a full-body MRI scan, including brain imaging, from this machine, Oct. 13, 2015. (Photo Credit: David Wagner/KPBS)

Health Nucleus

Above: Health Nucleus clients will receive a full-body MRI scan, including brain imaging, from this machine, Oct. 13, 2015. (Photo Credit: David Wagner/KPBS)

Health Nucleus

Above: Health Nucleus clients will receive a full-body MRI scan, including brain imaging, from this machine, Oct. 13, 2015. (Photo Credit: David Wagner/KPBS)

Health Nucleus

Above: Health Nucleus clients will receive a full-body MRI scan, including brain imaging, from this machine, Oct. 13, 2015. (Photo Credit: David Wagner/KPBS)

Benefits of precision medicine

Benefits of precision medicine

Benefits of precision medicine

Benefits of precision medicine

Improving diagnosis and treatment

A sounding board article in the June 2015 publication of the New England Journal of Medicine discusses the many benefits of precision medicine; the article cites the various fields of medicine in which precision medicine is used, including: cancer, hematology, infection disease, cardiovascular disease, pulmonary disease, renal disease, hepatology, endocrine disease, metabolic disease, neurology, psychiatry, pharmacogenomics, and ophthalmology (8). Of course he previously discussed cases of Beatrice’s long wait for diagnosis, and targeted Crizotinib therapy offer specific examples of precision medicine’s efficacy in improving diagnosis and treatment.

Newly classified diseases

Non-small cell lung cancers have traditionally been based on histology (9). In 1987, the KRAS gene mutation was identified as a unique molecular subset of the disease. Over the last 20 years, additional gene mutations have been identified which classify non-small cell lung cancer patients into subpopulations based on their responses to a specific drug treatment. Some of the classifications include EGFR Gly719X mutations associated with drug sensitivity, EGFR exon 20 insertions associated with primary drug resistance, and EGFR Thr790Met associated with acquired drug resistance. Similar methods of precision medicine could be utilized to improve classifications for many more disease.

Why Precision Medicine?

Precision medicine offers more effective diagnosis and treatment. (Image Credit: Dr. Thomas Wilckens)

Why Precision Medicine?

Precision medicine offers more effective diagnosis and treatment. (Image Credit: Dr. Thomas Wilckens)

Why Precision Medicine?

Precision medicine offers more effective diagnosis and treatment. (Image Credit: Dr. Thomas Wilckens)

Why Precision Medicine?

Precision medicine offers more effective diagnosis and treatment. (Image Credit: Dr. Thomas Wilckens)

Risks of precision medicine

Risks of precision medicine

Risks of precision medicine

Risks of precision medicine

Misinterpreting genetic and health data

Several hundred genes have been linked to various cancers, 3,600 genes identified across various rare disease, and 4,000 genetic loci have been linked to common disease (10). However, genomic knowledge still contains significant gaps—e.g., the specific gene mutation causing a disease, or identifying which mutations are harmless. A June 2015 special report in New England Journal of Medicine notes that a family member who was positive for a genetic variant linked to sudden cardiac death five years ago, is now at less risk because that same variant is no longer considered harmful based on more recent evidence (11).

Conversely, a different family member who was negative for the same variant is now positive for a newly discovered variant and as a result undergoes a medical procedure to reduce the risk of sudden cardiac death. A collaborative Clinical Genome Research program called ClinGen has been initiated to promote transparency and advancement in genomic research; projects such as ClinGen address and seek to reduce the risks of precision medicine over time.

Violating the privacy rule

The U.S. Department of Health and Human Services office for Civil Rights finds that, since October 21, 2009, there have been 1,400 breaches of unsecured protected health information affecting 500 or more individual people (12). In response, the White House implemented the Privacy and Trust Principles to provide guidance in maintaining data integrity, responsible access and use of data, empowering participants and respecting their preferences, promoting transparency, and creating a governance structure (13). This governmental project aims to maximize precision medicine’s benefits and reduce the risks.

What are the costs of precision medicine?

What are the costs of precision medicine?

What are the costs of precision medicine?

What are the costs of precision medicine?

Anyone in the U.S. can voluntarily enroll in the Precision Medicine Initiative either through a participating health care provider, or a government website which is currently under development.

The Health Nucleus platform is not presently covered by private health insurers or the federal Medicare program; both institutions remain hesitant to reimburse commercial genetic tests of precision medicine.

Foundation Medicine (specializing in manufacturing and selling genomic analysis diagnostics for cancer) announced on December 21, 2015, their national agreement with private health insurer, United Health Care. The partnership provides a pan-cancer genetic test, Foundation One, that sequences both 315 cancer-related genes’ entire coding sequences and 28 genes’ introns in patients with metastatic IV non-small cell lung cancer (14). This agreement is an important step toward broader genetic testing reimbursements from health insurers.

Precision medicine is not simply improved disease diagnosis and treatment; it offers patients hope for better health. Precision medicine promotes the development of anti-cancer treatments, and has the potential to transform biomedicine and healthcare in years to come. However, there are obstacles in incorporating precision medicine into everyday clinical practices. Further research must prove that precision medicine improves health outcomes, that its benefits outweigh patient risk, and that it is a financially viable tool for health care providers and patients.

References

  1. Father’s genetic quest pays off [2013-06-27; Brendan Maher. Nature. 498:418-419] [Nature]
  2. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome [2013-07-03; Hugh Young Rienhoff, Chang-Yeol Yeo, Rachel Morissette, Irina Khrebtukova, Jonathan Melnick, Shujun Luo, Nan Leng, Yeon-Jin Kim, Gary Schroth, John Westwick, Hannes Vogel, Nazli McDonnell, Judith G Hall, and Malcolm Whitman. American Journal of Medical Genetics. 161A:2040-2046]
  3. Precision Medicine Is Already Working to Cure Americans: These Are Their Stories [2015-01-30; Chris Evans, WhiteHouse.gov]
  4. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease [2011; Committee on a Framework for Development a New Taxonomy of Disease, Board on Life Sciences,Division on Earth and Life Studies, National Research Council]
  5. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer [2010; Eunice L. Kwak,et al. New England Journal of Medicine.363:1693-1703]
  6. NIH framework points the way forward for building national, large-scale research cohort, a key component of the President’s Precision Medicine Initiative [2015-17-09; nih.gov]
  7. Geneticist Craig Venter helped sequence the human genome. Now he wants yours [2015-05-11; Carl Zimmer. statnews.com]
  8. Precision medicine – personalized, problematic, and promising [2015; J. Larry Jameson,and Dan L. Longo. New England Journal of Medicine. 372:2229-2234]
  9. New driver mutations in non-small-cell lung cancer [2011; William Pao, and Nicolas Girard. Lancet Oncology.12:175-180]
  10. Cutting the Gordian helix – regulating genomic testing in the era of precision medicine [2015; Eric S. Lander. New England Journal of Medicine.372:1185-1186]
  11. The clinical genome resource [2015; Heidi L. Rehm, et al. Cancer ClinGen – New England Journal of Medicine.372:2235-2242]
  12. Breaches affecting 500 or more individuals [U.S. Department of Health and Human Services Office for Civil Rights]
  13. Precision medicine initiative: privacy and trust principles [2015-09-11; WhiteHouse.gov]
  14. Interest in precision medicine grows, but reimbursements slow to follow [2015-23-12; Andrew Joseph. statnews.com]

Credit: English Text curated by Jinnah Griffin

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.


The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.