Guest Blog
by Jennifer Levin Carter, M.D., M.P.H., Founder, Chief Medical Officer, N-of-One

Jennifer Levin Carter, M.D., M.P.H.

The pace of scientific development is proceeding unlike any other time in the history of health care. New technologies, diagnostic tests and drugs are being introduced at record speed. However, to keep abreast of this unprecedented progress and to realize the value of personalized medicine, physicians must be empowered to efficiently and effectively utilize molecular testing to match patients with the most promising treatments.  This is not getting easier — physicians must have access to accurate, timely and cost-effective clinical interpretation to enable the delivery of data-driven therapeutic strategies to every patient.

Oncology is leading the way in the personalized medicine revolution. The oncology pipeline has expanded by 63 percent over the past 11 years,¹  and oncology drugs accounted for 50 percent of all personalized medicines approved in 2016.² Approximately 80 percent of cancer drugs in the pipeline are first-in-class therapies, and 73 percent target a specific biomarker.³ With this wave of new treatment options, how do physicians match their patients to the best possible therapy?

Much of the advancement in oncology drug development is a result of the uptake of next-generation sequencing in the clinic, and there is growing recognition that other molecular tests, like those evaluating copy number, fusions and protein expression, are becoming important tools for predicting response to therapies. New predictive tests for evaluating the efficacy of immunotherapies are in the pipeline. As patients are treated with targeted therapies and immunotherapies, novel resistance mutations, such as the EGFR C797S mutation after treatment with Osimertinib for EGFR T790M positive non-small cell lung cancer, are beginning to appear. Liquid biopsy tests have become a powerful method for identifying these mutations, especially in the absence of accessible tumor for biopsy. The results from these tests, if correctly interpreted, can prevent treatment with therapies that are no longer working.

Although this explosion of complex molecular data is vital for the advancement of personalized medicine in oncology, it also represents a critical challenge for clinicians. PMC’s Health Care Working Group notes that “to be successful, providers must deliver information about the significance of test results in a way that saves time and resources and allows for expansion that can keep pace with the rate of scientific advancement.”⁴

Due to the growing complexity of the molecular data and available therapeutic options, patient-specific clinical interpretation is required for helping the physician utilize molecular testing to select a therapeutic strategy for each patient. Each patient’s molecular test results must be analyzed to assess the effect of the clinically relevant alterations and the combination of alterations in the context of each patient’s cancer sub-type to determine the link to relevant therapeutic strategies. This must include sophisticated clinical trial matching.⁵

The key capabilities for patient-specific clinical interpretation necessitate:

1. Analysis of each patient’s molecular profile at the gene, variant and disease level, plus an assessment of the impact of the interactions between alterations on drug sensitivity, drug resistance and combination therapy. This requires oncology domain expertise for on-demand analysis to evaluate any type of cancer and assess novel mutations
2. Up-to-date clinical trial matching to address the growing complexity of patients’ molecular data and clinical trial design
3. Capabilities to update a patient’s analysis based on subsequent testing and evolution in the molecular profile
4. Integration of multiple types of tests to create a coherent treatment strategy, including immunotherapy approaches
5. Integration of relevant patient data into the clinical interpretation to further refine clinical trial matching
6. Delivery of therapeutic strategies to the point of care at the time of decision-making through the electronic medical record to enable physician-patient discussion

We as an industry can seize upon the opportunity to personalize the care of every patient. Molecular testing can play an increasingly valuable role in the diagnosis and treatment of disease. But for each patient to effectively receive this type of care, physicians must be empowered with exceptional clinical interpretation.

1 IMS Institute for Healthcare Informatics. Global Oncology Trend Report: A Review of 2015 and Outlook to 2020. June 2016. http://www.imshealth.com/en/thought-leadership/ims-institute/reports/global-oncology-trend-report-a-review-of-2015-and-outlook-to-2020. Accessed June 3, 2016.
2 Personalized Medicine Coalition. Personalized Medicine at FDA: 2016 Progress Report. 2017. http://www.personalizedmedicinecoalition.org/Resources/Personalized_Medicine_at_FDA. Accessed February 5, 2017.
3 Pharmaceutical Research and Manufacturers of America. Medicines in Development for Cancer: From Hope to Cure. 2015. http://phrma.org/sites/default/files/pdf/oncology-report-2015.pdf. Accessed May 15, 2016.
4 Pritchard, DE, Moeckel, F, Villa, M, Housman, L, McCarty, C, McLeod, HL. Strategies for integrating personalized medicine into health care practice. Personalized Medicine. Vol. 14, No. 2, 2017. Available at http://www.futuremedicine.com/doi/abs/10.2217/pme-2016-0064.
5 Carter, JL. Empower physicians to deliver precision medicine: The role of clinical interpretation. Personalized Medicine Coalition. Education & Advocacy. 2015. Available at https://personalizedmedicine.blog/2015/11/17/empowering-physicians-to-deliver-precision-medicine-the-role-of-clinical-interpretation/.

Guest Blog
by Konstantinos Lazaridis, M.D., Assistant Director, Mayo Clinic Center for Individualized Medicine

Konstantinos Lazaridis, M.D.

Perhaps more so than other areas, the emerging field of preemptive pharmacogenomics holds enormous promise to immediately improve the medical care of our patients. Patients would save time, money and untold suffering if they proactively had DNA testing to match medications to their individual genetic profiles. It is also important to integrate those test results into the patient’s electronic health record so they are available at the moment physicians are prescribing therapies.

Pharmacogenomics testing is currently one of the most promising tools in personalized medicine because of the potential widespread impact. The RIGHT study, done at Mayo Clinic, indicates nearly all patients could benefit. The study found that 99.9 percent of participants studied had a genetic variant that impacted the way their bodies processed medications. Conditions that hold the most promise for pharmacogenomics include:

• Pain and psychiatric treatment — identifying medications that balance effectiveness with side effects.
• Transplants — immunosuppressants keep the body from rejecting a transplanted organ, but leave patients vulnerable to infection.
• Patients with polypharmacy — taking several medications often means that a drug is not working. Pharmacogenomics testing can identify what drugs do not work and simplify medical therapy.

Finding the Most Effective Medication

It is likely not uncommon for patients with a chronic medical condition to be on a “therapeutic odyssey,” a term we’ve coined to describe the frustrations patients experience when they try medication after medication for years without getting any relief from the symptoms of their conditions. I further explain this phenomenon in Improving Therapeutic Odyssey: Preemptive Pharmacogenomics Utility in Patient Care, an editorial that appeared in the October 23, 2016 edition of The Journal of Clinical Pharmacology & Therapeutics.

Therapeutic odyssey represents a protracted journey in a patient’s quest to find effective therapy for a chronic disease, often leading to unsuccessful treatments, frequent visits to health care providers, poly-pharmacy, herbal or alternative medicine-based therapy options, and sometimes unwanted symptoms – or even adverse drug events. In fact, the Centers for Disease Control, in a study published in Journal of the American Medical Association (JAMA), reports one out of every 250 Americans visited the emergency room because of a harmful drug reaction in both 2013 and 2014. Now is the time for health care providers to proactively recommend pharmacogenomics testing for all patients and enter the results in the electronic health record in order to find the most effective medications.

Mayo Clinic has created 19 drug-gene rules that are embedded in the electronic health record, notifying prescribers when a genetic variation may have a harmful drug interaction. Those alerts in the electronic health record have prevented more than 10,000 drug reactions at Mayo Clinic since 2013.

Pharmacogenomics testing must become a standard practice in order to improve the safety and quality of care. Doctors, pharmacists, nurses and educators must all work together to adopt practices that make it possible for all patients to benefit from the individually tailored treatments that pharmacogenomics offers.

Dr. Lazaridis is the Everett J. and Jane M. Hauck Associate Director in Minnesota. He is also recognized as the William O. Lund, Jr., and Natalie C. Lund Director, Clinomics Program.

Guest Blog
by John Beeler, Ph.D., Vice President, Corporate and Business Development, Inivata

John Beeler, Ph.D.

The promise of personalized medicine gained momentum with the publication of the human genome more than 13 years ago. Enthusiasm grew over the potential to decode the genetic basis of disease and enable efficient utilization of a new generation of genomically targeted therapies. Precision medicine, whereby genomic information is integrated into clinical decision-making, intended to realize a more personalized approach and treat the right patient with the right drug at the right time.

Despite clear examples of success illustrated by the development of molecular technologies to identify genomic alterations with high specificity and sensitivity and to guide the use of targeted therapies against altered genes, including EGFR, BRAF, ALK and others, there has been a growing chorus of skeptics who infer that application of these targeted therapies to a broader population harboring respective genomic alterations is nothing more than hype. According to these skeptics, one of the primary reasons that precision oncology medicine is an illusion is the lack of data from randomized clinical trials that support the use of genomically guided therapies in more tumor diverse populations. However, there are several factors that have contributed to the paucity of data supporting advances in precision oncology medicine, particularly in patients with advanced stage disease.

The lack of tumor tissue available for molecular profiling is a primary barrier to more robust clinical data. Reasons for the lack of tissue necessary for broad molecular profiling include poor performance status, which precludes patients from being subjected to the invasive procedure necessary for obtaining a tissue specimen. On other occasions, it has been noted that tumors are inaccessible for a biopsy (e.g. bone metastases) and even when obtained, the limited amount of biopsy material can be insufficient for molecular profiling. According to published reports, approximately one-third of advanced stage cancer biopsies deliver tissue specimens that are either poor quality or have insufficient tumor material for a molecular analysis to be performed.

Tissue-based biopsies are further constrained by spatial and temporal limitations that may provide an inaccurate representation of the heterogeneous nature of the malignant growth, which results in the treatment of a patient based on an inaccurate molecular diagnosis. Finally, tissue biopsies are not conducive to serial sampling and are thus incapable of monitoring the molecular evolution when a tumor progresses. The failure to obtain a high-quality tissue specimen that accurately reflects the complete tumor biology may be a contributing factor to the lack of data supporting the realization of precision oncology medicine.

Fortunately, we now find ourselves at a potential inflection point, capable of positively impacting the field of personalized medicine. Recent advances in the application of “liquid biopsies” and the potential to harness molecular information in circulating cell-free tumor DNA (ctDNA) from the convenience of a simple blood draw offers a “game-changer.” Analysis of ctDNA represents a new generation of molecular applications that are capable of producing data that was previously unavailable, thereby helping to deliver on the full promise of providing health care that is both more precise and personal.

First identified more than 60 years ago by Mandal and Metais, advances in genomics and molecular methods now allow analysis of cell free DNA with unprecedented sensitivity and specificity to expand the range of opportunities for liquid biopsy applications that will impact the major aspects of a patient’s care. Analysis of ctDNA can identify genetic alterations that enable therapy selection, quantitatively monitor treatment progress, including disease recurrence via serial sampling, and detect new resistance mutations as they emerge. This liquid biopsy approach has the potential to revolutionize cancer care and improve and/or resolve many of the limitations inherent in current tissue-based standard treatment protocols for providing a broad molecular profile.

This is particularly relevant in non-small cell lung cancer (NSCLC), where a significant number of patients with advanced NSCLC are not receiving molecular testing for first-line therapy and even less are receiving a molecular profile at disease progression following first-line therapy. The opportunity to improve the availability of a molecular profile when one is not otherwise obtainable and provide valuable molecular information that impacts clinical decision-making offers to help deliver on the promise of personalized medicine.

In contrast to the current state of euphoria generated by the liquid biopsy approach and analysis of ctDNA, there is still significant work to be done to generate data illustrating the benefits of ctDNA. The data is necessary to address the limitations of current tissue-based testing, to drive adoption and utilization of this innovative approach, and to improve trust in the regulatory and reimbursement landscape. At Inivata we believe it is vital to get this aspect correct, most importantly for cancer patients, to fulfill the promise of personalized medicine.

by Daryl Pritchard, Ph.D., Vice President, Science Policy

Daryl Pritchard, Ph.D.

Barack Obama’s administration was clearly committed to the advancement of personalized medicine.  In addition to launching the Precision Medicine Initiative and the Cancer Moonshot effort, during his tenure President Obama regularly described personalized medicine as the future of health care.

“I want the country that eliminated polio and mapped the human genome to lead a new era of medicine, one that delivers the right treatment at the right time,” he said in his 2015 State of the Union Address.

The election of Donald Trump as the 45th President has led to a great deal of uncertainty on the future of personalized medicine and the fate of Obama’s signature personalized medicine programs.

Fortunately, Congress has confirmed its support for personalized medicine by passing the 21st Century Cures Act.  The law, designed to accelerate the pace of biomedical innovation, a goal that President-elect Trump has expressed interest in, provides continued momentum for personalized medicine. The House of Representatives voted 392 – 26 in favor of the legislation one week before the Senate passed the law 94 – 5. President Obama is expected to sign it.

“The 21st Century Cures bill supports personalized medicine,” PMC President Edward Abrahams said. “The Precision Medicine Initiative, the Cancer Moonshot and speedier access to innovative therapies based on molecular pathways, in particular, will all contribute to a healthier nation.”

Among other things, the bill:

• Authorized $4.8 billion in funding over 10 years for programs at the National Institutes of Health (NIH) that include the All of Us Research Program and the Cancer Moonshot Research Program, as well as $500 million for FDA to implement provisions to improve innovation
• Required FDA to make the patient experience a more central part of the drug development process
• Established a review pathway at FDA for biomarkers and other drug development tools
• Included provisions related to FDA’s oversight of diagnostics, albeit without addressing the longstanding debate on the regulation of laboratory-developed tests
• Modernized clinical trial design and evidence development as it relates to the consideration of real-world data and other topics
• Required FDA to pilot one or more inter-center institute(s) to help develop and implement processes for coordination of activities in major disease areas between the drug, biologics and device centers
• And enhanced the country’s capacity to deliver personalized medicine through improvements and incentives in health information technology.

The law is not perfect. Policymakers have pointed out, for example, that the amount of NIH funding is half of what was proposed in the 2015 version, and that the programs are authorized rather than appropriated, thereby not guaranteeing that they will be funded. Others object to using the Affordable Care Act’s prevention funds to pay for Cures provisions.  Furthermore, although proponents claim the law’s new measures will not weaken FDA’s regulatory oversight, some critics disagree, especially regarding regenerative medicine.

But despite these concerns, the 21st Century Cures Act has provided a more favorable setting for personalized medicine amid ongoing uncertainty under a new administration.

The Personalized Medicine Coalition applauds Congress for passing the legislation and delivering it to the President, who has indicated his strong support for its provisions.  By allocating resources for personalized medicine programs and encouraging biomedical innovation, the 21st Century Cures Act will help drive personalized medicine’s enormous potential for patients and the health system in a future that otherwise remains uncertain.

Guest Blog
by Ralph Snyderman, M.D., James B. Duke Professor of Medicine, Chancellor Emeritus, Duke University

Ralph Snyderman, M.D.

A Chancellor’s Tale:  Transforming Academic Medicine is a personal and intimate story of my 15-year journey as Duke University’s Chancellor for Health Affairs during a time of major upheaval in medicine. The story, I hope, will help demonstrate the importance of planning, leadership and organizational change to the advancement of the personalized medicine paradigm.

My experience as a scientist and a physician prior to assuming my role as chancellor did little to prepare me to deal with a highly complex and entrenched institution that, unbeknownst to itself, was in need of disruptive change. The story describes the path the institution and I took during my tenure as chancellor, during which time the Duke University Medical Center became known for innovations in medicine and the conception of personalized health care.

As CEO of the Duke University Health System, I saw that despite our delivering outstanding, state-of-the-art care, treatments were generally directed towards the reversal of episodes of late-stage disease.  By 2000, anticipating the power of genomics and associated advances in technology, my colleagues and I began to envision an entirely new approach to care.  Rather than being reactive to disease, health care could be proactive, predictive, preventive and personalized.  As health and disease are a consequence of one’s genetics and environmental exposures over time, the availability of technologies to quantify health risks, track disease progression and identify specific disease mechanisms could be a game-changer for how care is delivered.  Rather than starting with a disease manifestation and working back, clinicians could, in conjunction with their patient, anticipate disease risks and work to mitigate them and to treat them precisely when needed.  As a consequence of this thinking, my colleagues and I conceived of an entirely new approach to health care and in doing so, laid the foundation for personalized health care.

A Chancellor’s Tale tells the story of the major transformation of Duke’s academic enterprise along with the concepts that resulted in the creation of care delivery models for personalized, proactive, patient-driven care. The book describes the difficulties of making change in a complex academic institution including what worked, what went wrong and lessons learned.  My hope is that the personalized medicine community will find the stories interesting and my learning experiences useful.

The book is available for purchase at https://www.dukeupress.edu/a-chancellors-tale.

Special offer: Use coupon code E16SNYDR to save 30 percent on the hardcover edition when you order from dukeupress.edu.