Emergency medical genomes: a breakthrough application of precision medicine

While the full realization of a breakthrough application for genome-guided precision
medicine has yet to be recognized, there are at least two medical applications today
that may serve as models for genome-informed precision medicine. These applications
have a relatively high likelihood of yielding acutely actionable information. Study
of these applications can inform the business and design focus to cross the adoption
chasm.

The first is the differential diagnosis of single gene diseases where there has been
longstanding evidence that a molecular diagnosis at or near disease onset can markedly
improve outcomes. Clearly, for the approximate 60 genetic diseases tested by newborn
screening (NBS) programs, this was substantiated by the implementation of a state
precision medicine public health service since the late 1950s 6]–8]. The NBS precision medicine program is a coordinated system of services with five
parts (Box 1). The genetic diseases tested by NBS were chosen specifically based on
the availability of medical therapies that when implemented immediately decreased
morbidity and mortality, and prevented many, and in some disorders all, of the serious
clinical sequelae. The feasibility and benefit of early diagnosis for the remaining
~4300 genetic diseases has started to be addressed in six recent retrospective case
series. Totaling 3587 subjects, these studies reported molecular diagnostic yields
of 27–57 % (Table 1) 9]–13]. Furthermore, two of these reported that diagnoses changed acute clinical management
in 49–100 % of patients, findings which start to overcome the general misconception
that nothing can be done for most genetic diseases (Table 1). While no prospective studies of consequent change in outcomes have yet been published,
the retrospective evidence is strengthened by an abundance of case reports of the
clinical utility of genome- or exome-derived diagnoses.

Table 1. Results of five large, retrospective case studies of the diagnostic rate of genome
or exome sequencing in children with suspected genetic diseases, particularly neurodevelopmental
disabilities

The second medical application where genome sequences have a relatively high likelihood
of yielding acutely actionable information today is in oncology. The landscape of
cancer genomics is rapidly being described through efforts of large collaborative
groups, including The Cancer Genome Atlas (TCGA) of the National Cancer Institute
(NCI), the International Cancer Genome Consortium (ICGC), and the Pediatric Cancer
Genome Project 14]–16]. Genomic biomarkers have the potential to aid with cancer diagnosis and classification,
prognosis and, most importantly, molecularly guided treatment 17]. While the diagnosis and treatment of cancer has historically been based upon histologic
findings and extent of disease, cancers are now being reclassified by molecular subtype,
with treatment tailored to the pathways mutated. For example, recurrent and potentially
targetable genetic alterations that are predictive of poor outcome have been described
in childhood acute lymphoblastic leukemia (ALL) 18], 19]. Genotype-based selection of patients for the application of targeted therapies has
already had a substantial impact on the treatment of some cancers, such as tyrosine
kinase inhibitors in patients with nonsmall cell lung cancers 20]–24]. Furthermore, precision oncology represents a specialized case of pharmacogenomics,
where genome information can guide both the choice of drug and the drug exposure,
based on ADME (absorption, distribution, metabolism, and excretion) variants.

Prospective trials of the tumor genome, exome, and gene panel-guided treatments are
now in progress. For example, the Lung Cancer Master Protocol (Lung-MAP) trial is
examining whether targeted cancer therapy cocktails that are matched to the genomic
makeup of the squamous cell lung cancer tumors of patients are more effective than
the current standard therapy in halting or reversing the progress of the disease and
in extending the life of the patient 25]. Other such studies in development are the NCI-Molecular Profiling-Based Assignment
of Cancer Therapy for Patients With Advanced Solid Tumors (NCI-MPACT; ClinicalTrials.gov
Identifier: NCT01827384), NCI-Molecular Analysis for Therapy Choice (NCI-MATCH), and
Pediatric MATCH 26], 27]. These prospective trials remain limited to patients who have exhausted standard
treatment options and who have relapsed and/or have refractory cancer. Despite a greater
understanding of signaling pathways, tumor heterogeneity, clonal evolution, treatment
resistance, and the importance of epigenomic alterations, precision oncology is in
its infancy 27]–31]. The results of clinical trials incorporating comprehensive genomics data will help
describe the role of next-generation sequencing in cancer diagnostics and therapeutics
32], 33].

However, neither of these clinical applications has yet risen to the level of the
genomic breakthrough application. Physicians generally do not yet practice precision
medicine in such clinical situations. Lack of physician familiarity with the interpretation
of genome or exome tests, or of the guidelines for changes in management following
genomic test results, undoubtedly explains part of a slow uptake of physician-ordered
testing. Additionally, in the current era of evidence-based, standardized management
protocols, the use of precision medicine, focused on individualized care plans, is
counterintuitive. Refusal of payors to reimburse clinical genomes and exomes is also
a great hindrance to broad utilization. However, a less frequently considered issue
is the lack of scalable, timely results. The turnaround time for results from a medical
genome or exome is typically 6 weeks to 6 months, making the medical genome possibly
the most cumbersome diagnostic test in the world.