Genomic variants are either caused by germline mutagenesis, a central biological process and driver of most heritable variations in humans, or caused by acquired processes in specific tissues leading to cancer.
Genomic variants, in constitutional/germline disorders, can help establish or confirm a rare disease diagnosis. Some examples where genomic variants have helped diagnose diseases are cystic fibrosis, sickle cell diseases, complex disorders with genetic contributions like autism spectrum disorders and individuals with multiple congenital anomalies.
Whereas, in somatic/acquired genetic disorders (cancer) these variants can drive cancer and are amenable for targeted therapies. One of the poster examples in genome-driven tailored therapy for cancer is chronic myeloid leukemia (CML). In CML, the pathogenic BCR-ABL1 fusion can be targeted by an oral medication (Imatinib, small molecule kinase inhibitor). This approach has reduced the need of toxic chemotherapy and has increased long term survival.
Over the past decade, we have witnessed exponential and unprecedented advances in our technical ability to assay DNA sequences and to identify these genetic variants in high throughput, cost-effective, and in a clinically relevant time frame. This accelerated progress in genomic technologies has led to discovery of many novel variants for Mendelian disorders, complex diseases, and have helped understand the mechanism of oncogenesis in cancer thereby leading to molecularly targeted therapies.
These technological advances have heralded the era of “Precision Medicine” and has enabled the development of prognostic markers, tailored therapeutic interventions, and the strategies to predict and prevent complex disorders.
What is Precision Medicine?
According to the Precision Medicine Initiative, Institute of Medicine and National Human Genome Research Institute, precision medicine is defined as an “emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”
Historically, before the beginning of the precision medicine treatment paradigm, all patients with a specific disease would be given a standard therapy. While some patients benefitted from standard treatment, some would experience adverse side effects from treatment.
Precision Medicine is a significant diversion from the “one-size-fits-all” and “trial-and-error” approach to medicine by utilizing differences in genomic blueprints to create customized or personalized approaches for treatments.
Why Precision Medicine? Specifically, Why Now?
Improvements in technology coupled with significant reduction in cost of sequencing has helped drive the rapid adoption of genomic medicine. This includes clinical genetics and oncology clinics, as well as many other disciplines of medicine such as neurology, newborn medicine and cardiovascular medicine.
The potential of genomic medicine, as an important component of precision medicine, is to help healthcare providers make better clinical decisions through integrated genomic, clinical, and outcome data. The expected benefits are to improve tailored therapies, eliminate or reduce side-effects, improve prevention and prediction of disease, enable earlier disease intervention, reduce healthcare costs, and improve patient outcomes.
Medical care is in the midst of a paradigm-shifting revolution away from trial-and-error medicine and toward this new, targeted approach that utilizes patients’ molecular information to create more informed healthcare decisions.
Precision Medicine in Constitutional/Germline Disorders
One of the major utilities of using genomic medicine is in the area of rare undiagnosed genetic disorders. In most cases, this cost-effective approach has been useful in ending non-genomic clinical testing performed to establish a diagnosis for rare diseases.
Additionally, elucidating precise molecular alteration and mechanistic basis of disease may lead to targeted treatment. For example, the cystic fibrosis transmembrane regulator (CFTR) modulates therapy for cystic fibrosis patients based on specific molecular mutations and guides medical management with the goal of enhancing the patient’s outcome. Baylor Genetics serves as the only sequencing core of the National Institutes of Health-funded Undiagnosed Diseases Network and provides enhanced diagnostic capabilities through precision genomic medicine.
Precision Medicine in Acquired/Somatic Cancer
Cancer, a disease caused by genetic defects, is the second leading cause of global deaths. The global death rate estimated by the World Health Organization is over 10 million. Per the American Cancer Society, cancer accounts for more than 60,000 deaths in the US.
Evaluating the genetic defect in cancer has been implemented as a standard care for decades. However, this approach was limited to a few select genes by traditional methods and initially, the sequencing technology was limited to highly actionable hot spots—areas of the genome that are frequently altered and have an approved molecularly targeted therapy.
The turning point for precision medicine in oncology was the technological advancements in next-generation sequencing methodology, which provided improved turnaround times and made it a cost-effective alternative.
Today, the precision medicine approach is routinely utilized in oncology. With the removal of significant technical or financial hurdles, precision medicine has increased utilization for many different tumor types, improved outcomes, and has reduced morbidity and mortality in some tumors.
While some believe that precision medicine hasn’t yielded many results, like creating personalized cancer therapy for some patients, it has provided significant positive results for many cancer patients.
The Challenges with Precision Medicine
Despite recent breakthroughs and the growing force behind precision medicine, there are still substantial challenges and barriers to overcome for its broad implementation in medical practice.
The challenges to overcome for precision medicine are as follows:
- Innumerable economic, regulatory, social, and technical issues that need novel solutions.
- Convincing evidentiary support for precision medicine. Currently, more research is needed to make the case for precision medicine adoption, which would lead to significantly improved outcomes.
- Significant resources are needed to improve data collection, storage, sharing, and integration with EHR (electronic health records).
- Incorporating genomic information into clinical care and research is not yet achieved and will be crucial in many health care systems.
- Education is a key challenge because many physicians express little confidence in their ability to make clinical decisions when genetic or genomic information is involved. Educational efforts over the different sub-disciplines of medicine is needed. (Note: Baylor Genetics has been proactively providing continuing medical education courses in genomics for healthcare providers to help them move towards that goal and increase their confidence).
- Efforts are need to secure participant engagement and trust. Current deterrents for complete patient participations are patient anxiety, fear of unnecessary and expensive tests, procedures that might follow from a genomic result, and privacy concerns.
- Enhancing ethnic diversities is important to be able to translate genomic findings appropriately.
For the successful implementation of precision medicine, the global medical community will need a coordinated, collaborative effort that brings together the key stakeholders from the public, private, academic, and government sectors.
Over the past four decades, Baylor Genetics has been a pioneer in using many tools (e.g. 3000+ comprehensive genetic testing menu) in genomic medicine repertoire to further the mission of precision medicine. For more details on Baylor Genetics’ test offerings, please visit www.baylorgenetics.com.
- Science, 27 Sep 2019:Vol. 365, Issue 6460, pp. 1409-1413
- Dzau, V. J., G. S. Ginsburg, A. Chopra, D. Goldman, E. D. Green, D. G. B. Leonard, M. McClellan, A. Plump, S. F. Terry, and K. R. Yamamoto. 2016. Realizing the Full Potential of Precision Medicine in Health and Health Care: A Vital Direction for Health and Health Care. NAM Perspectives.Discussion Paper, National Academy of Medicine, Washington, DC.
- Nature, Vol 526, 15 October 2015, 336