Precision Medicine Strategies in Otolaryngology

Head and neck cancers, as well as some other otolaryngology-related conditions, represent an opportunity to use precision-guided therapies. “This is because many oral cavity and oropharynx tumors are easily accessible for serial tissue biopsy compared to tumors in other bodily areas that are anatomically sequestered,” said Rajarsi Mandal, MD, assistant professor of otolaryngology-head and neck surgery at Johns Hopkins School of Medicine, and director of the Head and Neck Cancer Immunotherapy Research Program at the Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore. “Access to tumor tissue from the head and neck allows for interrogating tumor-specific genetic and immunologic vulnerabilities. Subsequent targeted therapies can then be tailored to individual patients.”

Several factors are driving increased interest in precision medicine in head and neck cancer. First, there has been a 60% increase in head and neck cancer incidences, from 39,000 to 59,000, between 2005 and 2015 in the United States. This is partially due to a rise in HPV-related head and neck cancer, associated with stable HPV-negative or unrelated head and neck cancer incidence, said Antonio Jimeno, MD, PhD, professor of medical oncology at the University of Colorado School of Medicine in Aurora. And, although cigarette smoking has declined, use of alternative tobacco products such as chewing tobacco, vaping products, and cigars has increased. The discovery of immunotherapies, which has opened up new therapeutic avenues for the first time in 10 years, is also driving interest in precision medicine.

Precision medicine can also be applied to nasal and sinus disorders. “We are using it to improve three aspects of patient care: diagnostics, prognostics, and therapeutics,” said Benjamin S. Bleier, MD, associate professor of otolaryngology at Harvard Medical School and director of endoscopic skull base surgery at Massachusetts Eye and Ear in Boston. “We determine which substrates within a patient we can harness. For a cancer patient, that might include sampling their tumor or lymph nodes. In chronic sinusitis, we might sample inflamed tissue, mucus, or exosomes. We can then look at proteomics, transcriptomics, and genetics. By using these techniques, we can partition patients into categories that help us address these three aspects.”

Hearing loss is also uniquely positioned for the application of precision medicine strategies because it is commonly caused by a single genetic mutation, and relatively simple precision medicine tools such as population-specific gene panels can typically detect it, said Oliver F. Adunka, MD, FACS, professor and director of otology, neurotology, and cranial base surgery in the department of otolaryngology, head and neck surgery at The Ohio State University Wexner Medical Center in Columbus.

Pamela Roehm, MD, PhD, professor and director in the division of otology and neurotology at the Lewis Katz School of Medicine at Temple University in Philadelphia, said hundreds of different genetic causes of hearing loss are known, with more than 20 recently identified using next-generation sequencing (NGS).

Identifying genes associated with different types of hearing loss in children is helpful in predicting prognosis of hearing loss, especially in situations where hearing loss may significantly progress with time, said Charles Yates, MD, neurotologist in the department of otolaryngology-head and neck surgery at Riley Children’s Health in Indianapolis, Ind.

Outlook for Patients with Cancer

Looking ahead, Xiao-Jing Wang, MD, PhD, professor of pathology, otolaryngology, dermatology, and craniofacial biology at the University of Colorado School of Medicine in Aurora, believes that improved risk prediction and therapeutic individualization for inflammatory, sensory, and cancer conditions will be in the spotlight of precision medicine. “Studies to increase the number of patients with durable response to therapy, particularly while receiving immunotherapy, will be the field’s main focus,” she said.

For patients with head and neck cancer, the future of precision medicine lies in figuring out how to activate the immune system against cancer cells only. “Since tumor mutations are patient specific, each patient likely has a unique set of tumor neoantigens that their T cells can respond to,” said Clint Allen, MD, associate professor of otolaryngology–head and neck surgery at Johns Hopkins, and Johns Hopkins Otolaryngology Consult at the National Institutes of Health in Bethesda, Md., “In the future, by using the same DNA sequencing that was used to try and match patients with a specific small molecule inhibitor, we may be able to determine each head and neck cancer patient’s unique array of tumor neoantigens and activate T cells against cancer cells specifically.”

Precision medicine also holds great promise to improve the efficacy and side effects of head and neck cancer treatment. While treatment outcomes for patients with HPV-positive tonsil cancer are quite good, more than 30% of all patients with HPV-negative, advanced stage head and neck cancer have disease recurrence within one year of completing treatment, Dr. Allen reported. Additionally, many cancer patients who are cured are left with devastating functional impairments in voice and swallowing.

One major issue precision medicine will hopefully address is the flexibility to adapt treatments with changing tumors. “Whether using small molecule inhibitors or immunotherapies guided by mutational analysis, tumor cells that are more susceptible to initial treatments may be killed off, while less susceptible tumor cells are left behind after initial treatments to repopulate the tumor,” Dr. Allen explained. “Head and neck cancers tend to be very heterogeneous. This suggests that any single treatment may not treat all tumor cells and lead to treatment resistance. In order to keep up with changing subpopulations of tumor cells, cancers may need to be reassessed after initial therapies stop working to determine if new or altered treatments are needed.” Many clinical trials for head and neck cancer will use this adaptive design to try and evolve along with a changing tumor during precision treatments.

Applications beyond Cancer

Analysis of patient genomes may also improve the treatment of many congenital anomalies, syndromes, and hearing and balance disorders caused by genetic alterations. Furthermore, with recent breakthroughs in gene-editing technology, including the use of CRISPR-Cas9 gene editing, Dr. Mandal said it may one day be possible to target these mutations in germline cells.

Dr. Bleier said the future of precision medicine is in developing noninvasive biosignatures from patients. “By doing this, we can sample them over time prospectively and repeatedly without causing trauma,” he said. “This will allow a physician to make a diagnosis upfront and then track how a patient’s disease evolves and responds to treatment.”

Precision medicine might also fuel efforts to identify the microbiome of the oral cavity and sinuses as a factor in chronic inflammatory conditions such as sinusitis, and evaluate its importance in explaining the individual’s susceptibility to transition from acute to chronic disease. A research group at Dr. Wang’s institution is currently studying this possibility.

Dr. Yates said that a better understanding of the genomic influences on foods, drugs, environmental effects, lifestyle choices, noise exposure, and a host of other factors may ultimately prevent problems, although this type of research is in the early stage.

Hinrich Staecker, MD, PhD, professor of otolaryngology-head and neck surgery at the University of Kansas School of Medicine in Kansas City, said treatment of sensorineural hearing loss will be significantly improved through developing biomarkers for different types of sensorineural loss. Currently, serum-based biomarkers for diverse disorders such as noise-induced hearing loss and benign paroxysmal positional vertigo are being developed. Studies identifying subtypes of Meniere’s disease are underway. “Based on these studies, we will develop pharmacotherapy and molecular therapy targeting for different types of sensorineural hearing loss,” he said.

Dr. Roehm said techniques involved in precision medicine, which couples databank searches of large amounts of patient information with NGS and other genomic evaluations of patients, could potentially identify more genes and genetic loci involved in hearing loss and aid in its treatment, as noted in a recently published study (J Genet Genomics. 2018;45(2):99-109). “Personalized patient knowledge of their genetic makeup could potentially assist in avoiding the development of hearing loss,” she said. For example, factors that predispose to ototoxic hearing loss, such as deletions in the Sod1 superoxide dismutase gene, have been identified. Physicians could inform patients with this mutation to avoid exposure to aminoglycosides due to their increased risk of hearing loss from these antibiotics.

In the future, genetic treatments specific to an identified defect will likely help to target mutations, enabling the application of highly individualized treatment approaches. Precision medicine will also likely further subclassify sensorineural hearing loss. “This could be critical in various aspects of patient management, but especially in candidacy selection for cochlear implantation,” Dr. Adunka said. “Specifically, the success or failure of hearing preservation will likely match a patient’s genetic profile obtained through precision medicine testing.”

Challenges to Precision Medicine

In order to reap all of the benefits of precision medicine, large datasets need to be collected to make sense of whole genome sequencing data. This comes with privacy issues, such as genome-data sharing with physicians and between laboratories, and concerns for potential abuse of information by medical insurers, said Xue Zhong Liu, MD, PhD, Marian and Walter Hotchkiss Chair in otolaryngology and vice chair of research at the University of Miami Miller School of Medicine, and co-author of the Journal of Genetics and Genomics study.

To overcome challenges with data collection, Dr. Liu recommends ensuring de-identified genetic data and corresponding demographic and clinical information. “Research suggests that patients are open to sharing de-identified genetic and health data,” he said.

Dr. Adunka said informing patients about the success of precision medicine with a certain diagnosis can help patients appreciate the importance of data collection.

Another ethical challenge identified in Dr. Liu’s study is using pre-implantation genetic diagnosis in the selection for and against specific traits in fertilized embryos prior to in vitro fertilization, Dr. Roehm said. This could become an ethical issue if the technology is used to direct selective abortion following chorionic villus sampling or amniocentesis.

The speed at which new genetic and genomic technologies are being developed further complicates the field of precision medicine. “Technology is outpacing our ability to meaningfully interpret all findings and develop clinical and medical guidelines as well as the infrastructure for incorporating results into clinical care,” Dr. Liu said. “Without standardized guidelines, there is no consistency among practitioners. Most electronic health record systems aren’t equipped to handle genomic/genetic data in a straightforward manner. Finally, many physicians and patients don’t have the necessary background to fully comprehend the finding’s possible ramifications.”

To address this challenge, professional societies must stay abreast of changes in technologies and provide guidance to their members, enlisting the aid of genetic researchers, physicians, and counselors, Dr. Liu said. Electronic health record systems need to be adapted to capture data from these technologies and store it in a manner that’s useful to physicians. Educating physicians and patients must be done at appropriate levels so both stakeholders can make informed decisions and recommendations.

To get more otolaryngologists on board with using precision medicine, Dr. Liu recommends providing them with easily available information on how to obtain genetic testing and where to send for genetic hearing loss panels. Guidelines on when to send for genetic testing should be developed and published.

Courses in bioinformatics and statistical analysis of the results of precision medicine studies would help physicians once the application of precision medicine to human disease is more practical, Dr. Roehm added.

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Karen Appold is a freelance medical writer based in New Jersey.