Gypsyamber D'Souza and David Wong at the 2016 AAAS Annual Meeting. | AAAS
Over the past decade, David Wong of UCLA and his colleagues have been developing a method for detecting circulating tumor DNA in bodily fluids such as blood and saliva. The approach, known as a liquid biopsy, holds the promise of quicker, less invasive identification of cancers and easier tracking of disease status during the course of treatment.
In a news briefing at the 2016 AAAS Annual Meeting, Wong described a prototype device — called electric field-induced release and measurement (EFIRM — that can detect biomarkers in saliva for a malignancy called non-small cell lung cancer. The device has a high accuracy compared to current sequencing technology, Wong said, and is entering clinical testing in lung cancer patients in China this year.
The test requires just one drop of saliva, Wong said, and can be completed in 10 minutes in a physician's office. He envisioned using it in conjunction with other diagnostic tools. If a lung X-ray were to show a suspicious nodule, a doctor could do the saliva-based test to help quickly determine whether a cancer is likely.
The test can reliably find genetic mutations involving epidermal growth factor receptor (EGFR), a protein on the surface of cells, Wong said. It normally helps the cells grow and divide, but some cells in non-small cell lung cancer have too much EGFR, which makes them grow faster. Several drugs can block the growth signal from EGFR, and their use could be ordered promptly by a clinician.
Saliva-based tests might someday allow screening for a variety of cancers in a doctor's office or laboratory, said Wong, director of UCLA's Center for Oral/Head and Neck Oncology Research, He and his colleagues also has been looking at use of liquid saliva technology to detect a handful of mutations linked to cancers of the mouth and the back of the throat (called oropharyngeal cancers).
But enthusiasm for the liquid biopsy must be tempered by the complexity of the cancer process and the potential usefulness of the technique for specific cancers. Identifying surrogates for early detection of oral cancers remains a challenge, said Gypsyamber D'Souza, associate professor of epidemiology at the Johns Hopkins University Bloomberg School of Public Health.
She has a particular interest in the epidemiology of human papilloma virus (HPV), which now causes the majority of oropharyngeal cancers in the United States. "We have great hope," D'Souza said, for many biomarkers being explored as early-warning signs for the disease. But she said: "Right now, there are not effective screening modalities to detect HPV-related oropharyngeal cancers early."
D'Souza also noted that available evidence suggests it may take a decade or more for an HPV infection to progress to mouth or throat cancer. And the vast majority of HPV infections are cleared by the body's immune system within a year or two, she said. She cautioned against heightened anxiety about the level of risk from HPV-related oral cancers. Just having HPV in the mouth, she said, "is a terrible predictor of whether you will go on to get cancer."
Wong and others have identified some "signature mutations" that, collectively, may account for up to 80% of HPV associated mouth and throat cancers. If such mutations can be picked up through screening of saliva, he said, it could offer physicians and patients an opportunity for early intervention and treatment of cancers that have a five-year survival rate of about 60%.
There currently are no simple biochemical or genetic diagnostic tests commercially available for oral cancer, according to Wong. D'Souza said oral cancer typically is not detected until later stages of the disease when the patient starts to exhibit symptoms. The current standard for identifying oral cancer relies on a visual exam of the patient's mouth, she said. Definitive diagnosis often requires invasive biopsies and use of genomic sequencing technologies. Since HPV-related oral cancer is quite rare, D'Souza said, it is unlikely a screening test for that cancer — even if available — would be mandated for the general population. The HPV-16 variant of the virus associated with cancer occurs in only about 1% of the general population, D'Souza said.
But Wong said he and his colleagues have identified a dozen biomarkers for oral cancers not associated with HPV, and such research could lead to broader screening for oral cancer and eventually to development of affordable, saliva-based testing for a variety of cancers. Access to saliva will not be a problem. Wong said we each produce 1.5 liters a day.
Quite aside from the hope for easier detection, D'Souza said it is important to better understand the incidence of oropharyngeal cancer and its relation to HPV infection. HPV-related cancer is increasing in the United States, particularly among men, she said. Her research shows that their risk increases as they have more oral sex partners. For women, however, the number of oral sex partners is not as big a risk factor.
Her research suggests that a woman who has had a number of vaginal sex partners first is less likely to become infected with HPV via oral sex. A genital HPV infection can trigger a robust immune response that is protective for HPV infection via oral sex. "This suggest that where your first HPV exposure is may be important," D'Souza said. The immune response in men who are exposed to HPV via oral sex is likely to be smaller, she said, although most men clear the virus from their bodies within a year or two with no lasting effect.