Blood Test for HPV May Help Predict Risk in Cancer Patients

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

By Decoding How HPV Causes Cancer, Researchers Find a New Potential Treatment Strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers.

HPVs are responsible for the majority of cervical cancer and a substantial portion of head and neck and anal cancers, but therapy available to date is surgery and non-specific chemotherapy.

The new study, published Oct. 2 in the journal Oncotarget, found that E6, an oncoprotein produced by the virus, interacts with several other molecules in host cells in a manner that ensures infected cells cannot die. If they are immortal and continue to multiply, cancer develops.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, PhD, discovered in 1983 that HPV can cause cervical cancer. Recently, the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers,” says the study’s lead author, Xuefeng Liu, MD, associate professor of pathology at Georgetown University Medical Center.  Liu is director of Telomeres and Cell Immortalization for the medical center’s Center for Cell Reprogramming.

Liu and his team have previously found that the HPV E6 oncoprotein interferes with the well-known p53 tumor suppressor to increase telomerase activity that extends the life span of infected cells. A telomerase is a protein that allows a cell to divide indefinitely when it would have stopped after a certain number of divisions.

In this study, researchers found that E6 also interacts with myc, a protein produced by the Myc gene, which controls gene expression in all healthy cells. They concluded that telomerase activity is dependent on E6-myc proteins hooking on to each other.

This means, says Liu, that designing a small molecule that stops E6 from joining up with myc should shut down persistent activation of telomerase. A small molecule could bind to E6 in the same spot that myc would, or bind on to myc in the same spot that E6 would, thus preventing an E6-myc complex.

“This small molecule would not be toxic to all normal cells or, importantly, to master stem cells, because myc would not be affected,” says Liu. “It could be a unique treatment, targeted specifically to HPV cancers.”

Georgetown researchers are now working on a prototype chemical to interfere with E6/Myc binding.

Halving Radiation Therapy for HPV-Related Throat Cancer Offers Fewer Side Effects and Similar Outcomes, Mayo Study Finds

Mayo Clinic researchers have found that a 50 percent reduction in the intensity and dose of radiation therapy for patients with HPV-related throat cancer reduced side effects with no loss in survival and no decrease in cure rates. Results of a phase II study were presented today at the 59th Annual Meetingof the American Society for Radiation Oncology in San Diego by Daniel Ma, M.D. a radiation oncologist at Mayo Clinic.

“A common approach for treating HPV-related throat cancer is a combination of surgery followed by daily radiation therapy for six to 6½ weeks,” says Dr. Ma. “However, the radiation treatment can cause a high degree of side effects, including altered taste, difficulty swallowing, dry mouth, stiff neck and damage to the jaw bone.”  Dr. Ma says that patients with HPV-related throat cancer tend to be young and, once treated, are likely to live a long time with possibly life-altering side effects from the standard treatment. “The goal of our trial was to see if an aggressive reduction of radiation therapy (two weeks of radiation twice daily) could maintain excellent cure rates, while significantly reducing posttreatment side effects, improving quality of life and lowering treatment costs.”

Researchers followed 80 patients with HPV-related oropharyngeal squamous cell cancer with no evidence of residual disease following surgery and a smoking history of 10 or fewer pack years. That’s the number of years smoking multiplied by the average packs of cigarettes smoked per day.

At two years following the aggressively de-escalated treatment, the rate of tumor control in the oropharynx (throat) and surrounding region was 95 percent. Of the 80 patients in the trial, only three experienced a local cancer recurrence. One patient experienced a regional cancer recurrence. Patient quality of life largely improved or did not change following treatment, except for some dry mouth.

“Patients in our trial had a very dramatic reduction in side effects, compared with standard treatment,” says Dr. Ma. “For example, no patient in our trial needed a feeding tube placed during dose-reduced treatment; whereas, close to a third of patients had feeding tubes placed with traditional radiation therapy doses on other recent clinical trials.” Dr. Ma says the reduction in side effects did not lead to any reduction in cure rate, as survival rates were similar to traditional survival rates for HPV-related throat cancer.

HPV Testing Leads to Earlier Detection and Treatment of Cervical Precancer

Women who receive human papillomavirus (HPV) testing, in addition to a pap smear, receive a faster, more complete diagnosis of possible cervical precancer, according to a study of over 450,000 women by Queen Mary University of London (QMUL) and the University of New Mexico (UNM) Comprehensive Cancer Center.

HPV is a virus that can cause cervical, vaginal, penile and anal cancers. More than 520,000 cases of cervical cancer are diagnosed worldwide each year, causing around 266,000 deaths. A common screening procedure for cervical cancer is the Pap smear, which tests for the presence of precancerous or cancerous cells on the cervix.

The study, published in JAMA Oncology, used data from the New Mexico HPV Pap Registry in the United States. It is the first comprehensive evaluation of HPV testing on the long-term outcomes of women who had received a borderline abnormal Pap test result.

A total of 457,317 women were included in the study. Of these, 20,677 women (4.5 percent) received a borderline abnormal result through a Pap smear and were followed in the study for five years. Some of the women with borderline abnormal Pap smear results had an HPV test.

HPV testing led to a 15.8 percent overall increase in the detection of cervical precancers and time to detection was much shorter (a median of 103 days versus 393 days).

Virtually all cervical pre-cancers were detected in women who tested positive for HPV, suggesting HPV testing to be a good additional screening method after the Pap smear. Colposcopy, which is a medical examination of the cervix, could then be focused on women who would need it most: those with a positive HPV test.

At the same time, however, HPV testing of women resulted in 56 percent more biopsies and a 20 percent increase in surgical treatment procedures performed. Most of the additional biopsies were for low grade lesions which could have regressed, indicating some overtreatment due to HPV testing.

Professor Jack Cuzick from QMUL said: “This study shows that knowing a woman’s HPV status can help determine her likelihood of needing additional procedures, and prioritise immediate treatment and medical resources to the women who need them most.”

Professor Cosette Wheeler from the UNM Comprehensive Cancer Center said: “The benefits of HPV testing outweigh the harms observed but it’s important to understand and quantify the harms as well.”

The authors warn that, as this was an observational study, the use of HPV testing was not randomised. So, it is also possible that there could be socioeconomic or other relevant differences among health care facilities that have not been measured.

Study redefines HPV-related head and neck cancers

Much of what we thought we knew about the human papilloma virus (HPV) in HPV-related head and neck cancers may be wrong, according to a newly published study by Virginia Commonwealth University (VCU) researchers that analyzed data from The Human Cancer Genome Atlas. Head and neck cancers involving HPV are on the rise, and many experts believe we are seeing the start of an epidemic that will only get worse in the coming years.

The Cancer Genome Atlas is a collaboration between the National Cancer Institute (NCI) and the National Human Genome Research (NHGR) Institute that makes publicly available genomic information on tumor samples from 33 different types of cancers. Its aim is to help the cancer research community improve the prevention, diagnosis and treatment of cancer.

It is thought that there are two main forms of HPV-related cancers, episomal and integrated. In episomal variants, the HPV genome replicates independently. Integrated HPV has become part of the DNA of the host cell and relies on it for replication. Previously, it was believed that most HPV-related head and neck cancers had integrated HPV, as is what is believed with HPV-related cervical cancers. However, Windle’s study, recently published in the journal Oncotarget, found that HPV DNA is maintained separate from the human genome in the majority of HPV-related head and neck cancers, though, in many cases, the HPV genome can acquire a small piece of human DNA making it look like integrated HPV. This viral-human hybrid represents a new category of episomal HPV in HPV-related cancers.

“Our work challenges the idea that finding HPV DNA joined to human DNA means that HPV is integrated. With this new view of the state of HPV, we conclude that episomal HPV is the predominant state in HPV-related head and neck cancers,” says Brad Windle, member of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, professor at the Philips Institute for Oral Health Research at the VCU School of Dentistry and co-principle investigator on the study. “This is an important distinction because patients with episomal HPV cancer respond better to therapy than patients with integrated HPV cancer.”

Windle’s team analyzed the genomes of all 520 HNC samples in The Cancer Genome Atlas and found that 72 were HPV positive. The large majority of these cancers had a common type of the virus known as HPV16 present, so they focused on that virus type. The data showed that 75 percent of the HPV16 samples had the HPV genome in the episomal state, and about half of the genomes contained a piece of human DNA within their circular structure.

The researchers also found that 73 percent of the tumor samples were still dependent on proteins known as E1 and E2 for replication. This is important because when the HPV genome integrates with human DNA, expression of the HPV E2 protein–essential for independent replication–is lost. The presence of E2, or lack thereof, in tumor biopsies could be a reliable way for physicians to determine the cancer type and provide a more accurate prognosis.

“Perhaps our most striking outcome is the potential to target the E1 and E2 proteins for diagnosis and treatment,” says Windle. With nearly three quarters of these cancers dependent on E1 and E2 for replication, we could develop drugs that target these proteins and promote cell death.”

Windle’s team plans to continue studying the integration of HPV in HPV-related head and neck cancers, and suggests that viral-human DNA hybrid HPV should be further explored in HPV-related cervical cancers. His team is currently working with Massey clinicians in order to use this information to assess patients’ prognosis in the clinic.