New Test May Detect Difficult-To-Find Cervical Cancers

Scientists at the Montefiore Einstein Cancer Center (MECC) have developed a test for detecting a kind of cervical cancer that Pap tests frequently miss, findings that could have significant consequences for cervical cancer screening. Journal of the National Cancer Institute: JNCI released the findings today online.

“Our novel test appears sensitive for detecting cervical adenocarcinoma [ADC]—which now accounts for up to 25% of cervical cancer cases—as well as its precursor lesions, adenocarcinoma in situ [AIS], that often develop into ADCs,” said Howard Strickler, M.D., M.P.H., co-senior and corresponding author of the JNCI paper and a member of MECC.

“Because ADCs are often missed by current screening methods, they have higher mortality rates than the more common cervical squamous cell cancer,” Dr. Strickler added. “Our goal is to catch the disease early, before it develops into cancer.” Dr. Strickler is also professor and head of the division of epidemiology and the Harold and Muriel Block Chair in Epidemiology and Population Health at Albert Einstein College of Medicine.

A new strategy for testing

Over the past six decades, the prevalence of the Pap test, in which tissue samples are examined by a pathologist for abnormal cells, has considerably decreased the incidence of cervical squamous cell cancer. The Pap test is less successful at detecting ADC, which is possibly why the incidence of the condition has not dropped.

In recent years, the Pap test has been joined by testing for the human papillomaviruses (HPVs), which are largely responsible for all incidences of cervical cancer. Despite the fact that there are more than 100 different strains of HPV, HPV 16, 18, and 45 account for more than 70% of all instances of cervical cancer and more than 90% of cases of ADC.

All three forms of HPV are currently detected by the tests, which can warn infected women that they have a high risk of developing cervical cancer. Although safe and effective, multiple generations of women are past the recommended age for receiving the Gardasil-9 vaccine, which protects against nine HPV strains. Therefore, prevention of cervical cancer will still require screening and therapy for many years to come.

The HPV test created by MECC evaluated HPV 16, 18, and 45 in a novel way: by focusing on methylation levels. “The advent of next-generation genetic testing has opened up opportunities for us to more accurately detect oncogenic HPV strains and patterns in the genomes that correspond with the development of AIS and ADC,” said Robert D. Burk, M.D., professor of pediatrics, of microbiology & immunology, of epidemiology and population health, and of obstetrics & gynecology and women’s health at Einstein and MECC member, who co-led the study.

Methylation, which is the addition of methyl (CH3) groups to a section of DNA, occurs often in both viral and human DNA and is essential for changing how genes are expressed. The JNCI study, a joint effort with the NCI, a division of the National Institutes of Health, looked into the levels of methylation in cervical tissue samples taken from 1,400 women who had undergone cervical cancer screening at Kaiser Permanente Northern California prior to 2014 and whose cervical cancer status was known.

The methylation percentages for each of the 35 individual viral-genome sites were totaled in order to evaluate the HPVs in the cytological samples; each sample was then given a final “methylation score” that was equal to the average methylation percentage across all 35 sites. The probabilities of developing either ADC or AIS were extremely high for women with methylation scores in the top 25%.

“Our findings, if confirmed by clinical trials, suggest that women with a high methylation score may benefit from colposcopy and specialized tissue evaluation, beyond just a Pap test, which could lead to early diagnosis and treatment for ADC or the removal of AIS lesions before they develop into ADC,” said Dr. Burk.

Increasing equity in the detection of cervical cancer

“Given that our test uses equipment that could be simplified, it has the potential to expand testing in lower-resourced countries,” said Dr. Strickler, who has long studied HPV in women living with HIV, who are more likely to acquire an HPV infection.

The burden of cervical cancer is substantially higher in lower- and middle-income countries, especially those in Sub-Saharan Africa where HIV-HPV coinfections are frequent. Cervical cancer is still the fourth most prevalent type of cancer in women. Significant differences also exist inside the United States. The Bronx in New York City, which is home to the nation’s poorest urban congressional district, has cervical cancer rates that are 50% higher than those in Manhattan. This health discrepancy might be reduced with more frequent and efficient screening.

“Ideally, the new HPV methylation test would only need to be done once every three to five years,” said Dr. Strickler. “We are hopeful that this test will be able to increase cervical cancer screening equity in the U.S. as well.”

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