Economic Model Says Cervical Cancer Co-Testing with mRNA-Based MDx Could Save Lives and Money

NEW YORK (GenomeWeb) – A mathematical model of the benefits of co-testing for cervical cancer screening has shown that the approach could be more cost effective than Pap or human papillomavirus molecular testing alone, in part by reducing unneeded medical procedures. 

The analysis, which was performed by researchers at the University of Southern California Keck School of Medicine and Truven Health Analytics in Cambridge, Massachusetts, was presented last week at the International Society For Pharmacoeconomics and Outcomes Research meeting.

The model predicted that combining Pap tests to identify cellular abnormalities with HPV tests to identify the presence of the virus that causes most cervical cancers could detect 150,000 additional cases and prevent 100,000 deaths compared to using HPV testing alone. It could also save $4.4 billion over 40 years.

The study specifically modeled use of Hologic's Aptima test, an mRNA-based assay which authors of a poster presented at ISPOR noted has similar sensitivity to DNA-based testing but with fewer false positive results. 

In a recent discussion of the relative importance of HPV genotyping in screening tests, one commercial representative suggested an mRNA test may not be appropriate for screening. However, Juan Felix, an author on the ISPOR research, a professor of clinical pathology, obstetrics, and gynecology, as well as chief of gynecologic pathology at USC's Keck School of Medicine, begs to differ.

The intuitive first-glance interpretation may be that, when comparing RNA and DNA detection, an mRNA assay might not catch early cases because it requires a productive infection.

"That has turned out not to be proven," Felix said, noting that there are over a dozen head-to-head studies of mRNA and DNA tests for HPV, and "they are statistically the same."

The mRNA test, however, has a specificity benefit, so "the detractors of the RNA technology are pretty much doing it without having data on their side," Felix said.

There is currently ongoing debate among stakeholders about whether molecular testing for HPV alone is sufficient for primary screening of women, as opposed to the gold-standard Pap test, or a combination of the two.

The time interval between screening visits is also being considered by the various agencies responsible for creating guidelines, with ramifications on HPV test manufacturers.

The US Food and Drug Administration approved Roche's molecular HPV test for primary screening without the need for Pap testing in April, prompting more debate of the issue.

This approval was influenced by Roche's clinical evaluation, called the Athena trial, which enrolled 42,209 women and showed HPV testing alone was about as specific and sensitive as co-testing.

Researchers at Quest Diagnostics and the University of Pittsburgh Medical Center, meanwhile, determined the data supported current consensus guidelines for cervical cancer screening which recommend women ages 30 to 65 be co-tested with both Pap and HPV tests. 

Specifically, an assessment of 256,648 patients in the Quest study showed a positive co-test was more sensitive for diagnosing cervical cancer than either kind of test alone. In that study, the molecular test was Qiagen's Digene Hybrid Capture HPV DNA test.

Hologic provided funding for the economic model of co-testing versus HPV testing alone, but Felix said he chose to use an mRNA-based test for the model.

"We chose the test with the fewest false positives ... and there is only one of those around," Felix said, referring to the Hologic test.

The study does not endorse any particular brand of test, but "there is only one mRNA test out there," Felix said.

The group has not officially run its model with a DNA test, but Felix said a DNA test would not give the benefit of the specificity parameter, and therefore benefits of co-testing would be eroded.

Thomas West, division president of diagnostics solutions at Hologic told GenomeWeb in an email that this analysis can give health care providers, US payors, and policy advocates an important assessment of how cervical cancer screening strategies intersect with economic costs in the long-term.

"It comes at a critical time when the medical community is evaluating how best to screen for cervical cancer and reinforces keeping Pap and HPV together as the preferred standard for women ages 30-65," West said. "We believe that every woman deserves to have the most effective cervical cancer screening options available to her and are committed to raising awareness of the value of Pap+HPV together in all our communication and education efforts," he added.

Felix said he was motivated to undertake this research because there have been claims that adding a second test would cost more money.

"We know that cervical cancer screening is important, and we have data that shows that using two tests — the Pap test and an HPV test — is more sensitive, and better at preventing cancer that just using either test alone," he said.

However, he said that he and his colleagues on the frontlines of cervical cancer screening believe HPV testing can result in "an awful lot of additional interventions."

He noted that HPV infection is very widespread, and "just because a woman tests HPV positive doesn't mean she has a cervical cancer precursor, or cervical cancer, or that she will ever develop it."

Based on the mathematical model using co-testing with Hologic's HPV assay, fewer women will be referred to colposcopy, and fewer will require other procedures, including surgeries like cone biopsies or the loop electrosurgical excision procedure, also called LEEP.

On the other hand, "Primary HPV detection will result in many more women receiving colposcopy, and that's one of the reasons that our mathematical model showed a cost benefit to co-testing, " Felix said.

He also said reducing unneeded testing could reduce risk of fertility issues that can result when cervical tissue removal leads to cervical insufficiency.

And false positive results also have "tremendous impact on the life of a woman," Felix said, causing anxiety that she might have cervical cancer and well as the possible social stigma of having HPV.

"You really adversely affect a woman's life by telling her she has HPV, but you also have a very good chance of adversely affecting her health because a false positive will result in her having a much higher likelihood of colposcopy [or] a LEEP."

"There is a tremendous reticence among clinicians who actually take care of women to go with primary HPV because the only study that has done so in a prospective fashion is the Athena trial," Felix said, adding that there are no consensus guidelines for primary HPV testing but only interim guidelines that have been proposed and are "still unproven."

On the other hand, there are official guidelines for co-testing, and physicians know how to triage and manage patients.

"And when we modeled it mathematically, it turned out many more patients benefited from having the co-test in that there were fewer procedures that they had to undergo."

Screening intervals

Another aspect of this debate with the potential to impact the HPV testing market is test interval.

Current guidelines recommend that a woman with a negative HPV test be screened again in five years. But guidelines appear to be in flux, with a three-year interval also being considered.

The Keck and Truven group modeled both, and found a five-year interval resulted in an increased in number of cancers. "These are very low rates, but they're still greater, so the question is, why wait for five years?"

Felix said the model showed shorter intervals were actually less costly and did not result in more interventions or procedures than longer intervals or primary HPV testing.

"By testing every three years we get the benefit of reducing cervical cancer even more and we do so in a cost-effective way," he said.

In the future, Felix said the guidelines will likely firm up. "I think that this model will give further impetus to the folks who want to change the screening interval for women who have a negative Pap and a negative HPV test ... from five years to three years."

"There is no reason in the world why we should prolong the screening interval when we're not causing damage by shortening it, but in fact making it more cost-effective."

Felix said the manuscript describing the study is being prepared, and the authors will be submitting it for publication in the future.