MDx & Cervical Cancer

A look at the progress that has been made because of multivalent HPV vaccinations teamed with new technologies and evidence.

It has long been known that, with early detection, treatments can be aimed at preventing and curing cervical cancer. It is an area in which laboratories and clinical professionals are working together to transform the horizons of patient care.

While the complete eradication of cervical cancer in the U.S. within our lifetime is still a lofty goal, forward progress has been moved at least to the 50-yard line thanks to a long pass delivered by multivalent HPV vaccinations teamed with new technologies and evidence-based understanding of what high-risk HPV (hrHPV) assays can tell us about risk and/or disease status.

A spotlight was shone on the emerging role of molecular diagnostics in cervical cancer screening at an industry workshop, “Transforming Patient Care with Molecular Testing,” presented by the American Association of Clinical Chemistry (AACC) with support from a Roche educational grant at the AACC Annual Meeting and Clinical Lab Expo 2015 in Atlanta, Ga.

Data Tell the Story

“Data exist that show a path to improved outcomes. Early screening makes a difference and we now have tools that allow us to risk-stratify patients in ways that we were unable to do before,” said moderator Glen T. Hanson, PhD, director of clinical microbiology and molecular diagnostics at Hennepin County Medical Center in Minneapolis, Minn. He said labs must hold true to the belief that “evidence-based data and outcome-driven research will allow testing to have a place in our laboratories as we continue to struggle to learn for the most effective ways to help diagnose, treat and implement early screening interventions for HPV DNA.”

Workshop panelists-Mark Stoler, MD, professor (emeritus) of pathology and clinical gynecology at the University of Virginia Health System, Charlottesvile, Va.; Lee P. Shulman, MD, professor in obstetrics and gynecology at Feinberg School of Medicine of Northwestern University, Chicago; and Catherine Behrens, MD, PhD, FACOG, a ­consultant with Roche-ran with this intellectual ball throughout 90 minutes of presentations and Q&A. Their collective carries led to a persuasive conclusion: MDx allows for unprecedented opportunity for improvement to status quo in cervical cancer screening.

The panel described a new healthcare field on which the old-school annual Pap smear for cervical cancer screening has been largely sidelined. Instead, cytology testing is being paired with-or, in some cases, replaced by an FDA-approved hrHPV molecular test. There are currently four FDA-approved hrHPV assays for use in co-testing with cytology; only one-cobas HPV Test-is FDA-approved for primary screening (i.e., without cytology).

“If George Papanicolaou [founder of the Pap smear] were here today, he would be an advocate of HPV testing; he would be at the front of the line talking about HPV testing and its cervical screening algorithm. We really do have a better mousetrap. We really can reduce, and potentially eliminate, cervical cancer in the not-so distant future,” proclaimed Shulman.

Misperceptions Abound

Stoler commented that, in laboratory and pathology circles, “Anatomic pathology is either looked on as primitive and not sophisticated, or the gold standard by which we measure clinical diagnostics,” leading to ongoing debates about HPV Dx and whether hrHPV testing should be used as a primary screening test. He said, according to CAP in 2014, “clinically valid HPV testing does not just detect the virus.”

“And that statement pinpointed the No. 1 misperception in the entire field,” said Stoler. “hrHPV detects the virus at a clinically valid cutoff that optimizes the detection of cancer and precancer while providing maximal reassurance to the people who are not at risk and who can be followed at long intervals. Many microbiologists think hrHPV testing is just for viral genomes and nothing could be further from the truth. The hrHPV tests are molecular, PCR-based, DNA diagnostics that are calibrated to predict the risk of pre-cancer, cancer in the screen population.”

Evidence Is Compelling

Stoler said healthcare is charged with making cervical cancer screening more effective and cost efficient. “For screening, we need a highly sensitive test-high sensitivity is what drives a negative predictive value, the reassurance that allows us to extend intervals of what once were annual Pap tests to the current guideline recommendation of every 3 or 5 years,” he explained. “And for triaging those patients with a positive result, we must use an optimal triage tool to minimize false positive screening results. This will allow us to focus on the appropriate subset of patients who really need treatment.”

Stoler recounted ongoing limitations to cervical cytology. “One of the most significant is the relatively low sensitivity of the Pap test for the detection of high-grade cervical cancer precursors,” he said. “Another limitation of cervical cytology is it really only identifies what the patient has today. We are scraping the cervix, looking at cells, and if the cells are abnormal, they have to be coming from a lesion that is identifiable and treatable. But that doesn’t predict what is going to happen to the patient in the future.”

In contrast, he referred to recently published data from the ongoing ATHENA trial, “where we see the stratification of HPV risk through genotyping. You can see different HPV types-particularly HPV16 and 18-which can not only tell the risk of a patient with CIN3+ who needs treatment today to prevent cancer today, but also their ongoing risk over time given a one-time HPV positive result.”

Stoler said that review data presented to the FDA reveals that ATHENA compared three different screening strategies (cytology with HPFV triage was the reference point and was compared to primary HPV with HPV 16/18 and Reflex to Pap.) “The data show there is a statistically relevant difference between the performance of HPV testing and cytology co-testing-the primary HPV testing strategy was superior.” He said HPV diagnostics can interact with cytology to really improve the efficiency of cervical cancer screening, both by reassuring those who are not at risk and focusing on those who are at risk.

“For me, it’s really about data that has been presented in the literature now over the last 10 years, all pointing to the same result: The safety and efficacy of hrHPV primary testing is higher than cytology and equivalent to or better than co-testing, with the added benefit of algorithmic simplicity,” he said.

A Time for Change

Shulman was ardent in his agreement: “The one absolute truth is that we have never had this kind of literature before to support a clinical change in practice-ever.”

He also took some issue with the terminology used in the 2015 ASCCP & SGO interim clinical guidance, which said, “Because of equivalent or superior effectiveness, primary high-risk HPV screening can be considered as an alternative to current U.S. cytology-based cervical cancer screening.”

“hrHPV testing should not be considered an ‘alternative,’ because many in the healthcare community now advocate that ‘alternative’ as the preferred method of screening,” he said. “These same results, in multiple studies over a long time-in different communities, in different risk women-have been consistent again and again.

Shulman said that barriers to large-scale adoption of primary hrHPV screening can be found among clinicians. “There’s a tendency to just keep doing what we’re doing. And many pathologists fear that their practices will be decreased-that there will be fewer samples coming into their practice as a result of adoption,” he said regretfully.

Stoler took up the charge, noting, “There are still states where it is law that women are entitled to annual pap smears. We don’t need those. Conflicts of interest exist under the current payment systems. But there is no denying that we have the best data around what is best for patients regardless of cost-like nowhere else in medicine. Cost remains the number one barrier. Insurers need to get on board with better testing and getting their own payback through the greater length of intervals between tests. We have to reeducate physicians and primary care providers on how to best screen for cervical cancer.”

Only then can molecular diagnostics for cervical cancer be the game-changer it is.

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