Cervical cancer testing is one of the great success stories in the fight against cancer. In recent decades, the death rate from this cancer has dropped dramatically in the United States and other developed countries, largely due to cytology Pap testing. HPV testing has also evolved as a vital complement to Pap-based screening, by helping to identify the presence of the virus that causes most cervical cancers.
Last year, the American College of Obstetricians and Gynecologists (ACOG) issued revised guidelines on screening. The ACOG guidelines, which generally align with the recent recommendations of the American Cancer Society (ACS) and other medical organizations, recommend a Pap test every three years for women of average risk ages 21 to 29.
For women ages 30 to 65, the guidelines recommend Pap and HPV testing; if those results are normal, retesting is recommended every five years. Most previous medical guidelines recommended screening every one to three years for average-risk women, depending on age and other factors.
The new guidelines bring an evidence-based approach to cervical cancer detection and management. The aim is to identify women reliably on a population basis, while also minimizing the potential for unnecessary testing and procedures as well as anxiety in patients due to false HPV positives. These are commendable goals.
As a pathologist and cancer researcher, I am very familiar with the strengths and limitations of current cervical cancer screening technologies. Pap testing has been used since the early 1940s and is an important diagnostic tool, but experience has shown that many times it is not definitive, since it is providing a range of disease classifications that are determined largely through subjective analysis.
HPV tests are unable to predict which infections will resolve on their own or bring about malignancy. In addition, the presence of more than 100 types of HPV, each with molecular differences that pre-determine their development into malignant or benign lesions, places further limits on the use of generalized HPV testing as a diagnostic and prognostic aid.
A new generation of molecular diagnostics may offer important additional information that can assist physicians in assessing the risk of cervical cancer when used in support of present screening tests for cervical cancer. These markers build on the first two elements – cytology and HPV testing – to help clinicians identify molecular markers that may indicate an increased likelihood of progression to cervical cancer.
One example is E6/E7 mRNA, which is reported to be associated with a higher risk of progression to cervical cancer in women infected with up to 14 high-risk HPV genotypes. The new medical guidelines cite the potential for HPV false-positive test results as a limiting factor in the use of HPV testing in women under the age of 30. A marker such as E6/E7 mRNA may hold the potential to enhance the identification of HPV infections likely to resolve or progress to cancer.
Another example is the amplified human telomerase RNA component, or TERC, gene on chromosome arm 3q, which is reported to be associated with the abnormal changes which may progress to cancer. A study by the National Institutes of Health found the detection of 3q gain and amplification of TERC in routine Pap samples could assist in identifying low-grade lesions with a high progression risk and in decreasing false-negative cytological screenings.
New guidelines recommending less frequent screening intervals mean testing must be highly reliable to reduce the possibility that at-risk women are missed between screens. Novel molecular markers may help improve the detection of women at risk for progression to cervical cancer.
Some may argue that the new ACOG, ACS and other cervical cancer screening guidelines will detect the majority of at-risk women. We should not be content with settling for identifying a majority of at risk women; rather, we should constantly reassess the availability of useful tests to see if we can improve reliability. We should recall that many tests now considered standard of care, from HPV to HIV testing, were also once considered novel and lacked clear evidence supporting their use.
Assessing evidence that provides useful information to physicians is vital to the practice of medicine, and that is why is discovery and innovation is important, to help expand the physicians information base. It would be a tragic if a staunch commitment to evidence garnered by older tests and guideline-based medicine impeded the development and use of innovations, like molecular diagnostics, with the potential to enhance the detection and management of cervical cancer.
Dr. Jones is Medical Director, Cancer Diagnostics Services and Hematopathology for Quest Diagnostics. Quest Diagnostics offers a comprehensive menu of cervical cancer testing services, including Pap, HPV, TERC and E6/E7 molecular markers, and biopsy cervical cancer tests, affording physicians and patients with broad access in the United States.