New Technologies Will Make Early Diagnosis of Ovarian Cancer Possible

Many new and effective drug options have been added to ovarian cancer treatment (see Recent Developments in Ovarian Cancer Treatments). As ovarian cancer survival continues to improve, there is also notable growth in the tools used for early detection along the way. To date, no effective screening method for early ovarian cancer diagnosis has been accepted.

To make developments in early ovarian cancer diagnosis more understandable, Medscape contacted Associate Professor Dr. Rebecca Stone, an ovarian cancer specialist and gynecologic oncologist at Johns Hopkins University School of Medicine. We present a translation of this interview:

Ovarian Cancer Rates Have Declined in Recent Years. What Are the Likely Reasons?

The number of new cases in America has fallen over the past 20 years. Possible reasons appear to include:

• In the late 1990s, increased use of birth control pills,
• Precautionary removal of the ovaries in patients undergoing pelvic surgery (surgery on female reproductive organs),
• Women with a genetic predisposition to ovarian cancer receiving preventive measures such as risk-reducing gynecologic surgery.

Precautionary removal of the ovaries in patients undergoing pelvic surgery — which we call "opportunistic salfenjectomy" in medical language — was introduced about 10 years ago. It is a surgical tool for primary prevention of fallopian tube-ovarian cancer, removing both fallopian tubes instead of “tying the tubes” in women seeking permanent surgical infertility, or in women who have completed childbearing.

Early detection of ovarian cancer through a Pap smear performed during cervical cancer screening, with DNA tested for TP53 gene changes: what can you tell us about the new study showing that this may be possible?

The idea is that early events leading to the development of ovarian cancer, involving mutation can be detected by gene sequencing of genetic material collected during routine Pap smear screening for cervical cancers.

Samples collected in Pap tests are known to contain genetic material and cells shed from precancerous lesions thought to cause ovarian cancer, from the fallopian tubes where serous epithelial ovarian cancer predominantly begins.

P53 gene mutations are thought to occur early in ovarian cancer formation. Data indicate that these mutations actually arise in cells lining the fallopian tubes. On cervical fluid collected by Pap smear, polymerase chain reaction (PCR) -based DNA/gene sequencing can identify these p53-mutated cells shed from the fallopian tubes.

One strength of the study is its inclusion of a healthy control group. None of these people without ovarian cancer had p53 mutations detected in their Pap smear tests. A limitation is the small sample size. The findings will need confirmation in a large patient group.

The study also looked only for p53 gene mutations. Like other cancers, ovarian cancer is thought to arise largely when mutations accumulate in critical genes, resulting in uncontrolled cell growth and division. These genetic changes or mutations are acquired during a person's lifetime. There are therefore possible early genetic changes or mutations in addition to p53 mutations that ultimately lead to ovarian cancer. Detecting them together with P53 mutations may improve the sensitivity or detection rate of the screening strategy investigated by the authors.

In conclusion, this screening strategy may not prove effective for early detection of all histological subtypes of epithelial ovarian cancer or for non-epithelial ovarian cancers (epithelial ovarian cancer is the most common ovarian cancer subtype).

What Other Current Studies on Ovarian Cancer Diagnosis Should Doctors Know about?

Using circulating tumor DNA (ctDNA), liquid biopsies show promising results for detecting and managing cancer, including ovarian cancer. More studies are needed, however, to determine the minimum detectable tumor size or burden using ctDNA-based approaches. Large prospective studies are also needed to establish the clinical utility of ctDNA detection for early ovarian cancer diagnosis and its effect on patient outcomes.

DNA methylation is an early event in cancer development and can be detected in blood plasma samples from cancer patients. This year, at the American Society of Clinical Oncology Meeting (ASCO 2020), data were presented on the discovery and validation of candidate methylated DNA markers isolated from ovarian cancer tissues. The findings were subsequently evaluated in plasma from women with and without ovarian cancer.

In addition to blood, peritoneal fluid and uterine lavage are used to identify mutations in risk genes — TP53, BRCA1 and BRCA2. These bodily fluids may also serve as sources of tumor-derived material that can distinguish ovarian cancer patients from healthy individuals. 

More studies are needed to determine the specificity and sensitivity of other noninvasive tests for ovarian cancer diagnosis.

The American Cancer Society has stated that human papillomavirus (HPV) testing is preferred as an ovarian cancer screening tool. Why do they prefer HPV testing to the Pap test?

The American Cancer Society recommends beginning ovarian cancer testing (screening) at age 25. Women aged 25–60 should have HPV testing every 5 years. If HPV testing is unavailable, either a combined Pap and HPV test every 5 years or a Pap test alone every 3 years may be used.

HPV testing is widely available. An HPV test costs approximately 44 dollars (2014 United States unit price). A Pap test costs approximately 30 dollars (2014 United States unit price).

HPV testing is preferred to cytological testing (Pap) for several reasons.

• First, well-designed studies show that a single Pap smear has approximately 50% sensitivity for detecting a high-grade precancerous cervical lesion, which is less than optimal for a cancer screening test.
• Second, reliable cytology programs require substantial infrastructure, highly qualified personnel and a well-designed quality-control system, which has proved difficult and expensive to implement. This produces global differences in cytology-based cervical cancer screening programs.
• Third, although combined cytology and HPV testing is an option for screening programs, studies have confirmed that injury from adding a smear to HPV screening is limited.

Long-term Kaiser Permanente studies involving more than a million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with a negative HPV test were very unlikely to develop precancerous lesions in the following 5 years. The 5-year risk of uterine cancer or high-grade precancer following a negative HPV test was 0.14%, compared with 0.31% for women with negative cytology. The screening benefit of combined testing comes largely from HPV testing, not cytology.

In summary, HPV testing is preferred to cytological screening for cervical cancer, given its improved sensitivity for women, the opportunity for quality-assured automated testing and ultimately the possibility of reducing the overall number of lifetime screening tests.

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