Cervical cancer was once the number-one killer of women in the U.S. That all changed when the Pap test went into widespread use in the 1940s. As part of the test, clinicians take cells from the cervix — the cylinder of tissue between the vagina and the uterus — using a broom-shaped Pap brush. The cells are then analyzed under a microscope for abnormalities that could be a sign of cancer. The test can be done as part of a routine checkup, and in the decades since its introduction, cervical cancer diagnoses and deaths have plummeted by more than 70 percent.
Now, the Pap test is being adapted to screen for two other gynecological cancers that have overtaken cervical cancer as the most lethal malignancies: ovarian and endometrial cancer (cancer of the lining of the uterus).
“Almost 90,000 women are diagnosed with endometrial or ovarian cancer in the U.S. every year. About 25,000 women a year die from these diseases, and we don’t have any screening tests approved for them,” says Amanda Fader, director of gynecologic oncology at Johns Hopkins Hospital in Baltimore.
Fader is among a wave of researchers now focusing on screening applications called mutational diagnostics, that is, tests that help diagnose cancer by identifying cancer-related gene mutations. Fader and other Hopkins researchers have developed a gene test, dubbed PapSEEK, that analyzes DNA in fluid collected during, or alongside, a routine Pap smear. The PapSEEK test looks for changes in 18 genes — known as driver mutations — that commonly occur in endometrial or ovarian cancer. Their results, published March 21 in Science Translational Medicine, show promise for the use of mutational diagnostics in cancer screening.
The PapSEEK gene test found up to 63 percent of 245 known ovarian cancers and up to 93 percent of 382 known endometrial cancers in a sample of 1341 women. And the screen yielded just 1.4 percent false positives in women who didn’t have cancer. Still, it may be years before the test is ready for primetime.
The goal of a good cancer screening test is to detect an abnormality as early as possible, Fader says. The less invasive the test, the better. The test should also yield minimal false positives to avoid additional unnecessary testing. Currently, however, there are no screening tests or exams that meet these requirements for endometrial or ovarian cancer.
Up to three out of four endometrial cancers are found at an early stage. For these cases, five-year survival rates are 70 to 90 percent. Early detection of ovarian cancer, however, is elusive. Only one in five cases are found at stage 1 or 2 when five-year survival rates are greater than 90 percent. For cases found at stage 3 or later, five-year survival can be as low as 28 percent.
“Early detection of ovarian cancer is like the holy grail of gynecologic cancers,” says Jane Meisel, an oncologist who specializes in breast and gynecologic cancers at the Emory Winship Cancer Institute in Atlanta and was not involved in the PapSEEK study.
In the study, Hopkins researchers first sampled cells with a Pap brush in the same way cells are collected for a Pap test. They analyzed the DNA of the fluids collected and identified 81 percent of the endometrial cancers in the study cohort, 78 percent of which were early stage, as well as 33 percent of the ovarian cancers, 34 percent of which were early stage.
When the researchers collected cells with a Tao brush, which reaches beyond the cervix to the lining of uterus, the test’s accuracy improved significantly. For a woman undergoing the screening, the longer brush might cause slightly more, albeit momentary, cramping and discomfort than a Pap brush. “But overall, the data shows that women tolerate it, and it’s only temporary,” says Fader.
The minimal pain brought real gains. The test with the longer brush identified 93 percent of the endometrial and 45 percent of the ovarian cancers. “We were expecting to see a pretty high sensitivity for the endometrial cancers [with the Tao brush] because you’re actually sampling the cavity where the tumor is,” Fader says.
The sampling location also helps explain why ovarian cancers are still hard to pick up with the Tao brush, she adds. The brush doesn’t sample cells directly from the ovaries but rather cells that might have made their way from the ovaries into the uterus.
“With some fallopian and ovarian cancers, cancer cells can shed through the fallopian tubes down into the [uterine lining],” says Fader. But as ovarian tumors grow, they can block the fallopian tubes and prevent cells from shedding into the uterus.
To capture more ovarian cancer cases, the team added a blood test to the screening regimen. They tested plasma samples for circulating tumor DNA (ctDNA), which typically gets into the bloodstream once cancer has reached a later stage. As a result, the test identified some cancers that PapSEEK did not. In total, the researchers detected 63 percent of the ovarian cancers using either the PapSEEK or the plasma test. Combining tests in this way, says Fader, could be the key to early detection of ovarian cancer. Future studies will aim to improve sensitivity of these tests.
“It’s an exciting idea,” says Meisel. “I imagine [further] studies will show that it makes sense for some populations, but not all.”