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Ovarian cancer test exposes quiet killer

For women and their doctors, ovarian cancer is “the disease that whispers,” says Yale’s Gil Mor, M.D., Ph.D., associate professor of obstetrics, gynecology and reproductive sciences. In many cases, this deadly cancer grows silently, or sends out easily misread signs such as indigestion or bloating. If caught early, the disease has a 90 percent cure rate, but for most women the first sign of trouble comes when they are diagnosed with advanced, largely incurable tumors.

Trying to hear and heed that first whisper, Mor and colleagues have developed a new test for the early detection of ovarian cancer. Based on the levels of four cancer-related proteins in a sample of blood, the test accurately and sensitively picks out women with early-stage cancers.

The promising advance came from basic research in Mor’s laboratory, coupled with the work of Yale-New Haven Hospital clinicians in the Discovery to Cure program for ovarian cancer (see Out & About). The program was initiated two years ago to bring researchers and clinicians together to accelerate the application of basic research to the diagnosis and treatment of women’s reproductive cancers.

“This detection system, which could give a tremendous boost to early diagnosis of ovarian cancer, started out as absolutely basic science,” says Peter E. Schwartz, M.D., the John Slade Ely Professor of Obstetrics, Gynecology and Reproductive Sciences and executive director of the program. “Within the framework of the Discovery to Cure initiative, we were able to move the test quickly into our early detection program.”

Mor found the four proteins by a process of elimination, starting with 165 cancer-related candidate marker proteins. In collaboration with David C. Ward, Ph.D., then in Yale’s Department of Genetics and now director of the Nevada Cancer Center in Las Vegas, he used protein chip technology to measure each potential marker in blood samples from nearly 100 women, including newly diagnosed patients and healthy, age-matched controls. No one protein was found that could reliably distinguish between women with and without cancer, but further analysis revealed a set of four protein hormones whose combined profiles indicated with 95 percent accuracy which women had ovarian cancer.

The test is now being used experimentally in the Yale Early Detection Program for Ovarian Cancer, where it has delivered promising results under the direction of Thomas J. Rutherford, Ph.D., M.D., associate professor of obstetrics, gynecology and reproductive sciences, and Discovery to Cure’s clinical director.

For example, one young high-risk patient who had been previously treated for breast cancer elected to have her ovaries removed because she was concerned about the possibility of ovarian cancer. Although her ovaries appeared to be normal and she had no other signs of the disease, pathologists who examined the tissue after the surgery found a stage 1A cancer, “the earliest stage you can recognize,” says Mor. When blood that had been drawn from the patient before surgery was examined with the new test, it scored positive. “From 40 high-risk patients screened so far in this manner, we’ve had 3 positives who had all been shown to have cancer in the pathology lab.”

Despite its potential, the test is not ready for prime time: 95 percent accuracy means that 5,000 out of every 100,000 women tested would obtain a false-positive result. For widespread use, the screen needs to achieve more than 99 percent accuracy. Mor hopes to reach that benchmark by identifying additional protein markers, and plans are in the works to screen up to 1,000 more women in cooperation with the National Cancer Institute.

So far, Mor’s lab has been a wellspring of important clinical prospects in ovarian cancer. A few years ago he uncovered phenoxodiol, a new compound that is in Phase II clinical testing at Yale under a fast-track designation from the FDA. Now Mor is working on a personalized medicine approach that uses tumor samples from patients and laboratory tests to select the best course of chemotherapy for each individual woman.

“Whatever Gil can come up with in his lab,” Schwartz says, “we are happy to move quickly into our translational laboratory and then on into the clinic.”