Stopping the silent killer

New liquid biopsy technique a powerful diagnostic tool for early detection of ovarian, endometrial cancer

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DANBURY, Conn.—A game-changing novel liquid biopsy technique, with the potential to save lives, could soon become the first early diagnostic tool for ovarian and endometrial cancer, according to Dr. John Martignetti, network director of the Laboratory for Translational Research at the Western Connecticut Health Network (WCHN) Rudy L. Ruggles Biomedical Research Institute. Martignetti and colleagues at both WCHN and the Icahn School of Medicine at Mount Sinai have published a report suggesting this liquid biopsy is not only accurate and cost-effective, but non-invasive enough to be performed in a doctor’s office.
The early detection of endometrial and ovarian cancers has been a focus for several years, and research is making great strides, says Martignetti, corresponding author. Progress is documented in a number of publications, including the December 2018 Cold Spring Harbor Journal of Molecular Case Studies, in an article entitled “Detection of endometrial pre-cancer by a targeted gynecological cancer liquid biopsy.”
The report highlights the potential of this liquid biopsy technique, as there is no screening test for either ovarian or endometrial cancer.
“Early detection can save lives from cancers typically known as silent killers because symptom onset is often too late for effective treatment,” Martignetti says.
The American Cancer Society estimates for ovarian cancer in the U.S. for 2019 are that about 22,530 women will receive a new diagnosis of ovarian cancer, with about 13,980 deaths from this cancer type. It also predicts roughly 61,880 new cases of cancer of the body of the uterus (uterine body or corpus) will be diagnosed, with about 12,160 women dying from such cancers.
While endometrial cancer has been on the rise due to the obesity epidemic, high blood pressure, diabetes and the increased use of estrogens, ovarian cancer is the deadliest of all gynecologic cancers, surpassing uterine cancer and cervical cancer, Martignetti says. But as technology has improved over the years, so have the chances of early detection.
“When we catch these cancers early, 90 percent will survive,” he adds. “We can essentially flip the survival rates on its head.”
Endometrial cancer is the most common gynecologic malignancy in industrialized countries, and both its incidence and its associated mortality are increasing, the journal article states. The liquid biopsy is becoming an important transformative precision oncology tool, but barriers intrinsic to blood sampling have limited its use in early cancer detection.
“We hypothesized that using a more targeted sample for analysis—namely, a uterine lavage—should provide a more sensitive and specific diagnostic test for endometrial cancer,” Martignetti writes. “Using a custom 12-gene endometrial cancer panel, molecular analysis of uterine lavage fluid from an asymptomatic 67-yr-old female without histopathologic evidence of premalignant lesions or cancer in her uterine tissue, revealed two oncogenic PTEN mutations.”
Ten months later, the patient returned with postmenopausal bleeding and a single microscopic focus of endometrial cancer. DNA isolated and sequenced from laser-capture micro-dissected tumor tissue revealed the same two PTEN mutations—highly unlikely to occur by chance, alone.
“This case provides the first demonstration that future, tumor-specific mutations can be identified in an asymptomatic individual without clinical or pathologic evidence of cancer by using already established sequencing technologies, but targeted sampling methods,” according to Martignetti. “This finding provides the basis for new opportunities in early cancer screening, detection and prevention.”
Researchers over the past several years have recently explored the use of a uterine lavage to detect endometrial and ovarian cancers, he says.
Indeed, “sequencing cellular and cell-free DNA (cfDNA) isolated from uterine lavage fluid in a prospective study allowed detection of 100 percent of all endometrial cancers, including even microscopic stage IA cancers,” the article states. “The ability to detect microscopic-sized cancers by this targeted sampling approach immediately suggested the potential for early cancer detection and a broader-based approach toward endometrial cancer screening and prevention.”
“This illustrative case provides the first demonstration that future, tumor-specific mutations can be identified in an asymptomatic individual without clinical or pathologic evidence of cancer,” Martignetti notes.
If the uterine lavage and molecular analysis could be performed in-office, it would avoid the time and costs associated with uterine sonography and the costs, pain, discomfort, risks, time and need for anesthesia associated with an in-operating room hysteroscopy, he adds.
 “At the very outset of the patient care spectrum, precision oncology offers the holy grail—early cancer detection with the possibility of prevention,” Martignetti writes. “Our case report highlights the fact that although the opportunity exists, there remains an unexpected but surmountable bottleneck in immediately translating these findings to patients.
“In general, early detection would have marked benefits on patient survival, quality of life and health-care costs,” he tells DDNews. “We now need to establish the road map detailing the steps leading from pre-cancer to malignancy; and the converse, preventing pre-cancer from developing into malignancy, so that we can make the giant leap from laboratory to clinically relevant prevention and detection of earliest cancers.”
Martignetti and his colleagues have already begun a new study on 1,000 women with symptoms related to ovarian and endometrial cancer, with results expected before the end of the year.
“We would like to think that 20 years from now, with a liquid biopsy tool in place, an ovarian or endometrial cancer diagnosis will no longer be a death sentence,” Martignetti concludes.

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