Uterine Fluid Analysis May Aid in Early Diagnosis of Aggressive OC

Proteomic analysis — the characterization of all proteins present in a cell at a given time — in liquid biopsies from the womb may facilitate the early diagnosis of women who are genetically predisposed to develop high-grade ovarian cancer (HGOC), a study says.

The study, “Microvesicle Proteomic profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection,” was published in Molecular & Cellular Proteomics.

HGOC is the most aggressive type of ovarian cancer and is responsible for approximately 70% of all cases worldwide. Its poor prognosis and high mortality rates are directly linked to the stage at which it is first diagnosed: while patients at early stages of the disease have more than a 90% chance of surviving the next five years after diagnosis, those diagnosed at later stages, when the cancer has already spread, have much lower chances.

“Regrettably, [approximately] 75% of HGOC cases are diagnosed at late stage regardless of adherence to testing recommendations. This grim reality stems primarily from the lack of effective screening methods and of early-stage biomarkers,” the investigators saidf.

“If we could change this reality by detecting (ovarian cancer) at a curable stage, we could save many lives,” Keren Levanon, a physician-researcher at Chaim Sheba Medical Center in Israel and corresponding author of the study, said in a press release.

In an attempt to develop a new diagnostic test that could be used to detect early signs of HGOC, researchers led by Levanon and Tamar Geiger of Tel Aviv University used proteomic analysis in liquid biopsies from the womb to look for cancer signatures.

Because body fluids contain many proteins that can mask the presence of other cancer-related proteins, scientists decided to perform the proteomic analysis in microvesicles from the uterine fluid. These microvesicles are shed from cells and, unlike the fluid itself, do not contain plasma proteins that could mask the presence of cancer biomarkers.

The study (NCT03150121) included biopsy samples from 49 women with HGOC who were undergoing surgery and 127 controls (women who underwent surgery for reasons unrelated to cancer). They were divided into two groups: one devoted to the discovery of protein biomarkers and another to their validation.

To discover cancer-related proteins that could be used as biomarkers, researchers compared proteins found in uterine fluid microvesicles from 12 women with HGOC and 12 controls. Data was then analyzed with machine learning algorithms designed to look for patterns that would allow researchers to distinguish among the samples.

In all, 8,578 proteins were found in microvesicles from patients and controls. From these, nine — Myosin-11 (MYH11), Calcium-activated chloride channel regulator 4 (CLCA4), S100-A14, S100-A2, Serpin B5 (SERPINB5), Involucrin (IVL), CD109, Nicotinamide N-methyltransferase (NNMT) and Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) — had a significantly different pattern in cancer patients than in healthy controls.

Afterward, researchers tested whether they would be able to distinguish cancer patients from healthy controls based on a diagnostic test incorporating the nine cancer-related proteins they had found. The test was performed in a group of 37 women with HGOC and 115 healthy volunteers.

Results showed the diagnostic test had nearly 70% sensitivity, correctly identifying 25 of the 37 women who truly had ovarian cancer; and approximately 76% specificity, correctly identifying three out of every four healthy participants. The performance of the new test clearly surpassed other tests based on proteomic analysis, which had less than 60% sensitivity.

“We believe that this work is the first step toward translation of the signature proteins into a clinical test, and envision that such a test will use simpler [mass spectometry]-based targeted assays and shorter analytical times. The sampling technique that we propose … is suitable for routine testing of healthy young women at high risk for HGOC, including women who have not undergone vaginal delivery,” the scientists concluded.