New Progress Using Liquid Biopsies to Analyze cfDNA for Endometrial and Cervical Cancers

MSK scientist Britta Weigelt and MSK physician-scientist Sarah Kim

Dr. Britta Weigelt and Dr. Sarah Kim have used MSK’s own in-house liquid biopsy test, MSK-ACCESS, in research to find ways to improve prognosis and monitoring of gynecologic cancers.

Liquid biopsies have the potential to revolutionize cancer diagnosis and treatment decisions. Unlike biopsies that require removing tumor tissue, these tests use a simple blood draw to assess the molecular characteristics of cancer. Liquid biopsies can be done repeatedly and quickly, offering researchers a less invasive way to detect if a cancer has returned, watch how the disease is progressing, or predict which treatment may work best.

Liquid biopsies have been used primarily for lung, breast, and colorectal cancers. Recent research at Memorial Sloan Kettering Cancer Center (MSK) suggests these tests could soon be expanded to gynecologic cancers such as endometrial cancer (also called uterine cancer) and cervical cancer.

“Our resources and molecular tests for the monitoring of gynecologic cancers remains limited,” says MSK physician-scientist Sarah Kim, MD. “Given our collective experience in using methods for liquid biopsies in other cancer types, we have a unique opportunity to improve the lives of people with gynecologic cancers.”

Analyzing cfDNA for Cancer Clues

Liquid biopsies usually involve the analysis of cell-free DNA (cfDNA), which are small fragments of DNA circulating throughout the body. The DNA is found in blood plasma as well as other bodily fluids, such as saliva and urine. In people with cancer, cfDNA shed from dying cancer cells can be analyzed to yield valuable information about the disease.

Liquid biopsies are challenging for some gynecologic cancers because the tumors do not shed nearly as much cancer DNA into the blood.

Since 2019, MSK has used its own in-house liquid biopsy test, MSK-ACCESS®, to determine the genetic mutations (changes) driving the growth of a patient’s tumor. Doctors can use MSK-ACCESS results to sort patients into different risk categories or to choose a therapy that targets specific mutations. MSK-ACCESS has already provided important insights into several cancers, especially breast and lung cancers.

Liquid Biopsies for Endometrial and Cervical Cancer

MSK scientists have recently made progress in using MSK-ACCESS for endometrial and cervical cancers.

A pilot study led by MSK scientist Britta Weigelt, PhD, and published in Clinical Cancer Research showed that detecting mutations in cfDNA in the plasma of people with newly diagnosed endometrial cancer could help with prognosis (predicting outcome) and monitoring of the disease. Another study led by Dr. Weigelt and Dr. Kim is currently assessing the value of cfDNA as a molecular marker for cervical cancer.

The Challenge of Liquid Biopsies in Gynecologic Cancers

Liquid biopsies are challenging for some gynecologic cancers because the tumors do not shed nearly as much cancer DNA into the blood as some other cancers do.

“People with early-stage gynecologic cancers often have relatively small tumors, and they are usually confined to the abdomen,” Dr. Weigelt says. “Some of them also don’t spread through the blood as frequently as other cancer types. If they spread, it is often either through the lymphatic system or just directly, rather than traveling through the bloodstream.”

This makes detecting cfDNA from cancer cells — and distinguishing it from DNA shed into the bloodstream from normal cells — a major challenge.

However, in recent years, researchers have refined the tests to become more sensitive and adept at detecting these DNA fragments — like a stronger magnet pulling a needle out of a haystack. These advances have made it possible to pinpoint the scarce amounts of cfDNA from gynecologic cancers.

Results of cfDNA in Endometrial Cancer Study

The endometrial cancer study led by Dr. Weigelt examined cfDNA in blood samples from 44 patients newly diagnosed with endometrial cancer. The samples were taken before the tumor was surgically removed and afterward for over two years. MSK-ACCESS showed the more advanced the stage, the higher the cancer cfDNA levels.

In six patients whose cancer returned, changes in cfDNA mirrored disease progression and response to therapy shown by cells in the primary tumor. This provides evidence that the liquid biopsy may supply reliable information about whether the disease was advancing or starting to resist treatment. In two patients, it signaled that the cancer was coming back before the disease could be detected clinically.

“Our findings indicate that cfDNA analysis helps understand a patient’s prognosis as well as enables us to monitor the cancer progression and response to treatment,” Dr. Weigelt says. “As the next step, we are keen to take this forward to see which patient group would benefit the most from this approach. We’d like to see if it can be a valid test for predicting when endometrial cancer will recur — or even occur for the first time.”

Studying cfDNA in Cervical Cancer

Drs. Kim and Weigelt are now investigating cfDNA in cervical cancer. Despite advances in prevention, including the human papilloma (HPV) vaccine and the widespread adoption of screening guidelines, cervical cancer takes a major toll. Among gynecologic cancers in the U.S., cervical cancer is the third most diagnosed and the third leading cause of death.

“A lot of people think of cervical cancer as a problem of the developing world, but at MSK, we still treat many patients with cervical cancer,” Dr. Kim says. “And just like with endometrial cancer, we don’t have a good molecular marker that would show up in a blood test. More than one-third of women diagnosed with cervical cancer are at an advanced stage, when treatment options are limited.”

A new MSK study to assess the value of cfDNA as a cervical cancer biomarker has enrolled more than 50 people receiving treatment for the disease at MSK. In addition to looking at cfDNA levels and cancer-driving mutations, the study offers another avenue to explore. Could the liquid biopsy detect whether the cervical cancer is HPV-related — the most common subtype?

“A lot of cervical cancers are a direct result of being infected with a high-risk strain of HPV,” Dr. Kim says. “We want to see if the amount of virus in the cfDNA indicates whether the patient is at higher risk for recurring, or not responding to treatment. We’re tackling that question in this study as well.”

The MSK Advantage in Studying cfDNA in Gynecological Cancers

Drs. Kim and Weigelt say MSK has particular strengths that enable it to advance the research in this field — primarily the large number of patients treated with gynecologic cancer and the in-house availability of MSK-ACCESS. “Our team at MSK is embedded in a community of specialists who have been working with liquid biopsies for years, and we can capitalize on their expertise,” Dr. Weigelt says.

“[Chief of the Gynecology Service] Dr. Nadeem Abu-Rustum, MD, is very committed to pushing the research forward in gynecologic cancers,” Dr. Kim says. “There’s so much more to do to reduce the burden of these diseases on our patients.”

Research reported in this story was supported in part by an NIH/ NCI Cancer Center Support Grant (P30CA008748, MSK). Dr. Weigelt is funded in part by Breast Cancer Research Foundation and Cycle for Survival grants. Dr. Weigelt reports research funding from Repare Therapeutics, outside the scope of this study.