Cosgrove_8002Laboratory research led by physician-scientists at The Ohio State University may pave the way for personalized endometrial cancer treatments that improve long-term survival.

Their efforts, which complement the landmark molecular tumor profiling completed by The Cancer Genome Atlas (TCGA) in 2013, may help identify cancers that have a higher risk of recurrence — so those patients can be treated more aggressively up front.

Current predictive criteria lack precision

Today, there are more endometrial cancer therapies than ever before, but there is limited evidence to guide treatment decisions based on the genetic makeup of an individual patient’s tumor. 

Data suggest that the features historically used to predict risk of recurrence — including histology, lymphovascular space invasion and myometrial invasion — are suboptimal due to lack of reproducibility and other factors. This makes it difficult for physicians to determine whether patients should undergo harsh adjuvant therapies, including radiation or chemotherapy, after surgery.

“When assessing a biopsy sample, what you see under the microscope may not reflect the tumor’s biologic behavior,” says gynecologic oncologist Casey Cosgrove, MD, assistant professor in Ohio State’s Department of Obstetrics and Gynecology. 

“A fair number of recurrences occur in women whose tumor was initially identified as low risk based on current stratification criteria, including stage and grade,” Dr. Cosgrove, an assistant professor – clinical at the College of Medicine, says. “And, unfortunately, the best chance for a cure is at diagnosis; if endometrial cancer comes back, the odds of survival are much lower.”

Pioneering research, promising results

To help overcome these challenges, Dr. Cosgrove aims to help create a cost-effective, clinically accessible test that could more precisely stratify tumors. In 2018, he and his colleagues — including internationally renowned uterine cancer researcher and geneticist Paul Goodfellow, PhD — published results of a multicenter study that assessed a simplified classification system for endometrioid carcinomas.

Their goal was to determine if the test, which combines Lynch syndrome screening and molecular risk stratification, could accurately sort tumors into four molecular subtypes. These were based on an analysis of mismatch repair defects (MMR), POLE mutations, loss of heterozygosity and TP53 gene mutation.

“After testing more than 1,000 tumor samples from an NRG Oncology biorepository, we correctly classified 94%,” Dr. Cosgrove says.

Specifically, their results showed:

  • Forty-nine percent of tumors were classified as copy number stable (CNS). Among these patients, cancer-specific mortality was 5%.
  • Thirty-nine percent of tumors were MMR deficient, and cancer-specific mortality was 7.6%.
  • Eight percent of tumors were identified as copy number altered (CNA), with a mortality rate of 19%. This molecular class has worse progression-free and cancer-specific survival and is associated with TP53 mutation and expression status.
  • Four percent of tumors were POLE mutant, with 2.6% mortality. Even though this group had improved outcomes, the differences were not statistically significant.

“We confirmed that this classification system provided important prognostic information to help predict risk of recurrence,” Dr. Cosgrove says. “For example, knowing that CNA tumors are more aggressive should inform treatment plans.”

Corroboration through increased data collection 

In a related initiative, Dr. Cosgrove is participating in the statewide Ohio Prevention and Treatment of Endometrial Cancer (OPTEC) study to screen cancer patients and their biological family members for Lynch syndrome. Even though Lynch syndrome is an uncommon cause of endometrial cancer, it predisposes women to many other types of cancer and runs in families.

“Not only are we collecting tumor samples to test for Lynch syndrome, we will look for other molecular markers just like we did in our previous study,” Dr. Cosgrove explains. “Long-term, this will also help us provide treatments tailored to each patient’s tumor subtype.”

Ohio State is also in the process of creating its own biorepository with a contemporary cohort of endometrial cancer patients.

“I’m hopeful our efforts will provide validation for emerging classification systems that can be used alongside current algorithms,” Dr. Cosgrove says. “If we can help make molecular risk stratification a standard of care, it may eventually help clinicians reduce the burden of endometrial cancer worldwide.”

 

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