Understanding Molecular Classifications of Gynecologic Cancers

When it comes to gynecologic cancers, there are many genes and factors that are considered when doctors bring treatment options to the table.

Gynecologic cancer is not a singular disease, but rather a group of malignancies — each of which has subtypes that vary by their molecular makeup. Knowing the disease subtype may lend insight to the ideal treatment, explained Dr. Michael D. Toboni.

Toboni is an assistant professor in the Department of Gynecologic Oncology at the University of Alabama at Birmingham. At the recent CURE® Educated Patient® Gynecologic Cancers Summit, he discussed the molecular classification of ovarian, endometrial and cervical tumors.

“There are different factors and different genes that are expressed that allow us to give different treatments … which is why molecular classification is so important in this day and age,” Toboni said during his presentation.

Ovarian Cancer

Toboni explained that there are three different types of ovarian cancer. The most common one is epithelial ovarian cancer, which makes up approximately 95% of ovarian cancer cases, he said. This subtype of ovarian cancer originates on the surface cells of the fallopian tubes. Stromal ovarian cancers, however, come from the hormone-producing cells of the ovary, while gem cell cancers — which typically affect teenagers and women under the age of 30 — occur in the reproductive cells.

Genetics can play a major role in a person’s risk of developing ovarian cancer, Toboni mentioned.

“Approximately 25% of patients with ovarian cancer have a genetic mutation that led to the development of that cancer,” he said. “Specifically, BRCA1 and BRCA2 are the most common risk factors. BRCA1 has about a 40% risk of development of ovarian cancer, and BRCA2 has about a 20% risk.”

Patients who may be at risk should undergo cascade testing to determine if they have a BRCA mutation. If so, they may be able to undergo preventative surgeries to remove gynecologic organs and eliminate their risk for this type of cancer.

However, once someone is diagnosed, the most important type of molecular classification testing they should undergo is homologous recombination deficiency (HRD) testing.

“When we have a deficiency or we do not have homologous recombination, which what happens is we have an incorrect repair of the DNA, and that incorrect repair when it is replicated, can cause cancer to happen. The reason that cancer ends up happening is not because we're able to fix the double-strand break, but because we do so in a non-efficient way,” Toboni said.

The PARP enzyme, Toboni explained, is the “non-efficient way to fix the double-strand breaks.” Now there are drugs called PARP inhibitors that block PARP so that the cancerous DNA is not replicating at all, and the cell dies.

“So, what the PARP inhibitor is doing is stopping that enzyme from repairing your DNA in a poor way,” he said.

Endometrial Cancer

Similar to ovarian cancer, there can be genetic causes at the root of an endometrial cancer diagnosis. In this case, it is most commonly a condition called Lynch syndrome, which, according to the Centers for Disease Control and Prevention, is a hereditary condition that predisposes people to colon, endometrial and other cancers.

Lynch syndrome-related cancer may have DNA mismatch repair deficiency (dMMR) and microsatellite instability (MSI or MSI-H). dMMR occurs when DNA strands cannot be properly replicated, leading to mutations. These mutations result in MSI-H cancers.

“Those are common molecular classifications that we now have therapies for,” Toboni said.

Those drugs include Jemperli (dostarlimab-gxly), approved in August 2023 to be given in combination with chemotherapy, and Keytruda (pembrolizumab), which was approved in 2022.

Cervical Cancer

When discussing cervical cancer, Toboni opened by stating that these cancers are 100% preventable thanks to the advent of the human papillomavirus (HPV) vaccine.

After a person receives a diagnosis of cervical cancer, it is important that clinicians test patients’ disease for their combined positive score (CPS), which is a way of measuring the number of PD-L1 cells.

PD-L1 is a protein that can be found on both normal and cancerous cells. According to the National Cancer Institute, it acts as a brake to stop the immune system from finding and attacking the cells.

Patients whose disease is PD-L1–positive tend to have the best outcomes with immunotherapy drugs that block the PD-L1 pathway.

“If you had a PD-L1 combined positive score above 1, you did very well if you received (Keytruda plus chemotherapy), in comparison to not receiving (Keytruda),” Toboni said.

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