Getting to the Root of Better Gynecologic Cancer Treatment

In recent decades, researchers have gained a much better understanding of how gynecologic cancers develop, especially for women who carry genetic mutations.

“A lot of that has been learned from the people who have carried the genetic mutations, such as BRCA1,” said Jianyu Rao, M.D. “From that population, we learned about some precancerous conditions and how that cancer evolves.”

Rao, a professor and chief of Cytopathology at UCLA, sat down with OncLive, a sister publication of CURE, to discuss current treatment and understanding of gynecologic cancers.

“If we better understand the histogenesis, we can better understand cancer detection and approaches to eventually decrease the risk of having a very late-stage cancer. All of this would allow us to do better on the treatment side,” he said.

Histogenesis is the process that cells undergo when they differentiate into tumors, organs or even cancer. Understanding and catching this early — especially for ovarian cancer, which is typically diagnosed in the later stages — can improve outcomes and provide for more individualized treatment.

The molecular abnormalities of each gynecologic cancer differ. For example, there are two categories of endometrial cancer: one that is associated with high estrogen levels and one that is associated with low levels. Meanwhile, ovarian cancer is associated with estrogen levels, but also gene functions as well. And lastly, cervical cancer is typically associated with HPV infections.

While there is some overlap between the molecular abnormalities of endometrial and ovarian cancers, their treatment options vary. For example, testing for mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) in tumors, which can be present in endometrial tumors, are recommended to determine whether patients will benefit from PD-1 inhibitor therapy.

Therefore, patients with unresectable or metastatic, MSI-high (MSI-H) or dMMR solid tumors, such as endometrial cancer, that have progressed after prior treatment and who have no satisfactory alternative treatment options may be eligible for treatment with Keytruda (pembrolizumab), an immunotherapy agent.

“The only (mutations) that we really pay attention to are the genes that relate to mismatch repair in ovarian cancer and other tumor types, such as endometrial and colon cancer,” Rao said.

For ovarian cancer specifically, there are three PARP inhibitors for the treatment of women with BRCA mutations — Lynparza (olaparib), Rubraca (rucaparib) and Zejula (niraparib). Moving forward, Rao said that the way genetic testing is done may change for ovarian cancer.

“We will not only look at the microscopic change, which is very classic and traditional; we will probably be incorporating more molecular testing,” he said. “This includes analyzing not only genes associated with certain behavior, but also treatment response. This will become an important routine practice. On top of that, I’m hoping that someday we will have the mechanisms not only to treat cancer, but to prevent the ability for people to develop cancer.”