Expert Discusses Treatment, Histogenesis of Gynecologic Cancers

Jianyu Rao, MD

Pathology in ovarian and endometrial cancer has evolved in recent years, but there is still work to be done, explained Jianyu Rao, MD.

While there is some overlap between endometrial and ovarian cancer, there are some key distinctions in the histogenesis of these tumor types, Rao said. Endometrial cancer can be classified as Type I endometrial tumors or Type II serous cancers. Testing for mismatch repair deficiency (dMMR) and microsatellite instability (MSI), which can be present in endometrial tumors, are recommended to determine whether patients will benefit from PD-1 inhibitor therapy.

For example, pembrolizumab (Keytruda) is the first agent to be FDA approved based only on tumor genetics, not the location of the tumor itself. The PD-1 inhibitor was granted an accelerated approval in May 2017 for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-high (MSI-H) or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

Meanwhile, the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) are indicated for previously treated patients with ovarian cancer who harbor BRCA mutations. The 2 agents, as well as a third PARP inhibitor, niraparib (Zejula), also have approved indications for maintenance therapy in ovarian cancer, regardless of BRCA status.

OncLive: What are some key points you would like to talk about from your presentation?

How have these efforts evolved?

Would you say that testing for somatic and germline mutations has been incorporated into routine clinical practice?

What other mutations have been identified besides BRCA1 and BRCA2?

Across gynecologic cancers, what are some other molecular abnormalities that researchers are exploring?

What changes do you anticipate in pathology in ovarian cancer in the next few years?

You were asked a few questions by the audience following your presentation. Can you touch on some of them?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Rao, professor and chief of Cytopathology, University of California, Los Angeles, discussed the evolution of pathology in gynecologic cancers.Rao: The main topic of my presentation is about how someone can develop ovarian cancer, mainly the histogenesis, which means where the cells divide from. 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. In the last 10 or 20 years, there have been tremendous improvements in understanding the disease process, specifically where the cancer comes from. A lot of that has been learned from the people who have carried the genetic mutations, such as BRCA1. From that population, we learned about some precancerous conditions and how that cancer evolves. I would say so. From a pathologist's perspective, when we give the diagnosis of ovarian cancer to our clinical colleagues, they have very good algorithms on how to approach genetic testing and to ensure there are no germline mutations.The only one that we really pay attention to are the genes that relate to mismatch repair in ovarian cancer and other tumor types, such as endometrial cancer and colon cancer. Endometrial cancer and ovarian cancer have some overlaps, but cervical cancer has a completely different histogenesis that is usually related to HPV infection. Endometrial cancer typically has 2 categories: one is associated with high estrogen and the other is with low estrogen. Ovarian cancer, on the other hand, seems to be associated with estrogen levels, but also to the specific gene functions.We are probably changing quite a bit in the practice. We will not only look at the microscopic change, which is very classic and traditional; we will probably be incorporating more molecular testing. This includes analyzing not only the genes associated with certain behavior, but also treatment response. This will become an important part of routine practice. On top of that, I’m hoping that someday we have the mechanisms to treat cancer, but also prevent the ability for people to develop cancer. There was one discussion about having an understanding of the relationship with the genes and understanding of histogenesis: is there a way we can improve our approach to detecting cancer early? One thing that we see here is that we need to better understand the genes that are involved in the more sporadic cancers.

After that, we can develop noninvasive ways to detect cancer. Researchers from Johns Hopkins Medicine have developed very interesting algorithms for analyzing the proteins and the genes together to help them improve the early detection process. But, we still have to wait and see whether that can be proved to be clinically useful or not. So, we haven't gotten there yet, but it's a good start.

Sorscher, S. The importance of distinguishing sporadic cancers from those related to cancer predisposing germline mutations [published online June 4, 2018]. The Oncologist. 2018. doi: 10.1634/theoncologist.2017-0681.