Challenges in the Treatment of Ovarian and Endometrial Cancers

Sanaz Memarzadeh, MD

All gynecological cancers are poorly understood, but the lack of knowledge about ovarian, which is the deadliest, and endometrial, which is the most common type, have the biggest impact on women, says Sanaz Memarzadeh, MD, PhD associate professor of obstetrics and gynecology and UCLA, the director of the Gynecologic Oncology (GO) discovery lab at the university. OncLive spoke with Memarzadeh on why these two gynecological subtypes are so challenging to treat and what future research is needed to further understand these diseases.

OncLive: Why do you think there is a lack of understanding about endometrial and ovarian cancers?

Dr Memarzadeh: There are several reasons why they are poorly understood. I see part of the challenge being that there isn’t enough funding being allocated to studying gynecological cancers. For example, ovarian cancer and uterine cancer together have almost as many deaths as prostate cancer. But if you look at federal funding that is being allocated to these diseases, prostate cancer gets more funding compared to both these diseases combined. Certainty ovarian cancer and endometrial cancer funding is way behind funding in breast cancer. The wonderful news is that we see major advancements being made in prostate and breast cancers. The majority of patients survive these tumors, and that is thanks to the wonderful research that is being done in the area. We hope to see the same in ovarian cancer and endometrial cancers. One way to facilitate that is to increase funding in this area. That will encourage more scientists to become interested in these studies and the research.

What are the biggest challenges in treating endometrial and ovarian cancers?

In ovarian cancer one of the major challenges is that clinicians don’t have early detection tests. The most common early detection tests, biomarkers and imaging, have not been proven effective in catching these tumors earlier. Part of the challenge in that I believe is that we have in some ways been looking in the wrong place. The most common and deadliest subtype of ovarian cancer, was for years thought to originate in the ovary, and was hence called ovarian cancer. But research by many investigators has demonstrated that likely the origin of this disease is in the fallopian tube and not the ovary. I hope that this discovery will facilitate finding this disease earlier. Because we don’t have good early detection tests, patients commonly present with advanced stage disease; stage 3 and 4. As surgeons we do extensive operations and try to peel off every bit of tumor and then we treat these patients with chemotherapy, but unfortunately the majority of them relapse, despite this aggressive treatment. So these are the challenges I see in treating ovarian cancer.

For endometrial cancer it is a little bit different. It is detected earlier because the majority of women present with bleeding. However, the incidence of it is actually on the rise and I think primarily this is due to a rise in obesity. One population who I find challenging to treat in this area and I think require more research are the growing number of patients who are diagnosed with endometrial cancer in a reproductive age. These women would like to keep their uteruses so they can have children, but with endometrial cancer that is often a challenge. Standard treatment still is to remove the reproductive organs, and hence these women don’t have a fertility option. The one option we do have for them is treating them with the hormonal therapy, progesterone. This treatment is underutilized in clinical practice. This is partly because don’t understand which patients will respond to this therapy.

A second category of patients that are challenging to treat are patients that already present with metastatic disease, or women who have recurrence of disease that is metastatic. These women could also be eligible for hormonal therapy. But there are similar challenges, we don’t know which patients the hormonal therapy will work in and who is going to have a positive response to this treatment.

What are the main goals of your research?

We are interested in modeling the disease in a way in the lab that we can then assess response to therapy in each of these disease models. And what we’ve learned through this research and through the work is that not all cells within the tumor are actually the same. For example, in our studies in ovarian cancer what we’ve learned recently is while the majority of tumor cells respond to the traditional treatment with chemotherapy, a small subset of cells within the tumor are actually resistant to this treatment. The challenge there is the cells that don’t respond to this treatment are the very cells that are armed with the capacity to reinitiate the cancer. This is the reason why these high-grade serous ovarian cancers recur so rampantly in patients, despite existing therapies.

Our work in endometrial cancer has primarily focused on how endometrial tumors may or may not respond to hormonal therapy. Just like tumors of the prostate and the breast, endometrial cancers are also hormonally regulated. Clinical studies and clinical practice show that hormonal therapy is widely used in prostate and breast cancer, but it is not commonly used in therapy of endometrial tumors. Why is that? Part of the reason is that we haven’t understood how progesterone hormone works and when it works, and why it doesn’t work sometimes. Through our research we’ve learned something very interesting; that hormone actually exerts its therapeutic effects through a small population of cells that surround the tumor. So it is not directly the cancer itself but supporting stromal cells that actually surround the cancer. These cells are a small subset of the tumor cells so they are commonly ignored to some extent. But as it happens those are the very cells through which this hormonal therapy exerts anti-cancer effects. So trying to understand how these cells operate, how is it that they cause cancer to regress, and why is it that in some causes this therapy doesn’t work, are important questions that we are trying to address in the laboratory with the hope of expanding hormonal therapy to patients diagnosed with endometrial cancer.

What further research is needed on this topic?

There is a lot that needs to be done and we need lots of scientists and clinicians to work on these areas and to work together to translate the findings from the lab to the patients. In ovarian cancer one of the challenges is in high-grade serous cancers, while most tumors respond to chemotherapy, a small subset of tumor cells with cancer initiating capacity and the ability to repopulate the cancer are not being treated with existing treatments. Through our work I envision a handful of therapies being moved forward that can be simply coupled with existing treatments in therapy of these patients diagnosed with high-grade serous ovarian cancers. We’d like to test these in clinical trials to determine if they are more effective. That would simply entail adding one additional treatment to already existing therapies and tailoring it the patient’s tumor.

In endometrial cancer the application of hormonal therapy I think can have a major and significant impact and can provide perhaps a much better tolerated treatment option for patients that could be candidates for these treatments.

Are there targeted therapy options on the horizon for the subtypes?

There are a lot of targeted therapies that are being tested for the patients. But what I’ve learned from my experience is that one size will not fit all. The right targeted therapy has to be given to the right patient. The best clinical trials in my opinion are clinical trials that are designed based on fundamental, solid, laboratory work that is been taken to the clinic to be tested in the patients. This requires a dialog between the science community and the clinicians. As a clinician-scientist, someone who both studies these diseases in the laboratory and also treats patients, I hope that through research done by my team, we are able execute some of these visions.