Roadblocks to Advancing Treatment of Rare Ovarian Cancers

It is difficult for advances to be made in rare cancers because there are fewer patients. This makes it more challenging to conduct clinical trials for these diseases. Rare ovarian cancers are no exception to this.

Can you tell me a little about the rare types of ovarian cancer and what is important to know about them?

In an interview with CURE, David M. Gershenson, M.D., professor of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center discusses the treatments available for some of these rare types, as well as what the future could look like.There are several types of ovarian cancer: malignant ovarian germ cell tumors, sex cord stromal tumors and then the rare types of epithelial tumors: ovarian clear cell carcinoma, low-grade serous carcinoma and mucinous epithelial ovarian cancer.

There are challenges and barriers to studying rare ovarian cancer. It's very difficult to conduct clinical trials because there are fewer patients. It sometimes can take a long time to accrue patients on a clinical trial. There is also not a lot of federal funding for trials of rare cancers in general. The pharmaceutical companies are not that interested, for obvious reasons related to revenue. So, there are many challenges in trying to make advances in the study of ovarian cancers that are rare.

What are the current treatment options for a patient with one of these rare ovarian cancers?

Also, some of these rare ovarian cancers have a number of genetic or genomic abnormalities. Unlike high-grade serous carcinoma which is the most common type, rare cancers have many abnormalities that are difficult to treat. These types have fairly specific genomic aberrations that can be, in some cases, treated with targeted agents. I think that the emphasis over the past few years has been, and in the next decade, will be on targeted agents, combinations of targeted agents, and, in some of these rare tumors, hormonal therapies. For instance, for granulosa cell tumors, a type of sex cord stromal tumor, as well as low-grade serous cancers, these are relevant. There are many different targeted treatments and new treatments that we'd like to study, but again it gets back to the challenges that we have in conducting clinical trials.It varies. For low-grade serous carcinoma, there have been first generation trials of MEK inhibitors. MEK is a gene that occurs in the MAP kinase pathway and we know that there are mutations of KRAS and BRAF that occur in that pathway. There have been a number of trials of these targeted agents, these MEK inhibitors. One has been completed, three have been done in the second-generation, the last of them is finishing accrual later this year. That's one major area of research.

Another treatment option for low-grade serous carcinoma is hormonal therapies. We know that low-grade serous carcinoma has many features in common with ER+ breast cancer. We are studying aromatase inhibitors in upcoming trials in the neoadjuvant setting, in the recurrent setting, as well as in the frontline setting for maintenance therapy.

Clear cell cancer is another area where there are a number of aberrations in the pathways. There's a great opportunity to study targeted agents in that area. There have been some trials and there will be future trials as well.

Do these rare types of ovarian cancers have symptoms or effects on the body that differ from the most common type?

The other thing I would mention for clear cell cancer is immune checkpoint-inhibitor treatments. There have been some very interesting responses in clear cell cancers with immune checkpoint drugs. And there will be future trials, which are currently in development, focused on the checkpoint inhibitors.No. Most of these rare ovarian cancers have symptoms that are not really differentiated from those of women who have the most common type, which is high-grade serous. Abdominal pain, bloating, those kinds of symptoms occur at the time of diagnosis.

Some of the patients with certain types live a very long time, because the diseases are indolent. That would be true for granulosa cell tumors as well as low-grade serous carcinomas. These patients may experience side-effects from treatment. It is all related to the quality of life that they may have. Not only from cancer, but from the many treatments.

Sixteen is a very young age to encounter cancer. Can you discuss some of the specific concerns for those patients?

One of the areas where we're really reducing the amount of treatment is a success story with malignant ovarian germ cell tumors. The average age at diagnosis is about 16 and up. Until the 1970s, most girls and women who had this type died of their disease. We had no good therapy. The introduction of Platinol (cisplatin) in the late 1970s completely transformed that area. Now the cure rate is 95 percent. However, these girls and women experience some of the side-effects of chemotherapy. Now, there's a big move, and a recent clinical trial, that focuses on reduction in the surgical treatment of germ cell tumors, as well as trying to completely get rid of chemotherapy in some patients who have early-stage disease.Late-effects and fertility are the two major concerns. Fortunately, for instance with germ-cell tumors and granulosa cell tumors, they are almost always unilateral, they only affect one ovary. In almost all of these patients, you can preserve a normal contralateral ovary and uterus, so you preserve their fertility. However, if the patients does receive chemotherapy, there's about a 15 percent rate, or frequency, of acute ovarian failure, making them infertile.

A big concern for many patients with ovarian cancer is the high rate of recurrence. Does that apply to these rare types?

Most young patients are able to preserve their fertility. We’ve conducted studies to show that many of these young patients can go on to have normal pregnancies and normal offspring. That's good news. Once we start to reduce the amount of chemotherapy we're using in these patients, that will be even better, because then we won't have to face that 15 percent frequency of acute ovarian failure.It is, unfortunately. All three of the rare epithelial types: clear cell, mucinous and low-grade serous are not very sensitive to the standard chemotherapy, which is typically Abraxane (paclitaxel) and Paraplatin (carboplatin). The recurrence rate in all three of those tumors are high, in the 70 percent range.

Fortunately, low-grade serous carcinoma, despite its insensitive to chemotherapy, is an indolent disease, as is granulosa cell. Patients can still live for many years. Clear cell and mucinous are fairly aggressive types. When they recur, they're very difficult to treat.

What would you consider to be key to advancing research on rare types of ovarian cancer?

We need a grass-roots advocacy movement to lobby not only Congress but the National Cancer Institute to put more emphasis on rare cancers, specifically rare ovarian cancers. The only way we're going to advance treatments is to conduct clinical trials that prove that one treatment is better than the other. We really need the help of our advocates in that fight.