Hormonal Maintenance Therapy Improves PFS in Low-Grade Serous Ovarian Cancer

David M. Gershenson, MD

Women with stage II to IV low-grade serous carcinoma of the ovary or peritoneum who received hormonal maintenance therapy after primary treatment had significantly longer progression-free survival (PFS) compared with women who underwent routine observation, according to a retrospective database study published in the Journal of Clinical Oncology.

“There was a very significant difference in PFS that favored the women who received hormonal maintenance and we believe that it is potentially practice changing,” lead study author David M. Gershenson, MD, said in an interview with OncLive.

The median PFS for the 133 patients who underwent routine observation was 26.4 months, compared with 64.9 months for the 70 patients who received hormonal maintenance therapy.

OncLive: Can you provide an overview of the study?

In his interview, Gershenson, a professor of gynecologic oncology at The University of Texas MD Anderson Cancer Center, discusses the results for the retrospective study and the next steps going forward.Gershenson: This is a retrospective database study of women who have this rare subtype of ovarian cancer. We analyzed a total of 203 women, 133 of whom had been treated with primary cytoreductive surgery for stage II, III, or IV, low-grade serous carcinoma, followed by platinum-based chemotherapy and then surveillance. We compared that to 70 women who had the same treatment surgery followed by platinum-based chemotherapy, but were then placed on hormonal maintenance therapy with one of the antiestrogens that are used for breast cancer, such as aromatase inhibitors or tamoxifen.

We found that when we analyzed their PFS there was a significant difference in PFS with the advantage for those women who received hormonal maintenance therapy. The median PFS was 65 months versus 26 months for the observation patients, respectively. We looked at overall survival (OS), which was not statistically significant, but there was significance related to OS when we used stratified log-rank test. That was the main finding of the study.

We had estrogen receptor (ER) expression in 76 patients. We also found that patients who had hormonal maintenance therapy had better outcomes by ER or progesterone receptor expression, which was a secondary finding in this study.

What are the next steps regarding this study?

I think the main message of this study was that there was a very significant difference in PFS that favored the women who received a hormonal maintenance therapy and we believe that it is potentially practice changing. We're in the process of trying to develop a randomized clinical trial to confirm our findings.We work through NRG Oncology, which is an NCI-sponsored cooperative group and we are trying to partner with international colleagues. The study that is in development is a randomized phase III study that would take the same patients with stage II, III, or IV low-grade serous carcinoma of the ovary or peritoneum. They would all undergo primary cytoreductive surgery followed by platinum-based chemotherapy and that generally would be carboplatin and paclitaxel although there are some variations on that theme.

This will be a 3-arm study. Two of the arms would have the surgery followed by chemotherapy, but then in 1 of the arms the patients would go on observation while the second-arm would receive hormonal maintenance therapy with letrozole until disease progression. There would be a third arm that would consist of surgery but instead of chemotherapy, it would go straight to single-agent letrozole hormonal therapy. What are the key takeaways for community oncologists?

One of the takeaways is that there seems to be a striking similarity between low-grade serous carcinoma and ER-positive breast cancer. Again, we first noted in 1 of our prior publications that women who have recurrent low-grade serous carcinoma do respond in some cases to antiestrogen therapy with tamoxifen or letrozole.

Another similarity with ER-positive breast cancer is that we also found in a prior publication a couple of years ago, that women who were 35-years-old or younger had a worse prognosis with low-grade serous carcinoma. That's also true of ER-positive breast cancer—young women tend to have a worse prognosis than older women. Now, we’re finding that there seems to be a third similarity—that high-risk, ER-positive breast cancer is not frequently treated with chemotherapy followed by hormonal therapy.

An additional similarity is that ER-positive breast cancer is not as sensitive to chemotherapy as other types of breast cancer, which is also true for low-grade serous carcinoma. That is 1 of the reasons that there has been a search for novel agents.

What challenges are there in this setting?

The other area that has been the subject of various studies has been antiangiogenesis, since bevacizumab (Avastin) seems to also have activity in low-grade serous carcinoma. Of course, in terms of targeted agents we've been involved in clinical trials that include MEK inhibitors. There's an ongoing NRG Oncology study with the MEK inhibitor trametinib (Mekinist).The obvious challenge is that this is a relatively rare cancer making the accrual of patients to clinical trials difficult. Because it’s so rare, the pharmaceutical industry has not been that interested in developing clinical trials.

What other research are you involved with?

The second challenge is we need to learn more about the molecular biology of genetics of low-grade serous carcinoma. We already know that the MAP kinase pathway seems to be prominent in the pathogenesis of low-grade serous carcinoma. We know that about 20% to 40% of tumors have KRAS-mutations. There are also a few NRAS and HRAS mutations and then about 5% have BRAF mutations, hence the study of the MEK inhibitors. We need to learn even more about the alterations that occur in the MAP kinase pathway and about the biology of this tumor that will hopefully lead us to even more options in terms of novel therapies.We are in the process of developing some hormonal therapy trials for women who have recurrent low-grade serous carcinoma. We are developing a trial for women who have such extensive newly diagnosed low-grade serous carcinoma, who would normally be treated with neoadjuvant chemotherapy. We're developing a pilot trial with a neoadjuvant hormonal therapy instead of chemotherapy for those patients.

Gershenson DM, Bodurka DC, Coleman RL, et al. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum [published online February 21, 2017]. J Clin Oncol. doi:10.1200/jco.2016.71.0632.