One of the difficulties with low-grade serous ovarian cancer is that a lack of data and research can make it difficult for doctors to know what is the most appropriate treatment.
One particularly contentious question is whether there is a benefit to having chemotherapy when newly diagnosed – or if the outcome will be similar with just an aromatase inhibitor like letrozole (a type of hormone inhibitor treatment (also known as endocrine therapy)).
In this interview Dr Stephanie Galliard discusses the results of a retrospective study at John Hopkins which looked at outcomes in women who had aromatase therapy without chemotherapy. This has led to a new clinical trial which will hopefully answer the question for good.
She also discusses her research to identify genetic markers to predict whether someone will be a good candidate for endocrine (hormone) therapy.
“We’ve known for some time that low-grade serous and high-grade serous ovarian cancer are very different. Predominantly high-grade serous ovarian cancer which is the most common epithelial type of ovarian cancer, 95% or more are associated with P53 mutations. However low-grade serous cancers account for approximately 10% of epithelial cancers generally don’t have P53 mutations and have a higher percentage of BRAF mutations and KRAS mutations.
Despite knowing this for sometime now, we generally have treated these cancers the same way. Surgery up front is the predominant approach, followed by chemotherapy.
The question has been should we be treating them the same way given their biology is different? We’ve known for some time now that these low-grade serous cancers were more likely to respond in the recurrence setting to hormone therapy than high-grade serous cancers. Because this only accounts for about 10% of ovarian cancers it can be hard to do studies so we’ve been relying on retrospective studies for how to manage the disease.
But there have been a couple of interesting studies that have come out in the past couple of years. One from MD Anderson that looked at patients who received endocrine therapy after surgery and chemotherapy – and they found that there was an improvement in how patients did when they received endocrine therapy versus not receiving it. And then there was a retrospective study out of Hopkins, lead by Dr Fader that monitored patients that had surgery – did not have chemotherapy but instead just had endocrine therapy and found that those patients did very well even though they had never received chemotherapy.
So the question now is, is chemotherapy needed in for the treatment of low-grade serous cancer. We also know from retrospective studies in the recurrence setting that these cancers have a poor response to chemotherapy – again lending some question as to whether we should be using chemotherapy at all.
I think it’s been a little bit of a moving target and different institutes have approached things differently, and part of it has also been personal preference. Standard of care has included chemotherapy and so that is still probably the most common approach but is being brought into question.
There is an NRG Oncology study that is going to be opening soon that is going to ask that question. So specifically patients diagnosed with low-grade serous cancer are going to be randomised to receive chemotherapy followed by endocrine therapy versus receiving endocrine therapy alone. And that will hopefully help us understand whether chemotherapy is required at all.
I would say that right now, that I personally have been tailoring and having a discussion with patients with the different options to whether or not to try to do chemotherapy alone, chemotherapy plus endocrine therapy or endocrine therapy alone. And I would say that generally I don’t use chemotherapy alone anymore. But there are still some patients that are opting to try and do everything with chemotherapy followed by endocrine therapy.
Now that we are potentially using endocrine therapy more, and particularly the two studies I mentioned before have looked at aromotase inhibitors (AI) for the treatment of this malignancy – I became interested in the question of whether aromatase inhibitors, which we know in breast cancer can lead to the development of oestrogen receptor (ER) mutations, whether we find similar mutations in gynaecological malignancies. And have identified that to a small percentage it does occur. But even though it only happens in a few percentage of patients it has very important clinical implications.
Sometimes these ER mutations are present at the time of diagnosis. Those patients are unlikely to respond to an aromatase inhibitor so you may not want to use an aromatase inhibitor for those patients. For those patients who are treated with an AI and subsequently develop the ER mutation the question remains as to whether further endocrine therapy may be beneficial. And in some cases we have seen that switching therapy to tamoxifen or fulvestrant for these low-grade serous gynaecological malignancies can be beneficial.
So we need to understand a little bit better how to approach these. We’ll certainly be learning from our colleagues who focus in breast cancer in these mutations but I anticipate that we may see more of these mutation emerging as we start to use aromatase inhibitors more in low-grade serous ovarian cancer.
The reason I became interested in this to begin with because I had a patient that we identified a mutation in, and in her particular case at the time this was just when mutations were emerging in breast cancer so we didn’t really know what to do. But we saw the mutation and we knew that her cancer had not responded to chemotherapy at all. And so we actually opted to try fulvestrant. And it has been over four years and she remains on fulvestrant and is doing well. So based on that, that’s one particular case – we now have identified further situations where patients are responding to endocrine therapies.
The type of mutation that is present may determine whether further endocrine therapy is beneficial.”
– Dr Stephanie Galliard, M.D., Ph.D, Director of Gynecologic Cancer Trials, Assistant Professor of Oncology, John Hopkins Cancer Center