In 2019 Cure Our Ovarian Cancer was privileged to sit down with world renowned low-grade serous expert Dr Gersheson from The University of Texas MD Anderson Cancer Center. In Part One of our two part series, we discuss low-grade serous carcinoma treatments.
Jane: Thank you for joining us for part one of our Low Grade Serous Ovarian Cancer series. My name’s Jane, I’m from Cure Our Ovarian Cancer, and I’m joined by Kristen, another low grade serous ovarian cancer patient, and we’re very honoured to have Dr Gershenson with us. Dr Gershenson is based at MD Anderson and is widely considered the world expert in low-grade serous carcinoma so we are honoured to have you with us.
Low-grade serous carcinoma treatments
Jane: I thought that we could start with a basic overview of treatments. So what treatment options are available for someone newly diagnosed with low-grade serous carcinoma?
Dr Gershenson: Thanks very much Jane, so the options that are, I think, at the top of the priority list based on what we’ve learned over the last decade or so, would include primary cytoreductive surgery.
Some women whose tumours are not optimally resectable for primary surgery might be triaged in some instances to neoadjuvant chemotherapy.
But hopefully most women are candidates for cytoreductive surgery
And then the two systemic options that are most widely used today world-wide for systemic therapy, post operatively would include paclitaxel, carboplatin chemotherapy for six cycles followed by letrozole maintenance therapy.
Or some centres are using simply letrozole monotherapy without chemotherapy at all.
And so those are the two strategies that I think are most widely used.
There are still some physicians that simply recommend chemotherapy, alone without any maintenance therapy after.
The other strategy that’s used by some of the Europeans is chemotherapy combined with bevacizumab without letrozole maintenance following.
But of course for stage one patients where it’s confined to one or both ovaries the standard treatment would be surgery alone.
Jane: Brilliant. And you mentioned earlier in your talk today that letrozole , as a first option for a hormone inhibitor although there isn’t strong evidence, the feeling is that letrozole has an advantage over other hormone inhibitors.
Dr Gershenson: Yes the evidence is not conclusive at this point but there certainly are clues and suggestions that letrozole would be the first priority drug and may be more effective than drugs like tamoxifen or fulvestrant or some of the other anti-oestrogen hormones.
Surveillance and scans
Jane: And once someone has completed their initial treatment what’s your general recommendation in regards to surveillance? So what type of scans and blood tests and how often do you recommend them?
Dr Gershenson: Of course in our setting since we are usually recommending for patients the chemotherapy followed by letrozole maintenance the letrozole is given indefinitely as long as the patient does not demonstrate any disease progression and is tolerating letrozole well, then we would recommend it indefinitely.
Our routine would be, during the first year, although there is no absolute standard, to recommend that they have CT scans and CA-125 every three months, and then for the second year usually a little bit less frequently, maybe three times annually.
And after that usually twice a year and that’s pretty indefinite.
At some point, if someone’s done well for five years plus, we certainly could go to annual visits. But we try to minimise it but on the other hand, particularly in the first two years we want to do the scans every three to four months. But again you will find variation from one physician to another so I don’t want to suggest that everyone recommends that.
Jane: And the decision to choose a CT scan over an MRI, is that primarily a cost based decision, or are there other factors at play with that?
Dr Gershenson: I think the issue of CT versus MRI is not so much cost, although it’s a little bit, but it’s mainly, I think the evidence is that CT may be somewhat better than MRI not tremendously better, but somewhat better.
PET CT is very expensive and is also difficult many times, at least in the United States, to get authorisation from insurance for patients and also we don’t think it adds that much for patients. But we do know form our studies so far, some patients their CT is better than PET and in some patients it may be exactly the opposite, where PET is superior to the findings we see on CT. But in general we’ve used CT as a standard.
Kristen: If a scan does detect a recurrence, what is your current preferred treatment?
Dr Gersenson: Well it depends on many factors including the age of the patient, particularly the distribution of the disease, are we talking about one site, or multiple sites? There is the randomised study for secondary cytoreduction for ovarian cancer in general, that casts a shadow on whether that’s really helpful to consider a second surgery but that does not necessarily apply to low-grade serous since there were very few patients who had low-grade carcinoma in that trial. So I think the first option to at least consider and discuss with the physician would be secondary surgery.
On the other hand, if there is carcinomatosis with scattered small implants, that’s probably not an ideal setting for recommending surgery.
Whether surgery is recommended or not, there would certainly be some type of systemic treatment recommend and that would vary, depending on the patient’s past history but if it’s their first recurrence then if they haven’t had hormonal therapy that would probably be our first option.
If they recur or develop disease progression while they are on the hormonal therapy then we would look elsewhere. A MEK inhibitor? Maybe go back to chemotherapy. Of the chemotherapy agents pegylated liposomal doxorubicin is generally well tolerated by many patients, although not all. And we have seen patients who have had long periods of stable disease, and even occasional patients who have responded to that agent.
So there are many options and I think you have to base the recommendations on many factors, including prior treatments.
The role of diet
Jane: Fantastic. And there’s an international low-grade serous ovarian cancer Facebook group and they put together a list of questions and voted on them, and these were the most popular ones that we would like to know the answers to.
What are your thoughts on low grade serous ovarian cancer and sugar/glucose? Do you think it’s involved in cancer growth, and your thoughts on using metformin as a complimentary therapy?
Dr Gershenson: Well I think those are great questions, for both I don’t think we have the answers. You know there are a million diets out there that are being recommended on the internet but there is no scientific information that we’re aware of, that modifying diet is going to have a direct impact on the clinical course of the patient.
That’s not to say that we don’t promote allowing patients and encouraging patients to follow their own intuition in what they want to do.
One of the things that comes up is the relationship between oestrogen exogenously and low-grade serous. And one of the questions that we are frequently asked is related to soy products.
My answer to that is, I think in moderation I think it’s fine. I don’t think we have any absolute evidence that it’s harmful. But I think every individual has to make her own decision about that.
There are some studies in breast cancer that show that low fat diets are possibly helpful but in low-grade serous in general, I don’t think we know.
So that results in many patients finding their own balance in terms of what they want to do with their diet. But as a routine we do not recommend any special diet.
The issue of sugar and sugary drinks, there was just an epidemiological study that was published recently that said that patients who ingest more sugary drinks have a higher risk of cancer in general. It wasn’t specific to ovarian cancer or certainly not to low-grade serous.
So there may be a relationship between sugar and cancer but again, I don’t think we have enough information to make strong recommendations for patients.
Jane: And in regards to Metformin?
Dr Gershenson: For Metformin again, we don’t have any direct evidence that it’s beneficial. It’s general well tolerated by patients. We do have some evidence from endometrial cancer, that combining it with letrozole for instance, may be somewhat helpful. SO I don’t have any problem with patients considering it and taking it along with letrozole or another medication or by itself but we don’t really have enough information currently to know how effective it is.
Kristen: What about the role of immunotherapy in low-grade ovarian cancer? Is that an effective treatment option?
Dr Gershenson: I think it may be. In ovarian cancer in general we are just scratching the surface in terms of knowing how effective immunotherapy will be and that’s doubly true of a subtype like low-grade serous because it’s so rare.
KK Wong my colleague is studying immunotherapy in the laboratory. He has found that there’s an immune regulatory protein called B7H4 that is over expressed in both high-grade serous and low-grade serous ovarian cancers. And that maybe, this protein is very similar in some ways, although not altogether, to CTL4 and to PD1 and PDL1. And that if you can develop an antibody or an inhibitor of that protein that may result in better immunotherapy.
He has now in addition to other funding provided a Department of Defence grant to help study that.
There is also a Phase 1 trial at MD Anderson in all solid tumours with an antibody to that protein and they have one ovarian cancer patient in that study whose had a very significant partial response to the antibody, to B7H4.
We don’t know at this point whether that patient has low-grade serous or high-grade serous but this is an area that we are very interested in pursuing and hopefully can maybe even develop a trial for the B7H4 antibody in low-grade serous either as a single agent or possibly even combined with something like a MEK inhibitor.
Reducing risk factors for low-grade serous carcinoma
Jane: Brilliant. And one of the other things that women wanted ot know is, aside from taking hormonal therapy, either on its own or after chemotherapy, are there any other options or things they can do to reduce their risk of recurrence?
Dr Gershenson: Great question. Well, again, I think it gets back to the relationship with oestrogen. We still see some women who for instance had a borderline tumour initially and they have a bilateral salpingo-oophorectomy with removal of both ovaries and their physicians recommend oestrogen replacement therapy, well a few years later they may go on to develop a low-grade serous carcinoma and we think that there could be a relationship and it’s very possible that the oestrogen replacement therapy stimulated somehow the cells to transform from borderline to low-grade serous.
So that’s one thing that women can do selectively if they fit in that category. But in terms of lifestyle changes or other things, we know the birth control pill in general can reduce the risk of ovarian cancer, in general, not necessarily, low-grade serous, by 50%. So when women are young, that may be an option to consider.
Other than that we don’t yet have anything that we know of. For those women who have a serous borderline tumour initially and also have non-invasive peritoneal implants they’re at a 20-50% lifetime risk of subsequently developing low-grade serous carcinoma
One of the theoretical considerations would be to just take letrozole in order to protect them from developing subsequent low-grade serous carcinoma.
We don’t know if that will actually be effective. It’s not been done in a clinical trial and if one were to do a clinical trial it would literally take 20 to 20 years to get the results so that’s not something that is of great interest related to the length of trial.
But theoretically there are some women who have that diagnosis of serous borderline tumor and also have invasive peritoneal implants, who make a decision regardless of the lack of evidence to take aromatase inhibitors to see if that would protect.
Other than those issues relating to oestrogens and anti-oestrogens we don’t really have meaningful information at this point.
But I hope that we will have more epidemiological information in the future that will allow us to make better decisions.
Reducing the risk of recurrence
Jane: And in regards to women with low-grade serous ovarian cancer who say have had chemotherapy or are on hormone maintenance therapy on its own, is there anything they can be doing to reduce the risk of recurrence?
Dr Gershenson: Not really. Again they may be deciding to ingest various diets but we don’t really know what the impact of that is.
Whether things like exercise are probably beneficial? But again the evidence is not quite there at this point.
I am not aware of any other lifestyle changes they can make actively to have an impact on their future clinical course.
Role of genetic profiling
Kristen: What role does genetic testing have with low-grade serous? I mean there’s not mutations but are there some to look out for?
Dr Gershenson: So we believe that women with low-grade serous carcinoma have a low risk of having a BRCA mutation, and I’m talking about a germ line mutation from a blood test. But it’s not zero, again in one of the tests it was 6% of the low-grade serous patients tested did have a BRCA 1 or 2 mutation.
So we are currently, though we didn’t in the past, we have changed our recommendations to recommend genetic testing knowing that it’s a low risk of having a positive value.
But the other issue is the genomic profiling of the tumour. Again we are increasingly recommending that earlier in the course of the disease, even at the time of initial diagnosis, to store that information for future reference in case they do need treatment, later on, you’ll already have that information.
Jane: And are there any promising low-grade serous carcinoma treatments on the horizon?
Dr Gershenson: Well the one in addition to MEK inhibitors, and hormonal therapies, and we have to learn more about both. I think combinations with MEK inhibitors will be very much at the forefront over the next decade and that could be in combination with hormonal therapies, or CDK4/6 inhibitors, or other drugs like bevacizumab.
The other area of interest right now is CDK4/6 inhibitors combined with chemotherapy trying to mimic the experience with ER positive breast cancer.
And so I think there’ll be a number of trials. There’s already one ongoing, and there will be subsequent trials if the first trial looks promising which we hope it will. One of the things we’ve also learned in the pre-clinical studies that Dr Wong has done in the laboratory with endocrine signalling which is interesting to note and this has not been previously described to my knowledge that the oestrogen receptor that occurs in low-grade serous carcinoma in many instances has a different configuration than the one we see in ER positive breast cancer.
And so there are about six different variants of the oestrogen receptor that may occur in low-grade serous carcinoma and one of the things we need to learn is whether that has some impact on the type of anti-oestrogen hormonal therapy that they may respond to.
Jane: Thank you so much for your time, we’re really grateful to have you here.
Dr Gershenson: I’m happy to be able to spend time with you and talk about low grade serous carcinoma.
Kristen: Thank you.
We want to give special mention to the late Kristen Larsen for all of her assistance in producing this video.