In July 2019 Cure Our Ovarian Cancer had the pleasure of speaking with world expert – Dr David Gershenson from The University of Texas MD Anderson Cancer Center. This is Part 2 of a 2 part series. You can find Part 1: Low-grade serous ovarian cancer treatments on our about low-grade serous ovarian cancer page.
The video below was filmed at the Ovarian Cancer National Conference in Seattle, USA. A conference attended by women with ovarian cancer from all over America. Visit the OCRA’s website to register or learn more.
MD Anderson Research Interview Transcript
Jane: Welcome everyone we’re at the Ovarian Cancer National Conference in Seattle run by the OCRA and I’m Jane Ludemann from Cure Our Ovarian Cancer and I’m joined by Kristen Larson another low grade serous ovarian cancer patient.
We’re very honoured to have Dr Gershenson from MD Anderson joining us today. Dr Gershenson is widely recognised as the world leading expert on low grade serous ovarian cancer so we’re honoured to have him here today. So this is our part 2 series on low grade serous ovarian cancer speaking about research today.
Dr Gershenson I know your research lab at MD Anderson has really been at the forefront of low grade serous ovarian cancer research and you’ve been involved in a lot of studies, I was wondering if you could tell us a bit about the research you’ve already done on low grade serous ovarian cancer.
Dr Gershenson: Thank you Jane it’s great to be here. Right now there are three areas of investigation that we’re focussing on in the pre-clinical arena. One of them is immunotherapy and again my colleague Dr KK Wong has identified a protein which is an immunotherapy regulatory protein called B7H4 that is over expressed in serous carcinomas of the ovary, both high-grade serous and low-grade serous and he has received a Department of Defence grant to study this further. In conjunction with this there’s a phase 1 trial in MD Anderson with an antibody specifically against B7H4 and there has been one ovarian cancer patient who has responded to this antibody and had a partial response for a period of almost a year. And so we’re very interested in pursuing this strategy possibly using this drug either as a single agent or in combination for patients who have low grade serous carcinoma. So that’s one area of investigation that’s of great interest.
A second area is the area of genomics or genetics so we have recently completed a trial which is GOG 281 which was a phase 3 randomised trial of a MEK inhibitor trametinib versus the standard of care and in this trial we had performed pre-trial biopsies on all patients. They also had submitted archival formalin-fixed tissue to us for the trial. We recently received approval from the National Cancer Institute to study these tissues in collaboration with our partner Charlie Gourley who’s based in Edinburgh over in the UK and we are going to be sequencing all of these tumours from the patients on the trial using whole exome sequencing and hopefully we’ll be able to finally answer the question as of whether or not we can correlate response to trametinib with whether a patient has a mutation within the MAP Kinase pathway.
We’re also going to be measuring phospho-ERK because we have preliminary evidence from our first trail with selumetinib that women whose tumors had higher levels of phospho-ERK tended to respond better to the MEK inhibitor so those trials are on-going.
In addition to that in terms of pre-clinical investigations in the genomic area Dr Wong has found that about 25% of low grade serous carcinomas have a partial loss of chromosome 9. On chromosome 9 is a gene called P16 and we know that women whose tumors have loss of P16 may have better responsiveness to a drug called a CDK 4/6 inhibitor. So we are considering in the future a combination trial with the CDK 4/6 inhibitor combined with a MEK inhibitor in the next trial or so based on that pre-clinical work.
In addition in that area of genomics we have profiled 14 women’s tumors with whole genome sequencing which is a much deeper dive into the genome of the tumor and we found some genes that had not been previous described, some gene mutations, and Dr Wong is currently preparing a manuscript to report that information so that will be interesting as well.
And the final area of pre-clinical investigation is endocrine signalling. We have found that the estrogen receptor in low-grade serous carcinoma may in many instances be different form the one we see in ER positive breast cancer and have a very different configuration and we want to know if that somehow translates into the responsiveness of low grade serous carcinoma to various hormone medications. We may be able to find that if a woman’s tumour has a certain configuration in the oestrogen receptor the tumor may be more susceptible to one hormone, whereas another tumor may be susceptible to another.
And that’s really the bulk of our pre-clinical work right now. We also have a number of clinical trials as I mentioned we’ve completed the GOG 21 trial. The clinical information from that trial is being finalised and we hope to present that at the upcoming meeting of the European Society of Medical Oncology which will be held in Barcelona in late September.
The other trials that either have been launched recently or will be in the next month or so are the front-line trial for women who have stage 2, 3 and 4, low grade serous carcinoma who will after primary cyto-reductive surgery will be randomised to either chemotherapy followed by letrozole maintenance or to letrozole mono therapy and that trial is potentially practice-changing if we find that one of these strategies is superior to the other.
The other two trials involves CDK 4/6 inhibitors. The one trial is for women who have recurrent low-grade serous carcinoma combining letrozole with ribociclib which is a CDK 4/6 inhibitor based on the results that have been demonstrated in ER positive breast cancer. We hope we will see an improvement over letrozole alone indirectly and then can maybe move on to a randomised trial. The other trial involving a CDK 4/6 inhibitor was going to be given in a pilot study with an anti-estrogen injectable hormone called fulvestrant and this trial is for women who will be having neoadjuvant treatment based on the fact they present with very extensive disease and would otherwise have received neoadjuvent chemotherapy so instead they will be receiving on this trial nepadjuvent hormonal therapy and this will give us much better information about the susceptibility of low grade serous carcinoma to hormonal agent plus a CDK 4/6 inhibitor.
Jane: Can you tell me a little bit more about what areas of research are yet to be fully explored that you think could lead to survival improvements for women. I’m thinking of drug combinations, immunotherapies.
Dr Gershenson: – It’s mainly going to be in the area of combinations and I think we know that bevacizumab is active we know that hormonal agents are active, we know that that MEK Inhibitors are active. We don’t know exactly how active, we’ll know that form the results of our trial which will be reported later this year. So the next step I think in the long term strategy is to begin these agents and that will be somewhat empirical but that will be combining MEK inhibitors with CDK 4/6 inhibitors, with bevacizumab, with letrozole or combining letrozole with bevacizumab etc etc… So I think that’s going to be the focus over the next five to 10 years, it will be combination therapies.
Jane: Wonderful. Thank you so much for your time. Just one last question while we have you here: what made you interested in low grade serous ovarian cancer and to choose that as your area to study?
Dr Gershenson: Great question, not sure I have a great answer. So I was interested back in the even as early as the 1980s in serous borderline cancers. When I started my training at MD Anderson the senior pathologist there did not believe that borderline tumours existed. He thought that they were all really invasive cancers and there was no such thing as a borderline tumor and he would always say there’s no such thing as border line tumours there are only border line pathologists, which was a little bit humorous at the time. But what happened with that was that it resulted in over treatment of many, many women with multiple surgeries multiple chemotherapy regiments for borderline tumors and that was unnecessary. Once Dr Elvio Silva came to our institute at the same time I did. We developed an interest in borderline tumours and over the 80s and 90s began to study them. And we were most interested in those borderline tumours where they were associated with the peritoneal implants because we recognised that that had a different prognosis than if it was limited or confined to the ovary. And from that we then found that these women who had borderline tumours as well as peritoneal implants on some occasion would subsequently develop these invasive cancers. And even some of the world‘s experts at the time and this was back in the 90s mainly, but even as recently as 2000, were sceptical that you could have a diagnosis of a borderline tumour and then later on have low grade serous carcinoma. So we were able to demonstrate that I think convincingly with a series of studies and then that just led to the development of the two-tier grading system where we wanted to focus on the serous carcinomas and not be left with this amorphous three-tier grading system that we had for many, many years. And that then led to the clinical studies, the observational studies, and then onto the clinical trials. So it was a kind of progression of interest from borderline tumours on to invasive low grade serous.
Jane: Well we’re definitely very grateful for all the work you’ve done for our community and thank you so much for your time here.
Dr Gershenson: Thank you very much Jane. I appreciate it Jane. Thank you you’re doing great work.