Speaking of Science: Ovarian Cancer Awareness Month- Early detection, risk prediction and improving prognosis

Speakers

• NHMRC CEO, Professor Steve Wesselingh
• Professor Susan Ramus

0:00
NHMRC CEO, Professor Steve Wesselingh: OK. I think we might start. I hope everyone can hear and see us OK. And I'm very excited today to have the first of our webinar series Speaking of Science. But before we start, I'd like to introduce myself. I'm Steve Wesselingh. I'm the CEO of the NHMRC and I'd like to acknowledge the Ngunnawal people on whose lands we are today here in Canberra. And also acknowledge all the other lands across the country which everyone else will be on and

0:30
acknowledge any Aboriginal and Torres Strait Islanders who are on the call today. So as I said, this is the first of our webinars Speaking of Science and we really decided to do this because of our relationship with the sector. NHMRC obviously is Australia's biggest funder of medical research, health and medical research and and we have this fabulous relationship with the sector, but we don't often portray the fantastic science that has been done across the country.

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And and so this webinar series is aiming to do that. And we'll be having these webinars on a regular basis and we'll be having some of the fabulous scientists that we fund across the country presenting their research in all sorts of areas, basic science, clinical, medicine, health services and public health

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and obviously everything in between.

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And as I said, we'll be hosting it, but we really want some interaction as well. So we're keen for you to think about questions and put up questions in the chat box. And we'll have that opportunity to have those answers at the end. If anyone's not able to watch the webinars, they'll be recorded and they'll be on the website and people can download them and watch them so. So as I said, this is a new thing for NHMRC, but we're very excited about it and we hope you'll be excited about it

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as well. But that's enough for me. I'd like to welcome today's speaker, international ovarian cancer researcher Professor Susan Ramos, and she's our guest speaker for February. And February is also  Ovarian Cancer Awareness Month. So we thought that was appropriate.

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Susan is the Professor of Molecular Oncology at the School of Clinical Medicine, the University of NSW and she's an international expert in Ovarian Cancer Research with the focus on genetics and genomics. She's led very large consortium projects on both ovarian cancer, genetic susceptibility and tumour profiling and she's established and co-led the Ovarian Tumour Tissue Analysis Consortium. She's also on the steering committee of the Ovarian Cancer Association Consortium.

2:50
She is also very familiar to us because she won the NHMRC Elizabeth Blackburn Blackburn Investigator Grants Research Excellence Award in 2021 under the Basic Science Leadership category for her relentless work in improving the prognosis of women diagnosed with ovarian cancer. So I'd like to thank Susan for being the first, the sort of test case for our new webinar Speaking of Science, and I'd like to hand over to Susan. I'm really looking forward to listening

3:21
through her webinar. Thank you very much.

3:26
Professor Susan Ramos:  Thank you very much for inviting me to give this talk. I'm really, honoured to give this talk and raise awareness about ovarian cancer.

3:35
I'm going to talk to you today a little bit about early detection and risk prediction and improving prognosis for ovarian cancer.

3:50
So just a brief overview about ovarian cancer for anyone who's not that familiar with it. There's a lifetime risk of one in 87 women who will be diagnosed with this disease. It's often diagnosed at a late stage and the five year survival rate is only about 50%.

4:08
One of the strongest risk factors for ovarian cancer is having a family history of ovarian cancer and the majority of cases are diagnosed in their 50s and 60s with the median age of diagnosis at 63.

4:21
Ovarian cancer is made up of several different histotypes, so different types that can be seen under the microscope as different types of cancer. The majority of cases are high grade serous ovarian cancer. They make up about 70% of all the cases and about 80% of them are diagnosed at a late stage. The other histotypes some much less common and the majority of those are diagnosed at more at an earlier stage. They have different tissues of origin, and there's different molecular changes in the tumours

4:52
as well.

4:55
So ovarian cancer has quite nonspecific symptoms and the cancer is often advanced when these symptoms appear, and these may include pain, swelling or pressure on the abdomen or pelvis, frequency of urination, trouble eating or feeling full, a lump in the pelvic area, or problems gastrointestinal problems as well. So there's a nice diagram here from

5:23
Ovarian Cancer Action, just trying to get women to be more aware about the symptoms. But as you can see, these symptoms are also symptoms of many other illnesses as well. And then other symptoms that could occur again are very general and could be many different diseases.

5:42
So on the premise that the non-specific symptoms can lead to late diagnosis and therefore the poor survival,

5:51
people have looked to see what the difference in survival is between the late stage cases and that's only about 20 to 40% five year survival. Whereas if a woman was diagnosed with early stage disease then there's a 90% five year survival. So really what everyone would like would be a population based screening test for ovarian cancer similar to mammograms for breast cancer or Pap smear for cervical cancer or Gleason score for prostate cancer. And so that's really what all of

6:21
all of us would would love to happen.

6:25
However, there's many issues with doing population based screening. So particularly for a rare disease like a ovarian cancer, if you screened all the people who were more than all the women that were more than 40, you would expect 25 women to have ovarian cancer out of every 100,000 women screened per year. And if you looked at women over 50, it only increases to 30 women per 100,000 or if you screen everyone over 60, it just increases to 40 women per 100,000.

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And if you have a test that has a sensitivity and a specificity, specificity of 99% here in this first example, you can see that you would have 1000 women who have a false positive test. And so 1000 women would have to have

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invasive procedures to try to identify whether they do have a ovarian cancer. And there can be, you know, side effects for having these investigations.

7:21
If the sensitivity and specificity was 99.5%, there's still 500 false positive cases out of every 40 real cases that are detected. So it has a positive predictive value of only 7.4%. So because it's a rare disease, we're getting a lot of false positives even with very high sensitivity and specificity.

7:43
There's other issues with population based screening as well because it could not just be because of the non-specific symptoms that there's late diagnosis, but features of the tumour or rapid growth. So there's potentially a very short window of opportunity to detect aggressive cancer cancers early. They could be growing quite rapidly and then you're more likely to detect the less aggressive cancers with the screening program.

8:11
So CA125 is currently the best marker that is available for detecting ovarian cancer. It's been used for about 40 years or more and in the diagnosis of ovarian cancer, so it's used as a a blood based biomarker in symptomatic cases to identify ovarian cancer. The UKCTOCS clinical trial ran for 20 years at University College London. I was there for nine of those 20 years and they enrolled

8:41
200,000 women into the clinical trial, 50,000 were having CA125 longitudinal screening, 50,000 were having transvaginal ultrasound and 100,000 controls, and by having serial CA125 measurements as well as doing transvaginal ultrasound based on their risk, they ended up with the sensitivity of 85.8% and a specificity of 99.9% and they ended up only having 4.8 surgeries needed for every case of ovarian cancer

9:12
found. So things were looking pretty good in the screening trial. They actually found a a stage shift, so there was lower stage cancers detected in the screening. So therefore there was earlier detection, but unfortunately there was no improved survival in the in the cases and therefore it is not been recommended as a screening test for ovarian cancer. And then the PLCO [Prostate, Lung, Colorectal, and Ovarian Cancer] screening trial, which also ran for about 15 years, I think also suggested CA125

9:43
was not useful as a population screening test. So we need something better than CA125. But what's important to note is that any studies that are identifying new biomarkers also need to have similar, similar levels of testing. So there's not going to be a population based screening test for ovarian cancer that will be rapidly available. So we need to look at other alternative ways of identifying women before they get cancer.

10:10
CA125 is potentially been used for screening for women with a family history of ovarian cancer. So remember the increased risk, what they would do is individuals who have BRCA1/2 mutation or and or have a strong family history of ovarian cancer, were eligible to have screening with CA125. However, the benefits are controversial in the studies that have been completed and because some of these people are high risk,

10:41
they potentially could have surgery as well. So it's it's controversial whether CA125 should be used in these cases.

10:49
but what we really need for ovarian cancer

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essentially is if we can identify from a group of individuals who has a high risk of of the increased risk individuals rather than a population based screening. However, CA125 might not be this marker and hopefully we need more improved markers in the future.

11:12
So what my group has been trying to do is to have two themes of study. One is, can we identify patients earlier. So using genetic studies and epidemiological studies through the Ovarian Cancer Association Consortium to try to identify risk factors for ovarian cancer and perform risk prediction so that the women can have prevention strategies. And the other arm is is can we improve treatments. So we've been performing tumour studies through the Ovarian

11:43
Tissue Analysis Consortium and

11:48
doing this, we're trying to look for prognostic markers and signatures where we can personalise treatment decisions for women,

11:59
So to identify people with increased risk, we established a large international consortium which was the Ovarian Cancerous Association Consortium in 2005. And this has grown to now more than 25,000 women with ovarian cancer as well as 40,000 controls. And there's epidemiological data to identify lifestyle and other risk factors and also DNA for genotyping and sequencing to identify inherited risk factors as well.

12:30
So the slides I'm going to show you now are as basically summarising 10 to 20 years of work on each slide, just so it's sort of more of an overview of what what has been discovered. As I mentioned having a family history, ovarian cancer is the strongest risk factor for having ovarian cancer. This is listing some of the other

12:51
epidemiological factors that have been discovered to influence ovarian cancer risk. You can see here many of them are things like contraceptive pill or pregnancies, or menarche or menopause or menopause hormone treatment, but also things like breastfeeding, endometriosis, BMI, weight, and whether people have smoked or not. But if you look here, the relative risk it's it's not a very large increase in

13:21
in the risk for these. So you'd have to combine different features together and also a lot of them are more are stronger in the more rare histotypes of ovarian cancer. So in the endometrioid and clear cell, a few of them are are important in high-grade serous which is the common one.

13:42
We've been focusing a lot on looking at inherited risk factors. So for the high risk genes, they're very rare in the population. And so some women have mutations in BRCA one and two and these have been used in clinical testing of families. It's used for risk prediction. And then the women can have preventative surgery and it also influences the patient's treatment so they can have PARP inhibitors if they have a BRCA1/2 mutation. And BRCA1/2 screening was very popularised

14:13
first by Angelina Jolie’s advocacy for this.

14:20
We've also looked for inherited risk factors that are more moderate risk. So these are rare in the population and we've performed large sequencing projects looking at very large numbers of cases and controls. And these mutations in these genes might account for some of the families that have no mutation in BRCA one and two. So the genes that were found here have been BRIP1, PALB2, RAD51 C&D in in the high grade serous cases and then the mismatch repair genes are more frequent

14:50
in in the endometrioid and clear cell types. And this here is summarising about 10 years of work screening about between 3000 to 6000 cases and controls in each of the studies. And so these have an increased risk in the in the cases you can see here. I'm not sure if the mouse is showing, but you can see the increase frequency in the cases compared to extremely low frequency in the controls.

15:16
And then we're also looking for inherited low risk factors. So these are single nucleotide polymorphisms or single based changes in the DNA. And so it's just like a single change

15:33
then what would be expected. And the frequencies in the population can be close to 50% or can be a little more low frequency, so 10% or less. And these there's millions of these changes throughout the genome and some of them are associated with ovarian cancer, but they are changes that are common in the population and have very low risk. So each one has a very small impact and you need to combine the changes together to determine the risk which we get a polygenic risk score and this is a way that we can sort the individuals

16:05
by by counting up their risk at each of the regions and determine who has a higher risk.

16:10
And so we've done the identifying of these loci by looking at a very large number of cases and controls and looking at them on a genome wide snip array. And you can see here we have several different regions of the genome that are associated with the ovarian cancer risk. So this can be used to predict the risk of individuals of ovarian cancer and also to try to understand the biology of ovarian cancer.

16:39
And again, this is summarising about 10 years of work or more, looking at different variants that could increase your risk. So all of these variants that we've identified in multiple papers again have a very small increased risk. So you have to combine all the different variants together to get a polygenic risk score.

17:02
And so how we can potentially use this is we can screen individuals and try to identify those increased risk. The individuals here this would be people who have a low risk and people who have a very high risk. You can see that majority of the population here have a a medium sort of risk and people who have the high risk genes would be up here at the end. People who have the moderate risk genes are sort of here towards the the the higher end, and then people can have a high risk based on their epidemiological risk or on their polygenic

17:33
risk. And both of these can also modify the risk of individuals here. So someone who is a high risk may have their their risk, high risk, from from having BRCA1 or 2 genes might have their risk reduced by having a low polygenic risk score or lower epidemiological risk. People who have moderate risk may end up either side of being high risk based on their other genetic and epidemiological features.

18:02
So the data that we've been generating for ovarian cancer risk has been incorporated into a a tool called CanRisk, which is a clinical tool which used for the risk of breast, prostate and ovarian cancer. It combines family history, genetic, both the high, medium, low risk as well as the lifestyle factors and this is run through the University of Cambridge and you can see here highlighted in in red,

18:32
It's in multiple different languages and people are using it all around the world to try to combine all these risk factors and determine for an individual woman what their risk is.

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So what options are available to a woman if they’ve got an increased risk. So if the risk is high enough they will have risk reducing surgery. They potentially can have genetic testing of family members to identify other people in their family who may also have an increased risk. And then other options which are sort of hoped for, for the future is that there may be some type of screening or early detection program for people with not the extremely high risk but more moderate type of risk.

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And then potentially modifying some of the lifestyle factors as well might be a a form of

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preventing ovarian cancer.

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And then in the area of trying to improve

19:33
prognosis our group is trying to develop tumour test, some of the aspects where we're trying to do this is, is whether a woman should have surgery or chemotherapy first and whether we can use factors within the tumours to determine which individuals should have chemotherapy first and which should have

19:52
surgery first.

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We also

19:56
are wanting to see if we can determine who should get the platinum-based chemotherapy or who do not have good survival on this treatment and potentially need an alternative treatment and whether we can perform some sort of molecular test to determine who might respond best to different new treatments that will become available.

20:17
So in the first project, what we're trying to do is predict residual disease. So as I said, women can either have surgery first or or chemotherapy first, which is neoadjuvant chemotherapy. And this has become more common since COVID and a lot of people are having NACT before surgery. There's no molecular test to decide which individuals might benefit from having the surgery first, but if

20:48
a surgeon can achieve no residual disease from the surgery, then it would benefit the patients to be able to have the surgery. It's been shown that the biology of the tumour influences whether there was there can be residual disease remaining or whether it can be all removed. So what we want to do is predict from the tumours if the surgery could result in no residual disease. However, since these tests would be before surgery, they would need to be potentially on some sort of metastasis like omentum tumour material

21:19
in the patients. So we're performing a large project looking at omentum tissue to see if we could use omentum biopsies in the diagnosis of patients.

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We've also through the OTTA consortium developed a prognostic signature for overall survival called OTTA-SPOT. And in this model we're using age and stage as well as the expression RNA expression of 101 genes in the signature. And then we can divide the patients up into five different groups. And what you can see here in the shaded areas here are the 95% confidence intervals. So very accurately

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predict predicting the response of patients because we have very large numbers of samples. So these were based on nearly 3000 samples in the training and more than 2000 samples in the test set as well. So we actually have a clinical trial in cohort study where we're performing prospective validation of the OTTA-SPOT. So we have been collecting 800 prospective cases over 2 years. And the reason this is important is that treatments are changing over time

22:32
and we want to see if this test will work in a a current cohort of patients and we're performing RNA expression in 180 genes and predicting the OTTA-SPOT score. And then we're going to follow up the patients for three to five years to determine if that score was able to predict their survival. And at the same time we're forming a a patient acceptability study to determine whether patients would be receptive to having a test that would tell them whether they

23:03
potentially would have or prognosis on the current treatments and might potentially need to have a clinical trial or or some sort of alternative treatment would benefit them. And we're doing this work as a co-design with our consumers and then we've run several different focus groups and now we're conducting the study of a large number of patients to to get their ideas about

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whether that sort of test would be acceptable and also how they would like the results presented as well to the patients.

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And in the third aim, we're trying to predict the response to new treatments in patients. So we have a large amount of genomic data from our very large cohorts of cases which have RNA expression as well as DNA copy number and other immunohistochemistry protein markers. And we want to see if we can classify these cases and then look at cell lines response to a range of drugs and PDX models with their response to drugs.

24:05
And then perform statistical, statistical modelling to try to predict what would be the best potential drugs for particular individuals in the population based on what their tumours look like.

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And then the final project I just want to tell you briefly about here, we're performing a study looking at long term survivors which is funded by the DoD [United States Department of Defense]. And so we're looking at individuals who have survived more than 10 years, who have high grade, high stage ovarian cancer and they, the long term survivors have survived more than 10 years. And we have a matched set of samples who survived medium which is 5 to 8 years or short term which is 2 to five years. And we're performing

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immunological studies, genomic studies and epidemiological studies to try to determine why some women will, can survive for more than 10 years. So that that information can then be translated to try to improve the survival for women who are surviving in the shorter time groups.

25:07
The last thing I want to emphasise is the importance of the role of consumers in the work. So we really want to be researching questions that are important to patients so we get their feedback on, on what types of work they're interested in, the direction and their input into the research as it's progressing and also disseminating those results into the community. And some of the key projects that consumers have been heavily involved in is in the patient acceptability project and also in the long term survivor

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project. We have 4 international consumers who attend all of our consortium meetings wherever they are in the world. And we have two local consumers who also advise on all of the UNSW projects.

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So I just want to acknowledge that this is a massive amount of work by a large number of people and not just me. I really want to thank the patients and the consumers and all of their team in my my lab as well as

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well the people working on the Germline and the Tumour projects and also the consortium members particularly Penny Webb on population based screening calculations. And then also thank the funders particularly NHMRC who is funding all of the work that's happening in my lab at the moment. Thank you very much.

26:34
Professor Steve Wesselingh: OK, thank you very much. What a, what a fabulous, fabulous talk and what a fabulous start to the webinar and and particularly for ovarian cancer awareness month that was just just so good  Susan that was just fantastic and you know the but the amount of research also and the international collaboration and the size of the cohorts and the data that you presented was just was just terrific. The one thing that hit me the hardest was the consumer engagement and which is something that NHMRC

27:05
is trying to champion and certainly I think across Australia in lots of areas it's working very well. Do you want to just comment on how you, how you've achieved so much in that area and had what looked like so such fantastic engagement across the community in terms of ovarian cancer?

27:25
Professor Susan Ramos: Yes. So we've been involving consumers for at least 20 years or more in our research. But particularly with funding we got from the Department of Defence from America, they were very keen on funding the consumers to attend our meetings. And so when we had our international consortium meeting the the consumers go to the meeting. So I was at a meeting in Los Angeles some week ago and there were four consumers there from England and

27:56
Canada and America and Australia. And so they interact and we have discussions with the consumers all the way through the meeting.

28:06
It's been really beneficial and we know them really well and we we meet them every year when we have the meetings apart from over COVID. But they also join our conference calls and they're involved in all of the discussions that we have when we're planning the projects and when we're talking about the results of the projects. And then I've had several different consumers in my group over the eight years that I've been back in Australia and they have been consumers that have come from

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Cancer Voices and we have got them engaged in a lot of the work and they do a wonderful job. They also working with Anna Skog as well and they were with the Translational Cancer Research project for that. So

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there's a lot of work that that consumers are doing. They're doing a lot of really good engagement work as well where they have programs of survivors teaching students as well and and teaching the medical students to to understand what it's like to be a ovarian cancer patient as well. So, yeah, I think the, the consumer work is really important, but really getting some funding that can be used to engage consumers, it would be really beneficial I think.

29:24
Professor Steve Wesselingh: Very good point. Yep. Now we'll take that on board Susan, thank you. A question online which was about lifestyle modification, has there been much work on on lifestyle modification, what people can do to improve their their outcome or their likelihood of developing ovarian cancer?

29:43
Professor Susan Ramos: So, so people are, people are working on clinical trials at the moment to try to see if some of the lifestyle factors can be modified and if they have benefits. There's clinical trials looking at at risk and then there's also clinical trials trying to look at survivorship as well. And whether you know, modification of of diet as well or other aspects can be used

30:09
to change. A lot of those lifestyle factors though

30:13
are are not changeable, but but some of them potentially are. Yeah. So, yeah, there's a lot of work going on, but I'm not actually involved in many of the clinical trials doing that work. Yeah.

30:25
Professor Steve Wesselingh: All right. Thanks for that. Another question online was about have you seen any changes in the rates of particular histology or other changes over time? And if if they are changing, could you hypothesise about why they might be changing?

30:42
Professor Susan Ramos: I think that they've been fairly stable over time. There is some difference in the frequency of clear cell cancer in Asian populations. They have an increased amount of clear cell, but generally otherwise the frequencies are fairly similar everywhere and they haven't really been, the frequencies haven't really been changing over time. There is a change in

31:07
in some of the pathology and what they call some of the tumours. So sometimes it can look like there's slight changes in frequencies of particular

31:18
histotypes, but it could be just better classification now. So some of the mucinous tumours are metastases from other sites and then some of the endometriods are actually high-grade serous and there's a few different ones. So we've done a lot of work within the consortium looking at the old

31:37
pathology calling of the markers and and looking at with the new, the newer guidelines as well. So they sort of some of the changes that changes just due to better classification.

31:50
Professor Steve Wesselingh: OK, thanks. Another question online is about First Nations and non-First Nations populations. Have we seen much difference in firstly outcome, I guess, and then in terms of biology as well?

32:03
Professor Susan Ramos: Yeah. Unfortunately I'm not very aware of what the frequencies are in the different populations. I think it's fairly similar.

32:13
The risk is fairly similar across the population, so I'm not sure about outcomes and probably need to get advice from an epidemiologist about that, yeah.

32:25
Professor Steve Wesselingh: All right, no, that's good. Maybe a question for our early career researchers. When you think back over your career, were there some particular things that were important in terms of developing a a career in health and medical research? And what advice would you give an early career researcher maybe about, you know, areas, places, travel, what what what were the some of the critical decisions that you needed to make and that you would advise

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someone you were mentoring?

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Professor Susan Ramos: OK, so it was quite different when I finished my pHD, So then, essentially when you finish your PhD was really expected that you left the country and you went overseas and you did a postdoc overseas. I don't think that's as important as it was previously. There's a lot of good labs here in Australia and a lot of good work happening. But if you get the opportunity to go overseas to a lab, I think that's a an important thing to do if it fits in with your life.

33:28
You get a lot of opportunities, I think. One of the things I really tell my mentees is it's really good once you've done your PhD to go to a different institution. So I think it it looks much better that you have taken the initiative to go somewhere else and you are getting different inputs and you're getting different ideas and and different things. So I think changing institutions and and moving gives you more of a broad feel of what's happening.

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And then I think, I think taking any opportunity you can to get involved with things like reviewing of grants or reviewing papers and things is important.

34:10
Accepting any opportunity to come your way. So if you get an opportunity to lead something or you can try to

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initiate, teams is really good. I think it's important to accept leadership roles when you can and sort of definitely collaborate I think is one of the most important things. Work with work with a lot of really good people and yeah, I think a lot of collaboration. I think, you know, you see some studies where people were just working within a small group. And I think, you know, you should just try to reach out to other people who have similar samples or similar interests or it

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gives you more opportunity to develop multidisciplinary teams as well and get other ideas. So I think collaboration is really key.

35:02
Professor Steve Wesselingh: Just looking at lots of questions online and I'll try and get as many as I can. And one of them was about the vague symptoms you talked about right at the beginning of your talk. So what's your advice to both, I guess clinicians and patients about those vague symptoms and where they should go with those? Because you know, they they, they are quite vague, aren't they?

35:22
Professor Susan Ramos: They are and and that's the problem that happens for you know, I can understand it's hard for GP's because there's so many different diseases that would have the same types of symptoms. I guess it's more about awareness. And I thought that little infographic was quite good from the UK just sort of showing people that, you know, if you've got these sort of things, don't ignore them. Like a lot of people just tend to think I'm just getting older and you know, things have changed. You know, maybe it's just, you know, menopause or maybe it's just I'm getting older. So I think going to the GP

35:52
when you have even

35:56
and it's not that they are vague symptoms, they have the symptoms but just could be very non-specific like could be multiple different diseases or it could be just nothing. So and then I think it's more about awareness of the GP's potentially to consider a ovarian cancer and to potentially do a CA125 test on people and become more aware that it's out there. I guess the issue is because it's a rare disease, you know they often don't think about it. So I think it's a lot to do with the awareness as well. So the more we the more we

36:26
raise awareness about more ovarian cancer, the more patients and doctors are thinking about it. But I had some meetings with some GP's as well just to sort of talk about what they could potentially do to to think more about ovarian cancer as well as an option.

36:43
Professor Steve Wesselingh: Thanks. Thanks. Thanks for that. Another question. And I should say all of these questions start with what a fabulous talk you've just given by the way. So I haven't, I'm not repeating that part of the question, but they they're all think that it's been fantastic. The ovarian cancer PRS can predict cancer risk, but can it predict survival due to the cancer?

37:06
Professor Susan Ramos: No. So we don't. We don't predict that from the polygenic risk score.

37:12
What we are trying to do is is use the tumour testing then to see if we can predict prognosis. And so that's what the OTTA-SPOT score is trying to do. So once somebody has a cancer, we are hoping that we can sort of identify those cases that need alternative treatments and can't be, won't respond well to the current treatments. But as I said, treatments are changing over time and that's why we needed to do the prospective study as well, because as I mentioned

37:43
women who have BRCA1 or 2 mutations, had PARP inhibitors which they weren't in the data set we had. So it will be really interesting to see if the SPOT score can be used for prognosis in in the more current cohort.

37:59
Yeah.

38:01
Professor Steve Wesselingh: And another question online about the genetic mutations, do they occur in a particular family of genes and what's the specificity for these mutations in regard to ovarian cancer or do they increase risk for other cancers?

38:15
Professor Susan Ramos: So BRCA1 and 2,

38:19
are increased risk for breast cancer as well. And then also other diseases such as pancreatic and prostate cancer and other diseases have increased frequency of those mutations. But when we look at some of the genes like RAD51 C and D and BRIP1 and PALB2, some of them increase breast cancer risk as well, but others are are more specific to ovarian cancer.

38:48
They are moderate risk genes. So not as high risk as the BRCA1 or 2, but as I mentioned they can also be modified by your other low risk polygenic risk score as well as as epidemiology as well. So that's why the CanRisk is really good because it looks at people's family history as well as the genetic mutation data and other factors. So it gives more of a personalised risk and it's a a registered clinical tool

39:19
in the UK Yeah.

39:22
Professor Steve Wesselingh: Just to follow up from that, do we understand much about the reasons those particular mutations lead to cancer in the pathogenesis and the process? 
Professor Susan Ramos: So, So what's been really interesting is we've performed not just those genes that have come up as being interesting, but hundreds of other candidate genes that we've selected from whole exome sequencing. So more of a agnostic approach to try to identify differences between cases and controls

39:52
and also candidate genes based on different pathways.

40:10
The majority of the genes that have come up have been indeed repair pathways and so they're really genes that are known in the Fanconi anaemia pathway which is where BRCA1 or 2 are

40:26
positioned as well. So they are all in a similar pathway in DNA repair. 

Professor Steve Wesselingh: Yeah, alright that's that's very interesting.

40:36
And then the perhaps this could be the last question. How accessible is DNA testing for ovarian cancer? Is there a significant cost

40:47
and are there subsidised options?

40:50
Professor Susan Ramos: Yeah, so I think all people who have non-mucinous ovarian cancer can have BRCA1 and 2 screening through Medicare I think. So I think it's accessible to everybody and then there's some cascade screening of ovarian cancer patients to test their all their family members as well. So mutation screening is very accessible and most of the mutation screening now is actually panel screening. So they don't just test

41:21
BRCA1 and 2 but a panel of other genes as well. So I think highly accessible now. Yeah. 
Professor Steve Wesselingh: And just I'm assuming there's there's quite a few consumers on the call today. If someone goes to their doctor and their doctor’s not sure about how to access the screening or the genetic testing, is there somewhere where they can go to get some advice about access?

41:44
Professor Susan Ramos: Maybe maybe somewhere like Ovarian Cancer Action or or something like that. So there's a lot of, or Ovarian Cancer Australia, there's a lot of different groups that can give advice about where to go. Yeah.

41:59
Professor Steve Wesselingh: All right. Well, maybe maybe the last question, Susan, is anything else you'd like to add about the ovarian cancer area given that it's ovarian cancer awareness month? Just to conclude on this fabulous presentation and and then

42:16
and I'll have to thank you again after that. But perhaps if you want to just give some concluding remarks.

42:22
Professor Susan Ramos: Yeah. So I think I think we're making making progress. I'm encouraged by some of the results that we're getting. And I really want to thank all of the patients and the consumers for their involvement in the projects. And we're doing our best to try to improve things as quickly as we can because it's such a a bad disease and we really want to make improvements in prognosis for all the women that are are diagnosed with it. And and I think just for the awareness of of if you have symptoms, go to the doctor

42:53
right away. And for the GP's, if someone comes with these types of symptoms, consider ovarian cancer as as one of the alternative diagnosis.

43:05
Professor Steve Wesselingh: All right, fabulous. I mean, I think our first webinar Speaking of Science has been such a success. And I and I also, as I, as I've already said, the fact that you've given us so much information during ovarian cancer awareness month and also such a fabulous example of consumer engagement, I think this has been brilliant. So I'd like to thank you personally for being the, the Guinea pig, the first webinar. But we're certainly going to continue on because this has been such a success. I want to thank

43:35
everyone who logged on to watch. If you didn't get your questions answered, please send them to us and we'll make sure we can get a a written answer. And we encourage you to tell everyone else about the webinar. It's being recorded so people can watch it offline and we'll let you know about the next webinar in the series. So thank you everyone. Thank you everyone at NHMRC for for helping to organise this. And again, thank you Susan for a fabulous, fabulous webinar. Thank you.

44:05
Professor Susan Ramos: Thank you.

End of transcript.