Full Transcript: Dr Ranjit Manchanda, Clinical Senior Lecturer at Barts Cancer Institute, interviewed by Erin Brodwin of Business Insider
On this episode of Sequenced, Dr. Ranjit Manchanda, Clinical Senior Lecturer at Barts Cancer Institute in London, sits down with Business Insider’s Erin Brodwin to discuss population-based genetic testing for cancer prevention.
Dr. Manchanda’s recent research found that population testing for multiple breast cancer genes has the potential to be both cost-effective and life-saving. Curious to learn more? The research abstract can be found here.
We’ve posted complete transcript of the podcast below. You can subscribe to Sequenced on Apple Podcasts, SoundCloud, Stitcher, and Google Play.
Erin: Hi, I’m a science reporter with Business Insider. My name is Erin Brodwin, and I’m covering nutrition, neuroscience and genetics as they apply to consumers’ day to day lives. Today I’m here having a chat with Dr. Ranjit Manchanda, a Clinical Senior Lecturer at Barts Cancer Institute in London. Hi, Ranjit.
Ranjit: Hi, Erin.
Erin: Can you introduce yourself to our listeners?
Ranjit: Sure. My name is Ranjit Manchanda, I’m a consulting gynecologist and Senior Lecturer at Barts Cancer Institute, Queen Mary University of London. I’m a clinical academic, so half the time I do academic research and I’m a cancer surgeon of gynecological cancers, so half the time I see patients.
Erin: That sounds like a fascinating field. Can you tell me how you got into it?
Ranjit: Well I always wanted academic gynecological, and so around in 2007 when I decided to take time out and do research, and I went out to do my PhD, and I met two really important people who’ve been mentors to me over the last 10 years. They were both Senior Professors running the largest ovarian cancer screening trials out of the UK. They actually ran UKC Talks, which is the largest randomized trial ever performed. And I had the opportunity to work in clinical trials, risk predictions, screening and prevention.
Erin: Wow.
Ranjit: I got extremely interested in the field, and I started my research with population testing. So and I’ve been working in the area of population testing for gene mutations now for the last 10 years, and I finished my PhD, went on to do a clinical academic fellowship, which combined my research with my clinical work, and then went on to a consulting post around three or four years ago. So that’s been my journey. And I feel quite passionately about saving lives and preventing cancers.
Erin: Great.
Ranjit: What’s really inspired me is a need and I think the opportunity we have now to do so in a big way. Yes.
Erin: You spoke about genetic mutations, which brings me to my burning question here, which is about two genes that are most commonly associated with breast and ovarian cancer risk, those are the BRCA genes, BRCA1 and BRCA2. Can you tell our listeners a little bit more about those genes?
Ranjit: BRCA, it stands for breast cancer gene. So the two of them BRCA1 and BRCA2, they’re both associated with an increased risk of breast and ovarian cancer. They are associated with about a 69% to 72% risk of breast cancer across someone’s lifetime. And the ovarian cancer risk is higher for BRCA1 than for BRCA2. The latest data suggests about 44% for BRCA1 and about 17% for BRCA2. Approximately one and six BRCA2 women will get ovarian cancer. Almost one in two (most likely less than that) women can get ovarian cancer who carry the BRCA1 gene. BRCA2 is also associated in men with an increased risk of breast cancer, an increased risk of prostate cancer, and an increased risk of pancreatic cancer. The BRCA1 gene has a very small increased risk of prostate cancer.
Erin: One of the things that comes up a lot when I write about these genes, and when I write about genetics more broadly is the big topic of risk, and that can be very confusing for some people. It’s a very confusing topic. So something that I think would help clear up some of that confusion is talking about how common these mutations are. Can you tell me a little bit more about how common these mutations are in the general population, and how common they might be in specific ethnic groups? I know women of Ashkenazi Jewish heritage, for example, are at higher risk.
Ranjit: Yes, the early estimates for BRCA mutation suggested they were present in about 1 in 400 women, or even less frequent. But the more recent estimates we show that they’re probably more frequent, and I suspect they’re about 1 in 200 women. So 1 in 200 in the general population may carry a BRCA gene mutation.
Erin: Okay, and that’s pretty low.
Ranjit: Yes, but that’s low. Yes, but that’s the general population. There are clearly populations and certain ethnic groups in whom these genes occur more frequently, and they are called founder populations, and the most well known example, of course, is the Jewish population. In the Ashkenazi Jewish population, it’s estimated that 1 in 40 men and women carry a fault in the BRCA1 or BRCA2 gene. And the Sephardi Jewish population is about 1 in 100. So the Ashkenazi population has three common Jewish founder mutations. The Sephardipopulation only has one of those three, so they’re certainly more common in certain ethnic groups like the Jewish population.
Erin: And why is that?
Ranjit: That’s a good question. When you hypothesize that in populations where you have a smaller gene pool, where there is more intermarriage, or there is just stricter gene pool size, the laws of genetic equilibrium may not hold, and therefore certain genetic traits could become more frequent, or for that matter even less frequent. And that’s one of the working hypothesis. There may be others.
Erin: Fascinating. I understand you did some recent research on population testing for genes associated with breast and ovarian cancer risk. And I’d like to talk about what you learned, and also ask some more specific questions. Why don’t we start with this? What were your main findings of that research?
Ranjit: We started our research in the Jewish population, and we looked at where they just possible test populations for BRCA mutations, or gene mutations, which are associated with increased risks of cancer. We chose the BRCA gene as a disease model. I was living in London, and we had a big Jewish population in North London. Also these genes are more frequent in that population. From a study design perspective, we needed a smaller sample size to look at the hypothesis of being able to test populations for cancer risk. We did a randomized control trial in North London population where we compared the current clinical model of family history testing to the new model of population testing. And we found that population testing was both acceptable and feasible. Compared to family history testing, it did not cause a detrimental effect on quality of life, psychological well being, anxiety, depression. We also looked at different models of delivery.
We showed it could be done on a community basis, and using a DVD or for that matter, a web based decision aid. It was as good as doing face to face. When you compare different modes of delivering this, from the point of your pre-test genetic counseling, and we showed that DVD-based approach was more time efficient, cost efficient, and not inferior to standard face to face counseling. We also looked at the health economics and the cost effectiveness of this, and we found that the population testing was cost-effective compared to family history testing, and that it saved both lives and money. So it is cost saving, not just cost effective. And there are not many interventions, I think, that both save lives and money.
But definitely testing for BRCA genes in the Jewish population is one of those. We subsequently went on to do some more cost effectiveness analysis in the last year, because we realized that a number of Jewish people marry non Jews, and therefore the prevalence or the frequency with which you might find the BRCA genes would be less frequent in those individuals, so we had to re-do some of our calculations and some of our analysis. And we tested for varying Jewish ancestry from one to four Ashkenazi Jewish grandparents, and also found that this would remain cost effective. And we also published on the Sephardipopulation, and showed that even for the Sephardipopulation, if you did population testing it would be cost effective. So that sort of completed the research we wanted to do on the Jewish population.
Erin: Great. Can you briefly tell me, especially for our listeners who might not be familiar, the difference between these population studies that we’re talking about compare to family history studies?
Ranjit: The current model of gene testing is based on family history or the history of cancer in the individual and the family, and the extended family. If someone fulfills certain criteria, which are based on your family history of cancer, then you can access testing. Some years ago, this used to be based on one in five, or 20% chance of carrying the BRCA gene mutation. The threshold was always a certain threshold above which you could have the test, and below which you couldn’t have the test, and it’s all based on a mathematical probability. That probability has now fallen to 1 in 10. The current clinical practice in the UK and across large parts of the world, is that it’s a 1 in 10 chance of carrying a BRCA gene mutation, so you can have the test. But if there’s a less than 1 in 10 chance, so if you have a 1 in 12 or a 1 in 15 chance of carrying it, you can’t have the test. But a 1 in 15 chance is not a 1 in zero chance. It’s been criteria based, and in the US you have the NCCN guidelines, which are also fairly similar.
This practice is common across the world, so it’s not unique to a particular country. It’s always been based on certain criteria based on family history, but these criteria therefore have limitations. We found that just using criteria may miss half the people at risk, so these criteria don’t pick up half the people who carry the gene mutation. Also you need to be aware of your family history, know about the significance of it, be able to see your general practitioner, who in turn needs to be aware of the significance, and then refer you to see a geneticist. There are multiple hoops to jump through. How many of us actually know the extended history of cancer in our families? Also it’s dependent on knowledge and communication between families, migration of population. We are smaller families, there’s maybe paternal inheritance, and the gene may not manifest. The other issue that we have with the system is that it waits for people in the family to get cancer before making a diagnosis of carrying the mutation. There are large numbers of limitations to the current system, which is why we’ve been keen to investigate the alternative option of population testing.
Erin: Yeah, that seems like a pretty big problem considering that early diagnosis is really critical for these diseases.
Ranjit: Yes, so it’s all about being able to detect people who are at higher risk, and offer them options of screening and prevention. If we can identify people at risk, we can definitely prevent cancers. And if we can optimize our ability to identify people at risk, we can prevent more cancers.
Erin: Right, that’s huge. So what are current price points for genetic testing? I mean, how much do these things cost the average person?
Ranjit: It depends on which country you live in.
Erin: Okay.
Ranjit:And it depends on which provider you go to. For example, in the UK when we did the Jewish study, the founder mutation testing was just about 60, 70 pounds. If in the US your provider costs vary from $200, $300 to, I don’t know, about $2,000 depending on which provider you go to.
Erin: That’s quite a big difference.
Ranjit: There’s quite a big difference. In the UK, in our study we had a cost of about 170, 175 pounds, which is very similar to how it in the US at the lower end of things.
Erin: Right, that’s about $200, $250.
Ranjit: About $250, yes. If you go to Asia, there are providers who will do it for about $250 or $200 actually. It’s very variable, but they’re all doing the same test. The bottom line is the testing is becoming cheaper.
Erin: Right.
Ranjit: So testing’s becoming cheaper, the whole cost issue is heading in the right direction to make it more affordable, and therefore…
Erin: And is that what’s happening here, essentially, no matter what you’re paying you’re buying the same product?
Ranjit: You should be if you go with the reliable provider. So if you’re doing next generation sequencing, and you have an accredited laboratory, then you should be getting the same result, ideally.
Erin: But I imagine that could be difficult to verify in a lot of places, if you don’t know what you’re looking for if you’re unfamiliar.
Ranjit: Well, the health system certifies laboratories. What you need is a clinical grade result, or a diagnostic, clinical grade result.
Erin: Right.
Ranjit: In the UK and other parts of Europe, we have CPA-accredited laboratories. The whole health system testing is done, and it’s just laboratories which are accredited to provide you a diagnostic test.
Accredited laboratories provide a diagnostic grade test, and they are laboratories with that accreditation who will do it more cheaply for you than others. So, it’s definitely becoming cheaper. What is important also is that you’re appropriately informed and have counseling before you have the test, so that you can make an informed decision on whether you want to have the test or not, and understand the implications, the benefits and the disadvantages. Nobody should be pushed to have a test.
Erin: The importance of a genetic counselor is something that I’m really interested in. Getting back to some of the bigger findings from this. What do you findings mean for cancer prevention and the way in which we currently deliver cancer genetic testing?
Ranjit: I think from the Jewish population perspective, we’ve shown in the randomized trial setting that it’s acceptable and feasible. It’s not causing harm, and it’s cost-efficient and cost-effective. Also, we look at it from a varying ancestry and Sephardi Jewish population point of view. For the Jewish population, I think there’s good data and good evidence to show this works and I think there’s good evidence to consider changing the paradigm to population testing. Definitely ourselves and other colleagues from other parts of the world have argued for this, but I think policy still hasn’t changed.
Coming to the general population, we recently published a paper looking at the potential cost effectiveness of doing panel testing of the general population for multiple breast cancer and genes. We show that this would be the more cost-effective strategies compared to family history testing. And we can prevent thousands more breast and ovarian cancers than the current approach. So that is a first step in the direction given that we’ve shown the Jewish model works on that general population testing, and could be cost effective. It suggests that we need to take this story further in the general population. We would need more research on the general population before decision-making bodies would be willing to consider changing policy in the general population. So there’s more work to be done there. But definitely, that’s the direction of travel, and that’s what we’re looking to do.
Erin: Interesting. Are there any means of doing this that you would not recommend, and what I mean by that is would you recommend doing this without the involvement of say, a doctor or a genetic counselor?
Ranjit: No, I would recommend you see genetic counselor or an appropriate health professional who can inform you of the pros and cons. Genetic counseling is going mainstream, so it’s not only genetic counselors who are doing counseling these days, it’s your doctors, your health professionals, your oncologist, people involved in the treatment of cancer. We’re moving into an era of genomics where all medical professionals will eventually learn, need to learn more about genetics and become comfortable with doing genetic counseling or conveying information about the pros and cons of genetic testing so people can make informed decisions.
That’s eventually going to need to happen over the next few years, or the next decade. As genetic testing becomes cheaper, acceptability increases, societal awareness increases, its role in medicine and precision medicine increases, people are going to need to do more and more of this, and our training systems will need to change to incorporate this into regular training and teaching. So yes, it’s important for people to see an informed professional who can talk to them about the pros and cons of having this genetic testing. The current models, it’s either genetic counselors or oncologists or people involved in cancer care who are trained in it.
Erin: What are the next steps for implementing this type of whole population genetic testing, especially when we talk about breast and ovarian cancer?
Ranjit: I think in the Jewish population, there’s adequate data to suggest we should change the paradigm, and people who make decisions from the health system point of view need to look at it carefully. In the general population, we need further research to confirm that the findings that we have in the Jewish population also translate in the general population from the point of view of impact on quality of life, well being, psychological health. We also need to understand if the people who do not have strong family histories of cancer take our preventive interventions the same way as people who do have strong family histories of cancer, because that’s a major thing underpinning a lot of the modeling we do. So that’s not being borne out in a prospective study.
We also need to scientifically evaluate the most cost-efficient model and effective model of delivering in a population basis. You can’t have everybody coming into a health clinic to see your counselor for a face to face session if you want do it on a population basis. There are a number of implementation issues that need to be ironed out, and that body of evidence is still lacking, so it needs to be generated, and it’s only then I think that providers and decision-makers will look at it from a general population point of view. But that should happen, and I hope that’ll happen, in the next few years.
Erin: That’s exciting. A follow-up question to that I have for you is then there’s the question of responsibility, and who’s responsibility is it to provide this type of testing?
Ranjit:Okay, so the first thing is to establish the evidence base for general population testing. For the Jewish population I think that evidence, the strong evidence base is there. It’s the job of health service providers to provide population testing, and in different countries the health service provider, or the system of healthcare differs. So for example, in the UK it’s a state-funded system, so the state national health system would need to consider it. In the US, it’s an insurance-driven market so the insurance, I suppose, would need to consider it. In other countries it may be a more hybrid system. Once the evidence base is there and guidelines change, then it becomes incumbent on providers of healthcare to offer it, just like they offer any other service.
Erin: Yeah, I lived in London for about a year last year, and enjoyed the benefits of living under a state-funded health system for a while, so I can understand how it would be some tricky terrain here in the US. I had a couple quick questions just around BRCA and the idea that it’s also not just genes that play a role in our risk for breast cancer. Can you tell me a little bit more about that? I know that there are tests that you can do to find out whether or not you are at increased risk for breast cancer based on whether or not you have a mutation on BRCA1 or BRCA2, but beyond that there are other factors that come into play, right? So there’s environmental factors and then family history as you obviously spoke about earlier.
Ranjit: The BRCA1 and BRCA2 genes account for a small proportion of cancer risk. About 10%, approximately, of ovarian cancers and 4% of breast cancers are associated with the BRCA1 and 2 genes. The large majority of cancers are not due to to BRCA1 and 2 genes. There may be other genes which cause ovarian cancer, breast cancer, but most of the risk is dependent on your environmental factors. They be genetic modifiers, or something called SNPs. They may be epigenetic, epigenetics may a play a role, so that’s the modification of your gene through what’s called methylation. So there could be a range of factors affecting both breast and ovarian cancer risk. For example, there’s how many children you have, whether you breastfeed, your contraceptive history, whether you have things like endometriosis or infertility. There’s a whole range of factors which can affect your risk.
Erin: Right. With epigenetics for example, we’re essentially talking about sort of the set of factors that affect how our genes are turned on or turned off or express.
Ranjit: Absolutely.
Erin: Okay.
Ranjit: So the risk is very complicated. BRCA1 and 2 account for a small proportion of overall cancer risk, but if you know about these genes, there’s a lot we can do to prevent cancers in these women effectively and save lives. Most of cancers are not caused by BRCA1 and BRCA2, and that’s an important point to bring across. And there would be other risk factors, which contribute to that risk. Also some of these risk factors may affect your risk of BRCA1 and BRCA2 carriers, too. So it is more, as you pointed out, more complicated than just simplifying it with BRCA1 and BRCA2.
Erin: Okay, great. If you do a test to find out if you have a mutation on BRCA1 or 2 without the involvement of a genetic counselor, is there any concern that someone might misinterpret those results and think that they are at an increased risk when maybe they are not, or think that they are not at an increased risk when in actuality they still may be at risk for cancer later on?
Ranjit: Absolutely. The whole issue of risk needs to be taken into context when someone talks to or evaluates someone’s risk. You need to look at the genetic test result, but also the extended factors which may affect risk, like family history and other epidemiological factors. The other important issue is the test result itself, and the interpretation of that. The test may show a fault or mutation in the gene which is not pathogenic, or which is not disease causing. And within the population about 2%, depending on which data you look at it, approximately 2% at least of people may end up with what’s called a variant of uncertain significance, or a VUS. This means that there is uncertainty on the implication or whether the mutation is disease causing. At the present point in time, it’s not known to be disease causing, but a small proportion of these tests, or these mutations, in the future end up being confirmed as disease causing. And therefore, it’s important that they be monitored. But it does not warrant surgical prevention or any preventive intervention just because of a variant of uncertain significance. So it’s not disease-causing today, but a very small proportion of these may become disease-causing in the future. So someone needs to keep an eye on them.
Erin: Okay, so that’s actually fascinated to me because it would suggest that once you submit your genetic information to a company or to a research association that you would sort of need to get it checked again once there’s more new science about what these different genes mutations do and the effect that they might have.
Ranjit: Yes, that is true. How to manage for us is going to be a really important issue to deal with, and ironed out in the future, especially if you want to do population testing. So it’s an issue we are working to address. We will need to develop models and systems or pathways to manage the VUS’s over the long term.
Erin: Great, so we were talking about mutations on BRCA1 and 2 and I’d like to ask, if someone finds out they have a mutation on either of the BRCA1 or BRCA2 genes, what are some preventive measures that she or he could take to reduce their risk.
Ranjit:For women who carry a BRCA1 and 2 gene mutation, there are a number of screening and preventive options which are available. For example, for breast cancer, there’s the option of having breast screening, which is more intensive and starts at an earlier age, at approximately 30 years. And initially it’s annual MRI’s, and later on it could become mammograms, or a combination of MRI’s and mammograms, as the woman becomes older. There’s also the option of having medical prevention or taking a drug such as Tamoxifen for reduced risk of breast cancer in the future. Then there’s the option of surgical prevention, or mastectomy, that’s removal of breast tissue, which significantly reduces the chance of getting breast cancer in the future.
Erin: Right. And that’s the one that actress Angelia Jolie kind of brought to light to in 2015, I think it was.
Ranjit: Yes. So she had bilateral mastectomy and reconstruction. So that’s an option. A significant proportion of women do opt for it, a number of them prefer not to have it done. It needs to be an individual choice. It involves intensive counseling, you need to see a breast specialist, a plastic surgeon, a psychologist, ideally, to help you understand all the pros and cons of having it done. The other options are lifestyle modifications, regular exercise, healthy eating, breastfeeding, having your children at an earlier age, possibly, so that you can plan your preventive interventions later. There’s something called pre-implantation genetic diagnosis, which is licensed. Not many women opt for it, only a small proportion do in our experience, but it’s available, and that…
Erin: What is that exactly?
Ranjit: That prevents the gene from going into the next generation. It involves IVF type treatment, where you select the embryo which does not have the faulty gene and implant it in the womb. You see a specialist, a fertility specialist who does this, and it needs to be specially set up for the couple concerned. But that’s available, it’s definitely something that some women opt for, but a majority may not. The other option for reducing ovarian cancer risk is taking the contraceptive pill. If you take it for five years it halves your risk. Ideally if you take it at an earlier age, then the impact on breast cancer risk is going to be likely to be less.
Erin: So we’re just talking about birth control, right?
Ranjit: Right, yes, birth control. Taking the birth control pill, the combined birth control pill, for five years halves your risk. The other thing that can reduce risk is removal of tubes and ovaries, so once the family is complete. If you have the tubes and ovaries removed, then that significantly prevents you from getting cancer in the future. There is a new option which is now being considered and advocated within the research setting, and that’s called early salpingectomy and a delayed oophorectomy. That’s a two-step procedure, instead of a one-step procedure. So when you’re pre-menopausal you can have the tubes removed, and once you become post-menopausal, you have your ovaries removed. The advantage of that is that you can retain your hormones for much longer, otherwise if your ovaries are removed at an early age, you have detrimental consequences of early menopause. This new option is only advocated currently within the research setting, as we don’t have enough data on the long-term outcomes of this.
Erin: Okay.
Ranjit: Ovarian cancer screening is not broadly available at the present, so that is still not available in the high-risk context. It has been investigated and we’ve been in all the various ovarian cancer screening trials. We used to do four monthly blood tests and a scan. But it’s not yet become clinical practice or national policy to offer ovarian cancer screening, at least in the UK.
Erin: Some of those lifestyle modifications sound rather invasive, but there are others that you mentioned that sound pretty easy. You mentioned healthy eating, you mentioned potentially having kids earlier could be easier. It kind of depends on your circumstances. But can you tell me a little bit more about those? I think you also mentioned breastfeeding.
Ranjit: Yeah, so breastfeeding, planning your family, considering contraceptive pill when you want to have contraception at a younger age. So, those, making those reproductive choices can benefit your…have a positive effect on your long-term risk.
Erin: Great. And I imagine having access to all of those options is really the key factor here, because then it would allow you to make those sorts of decisions.
Ranjit: Yes. If you’re aware of your mutation status, then you can make those choices to help manage your risk which range from more drastic interventions like surgery, less drastic ones like taking medication or even lifestyle and reproductive choices which can help minimize your risk.
Erin: All right, Ranjit, well thank you so much for taking the time to speak to me today. This has been incredibly informative for me, and I imagine for our listeners as well. So, thanks again so much. I’ve learned a lot.
