 Thank you Vince. I think I'm on. So I was asked to talk about breast cancer today and also to leave time for questions in case I don't cover areas that you're interested in. So my attempt will be to finish in about 40-45 minutes and leave 10-15 minutes at the end for questions. If there's a burning question feel free to interrupt this informal presentation. I want to start the presentation where I'm going to end the presentation. So for the non-radiologists in the room I think you can tell this is a domino CT scan shown in the circle again for the non-radiologist is a tumor in this woman's abdomen. Shown here a month or so later is the same region and for those of you in the front I think you can see there's the tumor is gone and this tumor disappeared because this woman was treated with a drug that was designed using knowledge of breast cancer genes not a drug that was used as a general tumor or an anti-growth agent but a drug specifically designed to the genetic makeup of her tumor. I will most of the talk will be about where the genetic and genomic advances can be implied to medicine. I'm going to bring in examples from breast cancer some of which actually and I'm sure some of you in the audience actually are applying them and others that are still in clinical trials but how did we get here and what are we going to cover today? We're not mostly about breast cancer genes but as Benz mentioned especially for BRCA1 and BRCA2 these are also ovarian cancer genes and I'm not going to cover that today but they're very important components of ovarian cancer in fact some of the treatment data that I will show you comes from ovarian cancer rather than breast cancer. So we'll talk a bit about what these genes are how we find them and how we use genomics and genetics to get to these genes what do these genes do in the body at least some of them the ones we know about and then there'll be a overarching kind of woven theme of how we can use this genetic knowledge to improve health. I just want to start with showing you the data that I think everyone in this audience knows is the mortality by different causes between 1950 and around 2000 and the red bars are the mortality in 1950 for heart disease, stroke, pneumonia and cancer and what you'll notice it's quite striking is that we made great progress in these areas over the last 60 some years. Cancer and it is unfair to lump all cancer together but for the purpose of this graphic we're putting all cancer together progress has not been as impressive for cancer. One of the reasons is because we don't know the mechanism for the cancer so the others obviously there are lots of different types of cancer. I'm sure that everyone in this audience also appreciates that breast cancer is a very common disease so unlike some genetic diseases which are rare this disease has 200,000 cases or so per year 40,000 deaths. The 1 in 8, 1 in 9 number if you're a woman your lifetime risk of being diagnosed less talked about is the fact if you're female your risk of death from breast cancer is a few percent currently. This is what the cancer rates have looked like for various cancers over the last 70-80 years and shown in this yellow line is ovarian cancer which is held relatively steady although there's been improvements probably in diagnosis uterine cancer nice example of advances in medicine in this case mostly surgical treatment decreasing cancer mortality by a lot over this interval. Breast cancer staying roughly the same over this interval and diagnosis and probably our worst experience as far as not a victory here is this great increase of lung cancer in women that obviously correlates with environmental exposure from smoke. If you zoom in on the breast cancer curves and shown for reference on the bottom are the lung cancer curves this is breast cancer over the last 30 some years and many of you will remember in this interval there was great concern about these rising rates of breast cancer in the 80s and it also corresponded with a great increase in awareness of breast cancer prior to this breast cancer was not a high-profile public disease even though it was still a common disease. This rate seems to have leveled off and if you look over here and I'll zoom in on this area this is a real decline that started in the early early in 2000 2003 and does anyone know what what has been attributed to this decline in breast cancer? So this is a decline is attributed to the decline in use of hormone replacement therapy and that coincided with practically right there with a landmark study that showed that hormone replacement therapy did not protect against heart disease it was always known that it was slightly increased risk of breast cancer but it was on balance thought to be a good thing if you protected you against heart disease which was more common. At this point in time HRT therapy dropped through the floor as far as uptake and probably can account for this decline in breast cancer risk. I bring this as an example not as to say we did the wrong thing but an example to show you that in addition to genes the environment is very important so here we have medical practice influencing the rate of breast cancer and essentially decreasing it through advanced studies. So why would we want to know about the genetics of breast cancer? There's always a reason to look at mechanism to try to better understand the disease but in breast cancer and ovarian cancer we hope that looking at genetics will help us with prevention early detection being able to better predict the course of the disease and tailored therapy and so today I'm actually going to talk about advances brought on by genetics in these two regions there there are advances in both of these other categories but I'll have time to talk about them today so I'm going to focus on these two areas during the talk. Before I do that I want to do one advertisement and one definition for you. You may have heard that cancer is a genetic disease and I think it's well soaked into the culture now that cancer is a disease of genes but you have to really divide this into two separate areas and that's why we're having two lectures and two talks on it. The first area that cancer and genes are involved is when cells essentially can acquire mutations that are associated with growth advantages and they escape normal controls and essentially form a tumor. This is a disease where the genome of the cells change. These are also known as somatic mutations. These are not inherited. They're not the topic of today. A month from now Stan Lippwitz who's here if he raises his hand will be talking about what we're learning and what we're being able to do in medical practice by understanding the genetic makeup of the tumor itself. It's a critically important and probably one of the most active areas of cancer research is understanding the genome of the tumor. Today what we're going to focus on is what comes before that and that's the genome of the individual. So this is the genome that you inherit from your parents that has a collection of genetic variants. Some of those variants increase your risk of cancer. So at birth based on what you inherited from your parents, your risk of cancer from one person can be different from the other and that's going to be the focus of today's lecture. Come next month to hear Stan talking about the changes in tumors and tailoring drugs toward tumors. This is the inherited variation. I want to just... Can you see the chromosomes there? They look a little washed out but these are an example of how risk mutations can occur in a cell. Here's two chromosomes and I don't know if you can see this. What I've done is delete one portion of that gene and that cell since it has another copy is probably fine but if it loses the other portion of this gene it now has no copies of this particular gene and will go on to essentially form a tumor. This is what happens in sporadic cancer where you lose both copies of a particular gene. These are called the top tumor suppressor genes. This happens rarely but since you have several trillion cells in your body, occasionally one cell suffers these two hits. This is what we think is going on in sporadic cancer. In inherited cancer and again I'm sorry they're not dark enough to see, here's the chromosome in a person with inherited cancer where they already have inherited a mutation or a deletion or something that knocks out one copy of their gene. Now in all of their cells all they have to do is lose the other copy and that's a much more common event and so people who are born with one mutated allele have a much increased risk of a particular cancer. This just shows you the deletion of the other allele. For the most part the cancer risk genes, the ones that are inherited, tend to fall into this category and in fact in we all know that family history is an important risk factor for all cancers and especially breast and ovarian cancer. In a small percentage of families the cancer really does appear to be inherited as a Mendelian trait and so what does that look like? Oh and that accounts for three to eight percent of breast cancer so not the majority of breast cancer, a small amount of breast cancer, but a small amount of a very large number and so what I'd like to do now is focus a little bit on our understanding of the topography of breast cancer risk and this kind of foggy, cloudy slide shows you where we were about ten years ago. I'm going to very quickly get to the identification of the breast cancer genes work that took about 15 years and really that could be done now probably in a few months with the right families due to advances in the genomic technologies and genomics. So what is the topography of breast cancer risk look like? I'll focus in on this graph for a second. This is the frequency, the frequency of the risk. So up here 30% frequency of risk would be quite high, a fraction of a percent down here and this is the relative risk so essentially if you have a particular variant, if you inherit a particular variant from your parent, how much does that increase your risk compared to someone who didn't inherit the variant and so what we can do is map the landscape. First of all there's boundaries that can be put in so down here where there are things that are very uncommon and very low risk, they probably exist but we can't find them because it requires studies of enormous size to find them. There's an upper boundary to this map up here and that we know that there aren't super high risk variants out there in the population that are incredibly common because if they were then breast cancer would be even more common than this and so the genetic variants have to fall into this landscape. What do they look like? So this is what a diagram of a sporadic cancer. Here's a woman with breast cancer. Is this familial? Is cancer in the family? Is it familial? Not because this person is not a blood relative even though it's cancer in the family and so this is finding out that you have an aunt or an uncle with a family history is not the same as mapping out the pedigree. This is a relatively common manifestation. We know that empirically that if this woman had breast cancer this woman who might be interested in knowing what her risk is. Her risk is doubled just based on their pedigree alone. This is the picture of inherited cancer. Here are the field circles again are women who have breast cancer and you can see multiple individuals in the bloodline. I illustrate this particular pedigree because those of you that have looked at genetics this is looks almost like a dominant pattern of inheritance with one exception. What about this guy? Does he have the risk allele? I see nodding. He almost certainly does but he doesn't have the cancer because there's a sex limited trait for this particular cancer. So we have heard from time to time of people being told don't worry about your cancer risk because it's all on your father's side and certainly there's no empirical reason to worry about which side of the family comes if there's cancer on one side of the family that counts as increased inherited risk. So obviously this woman would really want to know what her cancer risk is and your gut tells you that her cancer risk is probably a lot more than this woman's cancer risk and that is true. Using these families we're able to identify the genes that cause the high risk of cancer and how was this done? Shown here is the curve of rate of breast cancer and age of diagnosis. So as you might expect very little cancer is diagnosed early in life breast cancer is clearly mostly a disease of later in life. If you want to find the genetic basis for any particular condition would it be best to look at the average presentation or is it better to look at the more severe or earlier onset presentation? And so clearly the more severe and earlier onset is likely to have more of a genetic component because as you get later in life the combination of your genes and environment tend to tip toward environmental influences. Earlier in life it's more genetic influences and so to identify the major genes for breast cancer what was done is women who were diagnosed at very early ages in these families were looked at and that led to the discovery now, I think of 1994, sounds like a long time ago, of the BRCA1 gene or breast cancer gene 1. Soon after when these families that had lots of cancer were typed we realized that BRCA1 did not account for all of the families and so very quickly within a year after BRCA2 was identified these remain these two genes remain the major players for high-risk families in high risk breast cancer. When you study families that have breast cancer only and you ascertain breast cancer only you don't notice that they there are other cancers in the families until you start looking at family history and very soon after the genes were identified or that there were breast cancer genes were identified it was appreciated that there are other cancer associated with. So BRCA1 and BRCA2 are associated with roughly an eight-fold increase of risk so if your risk is one in one in nine one in eight and goes up eight-fold it gets up to be pretty high it's also BRCA1 mutations are also affiliated with breast cancer in males which is a rare but not incredibly uncommon disease about 1% of breast cancer that's diagnosed is diagnosed in men. Ovarian cancer as I mentioned at the beginning is a very major player for especially those with BRCA1 mutations in that carrying a BRCA1 mutation increases a woman's risk over and cancer 20 to 30 times sometimes 40 times depending on how you measure it. Had the studies been done differently BRCA1 probably would have been called an ovarian cancer gene and in men who carry mutations in this gene they're at two-fold increased risk of prostate cancer that's been replicated a number of times. So these breast cancer genes are also other cancer genes as well. Where do they fit in the in our topographic map of the landscape they fall up in here. BRCA1 and 2 the number of people carry mutations are quite rare probably looking around only one or two people in this room might carry variants or deleterious variants in these genes but they're very strong risk factors so they're up here. The other gene that is up there is the p53 gene which is involved in leaf-realmeni syndrome which has other cancers involved in breast cancer. So these genes very potent risk factors for breast cancer risk. What are the lesions in these genes look like? This is a slide that was originally made in December of 94. I can tell you I made it as a slide I think some of you probably remember slides and had to scan it in and shown on this line is a picture of the BRCA1 gene and it was identified two months earlier published in science two months earlier and all these arrows show you where mutations have been found in this gene in different families and I think you can appreciate within two months we realized that these genes were gonna have a lot of mutations. This is the untranslated part so the gray areas the part that makes the protein and so the protein is being hit all over the place in all the different families so the families that I showed you this it's extensive pedigree in general they tend to have different mutations from one another with a few exceptions I'll talk about in a second. This has led to as many of you know a genetic testing made available in the US almost exclusively by myriad genetics to find out who carries mutations for this gene and if you do the calculation these two genes are probably the most sequenced genes in the entire genome so worldwide there's probably been 250 300,000 individuals who have had their genes sequenced so we know a lot about the different variants in the gene. This is an updated picture of the gene a little more colorful now on the web from our database this just again the gene at the bottom shown here where the mutations are. There are so many mutations in this gene that some of the nucleotides have been changed to you know there's four four different possibilities at each nucleotide if it's originally a T we found that T is changed to a C and also to a G so we've almost hit kind of saturation of this gene. What you also will appreciate from this is that there's no hot spots there was no insight into function from looking at the mutation distribution. For some genes in fact maybe some that Stan will talk about there are hot spots in that show how they're activating mutations. This is a gene that BRC1 and BRC2 produces a risk by losing its function. As I said there are lots of different mutations but there are some groups which have the same mutation due to a founder effect and this is just due to common ancestry one that we've worked on is the Ashkenazi Jewish individuals who have one BRC1 mutation another BRC1 mutation and a BRC2 mutation so an aggregate one in four Ashkenazi Jews carries a deleterious mutation in the BRC1 or BRC2 genes. We use this effect more than a decade ago to do a study of and I don't know if it did anyone participate in the Washington area study to try to figure out what the risk was associated with and it was carried out in the Bethesda community. In Iceland there is one BRC2 mutation that is found in one of 170 people in Iceland. There are Dutch founder mutations there are founder mutations in these different areas of the world. This has the effect in that if you're going to get a genetic test for BRC1 and you're in a group that has founder mutations it makes more sense to look for that first before moving on to the more expensive test. I can tell you that the full sequencing test now approaches $4,000 of a charge in the U.S. of meriogenetics. The test for specific mutations is quite a bit cheaper of a few hundred dollars. If you look at the mutation types and don't worry too much about the different kinds of types just look at the total number of entries so there's as Vince mentioned there are thousands and thousands of different mutations in these genes. Distinct alterations means the different mutations so there's nonsense mutations which shut the protein off. At the time I made this slide there's about 176 different of nonsense mutations but the ones that are found in one family only are 84 so in each case there's a lot of different mutations and about half of them are found in a single family. This is why you have to test almost every new family because about half of them have something we haven't seen before. The top three rows are mutations that we know kill the protein so if a woman has is found to have or a family is found to have a nonsense of frame shift or a splicing mutation we can reliably tell them that that mutation is probably associated with risk. You know it's how I'm hedging a bit. The other case where there are mis-sense changes these are changes that change one amino acid for another so they proteins these proteins are very big they're over a thousand amino acids. You swap one amino acid for another we have a hard time with those and this has been called the unclassified variant problem or the variants of unknown significant problem and so in BRCA1 there have been almost 3,000 families that have had these there's 500 different mutations about 300 or so have been found only in one family and when the people get these test results they're told you have a variant we don't know what it means and sorry about that and that's a very active area research because when you go to get a diagnostic test if you have the pretest counseling you're prepared for getting it either a good result that you don't carry something bad or a bad result that you do carry something bad it's harder to prepare people for we have something interesting but we don't know what it means and roughly about 10 percent of test results 5 to 10 percent of test results turn up one of these variants that we just don't know the significance of and so there's a very active group trying to nail these down to figure out how many of them are deleterious and how many of them aren't. I bring this up because as you'll hear in other talks and you may have heard from Dave Valley in the first talk we're going to be sequencing lots and lots of genes going forward sequencing technology has become so spectacular that it's very easy to generate DNA sequence information we have to be prepared for generating information that we don't understand so that's a quick summary of the high penetrance meaning they have a very strong effect but low frequency genes and again BRCA1 and BRCA2 are the major players p53 produces leaf romani syndrome which is usually not confused for just breast cancer. What about the low penetrance meaning the low risk but high prevalence area and so these may have a low relative risk if you carry the variant it only increases your risk of cancer a little bit but they may have a high population attributable risk because lots of individuals carry them can we find those genes I told you that to find these genes individuals recruited very spectacular families and use the families to look via something called linkage analysis to find the genes for these genes we do what's called association studies in association studies linkage studies are relatively complicated association studies are very easy you just do case control type studies you look at people who have the disease match people who don't have the disease and you count up how many variants are present or how many genes are present in one versus the other this is just an example of one that was done quite some time ago to give you an idea of the scale you could identify the BRCA1 and 2 gene by having 20 nicely collected families you could you could identify those genes in order to identify these low penetrance genes you need large numbers of cases and controls and this I show you the raw data to give you an idea controls about a half a percent cariat in the cases about two percent cariat and so you're looking for something of relatively modest effect in this case about doubling of risk there are now genes that have been filled into this area so these are relatively more common the BRCA1 but still around one to two percent and there's a collection of genes in that area that we now know about in this landscape so the genes listed in here have rare relatively rare variants that are associated with roughly a doubling of risk that still leaves this big area down here and that's an area that's been filled in most recently by what we call whole genome association studies or genome wide association studies this just shows you an example as you compare the frequency of in some cases a million markers in your cases compared to your controls and certain markers this is a the p-value plotted in an inverse scale certain markers show out to be standing out that they're much more common in your cases compared to your controls this has been done for breast cancer the first one was published in 2007 you'll see that the scale gets to be quite large because you now need to pool lots and lots of cases so there's there were 147 institutional affiliations on this paper this is the first big association study of breast cancer risk and that has allowed us to fill in this region of the graph it's likely that there'll be more and more variants that show up in here and they have a very modest risk 30 increase a 20 increase remember that having a family history first-degree relative is a 100 increase so they're very modest they're in the scale of risk that's associated with certain diet choices and alcohol intake so how can we use this now landscape and this will be filled in a little bit more but i don't expect we're pretty sure there are no more genes up here we'll probably have a few more here this area will get populated with some more but we now starting to have the entire picture of what the genetic landscape of breast cancer risk looks like and so we now have a very clear picture how can we use it the first that i like to talk about is early detection early detection is the product of screening and that's generally probably using these and these and so if we go back to this family it's pretty obvious if this family has an inherited cancer whether or not we know they have a brc1 and 2 mutation this woman's surveillance and screening methods cannot be what we suggest for the population and so what is normally suggested is that mammography is done more frequently started earlier depending a bit on the family history in these individuals and prophylactic surgery is considered as well how it's as early as 20 something in some families i don't think there's a uniform recommendation there are the standard that's been used is that the earliest 10 years earlier than the earliest diagnosis in the family has been used at some point so if this woman was diagnosed at age 30 then you might push it to 20 so that's much earlier than you would do in the population the risk that these women face is been estimated originally up to 90 percent by looking at different study types the risk if you carry a mutation of having breast cancer it ranges depending upon how you do the study and this just lets us know that there's some heterogeneity in mutations and so right now women who carry a brc1 mutation are generally told they have a 50 to 50 to 80 percent or 50 to 70 percent lifetime risk of breast cancer so i think we're getting a good handle on these high-risk families but they tend to be rare what about the low penetrance high prevalence what about the clinic are they clinically significant and i think the answer is we don't know yet are they significant to the individual health we're not totally sure about that yet but could they be used as a public health style application of medicine and for that i want to show you some modeling that's been done by paul farrow in in the uk how do we do breast cancer screening now you reach a certain age you start mammography you do a self-exam and the assumption is that every one of a certain age has an equal risk so that's plotted here that if you're a 50 year old woman and i i screen 20 of the population i will catch 20 of the cancer if i screen 100 of the population i should catch 100 percent of the cancer that's based on the idea that all 50 year old women or all 40 year old women have the same cancer risk we know that that's probably not the case this is what risk probably looks like in the population if i again go back to my entire population of a thousand 40 year old women some of them will be at very low risk due to their genetic makeup others will be sorry others will be a very high risk and risk is distributed in the population uh genetic risk is distributed in the population almost like a normal distribution so if we go back to our screening algorithm and instead of making this assumption this is what a bell curve would look like of risk we assume that risk is not randomly distributed in the population but we can identify who is at higher risk if you could if you could implement screening programs that took this into account and you screen the 20 percent of individuals who are most at risk you would then pick up 60 to 70 percent of the the cancers that way this is not something we're ready to do we don't know exactly how to employ the genetics yet but is the potential for where genetic risk assessment can be done and this is genetic risk assessment be done at any time in your life presumably if we could sequence your genome uh early on we could give you a profile uh at a very early age of what that might be like i'm not saying that we have to do this but if you are going to employ resources that are relatively scarce and expensive you might want to use the genetic risk profiles to guide them the second area that that these knowledge of these genes is having impact already is in the tailored therapy the data I'll present are really from clinical trials they're not yet part of practice but they rely on our knowledge that BRS-8, 1 and BRS-2 are actually DNA repair proteins so your every cell in your body has a genome in it that genome is constantly calving mutations and constantly under attack your cells and the cells of actually all organisms have a very elaborate set of proteins and and gene products that are designed to repair that DNA took about a decade of work to recognize that that's what these two genes do in the cell in fact they're actually participate in a very specific type of DNA repair called double strand break repair so you could imagine think about DNA as a double-stranded molecule if you break one strand it's still attached by its connection by the overlapping but if you break both strands those molecules are free to drift apart and the cell cannot tolerate very many double-stranded breaks at all and BRS-8, 1 and 2 seem to be involved in BRS in double-strand break repair keeping that in mind a group in the UK thought very logically and said how can I use that fact to design a therapy and so I mentioned that any kind of insult can do DNA damage in fact oxidation does DNA damage so if you want to have your DNA be completely intact you should stop breathing which is not some not really an option every time a cell divides it introduces mutations so there are a lot of there's a lot of DNA damage going on almost all the time it's repaired quite efficiently so in normal cells it's repaired and the cell is viable these things that just show you the different types of repair if you don't have BRC-1 in the cell or BRC-2 you have a defect in one type of repair this double-stranded break repair if you take a another product out of the mix called PARP you don't have a type of DNA repair that repands single-stranded breaks if you don't have either of these then the cell dies and so what the group in the UK did was design an agent that inhibits these enzymes and so normal cell is okay if I inhibit this enzyme I'm fine if I inhibit BRC-1 viable although it might be a tumor but if I knock out both of those the cell is dead and in a person because you remember that these are tumor suppressor genes the only cells that are missing completely BRC-1 are the tumor cells and so if you add this extra layer you ended up killing the tumor cells and the tumor cells only that was the theory yeah at risk for wall insults to DNA or is it more specific to these double-stranded breaks in fact there you can insult DNA a thousand ways mutations as well as backbone breaks but it is very seems to be very specific for double-stranded breaks and so this may be a little bit of a difficult scheme to follow but did it work and so shown here as experimental data where these are tumors implanted into mice that are either have BRC-2 or don't have BRC-2 and I'll not go through all the data but these are the tumors that kept getting bigger and bigger and bigger in all the control mice and all the the mice that were treated except for the ones that were missing by BRCA-2 so the treatment plus BRCA-2 made the tumors go away in mice and this was work that was published several years ago was somewhat fast tracked into clinical trials and to show you some of the data from the clinical trials so this is a laparib which is again this PARP inhibitor there are several PARP inhibitors out on in various clinical trials this one seems to have had the most success and the blue line here are those that weren't treated here's the treatment regimen the red line was treated so you can see that there's progression free survival is essentially better in those treated with this drug that has relatively minimal cytophikes compared to normal chemo therapy it was a second trial published last year you know from where I'm sitting these don't look very good but these are novarian cancer people having another PARP inhibitor on top of standard therapy and again showing an effect of the drug tailored toward the gene mutation these trials are still going forward for breast cancer there's been less success and it may be due to heterogeneity for breast cancer there's a lot of excitement in the ovarian cancer world for using these to treat ovarian cancer because again many more ovarian cancers have BRCA mutations and many more ovarian cancers are more BRCA-like than they are breast cancers I think the company that one of the compounds is an AstraZeneca compound I think they were quite disappointed in the breast cancer results because obviously for them it's a larger market than the ovarian cancer I think if you have ovarian cancer you'd be pretty excited about anything that might be in advance in treatment from what I've heard these are being used essentially now off-label even though the clinical trials aren't done and I don't know if any of you in the room have experienced with any of these PARP inhibitors but I just want to close with showing you that these results again were driven by the genetics understanding the genetic mechanism understanding what the genes do have had an influence on the way to target these tumors and so by understanding mechanism and refining the characterization of the pathways been able to rationally design drugs to help treat the tumors I think that I've told you that we can use in theory use this knowledge of genetics of breast cancer to tailor early detection methods prevention is still somewhat up in the air I think many people reject prophylactic mastectomy as a preventative measure but it does prevent breast cancer and BRCA-1, BRCA-2 families as well as ufirectomy. There are some advances that have been had in prognosis in knowing who has a BRCA-1 and 2 mutation and I think a lot of the excitement it's been in the last couple years has been in the tailored therapy and and with that I'd like to close and thank you for your attention I promise that I would make time for questions. It kind of overpowers the other so the question was if you look at environmental risk factors reproductive history alcohol dietary exposure obesity do the BRCA-1 synergize with those environmental risks and I think synergy is probably not there it tends to overpower it there are there have been some studies done where oral contraceptive use seems to be a little bit more powerful of a protection in individuals have BRCA-1 data but it's not been great very large studies so they tend to be really overpowering risk factors as much as we would like to say that we could remove some environmental exposure and make breast cancer go away I don't think we can I think it's the internal environment right so the question was what about HRT hormone replacement therapy and I think from the it's not suggested or recommended for people who carry the the high prevalence mutations and probably not recommended or suggested for almost anyone now given that the breast cancer risk and the lack of cardiac protection sorry I didn't hear the last part the contraceptive oral contraceptives used early are somewhat protected from some epidemiologic data later in life yeah yes yeah so the the question is why is this gene so sensitive I don't think the gene is sensitive I we have a lot of mutations going on in our body the gene shows us peck pattern of mutations that is consistent with just internal environment causing mutations some of these mutations and the founder mutations some of those mutational events actually happened two three thousand years ago and are just carried through because the breast cancer is as awful as it is is not something it interferes for the most part with reproduction so it's not necessarily selective at disadvantage to having cancer cancer as a whole in that realm the current recommendation is to do MRI not not necessarily because of the radiation risk which has always been theoretical and controversial because radiation causes double-strand can cause double-stranded breaks in women who potentially may have their double-stranded break repair compromised the studies that have been done that I am aware of showed the MRI is just more sensitive and detects earlier lesions and so that's why they're shifting toward that recommendation in bsa1 or positive family history yeah I don't know the current and maybe Stan do you know for the I don't know the current asco recommendations as to interval I do know there's a lot of diversity some of these families the women show up every six months because they're very nervous about their risk I think the date hardcore data on efficacy is somewhat slim this question over there who are very high-risk but I like to advise them is that they alternated six months between demography and MRI so in the winter they have your mammogram and in the summer they have your MR so but these are patients who are at a very high level of surveillance and and at least of our population these patients are very much attuned to their level of risk but these are these are women who will have many many biopsies and many many benign biops what is your insurance company willing to tolerate I do have a question which is what correlation of any is here between the individual genetic analysis and the genetic archetype analysis that we're doing of the tumors themselves and are there any implications so the question is are there correlations between the individual I can say the germline the inherited profile and the oncotype type testing which actually looks at the expression levels in the tumors themselves and there are some correlations in that the phenotypes of especially in BRCA one of the tumors tend to correlate with the mutation a little bit I don't know in clinical care whether it makes any difference so BRCA one tumors tend to be the more the triple negative essentially estrogen receptor a negative type tumors they probably show up on the oncotype test is as well my guess is that if you had the germline knowledge and the oncotype test the oncotype test would kind of overrule the germline knowledge you might predict the oncotype test result from knowing the germline but you really want to know what's going on in the particular tumor and that's a case where I think what's going on in the tumor at the time you actually run the test is probably more important than the actual germline constitution a lot of triple negative a lot of basal tumors occur in women who are not BRCA one positive and so knowing BRCA one status alone is not enough it's a question in the back so the question is when I'm talking about increased risk in BRCA one or two am I talking about heterozygous or homozygous and it's an excellent question because the it's really a little bit of both the inheritance is heterozygous in that the person inherits one mutated copy and has one good copy so in that case the person is a heterozygous what we think happens is that the tumor loses the other copy and becomes homozygous for it but really when we're talking about risk we're talking about the heterozygous if you have two mutations in BRCA one one your maternal and one in your paternal chromosome you probably are not viable and so mice are that those mutations you can make in mice and follow their lethal in BRCA two they're mostly lethal there is one exception there are some mutations that you can have in BRCA two where you've got two alleles so your homozygous for mutation and that produces a different phenotype called phancone anemia which is usually identified through other reasons in the childhood time so for the most part one carrying one mutated chromosome increases your risk and we're talking about it in the heterozygous state so the question is can you have a one maybe a heterozygous for a BRCA one and heterozygous for a BRCA two mutation and the answer is yes that's been documented most in the Ashkenazi Jewish population where you have one percent of one and one percent of the other in the general population so you'd expect one in 10,000 individuals to have both and it's founded about that rate so there's probably not synergy in that you don't have worse disease but there's only been a very very small number of people documented who have that so it's a little bit hard to say with any conclusion but there have been people who have a heterozygous mutation in BRCA one and a heterozygous mutation in BRCA two but they're rare um but let me tell me yesterday that her mother and her sister are BRCA one or two positive and she isn't so does she have an increased risk of breast cancer over the population and excuse my ignorance but is this a test that you do just once in your lifetime or can people mutate later in life and you have to test again so the question was if a woman who comes from a family where her mother and her sister carry the BRCA one mutation a specific one and she's tested and she doesn't carry it is her risk higher or is the population risk it is probably almost certainly infinitely closer to the population risk can we say it's not a little bit higher no but generally the the surveillance and the screening recommendations drop down to the population risk and the second part of the question was do i have to get tested once or can mutations happen later and so these are inherited mutations we test them in the blood even though the that your blood DNA even though it's not your blood that's the affected tissue and you really should only have to do it once i'm going to defer to the radiologist the question was could you comment on the use of CT scans of the chest and the risk of radiation yeah well this is this is a very hot topic right now obviously um and i kind of have it in two camps of are the ways that i think about it one camp are the people who um they have a symptom or an issue or they already have to answer some other other problem and they're getting a CT scan to answer a specific question that will have immediate diagnostic or therapeutic impact the risk of radiation for those patients i think is in my way is based on extrapolated data we don't we don't really know what that risk is we think we know based on extrapolated data but nobody really knows what that risk is those people in my mind their risk of developing cancer in 25 years is marginal compared to the benefit that they're going to gain by having exams the second camp are people who are having exams that we think are maybe um not such great views people who have um total body screening for example i have strongly strongly discouraged this because uh there was no data to show that that there are improved outcomes for these patients um and obviously they're getting radiation um that they would not otherwise have there's a there's a certain amount of CT scanning that is done um particularly in patients who are seen in the emergency department uh and and it happens because of the pressures in that department to diagnose and uh and move patients quickly and i think we could do a little bit more with better utilization in those patients and decrease their potential risk by having CT scan um but that that's a much bigger problem that that we can't solve on an individual basis and that is a problem that will have to be addressed more globally as to what is considered appropriate utilization there are a lot of factors right now going into what is considered appropriate utilization there's a whole liability set against what we know as best practices and that's going to get worked out over the next i'd say five to ten years as uh it's helpfully flexible but if you have patients who have real problems and you need diagnostic information so this is where you have an impact on on diagnosis and treatment and the patient is 30 years old i i certainly wouldn't not have a CT scan of the chest because of the potential radiation to progress in that what about for the smokers the CT that they recommend CT of the chest of the smoking and when there's all the new information showing the utilization of screening CT if by the way all of our machines now and the way we set up our protocols are set up to minimize radiation but still be um of diagnostic accuracy there's a difference in imaging of what is um diagnostically accurate and what is a pleasing image to the eye and if you use more radiation you get a very pleasing image it may not have any more diagnostic accuracy than the very grainy noisy looking image um so there's a lot of sensitivity right now to using factors on in the skin parameters to minimize the dose of radiation but still have diagnostic accuracy thank you