Breast Cancer Common

>> okay we're going to get going, and the good news is we've had about 30 people sign up to visit the cores, or the tumor boards so this is the last day that you can sign up. and if anyone in the class wants to, i brought some sheets you can just get them from me and

fill them out. and we're sort of switching the schedule, our first lecture today is jill smith she was a psor at penn state and then she came to nih for a year, and now she's a professor of medicine at george town. she's going to discuss

translational research bench to bed side clinical trials. jill. >> thank you. how many of you in the audience are ph.d.'s? working on ph.d.'s? how many md's? and other students, or- -

rn's or- - staff, okay. well, okay. so i do have a couple of disclosures that i'd like to say, i'm an inventer, i have a few patents and i might mention some in the work here, and i also am a director for a

consulting firm, and i help companies get drugs developed. the objectives of what i'm going to discuss today is, first, how to understand to take an idea from the research lab to patient care. learn the steps on how you conduct a clinical trial, and

comprehend some of the obstacles that we have in overcoming for drug development, and then i'm going to give you some examples that i've had from my experience with translational projects, and then the pitfalls and the prize. so first of all, we all have dreams.

you wouldn't be here if you didn't have a dream, you know? i want to cure cancer, i want to find a cure for aids, i want the nobel prize. you know, that was always my dream, i wanted to get the nobel prize. and we all have dreams and of

course nelson mandela talked about how there's no easy walk to freedom anywhere, and then you have to go through these difficulties in the valley of the shadow of death again, again, and before we reach our mountain top desires. ed mund hillary, who was the

first person that summited mount every everest and he stood before a beautiful picture of mount everest is and when he failed the first time he tried to ascend mount everest all of his people in his team died and he came back and he spoke to the parliament or whatever and he

turned and he looked at the picture and he said mount everest you have defeated me but i will return and i will defeat you. because you can't get any bigger, but i can. and then of course martin luther king, he has the dream, you

know, the dream his great speech about the dream. so we all have dreams and aspirations about where we want to be, what we want to do, or you wouldn't be here at the nih studying and learni more. so pie talk is going to be about research and drug development

and translational research. and of course there's tons of research that's going on in the preclinical arena, and the problem is, is that in spite of all these reser arch projects going on, very few of them actually make it all the way into clinical trials.

so there's this bottle neck, and things get weeded out for one reason or another. or is the real bottle neck--i'm not supposed to say this at a federal facility--is it washington? is it a political problem? >> we can't get funding, there's

not enough money for research or whatever. so where is the bottle neck really? if we had more money we could do more research, right? so first of all, the first thing you need to get started in your research project, and i presume

all of you are working on different research areas, is you have to have an idea. you have to have a hypothesis. and then you have to decide, what is the problem that's at hand? what needs to be done to solve this problem?

and how can your research change the problem? so the last thing that you have to have is you've got to have passion for what you're doing. if you don't like what you're doing, do something else. you really have to have a passion.

you've got like, your gene is the gene that's going to change the world. you know you have a protein that you know is going to make a difference in someone's life. you have to have a passion about what you're doing. okay.

i'm going to talk a little bit about the different phases of clinical trials, and most trials go through, for new drugs, go through a series of steps. first of all, how many of you are working in a research lab with cells and animals and things like that?

so that's in the preclinical phase, okay? and those are all just as important for research. that's where it all starts. so we work with cells in culture, with animals in vivo experiments and once we go beyond the animals we want to

take it to human trials then we go through four different phases, phase 1, 2, 3, and 4, and there's different types of trials. we have treatment trials, prevention trials. early detection, diagnostic, genetics, quality of life and so

on. the phase 1 trial is usually the first in human when you're going from your animal to human, and is not a lot of people, and the whole purpose of the phase 1 trial is to determine, is the compound that you're going to use safe?

how toxic is it? and then you twoont know how should it be given? do you have to give it intravenously because it's a protein and it's going to be degraded if you take it orally? you have to study the pharmaco kin et ibs?

what's the half life? and what is the toxicity, the treatment effects on the body? so that's what the outcome should be of your phase 1 trial. it's not does it work or doesn't work, it's is it safe? the phase 2 trial is actually efficacy.

does it really do anything? so, and usually the first phase 2 trial is not a whole lot of people but you have to have a primary end point. most phase 2 trials are done unbiassed meaning they're blind in fashion, and that you want to know, does it work?

you might compare your compound to a placebo to see if you get a better effect. sometimes in cancer treatments we compare it to standard treatment. we don't want to put our cancer patients on a placebo. then a phase 3 trial is usually

hundreds to thousands of people, and you want to see if there's an equal chance to be assigned to one group or the other. you want your groups to be very comparable. and the purpose of this is to determine how the new treatment compares to either the current

treatment, or to a placebo. and these trials are usually done as a superiority trial, yes our drug is more superior than the standard of treatment, or a non-inferiority trial meaning that it's the same, but maybe it costs less. so there's reasons for doing

non-inferiority trials but you have to decide if the onset of your protocol design what type of trial it's going to be so that you can reach your outcome. and then lastly, there's phase 4 trials which are hundreds of thousands of people and this is for example like a vaccination.

once a vaccination gets approved, if we get a vaccination for ebola it's going to go into clinical trials, and like the hepatitis b vaccinations it was years later in testing to see what was the efficacy in decreasing the outcome of exposure to people

with hepatitis b and that was after it had already been approved. so that's the post-marketing phase of the trial. so when we do trials, we typically do randomized trials. meaning there's an equal chance of being assigned to one group

versus the other. and one group typically gets the most widely-accepted or standard treatment, and the other group, you know, gets the treatment you're going to be testing. and you want the groups to be very similar. so if your outcome is going to

be based upon a certain blood test, say like a c-reactive protein, you want to make sure when you enroll the people into the study that it's equally group a have the same starting level of c-reactive protein as those in group b. otherwise you're going to be

changing your end point. so this will provide the best way to prove the effectiveness of an agent. and then you could do a small pilot trial. typically when we have no idea how many patients we need for a sample size, we'll do a pilot

trial without even having a placebo, just to see, well, does it change the outcome? does it shrink the tumor? and that griives you a tentat idea of how many people you're going to have to enroll to get your p-value of .05 to show it is better or not better.

so that provides the tentative response rate to estimate your sam p sample size. the other thing you need to keep in mind is whenever we do clinical trials you're dealing with human subjects. and there's human subject protection offices.

and patient rights have to be protected. so there's ethical and legal codes that govern our medical practice, and they apply to clinical trials. you have to get an informed c, the patient has to understand what's going on, and

they have to comprehend it. for example, if you ha somebody who does not speak the language that your consent is written in you cannot have a family member interpret it to them, because you have to have somebody who is not related to the patient interpret it.

so there's all these little details that are important. once you go into the clinical trial, there are review boards. so there's a scientific review for a lot of the cancer studies, and then there's the institutional review board which will approve or disapprove or

ask you to modify your protocol in order to protect the rights of the patients. and then once the study starts going, often there's a data safety monitoring board that will be monitoring your study as you go along, and you may not know who's on what treatment,

but the safety board will know. and we often have early stopping rules. so for example, if you find treatment a is much better than treatment b, and the people getting treatment b are not surviving as long, the data safety monitoring board may stop

the study, an early stopping rule, and make you treat everybody. so that's what a data safety- - or it if they find your treatment is causing harm to people, they may as to' it early. so that's their job.

so the other thing that's very important today, now that we're doing a lot of genetic testing, it's required that you have a paragraph in your consent form, if you are going to be keeping patients' blood samples or dna for possible genetic testing, because that may have outcomes

for insurance purposes. and patients have to understand that. even if you de-identify the data it has to be placed in the consent form. so how do you do it? what are some of the nuts and bolts of going from your cell

culture in mice to going into humans? and i'll just give you some examples from my experience. my research is primarily with pancreatic cancer. so pancreatic cancer is the fourth leading cause of cancer-related deaths in the

united states, and the median survival is only 3-6 months from the time of diagnosis. it is the only cancer that's a five-year survival is in the single digits. and most cases are not diagnosed early and there is no effective therapy if it's not surgely

treated. surgically treated. looking at this graph the incidence of pancreatic cancer is actually on the rise. and this paper that was published in cancer research on the left-hand side of i don'tor your screen, shows by 2020 it

will exseat colorectal cancer and breast cancer to become the second leading cause of cancer-related death in the cer which is dr. moody's ng talk. now, how do we treat pan krcreatic cancer? shown on this slide is the

standard treatment we have today for advanced pancreatic cancer, and this is, both published in new england journal of medicine and one study involved fofurinox and the other is genabraxane. even with the best that we have today the survival does not make it out one year.

so it's really awful. so we have tried over 70 different chemotherapy put i can regimens in pancreatic cancer. we have o thrown ever toxic agent we have at pancreatic cancer is resistant. and because of this congress has declared pancreatic cancer to be

one of the recalcitra in ks t cancers and asking for more funding for this area so things will change in the future. so first of all with pancreatic cancer for any of you in the lab into cloning you can't expect to change the outcome of pancreatic cancer if you keep doing the

same thing. you've got to change your strategy. i think one of the problems with pancreatic cancer is that, in spite of all of our genomicgenomics, our advanced technology and imaging, survival from pancreatic cancer has not

changed in 50 years. and one of the reasons, i think, here's the belt way, is that see this guy is going in the wrong direction. so maybe we're going in the wrong direction, here. we have to think of other ways and think outside the box.

so now you come along, you say, okay, what is the problem? well what's the reason why pancreatic cancer prognosis is so poor? well there's no method to detect it early, there are no screening tests for people who are at high risk.

it's resistant to chemotherapy, and we really don't understand the biology of this cancer. so one of the areas of my researchs with g-protein coupled receptors and one of those g-proen protein coupled receptors is opoid receptors and my interest is they serve at

potent growth regulators. what increases indodge nows open yo opoids, one is eating chocolate, especially dark chocolate. i like that one. the other one is exercise, and we all know people get that euphoria from the endorphins

they go up if you have a good workout. the other is a religious experience, and a fourth thing that raises endogenous enkeplins and endorphins is actually sex. but that's sensored for this so what are the opoid pep tieds and their receptors?

so the endogenous opoids which are enkellins and even dor fins, ogf, open yoid growth factor is made within us, they can cause euphoria and the runner's high. we're all familiar with opiates, that's the pain pills, narcotics, morphine, demerol, and those are used to treat pain

and cause they help diarrhea. so some of my colleagues up at penn state were looking at metankeflin they found a decreased growth of cancers and it does this by diffusing into the cells and it up-regulates p-16 and p-21 which are inhibit inhibita

inhibitary prime aces. when it does that it binds to the nuclear envelope so it's a nuclear receptor and in doing so it decreases dna sin thing sis and decreases growth. so it's a negative regulatory pep tied. one of the things we did is we

thought well we should look at t my partner dr. zszabo was working in nutrition. i wonder what it does to our hiypothesis was ogs could in inpibt pancreatic cancer. so we did some preclinical experiments and we do pancreatic cancer cells in cultures,

treated them with the ogf and looked to see how it affected growth, we studied the signalling pathways and an animal model. to make a long story short, here's our controlled pancreatic cancer cells when we treated them with ogf we inhibited

growth. and when we mroked the recreptor with an opoid antagonist we reversed it, we knew it was a receptor mediated growth and the concentration of the and take go nis that will not have an effect on growth itself. and then we also did receptor

binding and we found that there were indeed ogf receptors on human pancreatic cancer cells. we went from cells into mice and we treated our mice and you can see they have these really ugly tumors, and we treated them with 5 milligrams per kill gam of the ogf three times a day to shrink

their tumors, and, indeed, we could shrink the tumors. so this was really exciting. but then we wanted to say well does this work in human beings? so if you're treating a mouse it's 5 milligrams per kill gram three times a day then you have to calculate how much am i going

to give a 70 kill gram person? so there are different method that you can kind of calculate the dose and then you reduce it like ten fold. so that's basically what i did. so getting back to the hypothesis-driven research, so we have a problem, pancreatic

cancer, and the problem is that it's got a terrible prognosis, three months' survival. our hypothesis was that ogf could inhibit the growth of the cancer cells in mice and in cultures so maybe it would work in humans. so we started with a phase 1

trial, looking at safety and toxicity. but before you get to the phase 1 trial, you have to get approval from the food and drug administration before you can take a compound that's never been given to humans before and give it to humans.

because it's not approved. so you have to apply for what we call an ind, or an investigational new drug number. and in order to do that you have to fill out these two forms called a 1571 and a 1572, and then you have to have a protocol that will be approved by the fda

that will tell them exactly what you're going to do, what doses you're going to use, how you're going to give it. you have to get your consent form, you have to get approval from the research committee, and of course it's good to find a funding agency that will sponsor

your research. that's probably the hardest part. a lot of times people at this point will go to a company. we were fortunate that i got an nih grant that supported this. and then there's different responsibilities.

and of course you have to upload your clinical trial before you treat the first patient on the clinical trial.gov web site. otherwise you cannot publish your results. so that's mandatory. so there's a web site that you have to go to, and that's where

patients can search for what trials are out there. this is just a copy of the 1571 form, and it has to be stted, you have to put your ind number every time you communicate with the fda, and you send in a revised protocol or anything, you have to send in

another copy of this form. so this just happened to be my ind number for the ogs, and you have to put in here the serial number of, this is the first time i'm submitting this application so this happens to be serial number 1, the next time i communicate with the fda

it's dpg to be serial number 2, and so forth. and then you have to say what you're submitting o enthis report. this is a new protocol, this is a revised protocol, and you tell them what you're doing. so then what were the aims of

our phase 1 study? well, we wanted to look at the safety and toxicity of giving ogf to humans. i wanted to know what dose to use? w the maximum tolerated dose before i got to toxicity, and i wanted to study some of

the pharmaco kinetics. how is it me tab lied? can we measure it in the blood? and what's the best route of add men stragadministration. i know it's a pep tied so i couldn't give it orally. we were going to try giving it intravenously as well as

subcutaneously. i calculated based upon the mice, or tentative dose i backed that down and came up with this dose for humans of 25 micrograms per kill gram, and this is a classic, what we call dose escalation, 3 by 3 study design. so you enter 3 patients at the

top, at the lowest dose, and then you look for any toxicity. if there's no toxicity then you go on up to the next dose. if there's no toxicity you go on up to the next dose and so forth. but if you have a do have a toxic event you have to enter

more three more at that dose, or two toxic events you can't go any further. so that's the typical way of doing it. so we started at 25, and i will say that the first patient that i treated with pancreatic cancer ended up in the hospital that

weekend with abdominal pain. and i had to make a decision whether it was due to my treatment, or was it due to her and it wasn't- - it was a known side effect of pancreatic cancer, so i went ahead and treated the other two patients and they did just fine.

but you know, i could have possibly said oh, no, i'm not going to go any further. but i went ahead. and actually that was at 25, and we ended up going all the way up to 250 micrograms per kill gram before we reached toxicity. so that was our mtd, or maximum

tolerated dose. we also measured blood levels, and we measured them after giving it subcutaneously and intravenously and we could actually get higher blood levels if we gave it subcutaneously but the patients were having to inject themselves a couple of

times a day and i just didn't have the heart for that. so we ended up giving it in our study by an infusion over 30 minutes. so after we did our phase 1 trial and we looked at safety and toxicity and we also did chronic treatment with that to

make sure it was safe, then we moved on to the phase 2 trial, and we did the phase it trial at the dose that we had determined was the best dose in the phase 1 trial. we did it first as an open label stud and then a sample size based upon what we did in the

phase 1 trial, i knew how many patients i needed to have. i needed to have at least 50 subjects to be treated, and we ended up having 166 control patients. so we treated patients who had unre treatable pancreatic cancer.

the caveat is i went round and round with the fda. i would have loved to have compared it to standard treatment but they said, you can't do that because we don't know if your compound works or doesn't work, and you might be preventing someone from getting

a possible therapy that could be useful, even though we know those treatments don't work. so they made me treat people who had already failed therapy, which if you know pancreatic cancer by the time you fail therapy you're already close to the end.

but that was the best we could do. but so we did this study, and we compared it to people, people who had failed therapy, they had the option to enroll in this study or not get any treatment. so we had a control group of people and they were equally

balanced. and so we looked at survival, we looked at the kinds of progression, the clinical benefit and quality of life in these patients. actually found that many and patients who were on this study had stabilization of their

disease, or decrease in the size of their tumors. and what we found was when we looked at survival, that our ogf-treated patients had significantly increased survival, compared to the untreated patients. so this is a phase 2 trial.

it's efficacy, and yes, it does have some effect on pancreatic so that's one compound. now, another area of g-protein coupled research i do with choleckynan receptions or cck recepto receptors. that's the classic g-protein

coupled reaccepts septemberors, and the primary log-ins are coaly cystic kinan and gastrin. there are three different types of receptors i don't know how many of you have had gi physiology but if you haven't, i'll view it. the a was call ld the a because

it was found in the alimentary track and it has a greater affinity and it's in the, the b receptors washington found in the brain by dr. stephen wenk, he cloned this receptor he's the one that discovered this. and it's the main receptor that's in the stomach and in the

human pancreas. and it has an equal affinity for the two, and then there's the cck-c receptor my lab discovered and it's a spliced variant of the b receptor that occurs only in cancer and has a greater affinity for gastrin that than for cck.

and we started looking at human pancreatic cancer cells and compared them to a normal pancreas. and again, this is back to the lab. and what we found was that pancreatic cancer mark edly over-express the cck-b receptor.

these cancers are listed in order of how differentiated they are. so pank 1 cells are the most po poorly differentiated and they have the most number of receptors compared to the normal when we took these cells in cell

culture and treated them or we found that we could stimulate the growth of the cancer cells. so another interesting thing is gastrin, one of the ligans that binds to the cck receptor is normally present in the fetal pancreas and where it aids and grows in differentiation but

it's shut off at week 14 in both humans and in mice, and then it's not reexpressed again until early pre-cancerous lesions. and what we found is we looked at normal pancreas and we looked at these pancreatic cell lines and one of these is messenger rna for dpks astrin and the

other one is peptide and gastrin becomes reactivated and is over-expressed in pancreatic and what we found here is this is gastrin staining and we looked at our human pancreatic cell lines, what we found was when we grew them as tumors in nude mice their growth rate was

directly proportional to how much gastrin they made. so that's one of the drivers of pancreatic cancer and it does so by stimulating the cck-b and so we thought okay, so what happens if we get rid of gastrin? will the cancer cells still

grow? so we measured, we did knock-down experiments with anti-sense and some stable clones with sh rna and we knocked down gastrin and this is showing it's knocked down by qiptcr. when we tried to grow the

knock-down clones in cells we found those that had greater than 90 percent of the gastrin did not form tumors. those that had like 70 percent knockdown still formed tumors but the growth was delayed. so this is the normal wild type so if you knock out gastrin you

can slow down the growth of so that's easy to say that you can do an si-rna in the test tube but how are you going to use that to treat human beings? so one of the projects that i'm working on with the guys at the national nanocharacterization lab in frederick, we've designed

some nanoparticles, and nanoparticles can protect the si rna, we can put it inside these nanoparticles and we can deliver the si-rna safely to the tumor so it won't be did i jested in the blood. the other thing we can do is we can make these nanoparticles so

they're target specific and they go directly to the cck receptors, so it will go just to pancreatic cancer and not to all the other tissues to give you that off-target toxicity like chemotherapy does. the other thing we've done is put fluorescent probes inside so

we can look and see where do these nanoparticles end up in the mice when we do it? some examples of things that we've been working on, this is a mouse and that's actual luciferous, they have an ort oh topic pancreatic cancer and we treated these groups, one got

empty lipisum meaning nothing was inside of them. some had a scrambled rna control and the third group down here got the gastrin sirna. we injected the mice and we found indeed we could inhibit the growth of pancreatic cancer by targeting the dpks astrin and

shutting it down. and this was good but we wanted something a little bit better. these particles in this experiment were what we called non-targeted. they went anywhere in the mouth, they weren't going directly to the receptors.

so we used a different formula, and we congugated ligins so it would combine with the cck receptors it would normal eyes and knock down gastrin. we put the fluorescent probe so we made sure it went to the what you have on the left is a mouse, i operated on the mice

and gave them cancer in their pancreas and we injected them with the nanoparticles that had the fluorescent probe in them but they weren't targeted to go to the receptor. and you can see after seven hours they're kind of scattered throughout here, but then after

24 hours, there's not a whole lot of activity. however, in the particles that we designed that will target the cck receptor, we found not only at seven hours but at 24 hours they stayed in the tumor, in the so now we can try to design therapies that will go to the

cancer, and not have this toxicity effect that will hurt other organs. well what about using gastrin in human beings? there's a company they're called cancer advances they actually took my idea about knocking down gastrin and developed a vaccine

for it. it's already been through six clinical trials and they found when they took patients who had pancreatic cancer and they vaccinated them so that they would raise their own antibodies to gastrin, to knock it out another way, what they found was

that in those people who responded and developed antibodies, their survival was significantly improved--better than the chemotherapy that we're seeing. so if you can- - this is proof of principle. if you can knock out the

gastrin, which is one of the drivers for pancreatic cancer, and this is, hopefully going before the fda to get this approved for therapy. so it's based upon basic science resea taking it to clinical so just to review a little bit, there's receptors a normal

pancreas and these receptors, the cck receptors will bind cck or gastrin and in the normal condition it releases enzymes to help you digest foods. in cancer they're over-expressed and there's a mutated receptor but they don't make enzymes when the receptors are activated they

cause cell growth. and then gas trin gets activated inside the cells and released into the media where it stimulates growth. this is what we call the cck-c receptor and that's the third receptor i wanted to mention to years ago when i was just doing

rtprc and looking at the cck-b receptor in human pancreatic cancer specimens we found a large number of specimens had a larger size pcr product and i didn't know why. and we ended up finding out there were some specimens that re{feign|feint}s the fourth

entrons. in the wild type normal ckk-b receptors it spliced out. but for some reason in the cck-c receptor the fourth entrons remains there and we found that this is due to a single nook leo tied poly morphism that occurred within entron 4, so they missed

this mutation when they were doing their large studies because it's an entronic snip. and it changes a c to an a, and when that happens, you don't splice out the foufrt entron and you get a longer sized piece. and the reason why this was never found when people were

doing research with mice, this is a plug for why you have to always think about using human tissues, because not everything is the same. so when you look at humans and you look at the fourth entron here of ckk-b, it has 207, which is did i advicible by three so

you get three codens. but also down if you look at entron 4, humans have an open reading frame throughout this fourth entron, so if it's misspliced you can transcribe it and translate it into protein. however in rodents there's a stop code right at the beginning

of entron 4 so they never transcribe it. so what happens in humans who have this snip? and the snip is actually in 40 percent, 35 to 40 percent of people with pancreatic cancer, is that they missplice the fourth entron and that is

translated into a 69 an mean oh acids, and this happens to be within the third intercellular loop of the recreptor, the protein coupled receptor which is the area of the receptor that's involved in gtp binding and cell proliferation. we've raised an antibody to

this, and so why does this happ happen? so what we have figured out is that in people who have the wild type b receptor and have the c geen g ks geno type, it allows binding of this splicing protein to the premessenger rna then you

splice out the entron. in people who have the snip, and h the transition from c to a, they do not have the binding of this splicing protein so they fail to splice out the entron. well, is this clinically relevant at all? we did a large study, so this is

where you go back and you do studies. and we did a study in 761 patients who had pancreatic cancer and we gene oh typed their cck-b receptors and we also looked at their suf viefl. if they had the snip, did it affect their survival?

and indeed it did. because our hiypothesis was that because it's in the third intracellular loop and it's driving gtp proteins in proliferation, if you have this it's going to accelerate the growth of the cancer. and indeed, if you have this

snip, you die very rapidly from the disease. you die very rapidly anyway from pancreatic cancer but this may contribute to why the survival from pancreatic cancer is so poor. because 35 to 40 percent of the people have this snip.

not only is this important is that you know snips are germ line mutations they're not somatic mutations and because of that it's possible we might begin to screen high-risk families for this snip to see if it may predispose them to get so it does have some clinical

relevance. so last thing to mention here, intellectual property. whenever you're doing research, you know, you have to submit an invention disclosure or some provisional patent, especially if you're going to present the research publicly, including

posters. because once you present it, it's public domain. so just submit something so that they know that you claim this is your work. and then the other thing is, is that the patent belongs to whoever you work for.

m ogf patent belongs to penn state, and you know, so they get most of the royalties on it, and i get lunch, you know? but once you do this, and you make a discovery, and you have a patent, then you can assign the rights to a company, and then you license the patent and you

try to develop the drug. and basically, companies are only going to be really interested in your research if it's patentable because that's how they're going to make their money. so think about that, you know. of course we as scientists are

more interested in coming up with a discovery but you have to think of the realities of the things if you're going to get your compound out there and get a company to develop it, they only want to develop it if they have rights. so what are some of the

obstacles with translational research today? well of course money is always a problem, lack of funds or misuse of funds or disparity of funds. i'm a clinician, and it's hard for clinicians to get protected research time. they would rather i be off doing

screening colonoscopies than trying to solve pancre so there's a big chasm between tri, the nih and academia. and i know that when i worked for the nih i wasn't allowed to talk to industry. and when you're in academi they have you sign these

disclosur disclosures, industry doesn't like sharing their ideas with academia and vice versa. we all need to come together. there's a lot of great ideas that are developed in research labs, and you know, as long as those can be licensed to

companies they just need to work together so that we can develop these ideas. there's always a problem with trying to recruit patients into patients often say oh, am i going to be a guinea pig? you know, that's always one thing they ask.

but you know, i think of all the patients that i've treated, they've all been so satisfied and delighted that they were able to participate in a research study, even if it didn't help them, they know that they're advancing science. and then the other important

issue is that there's no no man is an island. it's all about team science. you know i couldn't have done this work without having my colleagues, who are in chemistry, who are in, you know, the ph.d.'s in the lab, who do the other stuff, we all have to

work together. t nanoparticles, i mean it's a team approach. i bring something to the table, they bring something to the table, we all have to work together, and that's how we advance science, and we share ideas and we work together.

so in order to cure pancreatic cancer, i say we have to think outside the box, and rather than doing what everybody else has this is really the person that's going in the right directi and we all need to sit back and think, when we're doing our

research, you know, it's okay to think outside the box. it's those out-of-the-box ideas that change the world, and change science. so- - and don't be afraid to take some risks. you know, if i had stopped at

that first patient who had some abdominal pain when i gave her the first dose of ogf, it wouldn't be going through the fda right now for approval for so sometimes you have to take some risks to move forward. and the bottom line is, does research have any clinical

relevance to people? well these are some of my patients that i've treated with pancreatic cancer, who were just delighted to have their picture taken because they participated in research, and it changed their lives. so yes.

i mean for each one of those patients, you know, if i can change one life it's worth it. so i also want to say, don't give up. if i can tell all of you who are starting off, you know, whatever mistakes you make in the lab, i've made every mistake.

you know, will i ever get the nobel prize? maybe not but i hope one of the people i've trained or one of my students will get the nobel and it's important that you have to stand up for what you believe in. and what i say, is if you don't

believe in yourself or in your dreams, no one else is going to believe in you either. so you have to believe in what you're doing. you have to have faith in your work, and you have to not give up. okay?

so i want to give thanks to my lab and of course all the animals who gave their lives for my researc and thank you very much. any questions? (applaus (applause). (questio

(question). >> so the question is, is when gastrin expressed? it's expressed in the developing fetus up until about week 14 and then it's shut off and it's not detected at birth in the adult, in mice and in humans. the only place where gastrin,

not in the pancreas, but the only place where gastrin is present is in the stomach, and it's made in the g-cells of the antrum of the stomach but not in the pancreas. now it gets turned back on and so we don't know, is this the microrna or what's controlling

it to be shut on and shut off? looking at.ome of the areas but it gets turned back on in precancero precancerous, they're called panin lesions of the pan kree as. that's when it drives the progression to pancreatic

so the question was, how did the company make the vaccine against the gastrin so we know that the cancer cells can respond to gastrin from two stores, one is a pericrine which is the gas continue we make in our stomachs, and causes the release of gastric acid.

that's the exogenous pericrine effect. we have it floating in our blood. but the second place where gastrin is the auditory effect when they stimulate their own so there's two methods, but gastrin is still the ligand

regardless of where it's coming that's stimulating the growth. so they develop the vaccine and actually hook up to the toxin and inject it and it causes an immune response. and part of that is because of adjuvants that they use to stimulate the immune response.

does that answer your question? so it's a pep tied so it's not going to bind to the receptor. it's not- - the question was, does it hurt their stomach cells at all? right. so the only advantage that it may have is if physiologically,

when we eat, your stomach releases gastrin which causes the release of acid in the stomach, and if anything, it would decrease gastric as itd so maybe you wouldn't have as much acid reflux. you wouldn't have- - and on the other side- -

that's a good thing, right. on the other side, you know, they were developing a lot of drugs to treat this, and when proton pump inhibitors came out, the proton pump inhibitors block acid release from the stomach's parietal cells and it blocks the feedback loop.

so the stomach thinks okay there's not acid there so i have to make more. it makes more and more gastrin so levels can actually go up in people who chronically take high doses of proton pump inhibitors. not to scare anyone, like imiprazol.

they can raise gastrin levels. so yes, there have been some studies where they looked at people who have aclorhydrian high gastrin levels. it's not that the gastrin itself causes the pancreatic cancer. however, if you were to have pancreatic cancer or if you were

to have a precancerous lesion like a panin which we know has cck receptors on it and you take a medicine that raises your gastrin you may stimulate the dproet of these precancerous lesions. perhaps, and i'm speaking speculatively, one of the

reasons why pancreatic cancer has increased in the past two decades is we've been using proton pump inhibitors and gastrin levels are going up. i don't know. that may be one of the reasons. so other questions? thank you very much.

diagnosed for every 100,000 women. the mortality- - i just want to point out that the incidence rate of actually has gone up by but i would say that's due more to early detection and the use of mammography.

the mortality rate was 22 deaths for every 100,000 women, and 12.3 percent of women will be diagnosed at some point in their life and this is data from 2009 to 2011. the breast cancer death to mortality rate has been declining steadily since 1989

when it peaked at a rate of 33 deaths for every 100,000 women. of those diagnosed between 2004 to 2010, 89.2 percent were expected to survive their disease at least five years. among white women the five-year relative survival rate was 91 percent, among african american

it was 78 percent. the increase in breast cancer survival, as i said, just now, and since the mid-1970's has been attributed to treating and so this graphing showing incidence and mortality by race, looking at the years 1975 to 2010, and for african american

females, we can see that the incidence rose sharply from 1975 to 1990, then it reached a plateau, and for white females the incidence has always been higher than african american females. it rose sharply between 1980 to 1985, then more recently the

incidence has declined and reached a plateau. mortality has been slowly declining for both african american females and white females, but there definitely remains a disparity in african american females to have a higher mortality.

this graph is showing a us mortality rates for cancer of the breast and the lung and the bronchus data from 1975 to 2010. from 1975 to 1990 the mortality for lung cancers steadily increased and then reached a plateau for both white females and african american females.

mortality rates for breast cancer have steadily declined since 1990. and again you're seeing a clear disparity exists between white females and african americans, for both white and african american lung cancer still is a higher mortality rate.

so what is breast cancer? it is cancer that forms in the tissues of the breast, and usually the ducts, and the ducts are the tubes that carry milk to the nippals and the lobul ks s as well. they're the glands that make the milk.

it includes in both men and women though male breast cancer can happen but it is rare. so this slide is showing you the structure of the breast. the breast is composed mainly of fatty tissue. so fatty tissue which contains a network of lobes- -

within the lobules, and so there's tiny ducts that connect the dmrands lobules and the. earl he detection, we want to talk about donning breast then once. >> please excuse me please excuse i'm going to check the transmission for technical

difficulties. age is a risk factor about 80 percent of breast cancer does occur in post-menopausal women. also if you have had a prior breast cancer that puts you at risk of having a second breast also, if you have a high risk prem premalignant lesion like glob

lar car sin open an that will put you at increased risk. also excess indodge nows or exogenous hormones such as if a person has an early men arc or late menopause, or if they take hormone replacement therapy we know that is a risk for breast cancer as well.

if if you've not ever had any children, a longer exposure to estrogen in your body that puts you at risk or if your first child at age greater than 35 you are, again, exposing your body to more estrogen and it is a women who have a history of breast biopsies for example it

could be for f.b.i. row cystic disease, or but we know that puts them at a higher risk of having breast cancer. patients who have radiation expos before the age of 40, for example, there are patients who have had we know cases who have had hodgkin's lymphoma and

they've been treated with radiation to the media sinum and in some cases have developed breast cancer after that w think that ma'am graphic density, dense breasts ot mammograms is a risk factor. also lifestyle factors, alcohol, lack of exercise, obesity, and

of course you know obesity, you produce more estrogen in the body. family history is an important risk factor. if your mother, sister, or daughter has developed breast cancer before menopause you are three times more likely to

develop the disease. if two or more close relatives for example your cousins, your aunts, your grandmother, have developed breast cancer, you are also at increased risk. we know that genetics definitely plays a big lowell. breast wan sers have been linked

to mutations in specific genes that we know. braca 1 is related to familial breast and ovarian cancer, braca 2 is linked to familial breast cancers, t-53, and blastoma 51 also linked to breast cancer, the her piece 2 are also linked to breast cancer.

women with mutations in p-53 and braca 1, they have a lifetime risk of breast cancer of 85 percent. we're going to talk about early detection and i do want to point out that october is breast cancer awareness month so you might want to share some of this

information with a family member or your mother, your sister, an au aunt. so the american cancer society guidelines for the early detection of breast cancer, annual mammograms they recommend starting at age 40 and

continuing as long as a woman is in good health. they recommend clinical breast exams every three years for women in their 20's and 30's, and annually after the age of 40. breast self-exam is an option for women starting in their 20's

and i'll talk about that in a minute. so the breast self-exam, that's an opportunity for a woman to become familiar with her own body so if there is a change, it can be detected quickly. if one does it, it should begin at age 20 and continue monthly

thereafter. so these are just some quick pictures to show you how a breast self-exam is done. you start by standing and looking in the mirror with your shoulders straight, with your arms on the hips. you look for any changes in

size, shape, color. you look for things that are not inverted nippal, or any nippal discharge. also in the position with arms raised above your head so you can look under the armpits where ther also breastish it use. the next step is to lie flat,

and feel your breath while lying down. use a firm, smooth touch. you want to keep your fingers flat and together. there are different ways to do it. one way is a circular motion but the most important thing follow

a pattern and cover the whole breast. so you do this both lying down and standing up or sitting. so i said that those self-breast exam is an option. so i'll explain it here. in 2002 the u.s. prevent irv service task force recommended

against teaching self-breast exams based on evidence indicating that a self-breast exam did not reduce breast cancer mortality. the decision was largely based on one randomized clinical trial indicating no difference in breast cancer mortal after

ten years in shanghai factory workers randomly assigned to receive self-breast examine strucks versus the control group. and the same study shows self-breast exams resulted in more breast biopsies and diagnosis of benign lesions.

but i just have to say that most clinicians actually do still recommend the self-breast exam. i think it's a good way to pick up things in between your physician visits, which for most people are just and are annually or every three years if you're younger.

but that is the data from the study. okay, as far as clinical exam, it should be performed by a doctor or trained nurse practitioner. the clinical breast exams have been shown to decrease mortality based on evidence from the

canadian national breast screening study. so the clinical exam is recommended every 2-3 years between the age of 20 to 40 and annually for women over 40. so abnormal signs and symptoms, so what are you looking for when you're doing your own exams, or

just paying attention to yourself during the year? you want to make sure that there's no change in breast size, there's no pain or tenderness, although i do have to point out that most breast w cancers there's no pain or

tenderness, it's often a painless lump that may be able to be felt and may not. it may be able to be picked up on mammography. redness, change in nippal position, changing around the nipples, sore breasts that don't heal, nippal discharge,

thickening of skin or lump or a knot or a retracted nipple. so mammograms--mammograms can be used as a screening tool to detect early breast cancer in women experiencing no symptoms. mammograms can also be used to detect and diagnose breast disease in women experiencing

symptoms such as a lump, pain, or nippal dischargle discharge. we know mammography reduces mortality by 25 percent in women 15 to 75 and 17 percent in women 40 to 49. there's probably a higher incidents in the 50 to 74 age other modalities of screenng in

high-risk women, digital mammography but in fact i think most institutions now do use digital mammography. the advantage is that an electronic image is stored as a computer file and the image can be enhanced magnified and manipulated so you can get a

look at what's in there as compared to the old films that people did. we also use mri, especially in women who have a greater breast density, which makes mammography difficult. but so the mri, it has sensitivi

sensitivity, it's higher than mammogr mammogram, so it's more often cause ti causative in disease but the sp specificity for mri is lower than mamo so you end up with more false positives and more

biopsies and that's the down side. so diagnosis, how do we diagnose breast cancer? so biopsy obviously is necessary to ascertain whether a lesion is benign or cancerous and involve go removing a sample of breast tissue.

there are several methods of breast by on op si these days. the most appropriate depends on the characteristics of the lesion, its size, location, appearance, and how it's accessible. so one of the most common ways is a fine needle aspira most

often done on a palpable lesion when you can feel it where the needle is going to go into. it's a per cutaneous biopsy using a fine-gauged needle and you can withdraw fluid from a cyst or it could take some cells from a solid mass. another technique is the core

needle biopsy. it is done using mammography and ultrasound guidance. therefore it can be used on non-palpable lesions. a hollow spring-loaded device is fired into the breast and you get one sample per firing. so the poor patient is subjected

to at least 10-20 samples from the different areas within the lesion, so it's 10-20 times they'll have to fire it to get the sample. then there is something called a vacuum biopsy, it's a mamotome biopsy using a vacuum assisted system.

it's also guided by utah tra sound guidance and stereo tactic guidance, that's a two-angled x-ray. it's very quick, there's no pain, it's actually more commonly done these days than some of the other procedures. it's three times more accurate

than core biopsy for early breast cancer. the reason for that is because it takes a wide area of tissue, and it allows for sampling of microc microcalcifications. the microcalcifications are very often seen in early breast

then there is the abbi method, which is automated stereo tact i cal surgical biopsy. and this cannula it's a large cylinder. the good thing about it is it takes a sufficient amount of tissue in one pass through the lesion.

and it's able to take, the cylinder is large enough you're able to take a sampling surrounding the uninvolved area which is good. and then open surgical biopsy is done by a general surgeon in the operating room, which is also, i guess, a good technique in that

you're able to get the whole lesion and you're able to get normal tissue surrounding. this is just a picture of a device for the vacuum-assisted or mamotome biopsy. this is just a picture showing you, you know like i said earlier, that sometimes a

lesions are not pap pabl but they're picked up on mammogram, and therefore the spir vengsal radiologist who's going to do the biopsy will need ultrasound guidance in order to locate the lesion and here you just see what the breast mass will look like on ultrasound and you'll

see the needle approaching it for the biopsy. sometimes something is seen on mammogram, and it turns out to be a cyst. and so oftentimes mammograms are followed up by ultrasounds to see whether the lesion is a sol ed lesion or a cystic lesion.

and here you see an ultrasound, how a cyst will look on ultrasound. it's biopsied and if the fluid that's withdrawn from the cyst is clear it's most often benign and cysts are most often benign. if it's mrudy you have to be concerned for malignancy, but

that's not often the case. so what are the types of breast as you know a pathologist will review the biopsy to give a final pathological diagnosis. so september oh car sin ohm an in situ, types of non-invasive dcif and lcif. so dcif is the most common type

of non-invasive breast cancer. the cancer is only in duct and it has not spread through the duct into wall of the duct into the tissue of the breast. nearly all women at this stage can be cured. the best form is mammogram because it's non-palpable and

asymptomatic and it's routinely picked up, if a woman comes and has a routine mammogram, and often these are the lesions that are the reason we are seeing increased incidence of breast but we are picking them up early and they're treatable and curable.

dmrob lar carcinoma in situ this begin's in the milk glands but does not go through the wall of the lobules into the breast tesh user, and also it's not a true cancer, it does increa your risk of developing a cancer later in life. so it's important that women who

do have glob globular carcinoma follow up with regular mammograms. as far as invasive breast cancer again you've got invasive ductal carcinoma and invase ifshg globulrar. ilc is the second most invasive bre cancer, it starts in the

duct, breaks through the duct wail and it invades into the tissue, from there it may enter into the lymphatics and spread to other parts of the body. from the lobules it can go through the wall again and into the breast tissue and it can enter the lymphatics.

but ilc accounts for only 1 tenth of the invasive cancers. we do really see a lot of idc in the community. inflammatory breast cancer. what is that? it's rare, it only accounts for 1 to 5 percent of all breast cancer cases in the united

states. it's the most aggressive form of and the symptoms include a diffuse erythema involving a majority of the breast, the breast looks like the skin of an orange, it'll have an edge which is redness at the edge, oftentimes there is no palpable

mass. and unfortunately this type of breast cancer has a significantly lower overall survival rate. compared with other types of breast cancer, inflammatory breast cancer tends to be diagnosed as younger ages.

we know that the median age is 57 years compared with the median age of 62 for other types of breast cancer. it is more common and diagnosed as younger ages in african american women. the median age of diagnosis in the african american population

is 54, and that's compared with a median age of 58 in white inflammatory breast tumors are frequently hormone receptor negative which means that hormone therapies are not effective in these cancers. and inflammatory breast cancer is more common in obese women

than in women of normal weight. so what is- - what causes inflammatory breast we don't know what causes it, but the appearance, the appearance is caused by the rapidly accumulating malignant cells this infiltrate and clog the lymphatic vessels in the

skin of the breast, which is the determine al lymphatics, and the blockage in the lymphatic vessels causes the appearance of the swollen and dimpled skin and the classic signs that we're seeing in inflammatory breast so what are the guidelines developed by an international

panel of experts? so the minimum criteria for diagnosis is the following. so patients often see when you' talking to a patient, this is the history that you often get from them. a rapid onset of erythema and swelling, and a orange-like

appearance and abnormal breast warment. sometimes they can feel a lump most often not. usually the symptoms last less than six months or they have seen it for less than six months. oftentimes the erythema can

cover at least a third or more of the breast, and the initial biopsy samples will often show invasive carcinoma. this is a picture of somebody with inflammatory breast cancer, it's an african american female you probably cannot appreciate the erythema but you can see the

skin that's dimpled and looks like an orange peel. very classic. these are also varied presentations of inflammatory i have to say that oftentimes it goes misdiagnosed because physicians, especially primary care physicians, seem to think

it's a mastitis. i ha seen too many unfortunately cases where patients will come in maybe six months after having these symptoms after being treated by antibiotic after antibiotic for a mastitis. especially unfortunately in

women who have had a recent pregnancy and are you know nursing babies, i think that a lot of physicians will think it's a mast ititis. but sometimes breast cancers do show up post pregnancy. they're very unfortunate but you have to be thinkig all the

time, this is something not good. so what is the prognosis for inflammatory breast cancer? because it usually develops quickly and spreads aggressively women diagnosed with this disease in general do not survive, unfortunately, as long

as those diagnosed with other types of breast cancer. the five-year relative survival for women with this, the statistics have shown from 1988 through 2001 it was 34 percent, ask that's compared with a 5-year relative survival of 87 be percent with women who have

been diagnosed with other types of invasive breast cancer. most commonly the idc. all right, so staging. once the cancer is diagnosed it has to be staged. so staging is a way of describing a cancer such as the size of a tumor and if or where

it has spread. staging is the most important tool doctors have to determine a patient's prognosis, and also the staj of the cancer dictates what kind of treatment options a patient has. just briefly i'll go through the staging.

so stage 0 it's known as a carcinoma in situ, the cancer has not spread past the ducts or the lobules, and it's a non-invasive cancer. stage 1, the tumor is less than 2 centimeters and there's no lymph node involvement. stage 2 a less than 2

centimeters and could involve 1-3 lymph nodes or 2-5 centimeters but has not spread to the lymph nodes. or no lesion in the breast but you could have 1-3 nodes that's 2-a. stage 2 b it can be 2-5 centimeters but it has also

spread 1-3 lymph nodes or greater than 5 centimeters and no lymph node involvement. 3 a, you can see nothing in the brea breast, or you can see any sized tumor and up to 4-9 lymph nodes. or you can see a tumor that's small clusters of cancer cells

in the lymph node, or greater than 5 centimeters and 1-3 lymph nodes. staging is always changing. it has changed so many times, they're continually refining the stag stages. stage 3 b, the tumor may be any

size but has spread to the chest wall and or skin of the breast causing swelling or ulceration. it also may involve up to 9 lymph nodes. so inflammatory breast cancer is at least a stage 3 b diagnosis. stage 3 c you can see no evidence of any disease in the

breast, or the tumor may be of any size and the cancer may have spread to the skin or chest wall causing ulceration. and you can also see 10 or more axillary lymph nodes or a lymph node above or below the collar bone which is known as the super- -

stage 4 breast cancer, stage 4, so breast cancer can be any size, but it has spread to different parts of the body and the more common places for breast cancers to go are bones, lungs, liver, chest, wall, or brain. so what is the lymphatic system?

circulatory system and it t of comprises a network of lymphatic vessels that carry a clear fluid called lymph for the heart. they act as filters and they remove foreign materials such as bacteria and cancer cells. so here you can see a cancer cells that are escaping into the

lymphatics, from the lymphatics you know they can travel through the body. at the top you see a normal duct, then you see a non-invasive cancer and at the bottom you see an invasive cancer that has broken through the duct wall and is now getting

into the lymphatic channels and into the lymph node. so what are the lymph nodes that are commonly involved in breast they are the supraclavicular chain, the axillary chain and the internal mammary chain. let's talk about axillary lymph node die section.

this is traditional for staging breast cancer it involves removing 10-30 lymph nodes closest to the tumor. the benefits are all of the lymph nodes can be examined for it's a reliable determn where the cancer is spreading but the draw backs here there's

always draw backs to everything, is that it could cause post surgical complications such as limp edema, infection, nerve damage, nerve damage from the surgery. well they're lymph edema that can result in infekdz and that could really be cumbersome.

so let's talk about sentinel it's it means to guard over or vigilant. the sentinel lymph node is the first node that lymphatic fluid passes through in a group of it is the protective node that acts as the first filter for harmful material.

a sentinel lymph node biopsy is less invasive to determine if axillary nodes contain cancer with fewer complication than a full die section. injections are in the tumor or under the nipple. the tracer and dye mix with fluids that travel to the lymph

node and the sentinel is the first node that receives the drainage. that is removed and sent for pathological review and if cancer is present then the surgeon will take out more lymph nodes if there's no cancer no more nodes are taken and the

patient is spared all the problems with a full disection. so we know that sentinel lymph node did i section identifies me takes ity sis of early breast cancer but it's not clear if you go ahead and today further die section does it affect survival? is it better in the long run?

there was a phase 3 randomized clinical trial that was done, it was conducted to determine the effects of complete nodal did i section on survival of patients with sentinel lymph node mass. so it was this study was open at 115 sites and enrolled back from may 1999 to december 2004.

patients with invasive breast cancer but no palpable adenopathy and 1-2 sentinel lymph nodes, that were obtained, they were the patients on the so those who are sentinel lymph node mass they were randomized to either getting a full axillary did i disection ever

ten or more nodes or no treatment at all. the primary end point was overall survival the sebdary end point was disease-free survival. results showed that a median followup of 6.3 years, five year survival was. the five year disease-free

survival was 82.2 percent with axillary and 83.nine with sentinel node. the conclusion was among patients with limited sentinel mass breast cancer treated with systemic therapy the use of taking the sentinel node at all did not result in inferior

survival. it's okay just to spare the patie patient, just do the sentinel node. so prognosis. prognosis is the likely outcome for our patients diagnosed with cancer and it is often viewed

that the chance will be treated successfully and the patient will recover completely. many factors can influence the prognosis including the type and location of the cancer, the stage of the disease, the patient's age, and overall general health, and the extent

to which the patient's disease spopds to treatment. so treating the cancer, these are the different things that we have to work with. so what are the basic factors that doctors will consider in planning breast cancer treatment?

again they'll look at the stauj of the disease, the pathological grade of the tumor, which can range from 1-3, 3 being more aggressive, hormone recept status, the patient's age and general health, menopausal status, and the presence of known mutation.

so as far as treating early stage disease for both dcis and early stage invasive breast cancer doctors recommend surgery to remove the tumor to ensure that the entire tumor is removed the surgeon will remove a small area of tissue around the tumor. though surgery aims to remove

all of the cancer, it is known that many times microscopic cells can be left behind either in the breast or elsewhere. so what is the next step in treatment after surgery? the next step in the management is to lower the risk of recurrence, and to get rid of

any hidden cancer cells that remain and this is called ajutant therapy. it includes radiati targeted therapy.one therapy the need for sdjutant therapy is based on the chance of residual cancer in the rest of the body, the chance of recurrence, though

it lowers the risk of recurrence it definitely does not necessarily eliminate it. inflammatory breast cancer, the treatment steps, i just want to make mention it's a multi-modal approach. systemic keomonevong keomonevong toe therapy to shrink the tumor

as to the normal routine of surgery followed by therapy. in this case we do systemic chemotherapy, surgery to remove and followed by radiation therapy. and then we, clinical trials have shown there are better responses to therapy and longer

survival with this approach. so metastatic breast cancer what are the goals of treat m here? as you know it is a stage 4 cancer, it's non-curable at this poi point. so prolongation of survival is the goal.

we want to improve the quality of life for the patient, and we want to improve their symptoms. but part of improving the quality of life is that you don't want to give medications that are so toxic that are more debilitating to the patient than the disease itself.

so in the case of breast cancer we do have the option of hormonal therapy and if that is the case for patients, that is what we prefer to do first. if chemotherapy is what we need to do, we prefer to use single agent therapy in met metastatic disease as opposed to

combination chemotherapy. let's talk about hormone so targeting the estrogen pathway. estrogen is a well recognized growth factor for the majority of breast cancers. that makes it a very lucrative preventive target, and for

treatment as well. so estrogen pathway can be targeted in two ways. you can use drugs that work at the receptor, the selected estroge receptor mod lators which include tamoxafin and reloxaphine and agents that interfere with estrogen

synthesis, for example the eromatase unhibtors, the ghr analogs and oophorectomy. the eromatase inhibitors they inhibit an enzyme found in peripheral tissues. it will convert to eventually estradyol which would interact with the estrogen receptor.

so eromatase inhibitors block the production of estrogen, tom tamoxafin is an agonist on the bone and uterus, and it's an antagonist at the breast. so with the uterus you have to worry about an agonist you have to worry about uterine cancers and that is the down side to

treating with tamoxafin. reloxaphine is used both in treatment and in prevention. it's an agonist on the bone it a like an estrogen on the bone, it can be used for osteoporosis, but for the uterus it's good because you don't have to worry about developing

uterine cancer with reloxaphine. it's a good agent for prevention and for patients who want to preve prevent osteoporosis but also have a high risk family history all right, so i just want to make mention that they at nci we have developed a tool that

weighs the benefits and risks of reloxaphine or tamoxafin to prevent breast cancer. so all those studies have shown that both can be used to reduce the risk of developing invasive breast cancer in high-risk women, the drugs can also cause adverse side effects.

tamoxafin the other side effect you have to worry about are blood clots, deep vein thrombosis, pulmonary embolism. these are not minor side effects you only want to give it to patients if you have to. so women and physicians must decide whether the potential

benefits of one or the other drug outweigh the risks in each patient's particular situation. so researchers from the nca and the dcp and dcpcs they have developed a benefit risk index to help guide decisions on who post menopausal women at increased risk should take

either drug. so the researchers who led the study they used data from previous prevention studies, and they considered a possible adverse effects like i just mentioned, bone fractures, blood clo stroke, end oh meetary al cancer, which which were

potentially increased or decreased. they identified each possible adverse outcome and calculated the probability that a woman with a particular rusk factor would have each outcome in five years with or without taking these medications.

so they used these calculations to create a color coded table for each drug that shows for each age group and five-year projected risk of invasive cancer, whether there is strong or moderate evidence that the benefits outweigh the risks or the risks outhardaway the

benefits for that particular patient. so this is being used clinically. this is just some data showing you that tamoxafin definite ly is beneficial. it does reduce the risk of recurrence.

so let's talk about tamoxafin pharmaco genetics. it's been a few years that it's been out we know that the dproet inhib inhibitary effects of tamoxafin is mediated by metabolites. the formation is can cat an lied by an enzyme.

zip 2 d 6 i'm sorry. so approximately 100 cyp have been identified, these manifest in the population of four distin distinct, so people can either have normal activity of this, or reduced activity, or no activity, or high activity.

so it can be speculated that gene oh type related differences in the formation of active metabolites influence their therapeutic respon to tamoxafin. everybody's different in how they me tab lies tamoxafin and how they will respond to it.

as far as aromatase inhibitors there are three approved by the fda. exoh methane has been used to treat early and advanced stage breast cancer, and they discovered that it substantially reduced the risk of breast cancer in post menopausal women

it at high risk of developing the mass 3 trials they looked at 4560 post-menopausal women and randomly decided to assign it daily for five years or getting a placebo. those who received eexomestane, 11 women got breast cancer and those who received the placebo

32 developed invase iive breast women were 65 percent less likely than women who took a placebo to develop breast it's the largest risk difference in any of the trials done to date. in previous trials tamoxafin and reloxapim, exoh mestane may

provide another option, the trial did not reveal seriou side effects such as those for tamoxafin and the followup is ongoing they need a longer followup it is still not actually approved, fda approved as a preventive agent. the systemic activan chemo.

so here in the graphs, so they're showing reduction in recurrence and mortality, and the two age groups age less than 50, age 50-69. and so that both age groups do benefit from the poly chemotherapy, but the greatest reduction in recurrence and

mortality is seen in those that are less than 50 years old. so poly chemotherapy is usually what we do as ajutant chemotherapy when we're trying to go for a cure. and it definitely has benefit over single-agent therapy. so this is just looking at

systemic chemotherapy and showing that different types of breast cancer have different sensitivities to chemotherapy. we can see that those breast cancers that are even dough christian dependent or hormone depend ept, they are more chemotherapy resistant.

and those that are indough christianed independent, or hormone independent, they are more chemotherapy sensitive. so all of these things are taken into account when physicians make a decision of treatment. i just listed some chemotherapies you can take a

look at them. so it's a member of the membrane type 1 receptor, comprising four closely related family members th they, by subsequent auto cross fortags, they're- - this results in recruitments of down stream signalling, and the

incidence of amplification is about 30 percent in breast cancer therefore it is a definite therapeutic target. hirtu, it target the hirtu protein it has a high affinity and specificity. is 95 percent human, 5 percent nurine it increases the oh

tension for immune oh genicity, it was approve for early stage breast cancer in 2005. when you add it to chemotherapy it increases overall survival and increases disease-free and this is just a graph that again shows you that when you add recept ins to chemotherapy

you increase disease-free survival significantly in patients that are hirtu pitive. triple negative breast cancer, it refers to specific subtype of breast cancer that does not express the genes for estrogen, proj he esther inreceptor.

it is diagno in young women, african american women, braca-1, it's less responsive to standard chemotherapy associated with a poor overall prognosis. you can see from this graph that survival as compared to luminal a survival with triple negative drops steeply after about 60

so here we're looking at- - so these are just agents we know that platinum agents are more effective and triple negative for breast cancer. bacalone has been shown to be a good agent. there's so few treatment options with these patients

unfortunately. so how can we do better? so we definitely need better selection of chemotherapy regimens and gene expression profiling to presikt response to ticket agents. we need a better selection of patients we need to treat those

patients most likely to recur and who will therefore benefit from the addition of chemotherapy. so that brings us to the taylor x trial. i guess i'll talk about that in a second. neoactive is a presurgical

chemotherapy that allows for assessment of tumor response because you're giving it before t lesion has actually been surgically removed to actually seeing if the chemotherapy is effective or not as reducing the size of the lesion. we often use this in clinical

and research settings. rece recently, last year odact approved, voted to approve genentec's drug for early stage and this recommendation was based on two phase 2 studies, and so actually it's on its way to becoming the first neosjuta

in ks t breast cancer approved in the u.s. and the first based on path lonl cal complete response. it was like 33 percent of the patients from the trials showed a pathological complete response with this agent. so full approval is still

pending and data are expected in 2016 from a study that's ongoing. so an important question in breast cancer treatment what is the likely hoot of distant recurrence of patients in breast cancer who have no involved lymph nodes?

this is poorly defined by histo pathological incidents and measures. so what do we do with these patients? so onco type dx a multi-step approach that was used to develop an assay for the expression of tumor-related

genes for use with embedded tumor tissue. so an rt/pcr method was, 250 candidate genes were selected from genomic databases and dna on frozen tissue. data was analyzed on 447 patients to test the relationship between gene

expression recurrence of breast they used the results of the three studies to select a panel of 16 cancer-related genes, and five reference genes. these were the ones with the best rt/pcr performance and the most robust predictions. they they had a recurrent score

for each sample being tested then they had to validate the test then they used pair fin embedded tissue samples from patients who were previously envolled in the b-14 trials and they used that to valid ate the ability of the 21 gene rt-pcr assay to quantify the likelihood

that these patients would recur distantly. so the patients from the nsa abp, b-14 trial were node negative, er positive, early stage breast cancer patients who had been previously treated with we don't know, they have a good prognosis but do we need to give

them chemotherapy? that's the question or can we just give them hormonal therapy? so here we see that the risks that was provided by the onco type ds assay appears to provide an accurate estimate of the chance of recurrence by risk category.

when they looked at the patients from the b-14 trial they saw that those who were placed into a low risk category, and they followed these patients for ten years, those patients had a low rate of distant recurrence, and those who were placed in a high risk category per the onco type

assay, they actually did have a high rate of distant recurrence at 10-year follow-up. so based on this study the recurrence has been validated as quantifying the likelihood of distant recurrence of tamoxafin treated patients with no recurrence of er positive breast

so patients with tumors that have a high recurrence score have a large absolute benefit of chemotherapy, so the more likely ye to recur, you will have a higher benefit from that's clear. and patients with tumors that have low recurrence scores have

minimal benefit if any from chemotherapy, and that's clear. okay, so there's ongoing research using results from the onco type dx assay, the taylor assay is a trial assigning individualized options for treatment and then there's another ongoing trial that's

using data from the onco type dx assay,. so running out of time, but taylor x is a landmark trial is represents the culmination of a major initiative to integrate molecular diagnostic testing into clinical decision making, the primary object jktive is to

determine whether ajutant hormonal therapy is not inferior to keomonevochem chemotherapy. these are the patients we don't know what to do with. like i said the ones who have a low score we know they're not going to benefit from the ones that have a high score

we know that they'll benefit. what do you do with the patients who have an intermediate yat range score? dpif them chemo? the taylor-x is going to answer some of these questions. they're also going to create a tissue and specimen bank for

patients enrolled in the trials, including tissue, plasma, and dna from peripheral blood. nca is identifying and assign treatment to more than 15,000 patients from the u.s. canada and peru. the research is ongoing and results should be around the

corner in 2015. so that this is the is schema for the taylor rx, but the key points it's going to examine whether genes that are frequently associated with recurrence for women with early stage breast cancer can be used to assign patients the most

appropriate and effective so can genes predict treatment? the results of the trial could spare many women the unnecessary toxicity of chemotherapy, at this point we really don't know what to do with a certain group of patients who are in the mid range.

most of them do end up getting and so it is one of the first trials to examine a method to personalize cancer treatment. this is the other trial that's ongoing right now it's the key trial evaluating the use of end christian therapy with or without chemo and the palmer

receptor positive or negative blest cancer. specifically this trial is going to look at women with recurrent scores from the onco type dx essay, 1-3 positive nodes mid range scores and the question is these are hormone receptor positive patients do they need

chemotherapy? approximately 9400 patients will be screened in order to randomize 4,000. it's still onand we are waiting for answers. the impact trial, what we are doing in the clinic rite now, so our clinic launched a trial in

january 2014 the purpose is to assess whether assigning treatment based on specific gene mutations can provide benefit to patients with met static tumors. during the screening process samples of tumors from patients with various cancers will be genetically sequenced to look

for a total of 391 different mutations in 20 genes. i mutations of interest are detected those patients will enbe involved in the trial and randomly as siemed from one of two trials. one will get a targeted treatment and the other

treatment arm will get another non-targeted therapy which is a good choice therapy but not targeted to the mutations. patients who progress over in b are allowed to cross over to a. we don't know whether it's effective at providing clinical benefits.

most tumors have multiple mutations and it is often not clear, you need to target in order to achieve the maximal once a gene is mutated it can lead to the act vegas of mull tip the pathways. so the trial that we're doing in our clinic the empack trial is

designed to determine whether people with specific mutations will benefi from specifically closen targeted interventions and if these interventions lead to better outcomes. do i have time to finish the last four slides? so tomorrow, okay, ending with

just a few slides. what are the goals in breast cancer research? i just want to finish with that. we will use a rapidly increasing knowledge in the fields of cancer genomics and cell biology to develop more effective and less toks i cans treats and

identify more cancers that are likely to recur this is exemplified by the onco type dx assay. we will tailor breast cancer therapy to individual patients. that's the key what we're interested in right now this is what the early drug doement

clinic is focused on is targeted for example, gene expression analysis has led to the investigation of five subtype cancers. this knowledge can be exploited in the development of treatment strategies based on the specific characteristics of a particular

woman's tumor. not tumors in general, but a specific woman's tumor. and then this is exemplified by the taylor x trial that i talked about a minute ago. so further more a patient's response to chemo is influenced not only by the genetic

characteristics of their tumor but also by inverted variations of genes that affect the body's ability to absorb me tab lies and eliminate drugs our knowledge will enable us to predict tumor responses to vitd therapy drugs or classes of drugs as well as the likelihood

of events for them. so this is specific to each different patients me tab lies drugs in different ways and when we know the variations, we will know which patients are better responders than others. this is exemplified by the studies on endoxaphin.

we'll use our increasing knowledge of the immune system to enhance the body's ability to destroy cancer cells our current knowledge has facilitated several vaccines under clinical investigation. and okay, i guess i'm done. but that was almost my last

slide. i definitely want to say that we will strive to understand address and eliminate factors that contribute to the higher mortality expressed by african american females because i think there are several slides that i showed you that disparities

greatly exist so we'd like to understand more about that. thank you.