Good evening everyone. It's a pleasure to be here. What I really wanted to do is give an overview of specifically what are the the most impactful Gynecologic cancers and really what's changing, you know What are the things that people should know about or should be watching for for future changes? Gynecologic cancer is a pretty focused area and yet within that it's complex There are six different sites where cancers can occur in the female reproductive tract So you can see it on my drawing here ovary uterus cervix, vagina, vulva and dimetrium And there's even one more that's not on the illustration there and that is gestational trophoblastic disease Which is unique in all of cancer in that it's a cancer of placenta And so unlike most cancers which arise in an individual a placental cancer is Essentially a transplant tumor. It's a tumor that has the father's genetics and that makes it quite unique with respect to any other cancer Given the constraints of time, I'm sure you all didn't want a full day seminar on this So I'm going to limit my talk today about the most common three of the gynecologic cancers So this would include endometrial cancers cervical cancers and ovarian cancers The others are quite a bit more rare on the other hand the endometrial cancers are fairly common about one out of every 30 to one out of every 40 women will be affected in her lifetime So I will begin with cervical cancer This is the third most common gynecologic cancer of women in the United States today but historically in 1940 if I were to give this talk it would have been the most common cancer of women in the United States and Notice that I didn't say the most common gynecologic cancer. I said the most common cancer of women It was more common than breast cancer. It was more common than lung cancer Colorectal cancers it is by far the most common cancer of women and a lot has changed now It's down about number 12 on the list for how common this cancer is among women in the United States We're pretty fortunate though because it's not that way around the world if we look around the world Cervical cancers are still the second most common cancer of women Worldwide and the burden of the disease is huge It's about a half million women per year in the world develop cervical cancer and about a quarter of a million die of this disease in The United States and in Canada and in Western Europe Where we have the advantage of robust health care systems and good screening infrastructure This is a relatively rare disease It's tragic when it does occur because it's so very preventable, which we'll talk about more today So we owe a lot in this reduction of cervical cancer over the last 60 or 70 years to George Pappinicholo He was the developer of what has been called the pap test or the pap smear over many years And this was first put into use in the 1940s Although his publications Occurred when he was at Cornell I would point out that he was at University of Michigan briefly for a part of his early faculty career So what the pap test has done is has allowed us to identify cervical cancer Before it becomes a cancer when there's a lot we can do to reduce the chance of it progressing to cancer And if it is a cancer to try and detect it as early as possible So we know a lot about what causes cervical cancer and this is fairly unique with respect to most cancers This is a cancer caused by the human papilloma virus. It's a very common virus It's passed primarily through sexual contact But can be passed through other means for example a mother who has the HPV virus when pregnant Can cause that virus to be passed through vertical transmission to her fetus and this can occur even prior to labor So although we think of it as a sexually transmitted disease. It's more complex than just that Smoking is a co-factor. We know that the more a woman smokes or if she's exposed to secondhand smoke The higher her lifetime risk that cervical cancer will develop The virus itself is interesting There are about a hundred different kinds of HPV virus and not all of them are predisposed to causing cancer So plantar warts for example, which many people have on hands or feet are caused by a human papilloma virus But they're typically caused by a different strain of the virus and not related to cancer production But types 16 and 18 most commonly do have a high chance of causing cancers not only in the cervix but also the vagina and the vulva and also in the Oral pharyngeal tract tonsillor cancers and even some lung cancers So the burden of disease affects women and men Particularly given that it affects the oral pharyngeal areas Now how common is the virus? Well, it turns out it's very common this graph comes from a study done at University of Washington and it Was a group of gracious women who allowed themselves to be tested for HPV every three months all the way through college So that was a pretty big commitment But it helped us to learn a lot about HPV and if we just monitored those women through their college years Those who had never been sexually active who started college Over the course of that four years about 60 percent were exposed to HPV virus Now if we look at that in terms of public health data available to us from around the world about 80% of all people men and women worldwide are exposed to HPV at some point in our lifetimes So this is a hugely common virus. It's not something that's very limited in its scope It's not something that's specifically one element of our society or one group of people at risk. It's all of us Now when that virus is Transmitted or if we are exposed to it in most of us The virus will run its course and our body's immune system will clear the virus this takes time It usually takes as you can see on the graph here a year a year and a half sometimes two years But it doesn't mean that every woman for example who gets HPV will go on to develop cancer In fact, it couldn't be farther from the truth most will clear this virus So what does clearing mean clearing doesn't necessarily mean that the virus is cured But it means that it's no longer detectable and in that non detectable state is not capable of causing disease Now if a woman is stressed physiologically So let's say she has a bad asthma flare and she's put on steroids or she's had a major life trauma or stressor in her life Sometimes this virus can reactivate or cause a new problem with the lower genital tract Very similar to what happens with chicken pox virus in people who get shingles Where people have had that viral exposure and then many years later It activates again for various reasons Now another important thing to know about HPV is it's very common in its overall prevalence But especially in adolescents and in young adults if we look at prevalence or detectability of HPV virus It rises very steeply in young women's teenage years Typically peaking around the age of 30 and then it usually falls Now this is population-based studies and it really tells us an interesting story about the virus And that is that cumulatively we as a population Develop this immunity and this ability to clear the HPV virus, but it takes time Now what that means is that in women under the age of 30 if we were to do screening tests for cervical cancer Based on prevalence of HPV We would get a lot of false positives Because these are women who have the virus. It's detectable and yet it's destined to go away. It's not destined to cause cancer It turns out that the women who go on to develop cervical cancer get it because the virus persists It persists past the age of 30 And so when we look at current recommendations with modern pap test screening of how we screen for people You'll notice in a few minutes when I show you that there's a difference in how we screen women Below the age of 30 and above the age of 30 because of this particular data So what are those recommendations for screening? Not all cancers have a good screening test But cervical cancer has a great screening test and that's the pap test Cervical cytology So the rules though for how often and when we should do pap testing have changed a lot because the technology is better Than it once was We used to say when a woman who became sexually active regardless of age. She should start doing pap testing now We say over the age of 21 a woman should start doing cervical cancer screening Why that difference because as we learned more about the HPV virus We recognize that even if a woman is 16 and sexually active and acquires that HPV virus It doesn't cause cancer right away. It only causes cancer if it persists for time And if we look nationwide at the incidence of cervical cancer in women under the age of 21 It's very close to zero statistically So we no longer recommend starting screening at young ages, but we do recommend starting by age 21 And this is a strong consensus Among all of these professional societies you see here the American Cancer Society the American College of Obstetrics and Gynecology Our pathology societies the National Comprehensive Cancer Network. It's unanimous If we look at some of the other rules about screening We also used to do pap tests forever But we know now that most cervical cancers happen around the age of 55 And once a woman has gotten well past that if she's never had abnormal pap The chance of her developing or dying of a cervical cancer late in life is very minimal So now we have a stop rule and that is that when a woman gets the age of 65 If she's had normal screens for the preceding decade, she no longer needs to do that pap test So we're starting at age 21. We're stopping at age 65 Now if a woman has had a hysterectomy, so hysterectomy is a hugely common operations about 600,000 cases per year in the US the majority of which are done for non cancer indications So let's say a woman has a hysterectomy for fibroids Well, she's had that hysterectomy. She no longer needs pap tests ever because the chance of developing a vaginal cancer Is only seven per million woman years of screened Patients that's less than the risk of a man developing a male breast cancer Even if there's no genetic abnormality in his history And so we don't test with pap tests anymore once that hysterectomy is done Now what if a young woman has been vaccinated against HPV with one of the vaccines? Do we do anything differently about paps? The answer is no She still needs to have the same screening as a woman who did not have vaccination As to how often we do this test If a woman is under the age of 30 and remember that graph I showed you where HPV is rising until the age of 30 In that group, we will now do pap testing every three years Now this is different from what used to be taught. We used to say let's do it every year But now we do liquid-based cytology the methods of interpretation are better So we do it every three years up to the age of 30 and Then once she is past the age of 30 the recommendations change to be every five years With what's called a co-test a co-test is a pap test But it also adds an HPV test and so the two together as a combined test are called a co-test If both components of that co-test are normal normal cytology That's the pap and normal HPV in other words no HPV of the high risk is present Then the risk of that woman developing a cervical cancer within five years is statistically close to zero It's about 0.016 per hundred thousand women and so that's about as close to zero as it can get and in fact If you followed that population even out to ten years the risk of cervical cancer is very minimum But we feel uncomfortable recommending screening every ten years and so we still recommend every five years with that co-test in Some communities the access to the HPV testing is not present And so in that group of women over the age of 30 where HPV tests cannot be done We still recommend the regular cytology test every three years Now what we would hope what we would wish for is that in a screened population We would drive the risk of cervical cancer to zero if we look at this historical data of the risk of a woman dying of Cervical cancer the curve is essentially logarithmic It fell very fast and very dramatically from the age from the 1940s on to the present However, you'll notice around 1985 to 1990 We saw a plateau Why didn't we drive cervical cancer all the way to the extinction? Point that we would have liked well turns out there are reasons for failure. Some of these we could Manage if we had the consensus to do so or the will to do so We know that most women who get cervical cancer in this country Are unscreened patients? They've never been to see a doctor. They've never had a pap test This is really an indictment of access to care and the more Regularly a woman has been screened the less likely she is to develop cervical cancer or its precursors In some women who've been screened previously, but now it's been more than five years That also accounts for about 10% of cervical cancers So you can see that 60% of cervical cancers happen just because they weren't getting the screening that they needed to get the minority of Cases occur because of technical errors like the pap was wrong or the doctor got an abnormal pap test result and Filed it without acting on it. This is a minority of cases So what if a pap test is abnormal? What do we do? Well number one is we get on our soapbox and encourage women to stop smoking and in fact We should all be doing that at every visit every time But we also do coposcopy where we look at the cervix with a binocular microscope Inspecting the dotted line that you see my red arrow pointing to which is the squamo-clumnar junction This is where two different skin types join on the cervix That's where the HPB likes to grow and in fact of all the places on the cervix where a cancer could occur 95% happen right at that junction. And so we look with the microscope We can biopsy under microscopic guidance and if we find a pre cancer What we can then do is in the office numb the cervix use a little loop that has Radiofrequency energy and essentially scoop off that pre cancer lesion. This does not affect fertility It's very well tolerated has a very high success rate This is what happens with screened populations of patients We stop cancers by removing the pre cancer before it turns into a cancer Now the other way that we deal with cervical cancer to try and prevent is vaccination So we know that it's a sexually transmitted disease. It's passed with the human papilloma virus Well, there are other papilloma viruses out there. For example, there's a canine oral papilloma virus that's present in many dogs Jensen and Schlegel studied beagle dogs. Hence the cute puppy here And developed a vaccine that could prevent almost 100 it was 99 plus percent At preventing the transmission of this canine oral papilloma virus This work later went on to be the Fundamental supporting work that led to the development of the FDA approved vaccines against HPV for human use So the first of the HPV vaccines was approved in 2006. There are now three FDA approved vaccines The first one was Gardasil 4 that prevented Transmission of four of the key HPV types types 6 and 11 which caused warts genital warts And types 16 and 18 which caused cervical cancer. They also cause Vaginal cancer vulvar cancer tonsillar cancer oral pharyngeal cancer and some lung cancers uh Second to be approved was Cervarix, which is against both 16 and 18 the virus types And then very recently within the last year Gardasil 9 was approved now this one is a vaccine effective against the nine most common HPV types This is a world vaccine The two the first two that were approved were really approved for vaccine Use or clinical use in the united states canada and western europe But there are other HPV types that predominate in other parts of the world like south america china africa That can be very deadly and yet were not really adequately prevented with the first two types of vaccines The Gardasil 9 now covers for the majority of them worldwide. And so this is now available for clinical use Current recommendation is that girls and boys should be vaccinated Ideally starting around the age of nine to 11 The goal here is to do it before people become sexually active And so one of the big misconceptions in the united states is that people will say oh my child is 10 He or she is not sexually active. I'll think about it later And so people tend to table this and think about it when their child is now a junior or a senior in high school But guess what it's too late because in many cases they may already be sexually active Once that virus has been transmitted the vaccine is no longer effective It's effective before exposure to the virus but not after And so we really need to change our thinking to say this is about prevention of an infection that can cause cancer in adults And it's effective when given as children I have two sons that are now both vaccinated But we had to essentially argue with our pediatrician to get them vaccinated Because the pediatrician was falling into the same trap of saying well, let's do it later And my wife who's also an oncologist and I said no we're doing it now And had to essentially force the issue But from my standpoint it as a cancer specialist when I take care of a 30 year old woman who has a cervical cancer That could have been prevented 100 with the vaccine. It's nothing short of a tragedy And so I really would love to see people get much more active in this arena of trying to prevent the diseases that can be prevented The vaccine is a safe vaccine. It's called a virus-like particle It's made out of proteins that the virus makes but it has no DNA in it So it cannot transmit an infection. It's a very safe vaccine in that regard It's been tested now in Actually several million women and men It has an extremely safe profile. It can cause local Pain or tenderness at the site of the injection. There have been some fainting episodes But there have never been any serious adverse effects that are reliably reported Now one other aspect of cervical cancer to talk about in terms of the what's new Is that yes, we can prevent with screening and with vaccination But if a cervical cancer occurs, we can also do some new fertility sparing options Now the schematic here shows you the uterus and those little yellow lines to the side represent ligaments Every woman has ligaments that go from the cervix to the side of the pelvis Essentially attaching to the bones to hold these structures in One of the difficulties with cervical cancers that tends to get in those ligaments So historically when we were going to treat this cancer, we had to remove everything within that yellow dotted line The uterus the ligaments the upper vagina cervix Well that of course would eliminate fertility But now we can do what's called a radical trachelectomy Where we remove the cervix the upper vagina and the ligaments, but we leave the top of the uterus in place This is a procedure that was developed in france by danielle d'argent in the early 1990s It's done in a limited number of centers around the united states including an arbor And it gives us an opportunity to treat cervical cancers while still preserving fertility that otherwise would have been lost Cervical cancers are treated based on the extent of disease For example, if a small cervical cancer is present, we can do that fertility sparing operation I just showed you But once the cancer gets off into the side tissues outside of the cervix An operation is no longer feasible. We have to treat with radiation and chemotherapy So as is true of most cancers early detection makes all the difference in the world I'd like to next talk about endometrial cancer This cancer is much more common than cervical cancer It is currently the most common gynecologic cancer in the united states And overall it's the fourth most common cancer of women So that's behind breast colorectal and lung cancers. So pretty common If we look at who gets this cancer It's very strongly linked to estrogen production And what many of you may or may not know is that fat cells in the body produce estrogen So we know that if a woman is overweight her risk for endometrial cancer goes up substantially If a woman is somewhere between 10 and 50 pounds over her ideal body weight The risk of endometrial cancer goes up three times Well to put that in absolute terms that's about a one in 10 risk lifetime. That's a pretty substantial risk Now if a woman is more than 50 pounds over ideal body weight and these are pretty stringent numbers So what do I mean by that? So if we had a woman who's five foot three By the insurance tables that calculate these risks she should weigh about 120 pounds Well, that's a pretty skinny person by our modern standards Overweight and even obesity is a very common thing in our society and in fact around the world So if a woman is 170 pounds and she's five foot three, she's now 50 pounds over ideal body weight Her lifetime risk for developing endometrial cancer is 10 times higher And put in absolute terms that's about a one in three risk So, you know, I'm a people watcher I Look at people when I'm flying and going through the airport and that sort of thing and I look around and I think oh my gosh I'm going to be busy forever Because obesity is a big big problem in the United States pun intended And these are patients who get endometrial cancer We also know that hormones given as medication can increase the risk So tamoxifen which is very frequently used as a hormonal treatment to prevent or to treat breast cancer Can increase the risk of this type of cancer I Unopposed astrogens which were given many years ago in the 1960s to treat menopausal symptoms caused endometrial cancer Now some of you might wonder about oral contraceptives. It turns out oral contraceptives are actually protective There are two hormones and birth control pills One of them being a progestin and that actually reduces the risk of endometrial cancer Some endometrial cancers are hereditary Now in the talk following mine today, you'll hear more about some of the genetics of cancers like ovarian cancers and endometrial cancers So I won't steal your thunder Other than to say that endometrial cancers can be hereditary. They can be acquired By genes that are passed from generation to generation within a family So how is this cancer detected? In the case of cervical cancers It's usually the pap test and a woman never really knows she has it other than that test In the case of endometrial cancer, this is a different disease. This is a disease that declares itself usually with abnormal pleading Most commonly bleeding after the age of menopause about 90 percent of women who develop endometrial cancer will present with that symptom The good news for all of us is that usually is a symptom that occurs when the cancer has not yet spread And that bodes well for this being a cancer caught early in most cases and therefore with good outcomes in most cases Now if that occurs, we typically will investigate With a biopsy and so the schematic here shows a little plastic tube That's an endometrial biopsy instrument. This can be done in an office setting. It's crampy like a menstrual cramp It typically takes less than 30 seconds to do Generally well tolerated and gives us a high Accuracy biopsy that allows the diagnosis to be made Sometimes the diagnosis will elude us and we will occasionally do what's called hysteroscopy Now this is most commonly done in the operating room And involves placing a very small telescope inside of the uterus to actually look and do directed biopsies This is a little bit more invasive, but if that office biopsy doesn't give us a diagnosis, this is the next step Now once an endometrial cancer is diagnosed, how do we treat it? This is a cancer that's treated in most settings with surgery So we do hysterectomy including removal of the uterus which you see in that initial circle But also the lymph nodes which are the glands to the side Lymph nodes are important because when cancers spread, this is true of cervical cancers and endometrial cancers The first site of spread is usually those nearby lymph nodes. And so in both cancer types, we remove those lymph nodes I Chemotherapy and radiation are not usually needed if the cancer has not spread But if it has spread, then we have to add additional treatment beyond the surgery The surgery itself has changed a lot in the last 20 or 30 years This used to mean a big incision But now most endometrial cancer operations around the united states are done laparoscopically So very small minimally invasive incisions You can see the four letters a b c d or a b I guess it's just a b up there in my drawing to show little band-aid size incisions where we can do the operations We started doing laparoscopic operations for endometrial cancer in the early 1990s and then around 2001 started doing robotic surgery Now there have been some misconceptions. I've had many patients come in saying well, I don't want the robot I heard that that breaks up the cancer. Well, that's actually not true. It's a misunderstanding This is what a da Vinci robot looks like the robot is on the far right You're seeing a surgery in progress These are very little instruments the instrument itself the shaft of it is smaller than a pencil the tip is very delicate The surgery is done by a surgeon at the console So one misconception is people think that a machine is thinking and doing the operation That's not true. It's the surgeon doing the operation But we are using very small mechanical hands to operate through little incisions Now what a robotic surgery is not is morselation Morselation means to cut up the uterus to remove it There had been a lot of press about this initially published by the well street journal and then the new york times in the last year About a woman who was an anesthesiologist in boston Who had a sarcoma of the uterus cut up with morselation and that caused dissemination of the cancer We as cancer specialists never morselate and never have morselated Morselation is completely different from robotic surgery and is never indicated if there might be a cancer present So how do we reduce the risk of endometrial cancer? Well, the best thing is to keep weight at the ideal body weight range So if the biggest Underlying risk is obesity then we need to focus very hard on trying to minimize that overweight tendency in our population Secondly, every woman should be aware that she should report abnormal uterine bleeding Especially after menopause, but even before menopause irregular or unusually heavy menses can be a warning sign Now birth control pills I mentioned reduced the risk and also intra uterine devices that contain hormones There is one called a marina that has a progestin hormone within it These are very effective for birth control, but actually very effective at reducing the risk for cancer of this type And in fact in some of our patients who come to us And so you might imagine, you know with this population of patients They are very heavy and often come in with diabetes and high blood pressure Sometimes aren't in the healthiest shape for me to do an operation Sometimes if that patient is too sick to operate on we actually put in an iud as treatment for the cancer And so these are effective strategies The last cancer I'll talk about is ovarian cancer. This is the one I think that people Are kind of aware is the worst of the lot and that's definitely true It's the deadliest gynecologic cancer But it's not as common as endometrial cancer. This is something that affects about one out of every 60 women in their lifetime It's something that people don't realize are actually many types of ovarian cancer There are three major categories The red line you see there is epithelial ovarian cancer. This is what most people are thinking about when they say ovarian cancer This is what gilda radner had. This is what president obama's mother had These are cancers that occur in women around the age of menopause tend to be very deadly often caught very late in the disease There are different types of ovarian cancer though the yellow line here germ cell cancers Are cancers that occur in young women almost never after the age of 30 And they usually affect only one ovary They're usually treatable with the intent to cure in other words We can usually cure them and even help that woman retain her fertility So it's important to realize that ovarian cancer is not one disease, but in fact a group of many diseases As to what causes ovarian cancer Most of what we know about ovarian cancer and its risks comes from the epithelial type the type that's the deadly type We know that Link to ovulations in a woman's lifetime increases the risk. Now, what do I mean by that? So if we had a woman who had mences every 28 days For 40 years from the age of 15 to the age of 55 And she never has been pregnant She has higher risk than a woman who had several children Or a woman who's been on oral contraceptives or a woman who for various reasons didn't ovulate So the number of ovulations increases risk We also know that there are some environmental factors that may increase risk Although this is still an area that's hotly debated and then Additionally, some of them run in family histories so the Most interesting and newest thing about our understanding of ovarian cancer Is that many ovarian cancers in fact most epithelial cancers probably don't start in the ovary at all They start in the fallopian tube And fall off the tips of the fallopian tube onto the ovary essentially seeding to that organ and then growing Now, what do I mean by the environmental impact? We've known for a number of years that if a woman has a tubal ligation So she's had her children. She's ready to have her tubes tied that actually reduces the risk of ovarian cancer In that woman's lifetime by about 40 percent No one understood this for many years But now that we understand that many if not most ovarian cancers are starting in the fallopian tubes It starts to make more sense when we ligate the tube we prevent passage of materials through the tube possibly including malignant cells But we also change the blood supply to the fallopian tube Which may make it more hostile to the development of a cancer And so we don't typically tie tubes just to reduce the risk of ovarian cancer But it is well known that if the tubes are tied it does reduce the risk The family history you'll hear more about in the next hour or so And so again, I won't dwell on that other than to realize that maybe up to a quarter of all ovarian cancers are hereditary And so we think a lot more about family history now than we once did So how do we diagnose ovarian cancers? You heard about cervical cancer where we have good pap testing with endometrial cancer We have abnormal bleeding with ovary. Sometimes we don't have very good symptoms Many ovarian cancers are asymptomatic where it's sort of a silent disease process But what we used to think of as a silent disease we now know really isn't there are some clues But what people don't realize is that those clues are usually Intestinal in nature not gynecologic in nature So a woman might present with bloating constipation nausea gas Well, she goes into her primary physician and says those symptoms her primary physician might say well I think you have constipation or you have Gastrosophageal reflux or you have irritable bowel syndrome Ovarian cancer is often very low on the list of possibilities But the data on this show that our previous understanding of a silent disease isn't really true Barbara Goff published some interesting material that showed that about 89 percent of women with early stage ovarian cancer have these symptoms So yes, these symptoms do occur with late stage ovarian cancer But almost 90 percent with early stage These are the patients who are potentially Savable with early surgical intervention the earlier we find the disease the better the outcomes for treatment So several professional societies Issued a set of consensus recommendations that were targeted both to the public But also to primary care physicians Because a woman who's developing these symptoms. She doesn't come see me first She goes to see her family medicine physician or she sees her internist Or she sees the physician assistant or the nurse practitioner in one of those practices And so what she comes in complaining of is bloating pelvic or abdominal pain difficulty eating feeling fall urinary urgency Well, those are symptoms that are common the key here is that if the symptoms persist that is cause for alarm So if any of us had bloating for a day or two or three, we wouldn't think much of it But if that symptom persists for two weeks She should be seeing someone for evaluation And on the physician side of this we should be thinking about the fact that those are not always irritable bowel syndrome And can be the only warning sign that we will get for ovarian cancer Now what about tests can't we do some test to find ovarian cancer and the answer is no not reliably Uh people have looked for many years about whether ultrasound Blood tests for tumor markers including markers like ca 125. Why don't we just do this on everyone? Well, the fact is that it's very unreliable If we use ca 125, which is a blood test many of you may have heard of it If we use that on all women and say is this going to help us find ovarian cancer It will be elevated in many women So women with endometriosis women with an infection in the tubes women who have a diarrheal illness Bad arthritis flare recent surgery all of those things can elevate the test Which can be many false alarms On the other hand if a woman has ovarian cancer And it's still an early cancer half the time the ca 125 is not elevated at all So the blood test has proven very ineffective all of these blood tests as Detection that can be used as a screening test for the population at large Ultrasound has similar weaknesses cat scans and pet scans have not been utilized for screening They're very costly. There's a fair amount of radiation involved Bottom line is we still don't have a good screening test none that any of the professional societies are advocating based on evidence Now what about a woman who comes in and she's got that bloating Sensation she's full Her physician does an exam and finds an enlarged ovary Well, now we can start doing tests to evaluate that enlarged ovary one of the most effective is ultrasound Ultrasound is a low-cost test doesn't involve radiation. It allows us to morphologically classify the ovary as to whether it looks like a thin walled fluid filled cyst which would be low risk Or a cyst that's got solid components within it, which is the patterns 9 10 11 12 on the bottom of this slide Those have a high likelihood of being malignant So here we're using the ultrasound not to screen the mass population at large But rather to triage a mass that has been identified and for that it's very good Now I mentioned the ca 125 blood test It turns out there about 13 different markers that we use For evaluating ovarian cancers and so this is again one of the reasons why it's impractical to do for everyone You know if a woman comes in and gets her one mammogram and then she's good for a while or she gets her pap test And she's good for a while. This is 13 tests and they have Sort of questionable reliability is a screen But if we have a mass Then they're very useful at helping us to know if cancer is likely That can also help of getting the patient into the right person's office In other words, should a subspecialist be doing the surgery if there is a high probability of a cancer Cat scans can be useful This is what a cat scan looks like in an advanced ovarian cancer But cat scans are also high cost tests and in most women who have a mass It's not an indicated test We don't need to spend that health care money In order to get a good answer ultrasound is much more directed and much lower cost Now what about needle biopsies? You know if a woman has a mass in her breast, it's very common to do a needle biopsy. We do them all the time But in the case of an ovarian cancer No, we don't want to do that And that's because in the breast the breast is a solid organ If we place a needle in it and if there is a cancer The worst case scenario is we might drag some cancer cells out along the path of the needle as it is withdrawn But if we then find a cancer the breast surgeon can go in and remove that needle track with high reliability In the case of an ovarian cancer, it's sitting within a very big abdominal compartment If you put a needle in it, it's like popping a water balloon It explodes and it explodes into the abdomen and spreads cancer cells throughout So we never biopsy ovaries with needles But we always biopsy breasts with needles and so there's a reason why it's okay in one area and not okay in another Now if we suspect an ovarian cancer Then it's time for a surgery and these can be very big surgeries The surgeries have multiple purposes one is called staging where we in essence Explore the entire abdomen to map the extent of disease The other is that we I use the information Of where the disease is to then do deep bulking where we remove as much of the cancer as can be removed Ovarian cancer is unique in this regard If for example a person develops colon cancer and that colon cancer has spread If a surgeon opens the abdomen and finds colon cancer all over the place There's really no Benefit of taking that colon cancer out. That's a bad situation ovary cancer is very different And an ovarian cancer if we find that if we find that there are 4 000 implants through the abdomen if I can remove the bulk of them She will do better. She will respond better to chemotherapy. She will live longer And so debulking operations can sometimes be very big long laborious surgeries Sometimes five or six hours in length Focused on getting every bit of cancer out that we can safely remove and that sometimes means we are removing the spleen or parts of the intestine or Peritoneum which is the sac that lines the abdomen because the more we get out the better people do And it's also been shown that the expertise of the surgeon matters here So a high volume surgeon in a high volume hospital has better outcomes Than someone who doesn't see ovarian cancer very much And so this is why it's important to use tests like the ultrasound and the ca 125 before the surgery In order to have our patient in the hands of the right surgeon for that operation Fertility sparing which is the last Line on this slide is sometimes possible with some ovarian cancers So it depends on the type and it depends on the stage in other words has that cancer spread when we're talking about could we or could we not preserve fertility another important concept with ovarian cancers is Are we going to be able to cure this disease or not? So the intent of treatment curative versus palliative is important If a woman has An epithelial ovarian cancer. This is the type that occurs around the age of menopause and if that cancer is spread Frequently we cannot cure that cancer Now we can often control that cancer for years So I have patients who've been through chemo Five or six times over the course of five six eight ten years And yet they're still alive even though i've never been able to say this disease is cured That's unusual many cancers don't act that way a colon cancer that has spread never acts that way A pancreas cancer that has spread never acts that way But ovarian cancers do So that's called palliative intent I'm going to control it to help give her quality of life So she can be out there living her life even though I can't cure the disease outright on the other hand The germ cell tumors that I mentioned occur in young women Those can usually be treated with curative intent meaning that they respond differently to chemotherapy And so I can leave in the other ovary I can treat her aggressively and I have a realistic chance that she will be cured for the rest of her life And so how we treat and the concept of what we will or won't do surgically is very different depending on which cancer type We're actually dealing with So where is the future of ovarian cancer headed? Well, there are several issues one is detection We know that ovarian cancers even the epithelial types that tend to be so bad If they are caught at stage one before they've spread We have a very good likelihood of long-term response long-term cures even in the mid 90% range The trouble is that we don't have the equivalent of a mammogram We don't have the equivalent of a pap test And until that happens We're really stuck with the fact that most women who get ovarian cancer come in with a stage three disease when I find them Because they didn't know they had it until it got pretty far along So a big focus for the future is whether new tumor markers might change Our ability to detect the disease early There have been some new markers approved by the FDA in the last couple of years One is called HE4, which we're finding very useful as a test to discriminate between cancer and endometriosis Endometriosis is not a cancer condition But it can mimic cancer And so in order to prevent a lot of unnecessary surgeries HE4 has been very useful OVA1 was also recently FDA approved This is a test that was designed to help the community-based physician know When to send his or her patient to the subspecialist And so it's an imperfect test But it is one that's at least designed to try and get the patient into the right person's hands to help her the most So we hope for more change here in the future, but it's still a very Uh dicey game of not having good tests Now another is risk assessment, which again you'll hear more about in the next hour But I would like to make one point and that is that publicity about risk reduction has improved a lot in recent years And for this as a cancer specialist, I really thank people who has started to talk publicly about risk reduction like Angelina Jolie As many of you probably know She has a brca mutation. She's been very public about it She went through a risk reducing mastectomy and had her ovaries and tubes removed for risk reduction Well the fact that she did that but she did did that publicly so that people would start thinking about it and talking about it I think has benefited many people And so the real trick here is learning to recognize who's at risk And that's what you'll be hearing about more in this next talk Other things that our Goals for us in the future for ovarian cancer include targeted therapies So right now if a woman has advanced stage ovarian cancer She'll go through this big debulking surgery that I mentioned and then as soon as she's adequately recovered moves on to chemotherapy And our current standard of care is we use two chemo therapy drugs carboplatin and taxol They're good drugs about 70 to 80 of our patients will respond to them But it doesn't cure their cancer. It's essentially a shotgun approach We're giving potent drugs that kill many cancer cells But not all of them and they are in no way targeted to each person uniquely based on the properties of their tumor So the concept of targeted therapies is to say well, could we Start analyzing each individual woman's cancer and start targeting what it is that's unique about her cancer In a way that might benefit her In the ovarian cancer world the first FDA approved targeted therapy is what are called PARP inhibitors PARP inhibitors are enzymes that we all have PARP enzymes we all have They have a job in life of repairing damaged DNA If a woman has a BRCA gene mutation hereditary cancer She can't fix her own damaged DNA very well, and that's probably why BRCA mutations promote cancers Well, if we inhibit PARP Then we inhibit the ability of that cancer cell to repair in response to chemotherapy or even self-destruct And we can take a woman who has BRCA gene mutation and improve the likelihood of her remaining disease free for longer That's a targeted therapy And this is the very first drug that's been approved by the FDA to target A specific group of women with a specific gene mutation In order to try and improve outcomes We hope there will be many many more in this category Now what's really driving this is there is a lot of improved technology and now some private companies offering as services genomic sequencing of ovarian cancers The challenge here is we're getting these huge reports. So if I have a patient who goes through sequencing analysis I may get back a 90 or 100 page genetic report of her tumor That's great, except I don't really know what to do with that information yet In the long run what I'd like to be able to say is okay if I see this mutation Then here's the drug that's going to treat that mutation That is what targeted therapy means. That's what the future. I think is really pointing toward but it's A process that is in its very infancy with ovarian cancer Now when you talk about breast cancers Targeted therapy and breast cancers is much farther along in its development Why is that? Well, there are about a quarter of a million women who develop breast cancer in this country per year There are about 25,000 women who develop ovarian cancer in this country per year And if you think about how clinical trials are done, you need people to participate Breast cancers are 10 times more common And so the studies are getting done 10 times faster in Essence and so we'll get there But it's very early on in development and this is what we really need to improve outcomes with ovarian cancer Clinical trials of course drive our change And so a big part of how we hope to have a better future a better Set of treatments to offer our ovarian cancer patients is to strongly encourage participation in clinical trials I have many many patients who will look me in the eye after I've talked about a clinical trial and say But doesn't this mean I'm being a guinea pig? And so we have to do a lot of careful education To really show the value of that and also the precautions and safeties that are built into clinical trials And yes, in in essence people are allowing themselves to participate in something with an uncertain outcome But then our standards of care that our FDA approved They don't cure everybody and so we have to keep trying to push those clinical trial accruals in order to do any better in the future And this would be how we develop new drugs, but also vaccines and immunotherapies In the immunotherapy categories, some of you may have heard about what are called checkpoint inhibitors that have Started to greatly improve the ability of tumors like melanoma to respond to treatment Well, this is an example of an immune modulatory therapy where you're changing the ability of the body's immune system to see and fight back On on a cancer and so there's quite a lot of clinical trial work being done right now in ovarian cancer On developing vaccine trials or checkpoint inhibitors that stimulate immune response And so these are exciting times in terms of saying what might happen with ovarian cancer But we are not nearly as far along in our successes here as we are with cervix where we can prevent the disease or Endometrial cancer where we find it early and we can intervene successfully This is a cancer that's much tougher and we have a lot longer and harder fight ahead of us And i'll close by saying what if a gynecologic cancer is detected, you know, what should you do? And this would be true for both patients and clinicians I would consult with refer involve a gynecologic oncologist. That's my discipline now. It's a bit self-serving of course But if I say well, what evidence do I have there is a lot of evidence in the literature That if you have an expert someone who's a subspecialist who does high volume surgeries high volume hospitals the outcomes are better It's very clearly been published Bristow published a wonderful study on ovarian cancer That said if you have a patient in that setting Survivals are substantially longer and this isn't unique to my own specialty You know if you needed a liver transplant or a kidney transplant or a major heart procedure The data very clearly show that if you go to a transplant center that does high volume transplants Your outcomes for that kidney transplant are much better And so it does mean That we all of us patients primary care physicians subspecialists Need to do the best we can to get patients into the right place for that Optimized care especially for diseases like ovarian cancer that are such a tough battle anyway And on that I will close. Thank you all for your attention And so as jones said part of my lecture will actually be explaining what it is that I actually do because genetic counseling is a growing profession and so it's something that People outside of the healthcare field may not be as familiar with But we'll be going over some things that dr. Reynolds touched on as well specifically talking about um specific gynecologic cancers and breast cancer and the concerns that we have for genetics What it actually means to have a predisposition for cancer Indications why you would go to a genetic counselor and what this can do for us And so these are the main types of gynecologic cancer. Dr. Reynolds already talked about he focused on the three most common gynecologic cancer. I'm going to focus on ovarian cancer and uterine cancer in addition to breast cancer because those are the most likely to have an inherited predisposition with them This is just a general list of all the population risks for um the gynecologic cancer is including breast cancer And this just shows you again. We can go from Fairly common about a one in eight risk specifically for breast cancer to one in 200 something thousand now Excuse me now breast cancer is Inherently the cancer that women are at highest risk for because we have breast tissue Men have breast tissue as well, but because they don't have as much their risk of developing breast cancer in their lifetime is less than One in 100 or less than 1 percent for women. It's much higher. It's about one in eight women or 12 percent And so that's one of the reasons that we Focus a lot on breast cancer and some of these cancers don't get quite as much attention such as ovarian cancer because this is the one that Everybody is at a significant risk for just because we're women It is the second leading cause of cancer related deaths specifically for women and that's behind lung cancer And the biggest risk factors for breast cancer are having already had A breast cancer in your lifetime and also includes a history a family history of breast cancer Dense breast tissue, which I think some of the government agencies are still trying to figure out what to do with that information And then benign breast conditions and then as well birth control like dr. Reynolds touched on One of the other big risks for uh, the couple of cancers that we're going to be talking about right now is diethyl bestial It is a drug that was commonly used in the 40s 50s and 60s To treat a number of different conditions specifically to help prevent premature birth or prevent miscarriage And unfortunately we have found out After the fact that it does give us a significant increased risk of specific cancers And this also extends to women who are considered des daughters Des daughters are the women who were exposed while they were in utero when their mom was actually taking this drug now It does give us a 30 increased risk of breast cancer It also significantly increases our chance of vaginal and cervical cancer And the breast cancer risk is specifically after age 40 This is something that while I don't deal with from a genetic perspective is something that in family histories is very important for me Kind of trying to parse out What might be more related to a family history and what might be related to this des exposure Unfortunately des has many many brand names And so there are many women I see that I'm sure don't even know that their mom had a high chance of being Of taking this when she was pregnant with them So again, it's something that I think about a lot, but I don't bring up with a lot of patients Ovarian cancer one of the other ones I will be talking about today is most common in Caucasian women As opposed to african-american women or native american women As dr. Reynolds suggested it is One of the harder ones to catch and so from a genetic perspective That's why the brc one and two mutations which I'll be talking about can be so important For helping us identify those women who are at an increased risk for ovarian cancer There are other populations that or risk factors that we consider Although these things don't mean that much to women who have already had cancers But it can give us hints Especially in their family who might also be at increased risk such as having an ashkenazi jewish background Again talking about obesity Trouble getting pregnant or having never had a child Primary peritoneal cancer is the film that's in the cavity of In in your abdominal cavity. It's also considered an ovarian cancer in many purposes Fallopian cancer like dr. Reynolds touched on again is Usually how an ovarian cancer actually starts for genetic purposes in particular We consider fallopian cancer and ovarian cancer to essentially be the same thing Again another risk factor It's really interesting having a family history of breast and ovarian cancer because we group those two things together Having an ovarian cancer in the family in particular increases our risk for developing one of these in our lifetime these screening tools for fallopian cancer that dr. Reynolds touched on again all have their Detriments or their lack of sensitivity which we wish we could change but That's part of the concern that we have again for those women that have increased risks for ovarian or fallopian cancer Is knowing that our screening tools aren't as good as they are for breast cancer And finally uterine cancer is the other gynecologic cancer that has a large That can have a large genetic component There are many other things that can lead to uterine cancer besides just a Just an increased risk from family history including all of those things that Dr. Reynolds touched on For the rest of my talk we're going to go over a genetics basis so that we're all kind of all on the same page For what genetics really means for us, especially when it comes to a cancer When we're talking about genetics, we're talking about our DNA and um, I know I have A couple of people in the office in the audience who have already seen me who have heard the spiel a lot before But our DNA is essentially our recipe book for what makes us us and what makes us human And so that is also when we share so much DNA with our mom and half of our DNA with our dad That's why we look so much like them sometimes, but we still look unique is that mixed together And so what our DNA really does is it codes for all of the things in our body that make up our body And what make us us and those proteins so those proteins that make your eye color and your hair color When we have changes to the DNA they change the way that protein works And that's where our risk for cancer can come in now throughout our lifetime if we're going to Talk about the cell cycle We have our cells have to make many copies of themselves over our lifetime We have billions and billions of cells in our body And what happens is throughout that process it's like copying a recipe book by hand You're going to make some mistakes somewhere probably a couple So what normally happens is this blue x up there represents a mutation or a change in the way The DNA is supposed to be written And so when this happens in our lifetime Our body has many proofreading mechanisms for picking that up and fixing it as you can see here It doesn't persist throughout that replication process One of the other things that our body can do is identify a mutation and say this is too hard to fix So we're just going to actually eliminate the cell for This you know the function of or the greater good However, every once in a while These can be mutations caused by smoking exposure caused by sun exposure or again Just through our body making many copies of itself throughout its lifetime For reasons that are not very well understood the A mutation can occasionally slip by and you can see in this diagram as opposed to being done It persists through That first cell The next problem is is once you start with that cell Once it's permanently in that cell's DNA Every time it makes a copy of itself that new cell is going to have that same gene change Eventually over our lifetime we can accumulate these gene changes all in the same cell So we have multiple gene changes that are changing the way that our Cell is functioning. It's probably making more copies of itself than it's supposed to It's making copies of itself faster It's taking up more of our nutrients than it's supposed to and that's really when it becomes a problem We actually will end up with a cluster of these cells that all have these mutations in them that are Taking nutrients from places. They're not supposed to and that's really what a tumor or a cancer is Is a clump of cells that are just not doing what they're supposed to This can show you The general progression again that I lined out you start with one cell That kind of starts this clump of cells that has a couple of gene changes Probably not doing too much damage in such a small area one or two gene changes isn't going to change anything too much But that's when we get that hyperplasia. Sometimes we talk about that with cervical cancer We'll say a hyperplasia is there. It's not a cancer, but it's something that we're going to keep an eye on But then you can see we get to a dysplasia where things are actually now really not working the way They're supposed to and progress to a cancer and then an invasive cancer A predisposition to cancer a genetic predisposition to cancer is when Every single cell Of a person's body or from the moment they're born somebody has a gene change And it's the same gene change in every single cell of their bodies And what this means is they have leapt that much farther Unfortunately along the path to developing cancer than somebody who is at the same age as them who doesn't have that mutation in every single cell of their body This is an example of a karyotype This shows all of the pieces of our DNA in one cell and this can just show us for example where that gene changes And again, this would be in a situation that it's in every single cell of their body The problem really occurs if we're talking about the brca one gene change for example, which is on The 13th chromosome Is if we get in our lifetime a second Gene change a second mutation in our other copy of brca one. That's when things can really start to go wrong The indications that we have so we can't really look at everybody at a cellular level So unfortunately what happens is we get people who have personal or family histories of cancer and clinic And then we kind of try and work backwards We look at their family history based on what cancers they have Who has them how old they are when they get this cancer is when we start looking at Does it look like a pattern that might suggest that somebody has a familial cancer predisposition? And there are multiple things that can indicate this the rare more rare a cancer is When we're talking about breast cancer versus ovarian cancer We're more concerned about ovarian cancer in general a single case of ovarian cancer in a family versus one case in Of breast cancer in a family because it's so much less common People who get multiple cancers in their lifetime People who get them at younger ages are a big indication too And then sometimes just the sheer number of people in the family who have the same kind or same family of cancers Going back to this chart when I when we talk about Predisposition to cancers it sounds very scary and for those people that have it it really is Or can be but when we're talking about the group of everybody who's ever been diagnosed with a cancer or specifically a breast cancer 85 percent or so Of those people do not have a genetic predisposition Then we have a smaller group of people that might have a familial cancer somebody We can't identify a specific gene change in but we recognize that There are more people in this family than typical who have breast cancer or breast and ovarian cancer Sometimes this is really hard to tell if it's actually Familiar or if it's an environmental thing where the family is maybe One mom was exposed to DES when she had six children And so all six of these girls have an increased risk for certain cancers Those things are really hard to parse out. So that's kind of why we label them that way And then we have that much smaller group of people five to ten percent of breast cancer as we would consider genetic From a genetic predisposition where we can find that one big gene change that we think is the reason that they were much More likely to get that breast cancer The question about this is why do we care? Why do we care if we can find this predisposition to breast cancer or ovarian cancer? And this is particularly a question that I get from people who already have cancer What does it matter what my increased chances were those numbers don't mean anything to me anymore? So again, I'm just bringing up the population risks and we are talking about Based on specific gene changes that we have we talk about the brc one and two gene changes We can actually have other cancers that we are at increased risk for besides the one that we already have For the braca genes when a woman has breast cancer and we identify a braca gene for her Braca mutation she has a significantly increased chance of developing ovarian cancer as well in her lifetime So that's one of the big things we look for for her And something that's very common with the people that I see and something that I find very touching is that most people are more concerned about their children than they are for themselves They want to know I have breast cancer. How does that affect my daughter's chances of getting breast cancer? Here is the name of a couple of different genetic predisposition syndromes These are probably things you're not going to hear about too much Except the hereditary breast and ovarian cancer syndrome, which is what it is actually called when somebody has a brca one or brca two mutation these other ones lynch syndrome has to do with Colon cancer and uterine cancer. So again, that one's a little bit more common But some of these are a little bit more rare, but they can demonstrate that point for why do we want to know this information in the first place When it comes to cowden syndrome, you can see over there on the right hand side That breast cancer is the highest cancer that these people are at risk for and that's how these people usually come to clinic But they also have this increased chance of thyroid cancer and uterine cancer and renal cancer And then a moderately increased risk of melanoma and colon cancer If we can identify this patient we can recommend screening for those other things or Identify children before they get a breast cancer Interestingly, this is one of the few cancer predisposition Position syndromes that actually has a clinical presentation Most people especially if you have a brc one or two gene change by looking at them, you'd never know Even for these people Most people who would give them a glance over would have no idea what they're looking at But if you find a medical geneticist, they might they might know what's going on But they can have larger than normal head size. They can have what looks like pimples But it's actually a different kind of benign tumor Um, and then they have a risk for more vascular tumors or even some developmental delay So these are clues that can provide us information for which genes to test Or tell us we need to look at everybody in the family When we talk about hereditary breast and ovarian cancer syndrome, this is the most common genetic predisposition syndrome that's out there it encompasses mutations in brca one and brca two Most people who have this are only going to have a mutation in one not both, although it is possible The ovarian cancer risk is higher in women who have a brc one mutation than for women who have a brc two mutation This is another Knowing the specific gene that is affected tells us specific information We might be more concerned for somebody who has a brc one mutation About her ovaries and keeping them or not keeping them than for somebody who has a brca two gene change This also includes risks for male breast cancer And that's something that is very surprising to most people that I talk to is they don't realize that their sons are at risk They're so concerned about their daughters that we need to make sure we're taking care of everybody including their sons Again, this can be more common in people who have a jewish ancestry Lea fraumini syndrome is another one that's very uncommon This does not have a clinical presentation But gives us significantly increased chance for multiple cancers and multiple rare cancers And the people that are identified as having these changes go under much more intensive screening and surveillance than even somebody who has a Brc one or two gene change We're talking about full body MRIs every couple of years those kinds of things. It can be very intense for these families Which brings up another point being able to find those people if we find a woman such as myself who has a Lea fraumini syndrome and we test my children and they're negative We can save them from having to do all of that intensive screening. We can actually take a An emotional or a mental burden off of me and off of those children So that's another reason we want to identify those families Um, this can show us the example of how we would Why we want to test children as well? So when we have an affected father and an unaffected mom So if dad is diagnosed with something like lea fraumini syndrome One of his copies of that gene is affected has that mutation in it that causes it not to work The other one is just fine When he has a child One of his sperm either has one copy the copy that's working or the copy that's not working So each child has a relative 50% or coin toss chance of having inherited that gene or not inheriting that gene and That leads to the point of there's a very, you know, it's not uh, oh your dad had Diabetes so you have an increased risk for having diabetes This is a case where you either have it or you don't but it's 50 50 And the only way we can find out is by doing genetic testing Uh, the ncc and screening guidelines these are the ones for the average population This is just to kind of give you a baseline of where Everybody should be and then what increased surveillance can mean from here So if we're talking about breast exams when we talk about having a yearly mammogram If we're talking about somebody who has a brc one mutation We would probably as long as she's above the age of 20 probably start giving her mammogram Immediately upon diagnosis as opposed to waiting until that age of 40 Or even for women who are identified as having a higher risk of breast cancer and don't have a gene change We will recommend mammograms starting 10 years before their mom was diagnosed for example I listed some of the screenings that we have for the specific cancers that were mentioned Including mammograms breast MRIs can be a little more diagnostic than screening But these are things that we can increase the frequency of or add on to somebody's clinical regimen or management For somebody who's identified at having an increased risk for these cancers For brca one and two we talk about having your mammogram every year like you normally do But then six months later having an MRI so every six months Some things looking at your breast tissue to catch a cancer as early as possible in its development And again, dr. Reynolds touched on some of the limitations of the ca 125 or the vaginal ultrasound But then the pap smear is again something that all women are recommended for and then colonoscopies And that's as opposed to prevention one of the biggest things One of the biggest personal decisions that somebody can make when it comes to preventing versus reducing their risk for breast cancer Or ovarian cancer When we talk about having a mastectomy having a prophylactic mastectomy So before somebody is diagnosed with cancer can reduce the risk of breast cancer up to 98 percent It's not perfect that 2 percent accounts for a couple of different things including Perhaps missing a little bit of breast tissue because our breast tissue kind of spreads up into our sternum It's a little bit hard to guarantee that we removed everything As opposed to if we were talking about a discrete organ like the uterus Um, but even removing our ovaries and our fallopian tubes can reduce our risk of breast cancer by up to 50 Now these are things that we don't recommend for every single woman to do You know, I can't just walk in and say today I feel like I want a prophylactic mastectomy because I just don't want to get breast cancer, which Has its pluses and minuses But these for women who have a brc1 mutation who have up to a 70% risk of developing breast cancer in their lifetime It's a Better chance than not that they're going to get breast cancer. This can be something very significant for them Touching on what dr. Reynolds said again having a salpingo ophorectomy that means removing the ovarian Removing the ovaries and the fallopian tubes is what gives you that reduced risk Having your ovaries removed alone because so many ovarian cancers start as fallopian tube cancer Does not give us that protection that we're estimating for here When we talk about uterine cancer, we talk about doing things like a hysterectomy Or based on the specific cancers that are indicated based on our gene change Um one i'm thinking of which is very rare gives us an increased chance of developing gastric cancer And for those very few specific patients, we actually recommend getting their stomach removed as soon as they're diagnosed But those drastic measures is what can save people's lives When it comes to breast cancer doing more surveillance or choosing to do a lumpectomy or only a mastectomy once a breast cancer is detected Those are much more Personal or individualized decisions because we can prolong life and quality of life either way When we talk about genetic counselors, we're the ones who actually Um, I mean other professionals do this too, but we're the ones who specialize in Parsing apart family histories and figure out who can be tested based on Our clinical guidelines who's most likely to get covered for testing based on their family history and what insurance will or will not pay for Because they won't pay for testing for everybody um We're also the ones who try and sort out the difference between some environmental exposures Or maybe you do have an environmental exposure, but we still need to do genetic testing And helping everybody in the family understand what's going on based on test results that we have Identifying other family members who need to be tested whether it's a positive result or negative results And helping them understand where they're at based on where they're at with their cancer Are we talking about prevention and screening because this is somebody who hasn't had cancer yet Are we talking about additional screening for somebody who's already had a cancer? Or even in the very rare cases that in the future are probably going to pop up We actually have one FDA approved test for um ovarian cancer for brca one and two um if individuals are identified with this FDA approved test they qualify for um A third line medication, but you have to have a brc one or two gene change And hopefully things are going more in that direction so that as time goes on We have those FDA approved tests that we say based on your gene change We also know what's better for your cancer or for your treatment What we ask during appointments we ask lots of questions during our appointments Or you get a wonderful 10 page packet from me in the mail that I ask you to fill out beforehand But we ask about pathology of tumors if we can find them We know that we don't always know everything about our family history We might know that mom got breast cancer when she was 45 But we don't know if it was an invasive ductal cancer or a lobular cancer any of those kinds of things But we do the best we can to track those answers down whenever we can And if somebody knows that we're going to take that information and we're going to use it Um, we also talk about cancer treatment and follow up what people are doing What screening family members are already doing is your 50 year old uncle? Did he already have his colonoscopy or is he not looking that can be really important when we find out Oh, we haven't identified any colon cancer in anybody on In anybody of mom's cousins, but none of them are doing the screening They're supposed to so we don't really know what's going on with them But we also talk about the type how frequently How frequently people are following these recommendations and guidelines And that's again to help us interpret that family history Genetic testing and this is something That a lot of my patients asked me about and I didn't realize they didn't know Genetic testing is usually a blood draw. It's nothing more traumatic than that Although it depends on how traumatic you think a blood draw is and I'm a pretty big baby when it comes to needles But the genetic testing actually looks at in your blood sample looks at your white blood cells Looks at your DNA and actually reads them like a sentence It's a pretty unclear sentence. They don't actually look like words They look like these a t g's and c's that you see up here But with our technology, we know we can compare them to reference sequences This is what an unaffected gene looks like and we figure out what's going on here But that can lead to those variants of uncertain significance that dr. Reynolds touched on in that Just because we find a result doesn't mean we know If that gene changes significant if it changes the way that protein works or not This is a this is from myriad genetics. It's one of the labs that does a lot of testing We have lots of different options now. We can test just brca one and two or we can test 25 different genes at once It's just to give you an example of what it kind of looks like when i'm trying to figure out what kinds of tests i'm ordering This is another lab. This is a much smaller test, but it focuses on endometrial cancer So we can kind of cast a wide wide net or we can cast a little bit more of a narrow net And some of that is up to patient preference based on what we talk about what they want to find out What amount of information they can handle The last thing that I wanted to touch on was gene of the genetic information non-discrimination act It was passed in 2008 I believe and it is something that's very important for most of my patients and that's because This act protects us against Our genetic information being used against us. This means that somebody who's identified is having a brca one gene change Their insurance company can't drop them from ensuring them for that reason. They can't hike up their prices because of this reason And this is Especially important for women who don't already have cancer For women who already have a diagnosis of cancer Usually we're discriminated against or men usually the discriminating factors that you already have cancer Um Gina specifically does not address life insurance, which is something that can come into play with me sometimes for especially my younger patients who don't have a history of breast cancer I have counseled a 17 year old girl before who whose mom had a brc one gene change And so we had to talk about specifically setting up a life insurance policy for the girl Before she could go through with testing because if she had that life insurance policy in place beforehand they couldn't Take it away from her or jack up her prices After the fact, but that's something else that we talk about and consider when doing genetic counseling and testing um There are specific individuals that this does not apply to Um, and that's on the next slide, but this again covers things like our eligibility our discrimination Um They can't require you to have a genetic test, which is something really important I don't think that's been so much of a problem But um, you can submit your genetic information for proof, but they can't make you have it and they can't Do anything about that information except understanding For example, saying that this woman needs to have breast MRIs every single year Using that as proof that that's why she needed needs it is her genetic test result Some of the limitations of gina unfortunately do not cover any military families Don't cover native american tribe associated families and doesn't apply to individuals who work with Who work under a company that has 15 or less employees, so it's not perfect But it does Cast a wide net and hopefully i'm hoping in the future will be expanded a little bit to cover some more of these people But that is it for my presentation. Thank you


Hello, welcome all. Welcome to video lecture on Z-Transform, myself S. N. Chamath Gouda from Walchand Institute of Technology, Solopu. At the end of this session, students will be able to determine Z-Transform of a given signals. Today in this lecture, we are going to consider two sided infinite discrete time sequence. So, let us consider an example here. So, x of n is equal to 2 to the power n u of n minus 3 to the power n u of minus n minus 1. Now, find find Z-Transform and ROC of the given signal. So, let us solve this one. We know that x of z is equal to summation n equal to minus infinity to plus infinity x of n into z to the power minus n, where x of n is equal to 2 to the power n u of n minus 3 to the power n u of minus n minus 1. By substituting x of n is equal to 2 to the power n u of n minus 3 to the power n u of minus n minus 1. In the above expression, x of z can be written as x of z is equal to summation n equal to minus infinity to plus infinity 2 to the power n u of n minus 3 to the power n u of minus n minus 1 into z to the power minus n, where the first term represents the right sided sequence and second term represents the left sided sequence. Therefore, the summation can be split it into two parts. Hence, x of z is equal to summation n equal to minus infinity to plus infinity 2 to the power n u of n into z to the power minus n minus summation n equal to minus infinity to plus infinity 3 to the power n u of minus n minus 1 into z to the power minus n here. Because of the unit step signal in both the terms, the limits of the summation are changed here. We know that unit step signal u of n is defined as u of n is equal to 1 for n greater than or equal to 0 and u of n is equal to 0 for n less than 0. Similarly, u of minus n minus 1 is a modified version of unit step signal u of n and this one is defined as u of minus n minus 1 is equal to 0 for n greater than or equal to 0 and it is equal to 1 for n less than 0. So, we are going to use these two definitions in our example here. Therefore, the x of z because of these two unit step signals x of z will be written as n equal to 0 to infinity 2 to the power n z to the power minus n minus summation n equal to minus infinity to minus 1 3 to the power n z to the power minus n here. Because of these two unit step signals, the limits have been changed in both the terms here. In the first term, it is changed into n equal to 0 to infinity whereas, in the second term it is changed into n equal to minus infinity to minus 1 here. Now, to understand how the limits have been affected because of the unit step signals, let us consider the graphical representation of the signal here. So, here summation are written as n equal to 0 to infinity 2 to the power n z inverse minus summation n equal to minus infinity to minus 1 3 to the power n z to the power minus 1. Now, to understand how the limits of these two summations have changed because of the unit step signals defined above here. Here you can see that u of n is equal to 1 for n greater than or equal to 0 and it is equal to 0 for n less than 0 and u of minus n minus 1 is defined as it is equal to 0 for n greater than or equal to 0 and it is equal to 1 for n less than 0. So, in the graphical representation, you can see that the first graph represents the 2 to the power n which is a growing exponential signal and in the second graph it represents the unit step signal as per the definition on the left side the values of u of n is equal to 0 whereas, for n equal to 0 to plus infinity the values are equal to 1 here. So, when we perform the multiplication between these two signals, we get the resulting signal that is which is equal to 2 to the power n u of n. So, on the left side 2 to the power n is multiplied with the 0 therefore, the resulting signal will be equal to 0 whereas, for n equal to 0 to plus infinity that is on the right side we can see that 2 to the power n is multiplied with the 1 therefore, you will get 2 to the power n here. Therefore, in this representation you can see that the signal exists from n equal to 0 to plus infinity hence the limits of the summation are written as n equal to 0 to infinity. Similarly, on the second on the right side you can see that another set of graphical representations are given here. The first graph represents 3 to the power n which is again a growing exponential signal and the second graph represents the modified version of unit step signal u of n which is defined as u of minus n minus 1 is equal to 0 for n greater than or equal to 0 and it is equal to 1 for n less than 0. According to that in the graph you can see that on the left side from n equal to minus infinity to minus 1 the values of u of minus n minus 1 is equal to 1 whereas, for n equal to 0 to plus infinity the values of u of minus n minus 1 is equal to 0. So, when we perform the multiplication between 3 to the power n u of minus n minus 1 we get the resulting signal has shown in this graph here. So, here you can see that for n equal to 0 to plus infinity the signal 3 to the power n u of minus n minus 1 is equal to 0. Whereas, on the left side from n equal to minus infinity to minus 1 you can see that the 3 to the power n u of minus n minus 1 is equal to 3 to the power n because 3 to the power n is been multiplied with u of minus n minus 1 that is 1 3 to the power n is multiplied with 1. Therefore, you will get the resulting signal 3 to the power n here. So, that is why the limits of the first summation has been changed to n equal to 0 to infinity and the limits of the second summation has been changed to n equal to minus infinity to minus 1 here. Therefore, x of z is written as x of z is equal to summation n equal to 0 to infinity 2 into z inverse to the power n summation n equal to minus infinity to minus 1 3 into z inverse to the power n here. Now, in earlier 2 example we have used the infinite summation identity that is summation n equal to 0 to infinity alpha to the power n the infinite summation identity that is summation n equal to 0 to infinity alpha to the power n is equal to 1 divided by 1 minus alpha. This infinite summation identity is valid for mod alpha less than 1 year. So, by comparing x of z with the infinite summation identity we can see that the first summation is identical with this infinite summation identity whereas, the second summation is not identical with the infinite summation identity. So, therefore, we need to first convert this second summation the limits of the summation identical to this infinite summation identity so that we can use this infinite summation identity to simplify the x of z further here. So, first we will change that limits of that summation here. So, to change that one so we are going to put k is equal to minus n k is equal to minus n in second summation here. So, k equal to minus n means minus plus n will be equal to minus k and similarly n equal to minus infinity minus n will be equal to plus infinity and minus n will be replaced by k. So, k is equal to plus infinity similarly n equal to minus 1 so minus n is equal to 1 here so minus n is replaced by k so k is equal to plus 1. So, these are the k values which we are going to use in the second summation here not in the first summation. Therefore, x of z can be written as summation n equal to 0 to infinity 2 z inverse to the power n minus summation k equal to infinity to 1 3 z inverse to the power minus k here. So, further this one written as n equal to 0 to infinity 2 z inverse to the power n minus summation the lower limits are written below the summation and upper limits are written above the summation. Therefore, k is equal to 1 to infinity and this is written as 3 inverse z to the power k here, but still the limits of the second summation are not identical with the infinite summation identity here. Therefore, we are going to use the concept that is a to the power 0 equal to 1 in this example here. Therefore, x of z is equal to summation n equal to 0 to infinity 2 z inverse to the power n plus 3 inverse z to the power 0 minus 3 inverse z to the power 0 minus summation k equal to 1 2 infinity 3 inverse z to the power k here. Now, we are going to merge these two terms here and this will be further written as x of z is equal to summation n equal to 0 to infinity 2 z inverse to the power n plus 3 inverse z to the power 0 is nothing but 1 minus summation we are going to merge these two terms. Therefore, k is equal to 0 to infinity 3 inverse z to the power k. Now, we can use this infinite summation identity in both the summations here to simplify x of z. So, in our example in the first term in our example in the first term in the first summation alpha is equal to 2 z inverse whereas, in the second summation alpha is equal to 3 inverse z. So, therefore, x of z can be written as x of z is equal to 1 divided by 1 minus 2 z inverse. So, x of z is equal to 1 divided by 1 minus 2 z inverse plus 1 minus 1 divided by 1 minus 3 inverse z here. Now, in the first term we multiply both numerator and denominator by z. So, therefore, it will be written as z divided by z minus 2 z inverse z plus 1 minus again in the in this term we are going to multiply in this term we are going to multiply numerator and denominator by 3 here 3 divided by 3 minus 3 inverse z into 3. So, 3 and 3 inverse will get cancelled here z and z inverse will get cancelled. So, this will be written as z divided by z minus 2 plus 1 minus 3 divided by 3 minus z. So, further x of z is simplified as z divided by z minus 2 plus 3 minus z divided by z minus 2 plus 3 minus z minus 3 divided by 3 minus z. So, 3 and minus 3 will get cancelled. So, this will be written as z divided by z minus 2 plus minus z divided by 3 minus z. Now, this second term is multiplied both numerator and denominator by minus 1. So, further this will be written as z divided by z minus 2 plus z divided by z minus 3 and this summation this x of z is valid if mod 2 z inverse is less than 1 and mod 3 inverse z is less than 1 here. So, this can be further written as mod z is between mod 2 and mod 3. Now, let us plot the region of convergence on the z plane here. So, region of convergence is as shown in the z plane shaded part represents the region of convergence and this region of convergence is between the two circles of radius 2 and radius 3. Thank you.