Novel and Personalized Treatment for Gynecologic Cancers

May 24, 2023

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Yale Cancer Center Grand Rounds | May 23, 2023

Presentations by: Drs. Elena Ratner and Alessandro Santin

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00:00Welcome to Yale Cancer Center Ground Rounds.
00:03I'm Doctor Miriam Lustberg
00:04and I have the privilege of
00:07introducing our two speakers today.
00:10Doctor Elena Ratner is a professor
00:13of obstetrics and gynecology and
00:16reproductive sciences and cochief of
00:19the section of Gynecological Oncology.
00:22She's a board certified gynecologist.
00:25Oncologist with special interest
00:27in chemotherapy,
00:28Targeted drug development,
00:29patient quality of life programs
00:32and early cancer detection.
00:35She's the current codirector
00:36of Discovery to Cure,
00:39Director of discovery to Cure Early
00:42ovarian cancer detection program and a
00:45founder and director of the Sexuality,
00:48intimacy and Menopause program.
00:51Her expertise?
00:52Is cytoreductive surgery for patients
00:55with advanced ovarian cancer minimally
00:58invasive procedures for patients with
01:01gynacologic malignancies or complex
01:03benign gynacologic conditions and
01:06robotic fertility sparing surgery
01:08for young patients with cancer?
01:11Doctor Ratner's laboratory is working
01:13on new targeted drugs for ovarian
01:16cancer in order to provide patients
01:19with truly personalized care.
01:21Her work additionally focuses on
01:23reversing chemotherapy resistance
01:25in ovarian and uterine cancers.
01:28Our second speaker is Doctor
01:31Alessandro Santine.
01:33Dr.
01:33Santine is a professor of obstetrics
01:36and gynecology and reproductive
01:39sciences and cochief of the
01:41section of Gynecology oncology.
01:43His clinical interests include
01:45cancer of the ovary, uterus,
01:47vagina, cervix, and the vova.
01:50Interperitoneal chemotherapy,
01:52tumor genetics, immunology and immunotherapy,
01:56tumor angiogenesis,
01:57radiation biology and experimental
02:00therapeutics, and gynecologic oncology.
02:03Dr.
02:04Santine's current research interests
02:05include immunotherapy for ovarian,
02:09cervical and endometrial carcinomas,
02:11refractory to standard treatment modalities,
02:14and development of therapeutic vaccines.
02:17Against the human papilloma virus,
02:19infected genital tumors and the
02:21use of monoclonal antibodies
02:23against chemotherapy resistant
02:25gynecologic malignancies.
02:27Dr.
02:27Santine has more than 300 original
02:29research and peer reviewed publications
02:32and has written extensively on
02:34various topics including cancer of
02:36the ovary Endometrium cervix as well
02:38as on tumor immunology and immunotherapy.
02:41I thank both speakers for sharing their
02:43expertise with us and I welcome Dr.
02:45Ratner to the podium.
02:46Thank you.
02:52Thank you so much that Collinsburg.
02:54Let me bring us to the beginning the
03:01oldfashioned way. I'm just going to bring it,
03:04we're sure this more sophisticated way.
03:06Here we go. So we are so excited
03:09to speak with you today.
03:11Thank you for giving us opportunity
03:13to present to you the work of our
03:15division and to discuss the state of
03:17the union of gynecological cancers
03:19especially in the State of Connecticut.
03:21Just like everything else
03:22in the Centina and I do,
03:24we are going to double team this.
03:25I will start with clinical presentation
03:28and Doctor Centine will discuss
03:30his very impressive research,
03:32so ovarian cancer.
03:35Continues to be unacceptably deadly.
03:39It's the survival of ovarian cancer.
03:43Interestingly,
03:43shockingly and unacceptably
03:45has really changed very little
03:48over the past 20-30 years.
03:50The reason for this is multiple call
03:54there is there continues to be a
03:57profoundly late detection ovarian cancers.
04:00There is a lot of research that says
04:04that ovarian cancers by the time that
04:07diagnosed usually have been there for
04:09as long as 24 months and frequently
04:11women has seen six other physicians,
04:14six other providers prior to
04:17actually finally being diagnosed.
04:20And that is why advocacy is so important,
04:22that's why education is so important and
04:25that is why we so profoundly and strongly.
04:29Support encourage personalized care,
04:33personalized care to patients in
04:36the setting of early detection,
04:38in the setting of prevention,
04:40which as I mentioned to you is so
04:43important in the disease because
04:44early detection is so difficult
04:46because the symptoms are so vague.
04:49Personalized care in terms of surgery,
04:51surgery in this disease and it's
04:54incredibly important and we will talk
04:56today about stratifying patients.
04:58To who is able to have this
05:00surgery minimally invasive and
05:01we'll talk briefly about hypec,
05:03something that one of our colleagues Bargain
05:06and Dekean is very passionate about.
05:09And then the Constantine will
05:10talk about the importance of
05:12personalized care and the treatment,
05:14the management,
05:15the maintenance of these women.
05:18We are incredibly blessed to be in
05:21a wonderful supportive environment.
05:23We are so happy that some of our
05:25team is here today.
05:26We have the most incredible research
05:29team and the most incredible clinical
05:31team and none of this would be
05:33possible for sure without them.
05:35So very briefly, we don't have much time.
05:37So I'm going to be skipping
05:38through a lot of things,
05:39but just kind of to set the stage today,
05:41we're going to be talking
05:43about epithelial cancers,
05:43you know,
05:44ovarian cancers.
05:45Ovarian cells in general have
05:47different kinds of cells,
05:48and epithelial cancers are the ones
05:49we're going to talk about today.
05:50Those are the most common ones.
05:52And when you hear about people
05:53talking about ovarian cancer,
05:54usually it's about epithelial,
05:56which is serious serous endometrioid clear
05:59cell we use in this or carcinosarcoma.
06:02Nowadays,
06:03things like genomics and things like
06:05mutations that drive the cancers
06:08is so much more important actually
06:10that the kind of Histology that the
06:13cancer has and again the Constantine
06:15will share all that with us.
06:17But in terms of prevention,
06:19in terms of early detection,
06:20in terms of treatment,
06:22in terms of clinical presentation,
06:24so much time and effort now is being
06:26spent on understanding predisposition.
06:29You know, we have not succeeded
06:30in curing these cancers.
06:31We have not succeeded not because of
06:34lack of trying in early detection.
06:36So the next best thing,
06:38and really just the best thing is prevention.
06:41We know that there's certain
06:43genetic mutations that increase
06:44the risk of bearing cancers.
06:45BEAR, C1, BEAR, C2 and Lynch all
06:49profoundly increase the risk.
06:50And that is why it is so important
06:53that women know their predisposition.
06:55We do a lot of advocacy and a lot of talks
06:58to talk to women about know your genes,
07:00know your predisposition,
07:01know what kind of genetic
07:03mutations you might carry,
07:04because a lot of these women
07:06could be saved not by cure,
07:08not by early detection,
07:10but actually by prevention.
07:12And so much now in treatment
07:15depends on the pathophysiology of
07:17these high grade serious cancers.
07:18And we know so much now about different
07:22DNA mechanisms that drive these cancers.
07:24One of the biggest one is
07:26homogeneous recombination.
07:27That is something that we have really
07:29explored widely over the past five,
07:31seven years and where a lot of
07:33the targeted drugs play a role.
07:37So briefly, ovarian cancer,
07:38second most common malignancy
07:40of the of the general tract,
07:42by far the deadliest.
07:44The incidence is actually not that high 1.3%,
07:48but as you see 21,000 women get
07:52diagnosed and 13,000 women die.
07:56So incredibly deadly cancer.
07:59It is very interesting,
08:01there's for sure geographic distribution,
08:03there's for sure high risk populations.
08:06Women with Caucasian populations,
08:08women that come from smaller family size,
08:12higher socioeconomic status and
08:13high fat diet all play a role.
08:15And what's interesting is that when women
08:18move from the region that's of lower
08:21incidence to a region of higher incidence,
08:24most sadly they acquire the higher risk of.
08:28So it's now where you're born,
08:30it's where you grow up,
08:31where you where you live,
08:32which is very interesting.
08:35So there's many different studies,
08:37of course, that talk about predisposition.
08:40And you know,
08:40we know that obesity plays a role.
08:42We know that women who have
08:46their periods start early,
08:47their menopause come late,
08:49women who do not have kids,
08:51women who have endometriosis.
08:52We know these women have a predisposition,
08:55and the reason for that is because
08:57there's two different theories
08:59of how ovarian cancers happen.
09:00One is that every time a woman ovulates,
09:03some sort of a process happens.
09:05And the more time she ovulates,
09:07the higher is her risk of
09:09developing ovarian cancer.
09:10That's why certain things are so protective.
09:12So, for example,
09:14women who have had five pregnancies
09:16and breastfeed each every child for
09:19one year have a 50% reduction rate.
09:22I've worked on the plan very, very different.
09:26The most same option is the
09:28birth control pills.
09:29So similar,
09:30any woman who uses birth control pills
09:33for five years has a reduction of 50%.
09:36So very, very impressive.
09:38Women who have used OCP's birth control pills
09:41for 10 years have reduction as high as 80%.
09:46And that is all cumulative and that's all
09:48respective to the woman personalized risk.
09:51So even somebody who has a BRC
09:53mutation and has a 40% risk,
09:55if they have used OC PS:,
09:57for five years,
09:57the risk goes down to 20%.
09:59They've used it for 10:15,
10:00it goes to 10:00 and 8:00.
10:02So with different modifications,
10:03we actually can do risk
10:06adjustment and decrease the risk.
10:08And then we know there's also
10:10inflammatory factors such as
10:12pelvic inflammatory disease and
10:13endometriosis that play a role as well.
10:16The second theory of ovarian cancer
10:18is actually that these cancers
10:20are not potentially not even
10:22ovarian cancers to begin with.
10:23They're actually fallopian tube cancers,
10:26especially in women with genetic mutations.
10:28And these cancers start in the Philippine
10:30tubes and only then spread to the ovaries.
10:32And that is why nowadays there's such a
10:34culture of actually removing fallopian
10:36tubes at different opportunities,
10:38because that creates a risk
10:40reduction as high as 50 to 70%.
10:43So here within our our institution,
10:45we actually have been able
10:47to influence the culture.
10:48And in the older days,
10:5010 years ago,
10:51when people when women used to have
10:53their tubes tied,
10:53they literally have their tubes tied.
10:55Now we actually remove the fallopian tubes,
10:57especially in women with higher
10:59predisposition to cancers.
11:01We are able to to provide a
11:03very substantial risk reduction
11:05just by that simple technique.
11:07In the older days,
11:08we used to leave fallopian tubes
11:09anytime we left ovaries when
11:11somebody would have a hysterectomy.
11:12Nowadays, for sure fallopian tubes
11:14would be removed because we know
11:16that there's a huge component of risk
11:18reduction by removing the fallopian
11:20tube and it's a very easy adjustment.
11:23But of course, out of all those things,
11:24the most highest risk is the family history.
11:28Anybody who has a family first degree
11:32family member who has ovarian cancer,
11:34that increases that woman's
11:36lifetime risk to 4 to 5%.
11:38And as I showed you before,
11:40this hereditary breast and ovarian syndromes,
11:42which account for 20% of ovarian cancers,
11:45but we really think,
11:46account for much more.
11:47We just don't yet know exactly which ones.
11:50They of course carry the the
11:52most highest risk.
11:55Very briefly.
11:56There's a very profound and very
11:58meaningful and very important racial
12:01health disparities in ovarian cancer.
12:04We have known this forever.
12:05We have known forever that
12:07women of color do worse.
12:10And we used to think that it's just
12:12because of the Histology of the
12:14cancer that the women who are non
12:16Caucasian get Histology that are
12:18more aggressive and that is indeed.
12:20Case, but unquestionably and deniably
12:22confirmed by many different studies,
12:25especially recently.
12:26We also know the women of
12:28color get worse care.
12:30They have more profound delays
12:33in diagnosis and chemotherapy.
12:35They don't get necessarily this term
12:38of care surgery now with the joint
12:41oncologist and another very important
12:43component is that women of color are
12:47under enrolled in clinical trials.
12:49Only 17% of clinical trial participants
12:53represent racial or ethnic minorities
12:56and African American women's
12:58participation only reached 9/11,
13:0010%, nine percent.
13:01So we believe that all of that plays
13:04a very important role and that is
13:06why so much effort is being is being
13:09made to improve this cruel into
13:11trials and open it to women of color.
13:14So very briefly just the state of our union.
13:17You an ecology here at Yale is very,
13:19very busy.
13:20We have a great number of surgical cases,
13:22new patients and it continues
13:26to increase every year.
13:28Our biggest we cover the entire
13:30state of Connecticut all the way
13:32from Greenwich all the way to New
13:33London with the great majority of
13:35our care that happens here in New
13:37Haven and then Bridgeport Hospital.
13:40And as you see the number of our new
13:43patient visits and surgeries grows.
13:46Each and every year,
13:47and this is the territory that
13:49we cover again,
13:50all the way from New York all
13:52the way to New London,
13:53so very profoundly so there.
13:57One of the things that have
13:58changed drastically in the care
13:59of joining College of Patients,
14:00something that I'm going to
14:01talk about briefly,
14:02is how much we are able to do
14:05surgically in a minimally invasive way.
14:08So when you look at that data that I just
14:10pulled up and the data that you know,
14:11I study very closely and extensively,
14:13the culture of this field is
14:16changing to become almost
14:18predominantly outpatient field.
14:20Great majority of our women used
14:22to have the surgeries and have
14:25a prolonged inpatient stay.
14:26And now great majority of women are
14:28able to have the same kind of radical
14:30debalking surgeries in a minimally
14:32invasive way that I'll show you in
14:33a little bit and are able to be
14:36discharged home literally same day.
14:38And that is why so much of our financial
14:42representation has now become an
14:45outpatient service versus the inpatient.
14:48So surgery is very,
14:51very important.
14:52Let me just get rid of that.
14:54I don't know if that's supposed to be here.
14:57There we go.
14:58So surgery in gynecology is
15:00of paramount importance.
15:01We know for many different
15:03reasons that women who have had
15:05very radical surgery and their
15:07cancer was removed entirely
15:09with no residual disease,
15:11have done profoundly better.
15:14You can see here the overall survival
15:17is significantly better for women
15:18who have had 0 millimeters of disease
15:21left at the completion of surgery.
15:23This is kind of what things
15:24look like when we begin.
15:25This is kind of how ovarian cancer presents.
15:28This is the cancer that spreads over the
15:30bowel or momentum over the pertinal surfaces.
15:34And very frequently we hear especially
15:36Yale give new adjuvant chemotherapy,
15:39which is chemotherapy before the surgery
15:41to increase the chances of successful
15:43debalking to no residual disease.
15:45So I want to talk briefly about approach
15:48to surgery and again why this has to be
15:52so personalized and so individualized.
15:54This was a big poster that
15:56was hanging in the office.
15:58Of my mentor and previous boss.
16:01And when I was younger,
16:03not that much younger.
16:04It was a big point of debate.
16:07The greater the surgeon,
16:08the bigger the incision.
16:10Certainly not the case.
16:12Granted, I now have his office and his job,
16:14so there's that.
16:18So many studies have showed the
16:21laparoscopy and minimally invasive
16:23approach to ovarian cancers
16:24and gercologic cancers not only
16:27safe but completely appropriate.
16:29We know that complications are less,
16:32We know that efficiency is the same.
16:34We know that effectiveness is the same.
16:37So again,
16:38everything has to be done in a very
16:40personalized way that has to make sense,
16:43the biggest thing in joint oncology
16:45surgery and something that we
16:46care so passionately about.
16:48Is that masses do not get spilled
16:50because when the mass ruptures,
16:52that's up upstages the patient
16:54and worsens their prognosis.
16:55So all kinds of things are done
16:58to prevent that.
17:00And again,
17:01in the older days used to be a big point
17:04of debate and big point of discussion.
17:06So I want to share some of the
17:08videos of mine and some of our
17:10partners Sudo Zodi that show how we
17:14deal with some of these concerns.
17:17So you know in ovarian cancer,
17:20because our patients are women,
17:22we use frequently the vaginal
17:25orifice as a site of of removal.
17:29So this is a young patient who had Carson
17:34Sarcoma that had isolated periodic mass.
17:39That you know in the older days,
17:42again few years back would have just
17:45been removed with a big incision,
17:47with a huge resection and huge
17:50recovery because of the concern
17:52both for the complexity of the case.
17:54So as you can see this is the great vessels,
17:57this is the ureter,
17:58this is the mask that was entirely
18:00resected and then the concern would have
18:02been how do you remove a mask like this.
18:05And this is something that
18:07we use a great deal.
18:08And something that we talk about a
18:10lot is that we're able to just play
18:12something right through the vagina,
18:15place the back into the vagina
18:18that is only very, very small,
18:21small 10 millimeter incision
18:23and then remove it like this.
18:25And this patient was able to
18:27go home same day.
18:27This patient also had a metal diverticulum
18:30that we we resected at the same time.
18:34And also was removed similarly
18:36like that as you can see.
18:38So this is the the bowel surgery,
18:40the reticulum similarly placed in the bag,
18:43similarly placed in the vagina
18:46and similarly patient went home
18:49same day and had minimal minimal
18:51recovery from from something that
18:53would have been very extensive.
18:55Natural or laparoscopy is so important
18:57and again we are lucky to be able to use
19:01vaginal orifice in our patients for this.
19:04So at times, again, you know,
19:06everything has to make sense.
19:08You know, this is the older patient who
19:10had a very many medical comorbidities
19:13who would not have withstanded.
19:16Overall, big large laparotomy,
19:17which is what we would have done
19:20usually for this 12 centimeter mass.
19:22But at the same time,
19:23we of course want to be very careful and
19:25not rupture the mass and not leak it.
19:27So we do all kinds of special techniques
19:30again in a very truly personalized way
19:32to be able to provide our patients with
19:35the best care specifically for them.
19:38So this patient,
19:39as you can see,
19:40everything was protected and then
19:41the mask was insulated and we were
19:43actually able to see inside the
19:45mask and then we were able to see
19:46that this was a malignant mask.
19:48Once the fluid was removed in the
19:51contained way and that nothing was removed,
19:54nothing was nothing leaked.
19:56And then same same way we were able
19:59to just tie something around it
20:01to make sure that nothing leaks.
20:04Remove it and then remove it similarly
20:05to the vagina like I showed you before
20:08and all the lymph nodes and everything
20:09else could be done laparoscopically.
20:11And again the spatial with multiple
20:13comorbidities was able to go home
20:16next morning with minimal recovery
20:20time and was able to have her
20:24cancer appropriately removed.
20:25We nowadays use something called high pack,
20:27which is what I mentioned to you before.
20:30Which is there's a lot of conceptual
20:34thinking that hyper hypothermia
20:36and neoplasia at the time of
20:39aggressive debalking really improves
20:42the overall survival.
20:43And this is again, this is before debalking.
20:45This is after debalking,
20:47we remove all the disease and then
20:49we're able to place a cyst plan into
20:52the belly for 90 minutes that improves
20:55direct permeation of the tumors.
21:00And there's some very,
21:02very strong literature that supports
21:03it in this population with pretty,
21:05pretty significant improvement
21:07and progression free survival
21:09and overall survival.
21:11In the next two minutes that I have left,
21:13I promised I consenting that
21:14I was going to be on time.
21:16I want to talk briefly about survivorship.
21:18So survivorship is so important.
21:20We for generations have undervalued
21:22under address the importance of
21:25survivorship in this population.
21:28It's because forever we,
21:29we thought the women get this
21:30cancers and then they die.
21:32That is not the case.
21:33As you see that as we're getting better
21:35in diagnosis is we're getting better
21:38in surgery as we're getting better
21:40in treatment, women are living
21:41longer and when they live longer,
21:43it is so important that we provide them with
21:46survivorship techniques to support them.
21:48I'm actually so happy to see that we
21:50have our teal team here that help
21:53us concentrate on nutrition this
21:55population because this is yet another
21:57one of those aspects that really has
22:00been undervalued and underaddressed.
22:02So in in Galactic Cancers survivorship
22:07has so many different aspects,
22:10fear recurrence, toxicities from surgery,
22:13toxicities of chemo and radiation and
22:15that's what they got financial toxicity.
22:17Psychological body image and
22:19then sex and intimacy,
22:20which is a very profound aspect of women's
22:24experiences that here at Yale we are
22:27very passionate about the dressing so
22:29I'll let this I'll leave this with Doctor
22:33Sentine to with one minute to spare.
22:36So in the one minute then I have I'm not
22:38going to I'm not going to give away the
22:40minute what separates us here at Yale.
22:43Is that we are truly patient driven
22:45and we are truly believe in the
22:48importance of personalized care.
22:50You know, we nobody,
22:52nobody treats the cancer anymore.
22:54We truly treat the women that we see.
22:56We see their lives,
22:57we see their experiences and then we do.
23:00Everything we can to address their
23:02personal experience from diagnosis to
23:04surgery to treatment and we'll we'll talk
23:07about and then to the survivorship and
23:09supporting them through their journey
23:12both during treatment and then after.
23:14And again we're only able to do it
23:15because of the amazing team that we have.
23:18Thank you
23:27so. Alina has already done a very
23:32nice introduction and this light
23:34for me is only to remind you that
23:37regardless to the how sophisticated
23:39our surgery can be and Alina show
23:43you minimally invasive approaches,
23:44sometimes we have to do ultra radical
23:47surgery to to remove again the tumor
23:50regardless regardless the adjuvant
23:51treatment they were able to offer
23:54to this patient such as radiation
23:56therapy as well as chemotherapy.
23:58A significant number of our
24:01patients still again develop
24:03progression and recurrent disease.
24:05And as I show you here,
24:07of the 100,000 diagnosis with a
24:09gynecological cancer in the US,
24:12about 1/3 of women still die every year
24:15because of this difficult to treat cancer.
24:18So the question is what can we do to
24:23improve the outcome of this patient?
24:25And this again and what I'm going to
24:28show you here is our scientific vision
24:31and goals that we really we we we
24:34started thinking about how we could
24:37really face up with some medical need many,
24:40many years ago and we developed
24:43or we tried to develop a program,
24:45a personalized treatment program.
24:47Adding to what Alina show you,
24:50so this excellent clinical and surgical care,
24:54adding a translational research program
24:57above that in particular targeting the
25:00difficult to treat gynecological cancer.
25:04And when I say difficult to treat it
25:06means that the problem is really in
25:09our specialties not to take care of
25:11a well or moderately differentiated
25:13uterine cancer.
25:14Is really to take care of the
25:17biologically aggressive such as
25:18the uterine serous carcinoma or the
25:20carcinos or comma or they grade
25:22ovarian that are widespread and so on.
25:24So we thought to really the one of
25:28the of the the the winning strategies
25:31was to provide access to our patient
25:34in particular this group of patient
25:37to precision medicine through a
25:39pipeline of both pharma as well
25:41as yield developed treatment.
25:43Again validated within rigorous clinical
25:45trial that I'm going to show you in a minute.
25:48But the other thing was really to to
25:51be able to build a multidisciplinary
25:53approach because if you want to be
25:56successful in a big Cancer Center,
25:58again the surgical is important,
26:00is important,
26:00the the,
26:01the chemotherapy or addition therapy
26:03is important by if you want to
26:05do one step farther and going to
26:08translational personalized medicine.
26:09This is really a team approach
26:11that goes outside our division.
26:13And that is what we try to build here.
26:15We involve and interact with other
26:18successful clinical as well as the
26:22research program present in our Yale
26:24Cancer Center and also of course take
26:28advantage of the cutting edge resources
26:30that we have available at Yale.
26:32And I want to mention the the
26:36genomic course sequencing facility
26:38that we have in the West Campus.
26:41As well as again the the pathology corps,
26:43Doctor RIM is here that is doing an
26:46excellent job is providing tissue to
26:47to all the research area of the Yale
26:49Cancer Center to be able to do what
26:51I'm going to show you internal
26:55personalized treatment.
26:57So a lot of people talk about personalized
27:00treatment but what is personalized treatment,
27:03what is precision medicine in the
27:06division of gynecological oncology Yale.
27:08As Alina show you,
27:10everything start with the surgical part.
27:13So we are surgeon but ovarian uterine
27:16cancer are surgically staged tumor.
27:18So we that is the first time,
27:20the first moment in the
27:22treatment of our patient.
27:23And as Alina told you,
27:25we try to remove all the disease that we can
27:28see to improve the outcome of this patient.
27:30But one of the thing that we've been
27:32doing now for quite a long time.
27:34Starting probably as one of the First
27:37Division in the US and worldwide
27:39was to consent our patient at the
27:41time of surgery before surgery
27:43also to donate a piece of tissue
27:46to go to our research laboratory
27:50and this piece of tissue was used
27:53to sequence to sequence the
27:57DNA of the tumor of this
27:59patient with the ultimate goal.
28:01To have a better understanding of the
28:04genetic landscape of that specific
28:07patient tumor and and as I told you
28:10we started close to 2010 to do that.
28:13At that time point the commercial entity
28:16that we were using to receive a some
28:20sort of FDAGMP approved report was
28:23Foundation Medicine but at the same time
28:26in parallel we are also able to perform.
28:30All Axon sequencing at the West campus,
28:33as you know all Axon sequencing
28:36is quite expensive,
28:37was very expensive about 10-15 years ago
28:40when we started is still expensive now.
28:42So the question that some of you can ask me,
28:45but there's something how have you been
28:47able to do that 100 or gynecological
28:49cancer patient without asking you
28:51know the patient to pay for it.
28:54The answer is that we.
28:57You know,
28:58we had this collaborative research program
29:01at Yale between Yale and Gilead Science.
29:04And this was a huge program,
29:06$70 million in 10 years provided
29:10to us through Doctor Schlesinger
29:12was the Chair of pharmacology
29:14that was able to establish this
29:17collaborative research agreement.
29:18And thanks to this significant
29:21amount of money,
29:22we were able again to sequence
29:24over 800 gynecological cancer.
29:27Again all Axon sequencing, 21,000 gene,
29:31all the gene encoded protein.
29:35Another thing that we have been doing
29:37for the last 10 years is a little
29:39piece of this fresh tissue was going
29:41to my lab and in my lab we were
29:44trying to establish primary cell line
29:46as well as patient derives senokra.
29:49So in few words the viable tumor tissue
29:52was both placed in the Petri dish.
29:55As well as in an animal with the
29:58ultimate goal again to establish
30:00the disease in these avatar animals.
30:03Why is that important is because
30:05as I'm showing you here,
30:07the ultimate goal was to develop the
30:10patient to get the pathology report
30:12to start the patient on the standard
30:14treatment that as we discussed
30:16unfortunately sometime is unable
30:18to cure the patient and having the
30:23genetic sequencing data available.
30:25To be able to identify potential
30:28draggable marker,
30:29test this potential drug in the avatar
30:32animal on the tumor of the patient
30:35when she was receiving the standard
30:37of care and be ready for her in case
30:40the disease come back or become resistant.
30:42We already had tested in for that specific
30:45patient a certain number of drug to
30:48provide her again with personalized
30:51treatment at the time of occurrence.
30:53Another thing that we've been able
30:55to to do in the last 5-6 years
30:58is also to provide personalized
31:01diagnostic to our patient.
31:02What does it mean?
31:04It mean to detect the present of
31:06circulating tumor DNA that is
31:09mutated DNA coming from the tumor
31:11and this was again possible because
31:14through the sequencing.
31:16We add knowledge about the potential
31:18driver mutation present in this patient,
31:21present the tumor of this patient.
31:23We design specific probe able to
31:26amplify this mutation present in the
31:29circulation of this patient and using
31:32a not invasive method that is a simple
31:35collection of of five to 10CC we were
31:39able and this is a tumor inform assay to
31:43detect the presence of the mutated DNA.
31:46That correlate with the
31:47presence of this in the patient.
31:48So this is a new approach of course to
31:52monitor and is called again personal
31:55like diagnostic type of approach
31:57because allow us to see the presence
31:59of tumor DNA in the circulation.
32:02But even more important being a tumor
32:05inform approach this type of technology
32:08become about 10 to 100 fold more sensitive.
32:12Then the standard approach of looking
32:15to again the Press of DNA when you don't
32:18know what type of mutation is pressed.
32:21So using this approach,
32:22let me show you a little bit the progress
32:25that we have done for the last again
32:28few years taking care in particular
32:30the difficult to treat patient and one
32:35of the most difficult uterine cancer.
32:40They were dealing with in the
32:42clinic are uterine seros.
32:43They are rare tumor 3:00 to 9:50 to
32:4710% over all of all uterine cancer,
32:51but they kill over 40% of our patient.
32:53Why is that is because they
32:55are biologically aggressive,
32:57they can start spreading very early
33:00and they're usually difficult to
33:03treat in thermal chemotherapy.
33:05One of the important thing is that.
33:07The Gynong division at Yale has been
33:10for a long time a really a place
33:14where this patient were affair.
33:17And this is because of course and this
33:19is because of the work of Doctor Schwartz,
33:21that work here for the last 50 years.
33:23Doctor Schwartz has a specific
33:25interest in studying this tumor.
33:28And when he asked me to join
33:30him 16 years ago,
33:31I kept on going and and work
33:33in specifically against this
33:34biologically aggressive tumor.
33:36So this is to say we see a lot of this
33:39rare tumor and because of that we were
33:41able to collect a lot of specimen and
33:44we perform and we reported the first
33:48comprehensive genetic landscape analysis
33:51of the rare manigancy and this was published.
33:55Again,
33:55over 10 years ago,
33:57as you can see here,
33:59what we found in this study there
34:02was by the way before the TC
34:05published before the TCGA data,
34:07okay,
34:07about six months before the first
34:10major comprehensive analysis done
34:12by the Tumor Cancer Atlas Network,
34:15important chronologically to say that
34:17this is what we found, we sound,
34:20we found something very interesting,
34:22namely.
34:23A small minority of this biological
34:26aggressive cancer called uterine series
34:288 to 9% had this characteristic year.
34:30They had a huge number of mutation.
34:33They were ultra mutated,
34:35but they were Microsoft and lie stable.
34:39They didn't have any mismatch repair
34:41deficiency. So what were this tumor?
34:44We didn't know at that time,
34:45but they had this genetic characteristic,
34:47the remaining group.
34:49There was again the striking majority
34:529095% where normal mutated tumor,
34:55very low number of mutation,
34:57MSI stable and cold meaning
35:01minimal inflammation,
35:02minimum inflammatory cell present
35:04in the tumor microenvironment.
35:07So of course we start looking to the 92%,
35:10right. And what I'm showing
35:12you here was our finding,
35:14we look to this 21,000 gene
35:17and we found specific pathway.
35:19That this aggressive tumor was using
35:22to survive hemotherapy and then come
35:25back after treatment and one of these
35:29again pathway that I'm you know I'm
35:31highlighting here was the hair to new
35:36PAKAKT enter pathway over 1/3 of
35:39this patient had amplification on on
35:42the C RB2 gene that encode for the
35:46epidermal glow factor type 2 receptor.
35:49This is well known in oncology.
35:51Why? Because there are specific
35:54treatment they target this pathway.
35:56The target have to new trust is
35:59monoclonal antibodies one of those.
36:02But the problem is that this was
36:05an antibody available for the
36:07treatment of breast cancer patient
36:09and later on gastric cancer patient.
36:12But there was really no report,
36:14no literature in the treatment
36:16of uterine serous carcinoma.
36:18So we decided to fill that gap and
36:20we designed a study here at Yale,
36:22we designed an investigator initiated
36:25trial there was again through a
36:28consortium of institution because as
36:31I just told you this is a rare cancer
36:34and we were and we were targeting
36:36about 30% of this rare cancer the
36:38one over expressing her to new.
36:40So we needed multiple side to do that.
36:42So we had eleven side going from
36:45John Hopkins to higher state and.
36:47The primary goal here,
36:49the primary objective was to understand
36:51if adding trust to the map this
36:54monoclonal antibody to our standard
36:55of care that is based on carbo packet
36:58tax could make the difference in term
37:01of increasing progression free survival,
37:03increasing the objective response
37:04rate and the overall survival
37:06of this patient and so on.
37:08And these are our result.
37:10So we were able to show that
37:13adding this monoclonal antibody.
37:15Without any significant increase
37:16in toxicity when compared to
37:18the Carbo Parkly tax regiment,
37:20we were able to increase of about 5
37:23month progression free survival and
37:25close to six month the overall survival
37:27of the entire patient population.
37:30They were both advanced stage as well
37:32as recurrent patient with uterine
37:34serous carcinoma with a benefit
37:37even much higher in the chemo naive
37:39stage 3 and stage 4 disease so.
37:42This study is important because
37:45not only ask recognized important,
37:48you know,
37:49listing it as a major advancement in 2019,
37:53one of the five major advancement of
37:56that year in the oncology literature,
37:59but also because this increase in
38:03overall survival caused the revision
38:06of the National Comprehensive
38:08Cancer Network guideline that are
38:10widely used as standard.
38:12Of care again in oncology by both
38:15clinician as well as insurance company
38:18and since that time 2019, Carboplatin,
38:22Parkly, Taxol and Trastozoma.
38:24So the yield regimen is now again
38:27recommended in old patient with
38:29utransitous carcinoma or expressing her
38:32to you in the US as well as worldwide,
38:37let me do now.
38:39Let me tell you a little bit more
38:41about the Poly ultramutated.
38:42So we look to this uterines of carcinoma.
38:47As I told you before,
38:48a small minority,
38:50a nine percent had this abnormal alteration
38:53in a gene called DNA polymerase epsilon.
38:56This is a DNA polymerase at that time.
38:59I remind you this was over 10 years ago.
39:01Nobody knew what this really gene was doing,
39:04but.
39:05Look into this tumor,
39:07we immediately realize that was
39:09really playing a major role
39:11in the proofreading capability of the DNA.
39:14Why is that? Is because this tumor
39:16had a huge number of mutation.
39:18So polymerase epsilon in normal cell again
39:21is endowed with proofreading capability.
39:24When the cell divide and the
39:26DNA duplicate the DNA polymerase
39:29epsilon proofread the sequence and
39:31if there is an error, a mutation.
39:35Stop and repair and fix the error.
39:38But if one of the two allele present in
39:41the cell encoding for the polymerase
39:44epsilon mutate and the majority of
39:46the special are also multi mutation
39:48so acquired during the lifetime,
39:50the cell survive but start acquiring
39:53error mistakes and start accumulating
39:55again mutation to the point where you
39:58have this monster tumor they have.
40:011000 and 1000 mutation much higher than
40:04any other human cancer including lung,
40:07Melanoma,
40:08bladder cancer that are well known to be,
40:10I mean have a high number of mutation.
40:13So when we look to this tumor specifically
40:15we saw that in the exonuclease
40:17domain of the polymerase epsilon,
40:20the majority of recurrent mutation
40:22with localizing that area and
40:24why is that important?
40:25Is because even if the majority
40:28of the polyultramutated USC,
40:30they do well when compared to the
40:33other that I told you still some
40:36of this patient where they come
40:38back with recurring disease and
40:40these tumor are relentless,
40:42they are resistant to chemotherapy,
40:44they are resistant to radiation
40:46treatment and they kill our patient so.
40:49Few years ago looking to the set
40:51to the genetic characteristic,
40:54to the fact they were all permutated,
40:56we thought they could be exquisitively
40:59sensitive to new checkpoint inhibitor
41:01and and again few years ago and
41:04here I'm showing you a case report.
41:05This is one of my patient treated in
41:08two or seven initially for an advanced
41:11stage type 2 mix again uterine carcinoma.
41:15She was treated with surgery.
41:18Chemotherapy or addition treatment,
41:20she did well for a few year,
41:22came back in 2012 with recurring disease,
41:24multiple metastatic lesion as
41:29usual and and at that time point
41:33she was retrieved with surgery,
41:34additional bowel resection,
41:37additional chemo and she start progressing.
41:40So she was referred to us by an outside
41:44medical oncologist for a second opinion.
41:47In reality,
41:48of course the referral was to for
41:50the patient to accept Hospice because
41:52there was really nothing that
41:53we could offer internal systemic
41:55treatment to this patient.
41:57When she came to see us,
41:59we sequenced the tumor with foundation
42:01medicine and what we found was that
42:03she had a Poly hotspot mutation
42:06in the exonuclearized domain,
42:08the P 2028 to 286 are this huge
42:13number of mutation present so.
42:17This is was a lucky patient because
42:19at that time was about 2014 we had the
42:24program on going at Yale with nivolumab.
42:27This was a program that doctor Roy
42:29Herbs as active in lung cancer at
42:31that time point Nivolumab there
42:33was the first immune checkpoint
42:35inhibitor before before pembrolizumab.
42:37OK true that everybody now is using
42:39was only approving Melanoma but
42:41because of this program I was able
42:44to. To the OR through a compassionate
42:47base approval to offer to this
42:50patient NI voluma for free.
42:51She signed a consent.
42:52I got the approval for the chief
42:55medical officer of the Yale
42:57Cancer Center was or Jerry or
42:59Lillenbaum and the rest of history.
43:01We start treating this patient.
43:03I don't know if you can see this is
43:06one of the metastatic deposit as big
43:09as a spleen as you can see here 7-8
43:12centimeter masses in the Donal cavity.
43:15This is her bladder nodule or two 3
43:18centimeter growing in the wall of the
43:21bladder causing constant bleeding.
43:23In a week the bleeding disappear
43:27and in about 6 weeks pain disappear.
43:32It took about 18 months to completely
43:36melt out these pounds of cancer that
43:39this patient had on the volume up.
43:42The patient is still doing is cure
43:44of the disease and I swear two
43:46weeks ago in clinic eight years
43:47after what I'm showing you here.
43:49So this was a terminal patient
43:52referred to us for again Hospice.
43:55We sequenced the tumor,
43:56we found that we are mutation,
43:58we treat the immune checkpoint
44:00inhibitor as visit response
44:02and of course we reported this,
44:04this is the first report of
44:07the successful treatment.
44:09Of a polyultramutated endometrial
44:11carcinoma and now the word know
44:14and everybody is looking to this
44:16patient and when they found the
44:19polyultramutation for their treatment
44:20with immune checkpoint inhibitor.
44:22Now the second tumor that I want
44:24to tell you in the last 5-6 minutes
44:27are carcinos or Comma, the uterus.
44:29Carcinos or Comma,
44:30the uterus are also biologically
44:33aggressive are rare 3 to 5%.
44:35But they account for over 20% of
44:38all death in uterine carcinoma.
44:41And one of the peculiarity about
44:43carcinofacoma of the uterine is
44:46that for over 150 years this tumor
44:48have been a subject of debate.
44:51And why is that?
44:52Is because they are mixed human,
44:54there is both an epithelial component
44:56as well as a sarcometus component.
44:59And the question is what are these
45:01mixed cancers? Are they carcinoma?
45:03That undergoes are comatus
45:05transformation or are sarcoma that
45:08undergo epitilla differentiation such
45:10As for instance synovial sarcoma.
45:13So we answer that question.
45:15This is another paper that we
45:18published few years ago.
45:19Again we sequenced over 70 carcino
45:22sarcoma of the uterus and we published
45:25again this high impact journal and
45:28what we found here is number one
45:31we were able through sequencing.
45:34We also perform multiple sequencing,
45:37so not only we sequence the 70
45:40specimen from the 70 patient but
45:42about five or six of this tumor.
45:45We were doing macro dissection and
45:47sequence area of epithelial tumor
45:49and other sarcometus humor tumor
45:51in the same patient and we were
45:54overlapping the old Axon sequencing
45:56data to try to understand are
45:58these tumor epithelial or this
46:00tumor mesenkimal and the answer is.
46:03Unequivocally,
46:04these are all epithelial cancer.
46:06They all start as an epithelia,
46:09uterine carcinoma,
46:10but they go through clonal evolution and
46:13part of the clone during the lifespan,
46:16lifetime of the disease.
46:19They differentiate.
46:20They acquire epithelium,
46:21mesenchemal transition and
46:22there's as I'm showing you here,
46:25some of these carcinos or coma acquire
46:28this epithelium mesenchemal transition
46:29in some of the clone relatively early.
46:32Some very late during their lifetime.
46:35The 2nd and very important finding of
46:37the study is that we have identify
46:40for the first time some recurrent
46:42mutation in Eastern core gene that
46:46regulate the transcription of the
46:48DNA and these were correlated with
46:52the mesenchemal transformation.
46:54Now we are clinician, right.
46:56So we are very interesting science,
46:58but what we want is translation science,
47:00we want to be able to help our patient.
47:02One of the thing that we found in
47:04carcinofer Com as well as you trying
47:06serous carcinoma doing RNA sequencing
47:08was that there was a appregulation
47:10of the messenger RNA encoding for a
47:14specific antigen called trophoblast
47:16cells or face antigen or Trop 2.
47:19And this is the work of two of
47:21our recent fellow Dr.
47:22Borazebek and Shannen Han.
47:24So we look to.
47:26Hundreds of this tumor and here
47:28of course we have done this with
47:30the help of our pathologist in
47:32particular Doctor Natalia Busa and Dr.
47:35Pei Wei.
47:36We did,
47:36we did tissue microarray and we found
47:40that indeed 60 to 90% of uterine
47:43serous carcinoma and the carcinosar coma,
47:47they were really overexpressed
47:48in tropoblast too.
47:49So in the way that I show you
47:52before we generate patient that
47:54like sinograph from this patient.
47:56And we start testing in the animal
47:59the activity of a new agent called
48:02Rodelvi that is now a commercial
48:05agent approved for breast as well
48:08as bladder cancer that target
48:10the DROP 2 receptor.
48:11And this is an antibody track conjugate.
48:14So it's a monoclonal antibody
48:16targeting DROP 2 as a cleavable
48:19linker and attached to the
48:21antibody there is SN38 that is.
48:24A topo isomerase 1 inhibitor and doing
48:29that we were able to show that again
48:33both in vitro as well as in vivo,
48:35this tumor were highly sensitive.
48:37This is actually the tumor in the
48:39animal that complete as you can
48:40see disappear when our control of
48:42course we're growing and this is the
48:44overall survival of this animal.
48:45So the question is PDX work,
48:48is it going to work in patient?
48:50Let me give you an example of that.
48:52This is again another of my patient.
48:54As you can see are 74 years old
48:57uterine serous carcinoma treated with
48:59a gold standard surgery followed by
49:02chemo by radiation recurring disease,
49:04more chemo to the point where the
49:06patient was progressing on anything.
49:08So at that time we have a Phase 1B
49:12trial ongoing a Yale with Trodelvi,
49:15so as you know calcium sarcoma rare tumor.
49:18So I had to convince the the
49:21medical monitor of the study.
49:23That time,
49:24at that time was Immunomedics to
49:26approve the treatment of this,
49:27you know of this uterine serocarcinoma
49:30patient rare tumor in the trial.
49:33But I was able to do so patients
49:36start receiving
49:37Trudelvi and again as you can see here,
49:39this is the baseline.
49:40She had huge liver, meth as well as
49:43carcinomatosis everywhere in the
49:45donor cavity and the patient start
49:48responding and we gave this patient.
49:51As you can see here dramatic shrinkage
49:54of all the disease over 66% reduction
49:57by this is 1.1 criteria in the in the
50:01inner disease and we have this patient
50:03ten month of very good life with
50:06again because this is also very well
50:08tolerated antibody in term of treatment.
50:12So this was one patient, right.
50:15You cannot change a guideline
50:16with one patient.
50:17You need to design the proper
50:19study and that is what we've done.
50:21We had designed an IIT,
50:23so an investigator in shady
50:24trial with his agent,
50:26not easy because Immuno Medics
50:28was purchased by Gilead, right.
50:29So that create a little bit of a problem.
50:32But we were able to convince or so
50:34Gilead to provide us with drug and some
50:37money to design and of course perform
50:40this phase two clinker trial with
50:43the ultimate goal to evaluate again a
50:46response rate as a primary objective.
50:48As well as overall overall survival,
50:51progression free survival and the
50:54safety as a secondary objective.
50:57And these are the result of
50:58this trial that I'm going to
51:00present in about 10 days at ASCO.
51:03This is a presentation.
51:04This is a preview.
51:06I shouldn't do that, but I'll do it anyway.
51:09And as you can see here,
51:11this study was designed as
51:13a Simon two stage design.
51:15That it means to enroll the
51:181st 21 a valuable patient,
51:20see if there was any response and
51:22in case of three or more of PROCR,
51:25so either complete or partial response
51:27would have been able to move to the
51:30second stage and enroll a total of 50.
51:32So as you can see here over two third
51:36of the patient enroll in this trial.
51:39Where specifically uterine serous
51:42carcinoma and carcinosarcoma,
51:44the most difficult to treat uterine
51:46carcinoma and we had seven response
51:50not three so 33 response rate either
51:53CR or PR and so positive stage one and
51:57we are now a rolling the stage two,
52:01so another 30 patient to try to
52:03see in an overall of 50 patient.
52:06How effective this agent is be,
52:08but there is no doubt that there
52:10is a strong signal and again this
52:12is an IIT trial developed at Yale.
52:15So I'd like to conclude analogy
52:17and thanking a lot of people.
52:19The particular Elena that is here
52:21my cochief they attending of the
52:24Juan oncology division that I listed
52:26here and here in particular I want
52:29to to to emphasize the the the
52:33role of Doctor Schwartz.
52:34A mentor for all of us that has been work
52:38here for over 50 years is just retire
52:41as well as of course the group here.
52:43The support staff and the clinical
52:46trial coordinators again that
52:48I'm showing you here that are the
52:50reason why again we are successful
52:53in provided to our patient
52:55clinical trial because they are
52:57the one that make this happen.
52:59The clinical trial office in the
53:01division of gynecological oncology.
53:03And finally last man or least the
53:06researcher the lab people that are
53:08doing they really the work with the
53:10animals we are to do the sequencing
53:12and of course these are all as you
53:15can see young they come they get
53:17trained in my lab they and after they
53:19leave to get their faculty position.
53:22So here is the Fania belona Dr.
53:25Belona the lab chief of for that has been
53:29working with me for the last 25 years.
53:32And of course she's of she's the
53:34person that I have to thank the most
53:35for the work that I just show you
53:37and I thank you for your attention.
53:49If there is any question of course we're here
53:56SD trial are you looking at the level
53:59of troop tube or was it just all comers
54:01and if you can repeat the question.
54:03Yeah. So Dr. Reem is asking if the.
54:07The Trudelvi trial that I'm going
54:09to presented ask whether we have
54:11look into the expression of the drop
54:14two that is a target or not and the
54:17answer David is yes in the phase one.
54:20So the stage one of this trial we
54:23specifically look to drop to expression
54:25and only patient with 50 with expression
54:28or drop to any expression 1 + 2
54:31plus or three plus in at least 50%.
54:34Of the tumor cell we are eligible
54:35for the stage one.
55:01This is a good question again the so how
55:04many of these tumor with recurring disease
55:06they have estrogen or progesterone receptor.
55:08So let me answer to your question this way.
55:12UTRAN cancer is a very heterogeneous
55:15type of tumor, so you have.
55:17From one side, the endometrioid,
55:19so the one that are really resembling
55:22very closely the normal normal
55:24endometrium that can be well,
55:26moderately or poorly differentiated.
55:28And on the other side of
55:30the spectrum you have the,
55:31what we call still called type 2,
55:34right, the uterine serous carcinoma,
55:36the carcinosarcoma, the clear cell,
55:40you know uterine cancer,
55:42so in general.
55:44If you want you to endometrioid they
55:46over express astrogen receptor even when
55:48they come back with recurring disease.
55:51But those are only a minority
55:52of the recurring patient that
55:54we are treating in our clinic.
55:56Majority of the recurrences as
55:57I show you they take place in
55:59the uterine serious group,
56:01the carcinoso coma group that are the
56:04one that usually they do not express
56:07astrogen receptor or the minority
56:10even when they do I must tell you.
56:13By 20 year experience,
56:15they do not respond to anti
56:17estrogen treatment because most
56:19likely the receptor is not active.
56:21It's present on the surface but
56:23the pathway is not really working
56:30sure.
56:45So what is what are the side effect of
56:48the trudelvides assitu Zumagovita can
56:50trial that is using this top poisoner
56:52is inhibitor as a toxic payload.
56:54So the answer is this is a very
56:57well tolerated drug and why am I
56:59saying that is because it does not
57:02cause the the bone marrow toxicity
57:04that you know they can cause.
57:06And the other thing that we have
57:09noticed is that even the GI toxicity
57:11that is typical of this drug.
57:13Is much, much smaller and this
57:15is once again is related to the
57:18targeted type of approach, right.
57:20So are only the tumor cell they
57:23overexpress drop two that they get that
57:26they get this toxic payload internalized.
57:291 important thing that I also am going
57:32to stress to ASCO is that the Cornell
57:36toxicity for instance that we are seeing
57:39with many antibody that are conjugate.
57:41Is not present with this antibody.
57:44So that is another great thing because
57:45as you know we're getting more and more
57:47approval in terrible treatment with
57:49antibody that are conjugate our patient.
57:51But we must have now enough
57:53ophthalmology before even starting to
57:54look to the corner for this specific
57:56type of a DC is not necessary.
57:59We don't,
57:59we don't really see that toxicity those.
58:01So it's overall well tolerated.
58:03The only patient that are really
58:06experiencing some significant toxicity
58:08are the patient that have a polymorphism.
58:11In EU GT2B7 that is again this
58:16is this mechanism right that we
58:18have in our liver to catabolize at
58:20the top of isomerase about,
58:22I'll say 1-2 out of 10 May
58:27have this polymorphism.
58:28They are more sensitive to the drug,
58:30they usually respond better their cancer,
58:32but there we have to do a dose reduction.
58:34We go down from 10 usually to 7.5.
58:41We have two more answers
58:55that
58:59yes, so we I show you here our
59:04initial work with trust to Zuma and
59:06we have shown again for the first
59:08time that trust to Zuma added.
59:10To chemotherapy helps but in the
59:12recurrent setting we have multiple
59:15trial using antibody that are conjugate.
59:18So we have used some one that
59:24is called symptom 985 that is a
59:29I don't know if you're familiar
59:31but again is a is the backbone is
59:34throstozoma the linker is clivable.
59:36The toxic payload is an alkylating
59:39semi synthetic calculating agent
59:41duocarmising extremely potent but also
59:44toxic and so we have seen dramatic
59:46response in the recurrence setting
59:48intrastuzumab resistant uterine 0
59:50carcinoma over expressing up to new.
59:53But the corneltosis it was significant
59:55in many of this patient we have to
59:57stop treatment for for several weeks to
60:00allow recovery and and that of course.
01:00:03Was not good because during those
01:00:0568 sometime more weeks,
01:00:06the tumor will start growing again.
01:00:07Yes,
01:00:22we do in a very special way.
01:00:24There's different ways to do it.
01:00:25She's doing it.
01:00:27So we only do it in the newest.
01:00:29So we already have the diagnosis.
01:00:33We give 3 cycles. We
01:00:36confirm the.
01:00:39But if it's
01:00:42done different ways, there's some
01:00:45studies that have it up front.
01:00:52Thank you.
01:00:54Thank you so much to our
01:00:57wonderful 2 speakers.
01:00:58Have a wonderful day. Thank you.