Novel and Personalized Treatment for Gynecologic Cancers

Transcript

• 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.