Targeted Her2 Therapy and Her2 Testing in Endometrial Cancer: Current Status and Future Directions
November 04, 2021Information
October 28, 2021
Yale Pathology Grand Rounds
Natalia Buza, MD
ID7121
To CiteDCA Citation Guide
- 00:04Start introducing your Natalia.
- 00:08Today's grand round speaker is
- 00:11Natalia Buza, our very own.
- 00:15Most of us know Natalia we work with her,
- 00:18we see her in the hallways
- 00:20and on the microscope Natalia.
- 00:25Did her medical schooling in Hungary
- 00:28from the University of PECS in 1999,
- 00:31and she joined the pathology
- 00:34residency program at the same
- 00:37place and after two years,
- 00:40not all year moved to complete
- 00:43the remaining two years of her
- 00:46pathology residency at National
- 00:49Institute of Oncology in Budapest.
- 00:53After her training in pathology,
- 00:57Natalia spent a year at Tulane
- 01:00University Pathology Department
- 01:02as visiting physician so early on,
- 01:06Natalia had established her
- 01:08career path in pathology.
- 01:11We were lucky to recruit Natalia to
- 01:15yell pathology residency program in 2006
- 01:19and Natalia finished her residency.
- 01:22Became chief resident,
- 01:24became a GY and and press fellow with
- 01:29Doctor Tavassoli and then in 2010
- 01:34Natalia became an assistant professor
- 01:37with US and in 2016 very quickly.
- 01:41She was promoted to be an
- 01:45associate professor.
- 01:46I first met Natalia in 2009 when
- 01:51Natalia was a hot seat resident.
- 01:55And she was freaking out because
- 01:57someone had just asked her 15
- 01:59minutes ago to go to the head and
- 02:02neck tumor board and present the
- 02:04hair and act him aboard cases.
- 02:06Uhm?
- 02:08Anyway.
- 02:11Natalia is in addition also the associate
- 02:14director of the GY and Fellowship program
- 02:17and the Director of the GY and Journal Club,
- 02:21which is one of the best run Journal
- 02:25club in our department. Altogether,
- 02:29Natalia has a total of 150 publications.
- 02:3487 of these are origonal peer
- 02:38reviewed papers. These include.
- 02:42These do not include 25 book chapters.
- 02:46Is book chapters do not include
- 02:4918 chapters in the Blue Book on.
- 02:55Tumors of the female genital tract and one
- 02:59chapter in the pediatric tumor blue book.
- 03:04In addition, she has 17 case reports,
- 03:08three chapters in pathology outlines,
- 03:11and she has contributed to or written
- 03:15the CAP guidelines on GY and receptions
- 03:19and all of this in the last 12 years.
- 03:23Because I noticed that Natalia's first
- 03:26paper was in 2009 with Doctor Tavassoli,
- 03:29so I would give a shout out not
- 03:33just to Natalia, but.
- 03:34Also to our department for.
- 03:37Making it conducive to this
- 03:42phenomenal body of achievements.
- 03:45In addition,
- 03:46Natalia is on the editorial Board of
- 03:49Human Pathology and the International
- 03:52Journal of Gynecological Pathology,
- 03:55and she is also an ad hoc reviewer
- 03:58in on major.
- 04:01Journals of pathology Natalia
- 04:05is prominent in Uscap.
- 04:08She is a member of the abstract.
- 04:11She has served on the Abstract Review Board.
- 04:14She has served as ambassadors.
- 04:16She is moderated platform sessions.
- 04:19In the past.
- 04:20She is also a faculty mentor of
- 04:23the men to escape mentoring.
- 04:25Academy earlier has had several
- 04:28short courses at a scab running for.
- 04:32I believe for four consecutive years
- 04:36and two of her short courses and and
- 04:40an interactive microscope session
- 04:43has been approved from 2022 onwards.
- 04:48So Natalia Natalia's eminence in US Capiz.
- 04:55Very laudable. She is.
- 05:01A favored invited speaker both
- 05:04nationally and internationally.
- 05:06She has spoken in Canada and two
- 05:11British societies and also in China.
- 05:14Natalia has been invited to give
- 05:17grand Rounds at MD Anderson.
- 05:20She has been a speaker at
- 05:23Princeton Symposium,
- 05:24one of the books that Natalia
- 05:27coauthored frozen sections in GY
- 05:30and pathology is actually in.
- 05:32Smilow frozen section.
- 05:34Sweet and it's I find it extremely helpful
- 05:38when I get a GY and broken section.
- 05:42And today's grand round is.
- 05:46Natalia is going to talk about it.
- 05:48This is her exemplary long-term
- 05:52work on bringing her to new.
- 05:56Therapy in GGY and oncology and
- 06:01with no further ado, I'm going to.
- 06:06Give the floor to Natalia.
- 06:10Thank you so much man.
- 06:11Due for the very kind introduction and
- 06:14and for this wonderful opportunity,
- 06:16it is really a special a pleasure
- 06:19for me to to speak in front
- 06:22of my colleagues and friends,
- 06:24even even though from my office.
- 06:25But I I feel like I,
- 06:27I'm I see all of you.
- 06:28So I'm going to start
- 06:31sharing my screen. Come.
- 06:35OK. Can you see it?
- 06:40Yep alright so as mentioned mentioned,
- 06:44this has been really a long term work.
- 06:47I've been working on.
- 06:50Or two in under meteor cancer
- 06:52for the past twelve years or so,
- 06:55and today, I'm going to give you an
- 06:58overview of the current status and
- 07:01future directions on this topic.
- 07:03First I'll start with.
- 07:06Brief overview of the Congo
- 07:09pathologic features of endometrial
- 07:11serous carcinoma for those of you
- 07:13not in GY and pathology and then
- 07:16give a historical overview of prior
- 07:20studies and trials and and her to
- 07:24anonymity of cancer and compare the
- 07:27features of her two expression and
- 07:30amplification with the with those that
- 07:33we know of breast and gastric cancer.
- 07:37And finally,
- 07:38I'll give practical recommendations
- 07:40and talk about future directions.
- 07:43So to start off, going back to the 1980s,
- 07:47two Seminole papers were published
- 07:50about the same time,
- 07:52one from a pathology group.
- 07:54Doctors Kempson and Hendrickson
- 07:56described for the first time.
- 07:58This tumor type uterine papillary
- 08:01serous carcinoma,
- 08:02which they recognized as a highly
- 08:05malignant form of endometrial adenocarcinoma.
- 08:08At the same time, Jan Bachman,
- 08:11a physician.
- 08:14From gynecologist from the Soviet Union,
- 08:18published the clinical features that
- 08:20he noticed that and meteor cancer
- 08:23really has to drastically different.
- 08:28Uniquely different that the genetic
- 08:29types and he called them type
- 08:31one and type two type 1 being the
- 08:35more indolent form associated
- 08:37with estrogen access.
- 08:39Compared with Type 2,
- 08:42which would include uterine serous
- 08:44carcinomas that had a much more
- 08:47aggressive behavior and had no
- 08:49association with estrogen access in patients.
- 08:53Later on,
- 08:54it was recognized that these tumors actually
- 08:57can have other architectural patterns,
- 09:00not just the capillary,
- 09:01although it's commonly seen here,
- 09:04you can see in the upper
- 09:06left corner papillary,
- 09:07but they can also have a glandular
- 09:10pattern or solid pattern,
- 09:11and so the terminology changed
- 09:13over the years and now we are
- 09:16the preferred terminology.
- 09:17Is endometrial serous carcinoma
- 09:19or uterine serous carcinoma?
- 09:22I also put a higher.
- 09:23Image higher magnification.
- 09:25Image here for you to see the
- 09:27nuclear features which are very
- 09:30important and a characteristic
- 09:32finding that helps recognize this
- 09:34tumor type as a very high nuclear
- 09:37to cytoplasmic ratio mark nuclear
- 09:39tipiya and frequent mitotic figures.
- 09:44These tumors can only can also
- 09:47be a very subtle and and present
- 09:50in a in a an early form of 10
- 09:55associated with endometrial polyps.
- 09:58Sometimes just signing the surface
- 10:00of the endometrium or lining the
- 10:03pre-existing and demetria glands,
- 10:05and this has been termed a somewhat
- 10:08miss miss leading or potentially
- 10:11misleading term of serious.
- 10:13Intrepid serial carcinoma or serious
- 10:16endometrial intrepid serial carcinoma,
- 10:18which is not really an insight to lesion.
- 10:21It has already the same capacity for
- 10:23spread as a full blown serous carcinoma,
- 10:26so that's another interesting feature
- 10:29about this tumor and another characteristic
- 10:33finding is that very often more than
- 10:3795% of tumors are associated with
- 10:40P53 mutations which can be used.
- 10:45With the immunohistochemical work up
- 10:47and here is an example of showing an
- 10:50apparent staining in one of these tumors.
- 10:55So clinically, again,
- 10:57often these women are post menopausal in the.
- 11:02Older post menopausal age.
- 11:05Designing with post menopausal bleeding.
- 11:09Most importantly, they have a poor
- 11:11prognosis and a five and 10 year.
- 11:13Overall survival is only 36%
- 11:16and 18% for these tumors,
- 11:19and that's mostly due to poor
- 11:21response to traditional chemotherapy.
- 11:25Despite the advances in
- 11:27cancer treatment and many,
- 11:28many other tumor types,
- 11:30there hasn't really been a lot of changes,
- 11:34and the chronicle of Behavior,
- 11:37clinical outcome of these tumors
- 11:39looking back into a study in 2006,
- 11:42you can see that they have a
- 11:45disproportionately high mortality rate.
- 11:47Only 10% of tumors are serious carcinomas,
- 11:50and yet almost 40% of the cancer deaths are.
- 11:54Related to this tumor type.
- 11:57And even compared to other high grade tumors,
- 12:00agreed, three endometrioid or clear cell,
- 12:02they still do worse.
- 12:04And Fast forward to 2015 again,
- 12:07compared to other tumor types,
- 12:09serous carcinomas have diverse recurrence
- 12:12free and distant metastasis free survival.
- 12:15And even the most recent studies from
- 12:18the PORTEK 3 and from the Memorial
- 12:21Sloan Kettering showed that these tumors
- 12:24have the most aggressive behavior,
- 12:26even compared to other P53 mutant tumors
- 12:29or compared to other high grade tumors.
- 12:35Some we learned a lot about the
- 12:38molecular characteristics of endometrial
- 12:40carcinoma's over the past decade.
- 12:43The seminal paper from the TCA
- 12:47identified 4 molecular subgroups and
- 12:51the one that series carcinomas belong
- 12:53to as the so called copy number,
- 12:55high or serious like group which is which
- 12:59contains most of the serous carcinomas
- 13:01and is enriched in P53 mutations.
- 13:04Also interestingly,
- 13:06you can see that many of these tumors,
- 13:11actually, I think on my next slide,
- 13:13is that 25% of them also showed herb
- 13:18two amplification by sequencing.
- 13:21Abandoned at the same time,
- 13:24Doctor Santini's group also published.
- 13:28Study on.
- 13:30Sequencing of serous carcinomas
- 13:33and found that 44% of them
- 13:36showed Erbitux amplification.
- 13:40Soum this is really a
- 13:43wonderful therapeutic target.
- 13:44It's been recognized in other tumor types,
- 13:47and there are so many potential drugs
- 13:50that can be used to target this pathway,
- 13:53and this cartoon is not even
- 13:55that recent is from 2018,
- 13:57but you can see the variety of drugs
- 13:59that are available in addition to the
- 14:02earliest ones that blocked the ****
- 14:05dimerization or heterodimerization,
- 14:07trastuzumab, pertuzumab there are
- 14:09now other drugs targeting the tires.
- 14:12And kinase domain of the receptor.
- 14:15There are other therapeutic approaches.
- 14:20To use antibody,
- 14:22drug conjugates and then even
- 14:24more recent developments,
- 14:26using bispecific antibodies
- 14:27or vaccines and so on.
- 14:29So there is really a variety of of.
- 14:34Drugs available to to be taken advantage of.
- 14:40So let's look at what happened
- 14:42in other tumor types and targeted
- 14:44her two treatment over the years.
- 14:47It's been a long, long history,
- 14:49so going back to 1998 I was still
- 14:52in medical school, went resume,
- 14:54it was first approved by the
- 14:56FDA for breast cancer.
- 14:58Dan, with a little gap, other drugs,
- 15:01or have also been approved for breast cancer,
- 15:04and in 2010 trust.
- 15:06Susan Webb was also approved
- 15:08for gastric cancer.
- 15:10So then since then,
- 15:12many other antibody,
- 15:13drug conjugates and other drugs
- 15:15have been approved as well
- 15:17on the bottom of the diagram.
- 15:20This is what happened in under media cancer.
- 15:22There was one trial that I
- 15:25will talk a little more.
- 15:28And a little bit about,
- 15:31as is the JIOJI trial that
- 15:33was published in 2010 and.
- 15:37After that it took so many years.
- 15:39Finally,
- 15:39in 2018 went resume AB was found to
- 15:43improve progression free survival
- 15:45and overall survival in endometrial
- 15:48carcinoma and that discovery was
- 15:51quickly followed by endorsement.
- 15:54From the NCCN guidelines,
- 15:56and also from the Society of
- 15:59Gynecological Oncologists.
- 16:02So what what?
- 16:03Why did it take so long to to
- 16:06these targeted therapies to be
- 16:10recognized for endometrial cancer?
- 16:12Well, the interest is not new.
- 16:15I took this statistics from PUB
- 16:17Med so if you do a search for
- 16:21her to an endometrial,
- 16:23there is this interesting.
- 16:26Double wave and you can see that
- 16:28we are in the second second wave
- 16:31of the her two publications,
- 16:33so there was there was a lot of interest
- 16:35and then after the first trial publication
- 16:38the interest went down a little bit
- 16:41and now we're in this growing phase.
- 16:43We're not even done with 2021 yet,
- 16:46and there's there's a lot of papers
- 16:48that not all of them are from you.
- 16:50So this is a review I wrote in 2012 and
- 16:54it's not for you to read in detail,
- 16:58just to show that there were a lot of
- 17:00studies already published before 2012,
- 17:02and the rate of her two
- 17:05overexpression was all over the place.
- 17:08Different criteria,
- 17:09different scoring methods,
- 17:12different antibodies,
- 17:13different case inclusion criteria.
- 17:16So the the rate of her two
- 17:19overexpression was reported between.
- 17:2114 and 80% and register same is
- 17:24true for her two amplification.
- 17:27The rates varied from 15 to 47%.
- 17:34There were also a few case reports that
- 17:38were encouraging showing response in
- 17:41patients with her two positive tumors.
- 17:44And then the GOG study that I mentioned.
- 17:48So just also for context they kind of
- 17:51collaged conchology group is really
- 17:53the major gynecological oncology
- 17:56clinical organization that runs large
- 17:59number of clinical trials with with
- 18:02several participating institutions.
- 18:04It's really the way that most.
- 18:10Oncology trials RR.
- 18:15Uhm conducted and and
- 18:17gynecological oncology so really.
- 18:19If if anyone could could could
- 18:21do and produce these numbers,
- 18:24that would be the jioji group.
- 18:26And despite of that they actually
- 18:29really had a hard time recruiting
- 18:31patients for this trial.
- 18:33It took them.
- 18:34It was running for seven years,
- 18:36took them seven years to recruit 33 patients.
- 18:39There was also a period of time
- 18:41when the study was shut down
- 18:42because of they called it.
- 18:44Investigator fatigue and any.
- 18:46Anyhow they the bottom line
- 18:49is that it showed no.
- 18:51Benefit from using Tris is a map,
- 18:53although it was also criticised
- 18:56for only using single agent resume
- 18:59app and including other tumors
- 19:01other than serious carcinomas.
- 19:06So so that seemed to be
- 19:08the that seemed to be.
- 19:10You know, that basically it's it's been.
- 19:13People have given up on on
- 19:16this on this potential targeted
- 19:18therapy for this tumor type.
- 19:20After this, except Dr.
- 19:23Centene persisted and I think you know,
- 19:26I really have to give him a lot of
- 19:28credit for pursuing this and and
- 19:30he really believed that that there
- 19:31could be a better way of designing
- 19:33a study and showing that this this.
- 19:36Treatment can be really efficient
- 19:39and so dumb. Uhm?
- 19:41His persistently persistence
- 19:43led to publication of two major
- 19:47papers in 2018 and 2020,
- 19:50showing that trust is a map in combination
- 19:54with the traditional chemotherapy is
- 19:57actually improving progression free,
- 19:59and overall survival in these tumors.
- 20:02So here is the diagram of this trial.
- 20:06There were a total of 61 patients enrolled
- 20:09in the treatment arm and in the control arm.
- 20:13And there was improvement of progression
- 20:17free survival with the best response
- 20:21in the advanced Stage Disease Group.
- 20:24Little less in patients
- 20:25who had recurrent disease.
- 20:27But still there was an improvement,
- 20:29and the same is true for overall survival.
- 20:32The patients who had advanced stage
- 20:35disease responded the best for treatment.
- 20:39So then there was a lot of publicity
- 20:42and Yale publications and also the
- 20:45ASKO named Justice and Map as one
- 20:49of the advances of the year in 2019.
- 20:53So that was that was a major
- 20:56breakthrough for these really.
- 20:58Aggressive tumors with high mortality
- 21:00that really gave gave a lot of hope
- 21:03with a lot of hope for patients
- 21:06and so to recognize that in 2019,
- 21:10the NCCN guidelines included.
- 21:14Carboplatin, paclitaxel cluster
- 21:15Susan map for these tumors,
- 21:17and,
- 21:18as I mentioned,
- 21:19the Society of Gynecological
- 21:21Oncologists also recommends testing her.
- 21:23Two testing of serous carcinomas
- 21:26and adding just zoom out and
- 21:29in the treatment regimen.
- 21:31So the question for us now in
- 21:33pathology is how to evaluate the
- 21:36hurdle status in these tumors.
- 21:39Come to answer that question,
- 21:41let's look at other tumor types.
- 21:43Again,
- 21:45here is the long evolution of
- 21:47the her two guidelines,
- 21:48and other tumor types and
- 21:51breast cancer starting.
- 21:53In 1998, with the FDA package insert,
- 21:57the first ASCO CAP guidelines came out in
- 22:002007 and then another two set of guidelines.
- 22:04Finally, currently,
- 22:06we use the 2018 ASCO CAP guidelines
- 22:10in gastric cancer.
- 22:11The tumor characteristics of her two
- 22:15expression and amplification were
- 22:18first described in the toga trial.
- 22:20Trastuzumab for gastric cancer trial.
- 22:24And based upon that,
- 22:26based upon the observations
- 22:28from that trial in 2016,
- 22:30they ask Cool CAP published the
- 22:32first official set of guidelines
- 22:35specific for gastric carcinoma,
- 22:37and most recently a.
- 22:39Clinical trial on colorectal cancer
- 22:42is using yet another set of criteria
- 22:46different from the other two tumor types,
- 22:49so it is recognized in other
- 22:51tumor types that there is there
- 22:54are differences in how the her
- 22:56two expression and amplification.
- 22:59Occurs and and how the treatment
- 23:03response is associated with these features,
- 23:06so that led to these
- 23:08development of different guidelines.
- 23:11And before I even go further,
- 23:14I want also wanted to emphasize that
- 23:17the clinical trial that I presented to
- 23:21you earlier started in 2011, when the.
- 23:26Guidelines the only guidelines existing
- 23:29for any hurt evaluation over the ones.
- 23:33Published by the ASCO CAP in 2007 that
- 23:36I'll come back to that in a little bit.
- 23:41So let's look at the features
- 23:42of her two and breast cancer.
- 23:44Approximately 15 to 25% of the tumors are
- 23:48her two positive heterogeneity of her two
- 23:52expression and amplification is uncommon,
- 23:54although there is a little bit more
- 23:58variety and the reported rates and her
- 24:02two heterogeneity or gene amplification,
- 24:05and for those cases it's been reported
- 24:08that they can be either a cluster.
- 24:10Heterogeneity or mosaic pattern
- 24:13of heterogeneity.
- 24:14The basal basal lateral staining
- 24:17pattern is quite rare, mostly seen in
- 24:20invasive micropapillary carcinomas,
- 24:22and in those cases that's considered
- 24:25a two plus score.
- 24:27And fish and I see are equally
- 24:30predictive of treatment response.
- 24:32So for that reason,
- 24:34the herd to testing algorithm could
- 24:37start either with IC or a fish.
- 24:44In gastric cancer, as I mentioned the.
- 24:47Guidelines were developed,
- 24:49developed based on the information.
- 24:51The data from the toga trial and there
- 24:55were several nice papers are written
- 24:57on on that in correlation with the OR
- 25:00in conjunction with the toga trial.
- 25:03And based on that we learned that
- 25:0522% of gastric or GE junction
- 25:08tumors are her two positive.
- 25:10Although there is some variability
- 25:13depending on the histologic subtype,
- 25:15intestinal type tumors are more
- 25:17likely to be her two positive and
- 25:20also based on the tumor location.
- 25:23So GE Junction tumors are
- 25:25more often her two positive.
- 25:30Heterogeneity, unlike in breast cancer,
- 25:32is very common and it's present
- 25:34in up to 50% of tumors.
- 25:38The concordance between ISC and
- 25:40fresh has been reported to be high
- 25:43and another important difference
- 25:45from breast cancer is that protein
- 25:49expression shows the highest.
- 25:51The strongest association
- 25:52with the therapeutic response.
- 25:54So the testing algorithm has to
- 25:58start with immunohistochemistry
- 26:00and only tumors with a two plus
- 26:04immunostain will be reflex with.
- 26:07Her two fish, although there's some
- 26:10data and one of the trials that.
- 26:14IC negative and fish positive tumors
- 26:17may also benefit from treatment.
- 26:21Come just to illustrate or what I
- 26:23mentioned about the gastric tumors.
- 26:25There is the characteristic
- 26:29basolateral staining pattern,
- 26:32lack of epical staining.
- 26:35And so.
- 26:38And so at the beginning of the clinical
- 26:41trial for endometrial carcinoma,
- 26:43we decided to look at the characteristics
- 26:46of serious carcinomas to see if
- 26:49they also have unique features that
- 26:51should be taken into consideration.
- 26:54So we looked at 108 cases,
- 26:58most of which were pure serious carcinoma.
- 27:01Some of them are mixed tumors.
- 27:04And we performed a immunohistochemistry and
- 27:07her two fish on all of the two plus cases.
- 27:12And compared the scoring systems,
- 27:14the original FDA package insert score
- 27:18plus the 2007 ASCO CAP criteria.
- 27:24I'm using the two different scoring criteria.
- 27:27We found that there was of course
- 27:30some differences in the her
- 27:32two positive positive ITI rate,
- 27:35about 30% of the tumors were her two positive
- 27:38using the ASCO CAP 2007 criteria and.
- 27:43More importantly, in terms of the
- 27:46icy fish concordance to 2007,
- 27:48breast criteria gave a higher concordance.
- 27:52It was 86%.
- 27:55Another very important finding from this
- 27:58study was recognition of heterogeneity.
- 28:01It is very common in these tumors.
- 28:05More than 50% of the her two positive
- 28:08cases and you can see some examples
- 28:11here where there are several neoplastic
- 28:13glands on the right hand side and
- 28:16only a few of them are positive
- 28:18for her two on the left hand side.
- 28:22Same thing you know.
- 28:23You have several neoplastic areas
- 28:26that are her two positive in with an
- 28:30intense training and then in the upper
- 28:33right corner of the slide there is.
- 28:35There is no.
- 28:38Expression even within the same
- 28:40gland you can find different
- 28:42protein expression levels.
- 28:46And in addition to that,
- 28:48similar to gastric cancer,
- 28:50these tumors also frequently lack the
- 28:52ethical staining resulting in this
- 28:56lateral basolateral staining pattern.
- 28:59We also looked at a smaller number
- 29:01of cases by fish to see if the
- 29:04heterogeneity can also be observed
- 29:06at the gene amplification level,
- 29:09and we found two patterns of amplification
- 29:15and named them similar to what the
- 29:18breast cancer literature used.
- 29:20Cluster amplification,
- 29:20which is where you have a large cluster
- 29:24of tumor cells showing amplification
- 29:26and in next to another class.
- 29:29Clustered at that has no amplification.
- 29:32And another case where we found
- 29:35a strong correlation between the
- 29:38immunohistochemical expression of
- 29:40the protein and the gene application.
- 29:43You can see that the the.
- 29:46Her two positive areas corresponded
- 29:48to the amplified area.
- 29:51Her two week expression corresponded to
- 29:54the her two non amplified area on fish.
- 29:58And then we also saw some cases with
- 30:01a mosaic amplification pattern where
- 30:03there were individual tumor cells showing.
- 30:07Her two gene amplification in the
- 30:09background of non amplified cells.
- 30:14So based on our. Observations
- 30:17at the beginning of the trial,
- 30:20we decided to use the existing
- 30:232007 ASCO CAP scoring system at the
- 30:28time with specific modifications,
- 30:30namely that CIRCUMFERENTIALLY.
- 30:34Staining was not required.
- 30:36U shaped or based on lateral.
- 30:38Lateral pattern was also accepted
- 30:40for the her 2/3 plus score.
- 30:43In addition,
- 30:44due to the heterogeneity we decided
- 30:48to do the immunohistochemistry on the
- 30:52hysterectomy specimen to identify a large,
- 30:54larger amount of tumor.
- 30:57Uhm, for testing and also to do the
- 31:00fish on two plus cases in correlation
- 31:03with the IC stain slides so that
- 31:06we look at the area with most
- 31:09with the most protein expression.
- 31:11Also, we typically selected a large,
- 31:14larger area for fish,
- 31:16unlike in breast cancer and her
- 31:20to 17 ratio of two or greater
- 31:23was used as a cutoff for fish.
- 31:26So I would stop here for just a minute
- 31:30to say that. Well, it would seem.
- 31:35Uhm?
- 31:36It would seem logical to at this point
- 31:40use these clinical trial criteria too.
- 31:462. Idento to come.
- 31:49Evaluate or two staining moving on in
- 31:53these tumor types at the same time.
- 31:56Since then, two different sets of
- 31:59criteria have been proposed for or
- 32:01have been published for breast cancer,
- 32:04and there are some authors who would
- 32:07advocate for using the 2018 breast criteria,
- 32:11saying that, well, you know,
- 32:13just for simplicity sake,
- 32:14why don't we use the criteria that everybody
- 32:18is already familiar with and this?
- 32:20This is my my cartoon.
- 32:22Just to show that I think one of
- 32:25the arguments in addition just
- 32:27to to the fact that, well,
- 32:29this is the the criteria I just mentioned
- 32:31are the ones that were shown to
- 32:34correlate with response and the covert trial.
- 32:37In addition to that, if we use the
- 32:39criteria from another tour type,
- 32:41then we'll have a moving finish line.
- 32:44You know it's not over and breast cancer.
- 32:46I'm sure that or I'm I'm I'm.
- 32:50I, I suspect that there will be no
- 32:52as data accumulate and new studies
- 32:53come out and pressed it.
- 32:55It's entirely possible that they will
- 32:58adjust the guidelines accordingly,
- 32:59and there will be a new set
- 33:01of guidelines for breast.
- 33:02So are we going to change our
- 33:05interpretation criteria every time
- 33:07based on another tumor type on breast
- 33:09or or on gastric for that matter?
- 33:12So I really think that it's
- 33:15important to establish endometrial
- 33:17carcinoma specific guidelines on.
- 33:20At this point and and for that reason,
- 33:24based on our experience,
- 33:25I proposed her testing algorithm
- 33:29and and scoring criteria for
- 33:33an Demetria serious carcinoma,
- 33:36and this is of course just the first
- 33:39step and there will be many more
- 33:41steps to really identify the best.
- 33:44Testing algorithm and and there
- 33:46is already currently a lot of
- 33:49groups interested in.
- 33:53In studying these tumors and and uh.
- 33:57There is many more publications that
- 34:00I expect to come out on this topic.
- 34:04We also performed an interobserver study
- 34:06to look at the reproducibility of this
- 34:10scoring system and found that it had a good.
- 34:15Interobserver uh agreement.
- 34:19Kappa, which is comparable to what's being
- 34:23published in breast and gastric tumors.
- 34:29There are several remaining practical issues.
- 34:32On this topic, we still have to.
- 34:37Do more investigations to find out what
- 34:40correlates best with the clinical response,
- 34:43immunohistochemistry or fish.
- 34:44We have not done fish on all of the
- 34:48tumors and potentially there could
- 34:50be icy negative fish positive tumors
- 34:53that may also benefit from treatment.
- 34:56We don't know the full clinical
- 34:58impact of intratumoral heterogeneity
- 35:00in this tumor type.
- 35:02Also another question is sample selection.
- 35:04Should we do testing on the biopsy
- 35:07or grading versus the hysterectomy?
- 35:10Should we test primary versus metastasis
- 35:13and finally specimen handling and fixation
- 35:17time and and the issue of control?
- 35:22Slides on the on the topic of
- 35:25heterogeneity data from breast
- 35:27and gastric cancer have shown that
- 35:30homogeneous her two overexpression.
- 35:33Has more benefit from targeted therapy
- 35:36compared to heterogeneous her two expression.
- 35:40On the topic of sample selection,
- 35:44there are several considerations
- 35:45and this is an interesting.
- 35:49Topic for that reason because first of all.
- 35:53Comparing biopsies versus hysterectomy
- 35:55of course fixation is probably better
- 35:58and and a better controlled and biopsies
- 36:01gradings compared to hysterectomy,
- 36:04especially if they're not open right away.
- 36:07Also we have to take the
- 36:10heterogeneity into consideration.
- 36:11What will give us a better
- 36:14sampling of the tumor?
- 36:15Is it if we select one block from the
- 36:19hysterectomy or is it potentially
- 36:21a more spatially?
- 36:23Heterogeneous sampling, and inoculating.
- 36:27Also, the timing of the sample.
- 36:30In breast cancer? UM, it's a.
- 36:34It's a very important to have the her
- 36:37two status information before the.
- 36:42Definitive surgery because
- 36:44oftentimes based on that result,
- 36:46the patient will be offered
- 36:48neoadjuvant chemotherapy.
- 36:49So that's why I think it's a.
- 36:51It's a straightforward to do the
- 36:53started testing on the core biopsy.
- 36:56There is no such consideration or
- 36:58it's much less common in dimitriou
- 37:01cancer patients don't typically
- 37:03get neoadjuvant treatment,
- 37:05so for that reason,
- 37:06the the testing could wait until the
- 37:10hysterectomy in most of the cases.
- 37:12The question also,
- 37:14should we test multiple blocks?
- 37:16Should we test the metastasis if the?
- 37:20Primary was negative,
- 37:21so so to answer these questions,
- 37:24we can again take a look at the gastric
- 37:28literature and and learn from what.
- 37:31They found in gastric carcinomas a
- 37:34nice study from University of Rochester
- 37:38showed that the more specimens you test,
- 37:41the higher the likelihood that
- 37:43you'll get her two positive result.
- 37:46So comparing patients with only one
- 37:50specimen from 12% positive ITI rate,
- 37:53you go up to 24% of positive
- 37:57ITI rate if patients have.
- 37:59More than more than one specimen so.
- 38:03Based on that, we designed a study
- 38:06that Douglas was working on and and
- 38:09published last year to compare the
- 38:12her two status in paired biopsy and
- 38:15hysterectomy specimens and showed that
- 38:17the concordance was a lower than what
- 38:21was reported in breast tumor literature,
- 38:25so only 84% concordance,
- 38:27and so if we only tested the endometrial
- 38:31passes or grading the we would have a 15%.
- 38:35False negative rate,
- 38:36and if we only tested the
- 38:38hysterectomy you would have almost
- 38:40a 30% of false negative rates.
- 38:43So it really is true also for
- 38:46endometrial cancer that if we test
- 38:48multiple specimens then we increase
- 38:50the rate of her two positive ITI.
- 38:53Here are the six cases from this
- 38:55study that had a discrepant result
- 38:58between the biopsy and hysterectomy
- 39:01and most of the cases the change
- 39:03went from positive in the biopsy
- 39:06to negative and the hysterectomy.
- 39:09Here is one of the examples where the
- 39:12biopsy was strongly positive or three
- 39:15plus and hysterectomy was a one plus.
- 39:21Nice study from the Netherlands.
- 39:23Looked at paired primary
- 39:25and metastatic tumors,
- 39:27metastatic and amitiel or carcinomas,
- 39:30including serious carcinoma,
- 39:31and they found that overall
- 39:34there is a 23% discordance rate
- 39:37between these tumors and again
- 39:40the change could go both ways.
- 39:43It could go from a positive
- 39:45to negative or from a her two
- 39:47negative to her two positive.
- 39:50For specimen handling.
- 39:53The current recommendations for best breast
- 39:56and gastric cancer is cold ischaemia.
- 39:59Time of 1 hour or less and at
- 40:02least six hours of fixation. Uhm?
- 40:07So in terms of future on directions. Uhm?
- 40:11We still need to work on identifying the
- 40:17the correlation between clinical response
- 40:21and her two IC and fish characteristics,
- 40:24and in addition to that,
- 40:26there are new her two testing methods,
- 40:28namely sequencing, that may also be
- 40:32used for evaluation of her two status.
- 40:37In addition, there is a question about
- 40:41should we test the for the extracellular or
- 40:44the intracellular domain of the receptor?
- 40:48And also, what about her too
- 40:50and other gynecological tumors?
- 40:51High grade endometrial carcinomas,
- 40:54or carcinosarcoma?
- 40:56There is also a lot of history
- 40:59type agnostic clinical trials.
- 41:01What should we use for those trials?
- 41:04Scoring criteria?
- 41:05And then finally what?
- 41:08Is there any correlation between
- 41:11the her two status and prognosis?
- 41:14In terms of the next generation sequencing,
- 41:17there is a study from a MSK a couple
- 41:21years ago showing very nice very high
- 41:24concordance between the her two IC and
- 41:28fish and the MSK impact sequencing platform.
- 41:34And similarly,
- 41:34just this year,
- 41:36published from Brigham UM,
- 41:39they identified 100% concordance
- 41:42between next generation sequencing
- 41:44results and the combined.
- 41:46I see fish interpretation and
- 41:48under meteor serious carcinoma.
- 41:50So this this almost sounds
- 41:52too good to be true,
- 41:54and I think one of the issues with
- 41:57this study was that almost very
- 41:59high percent of the cases 75% of
- 42:02the tumors were her two negative.
- 42:05So it's it's it's easier
- 42:08to achieve concordant.
- 42:10Uhm,
- 42:10result when when the tumors her
- 42:13two negative only 20% were two
- 42:16plus and only 4% were three plus.
- 42:19And also fish was only performed
- 42:22on a smaller number of tumors.
- 42:26Uhm,
- 42:26a couple of years ago we also
- 42:29presented our data on the
- 42:32correlation between icy fish and next
- 42:35generation sequencing or sequencing.
- 42:38Results were from mostly just.
- 42:42Retrieved from the foundation medicine
- 42:45or the tumor profiling lab results
- 42:48and we found that indeed we have 100%
- 42:51concordance among the negative cases,
- 42:53but the concordance is much lower when
- 42:56we look at the positive cases only 43%.
- 43:01Concordance rate,
- 43:02but that still gives an overall
- 43:0487% concordance for these tumors.
- 43:11An enemy to our cancer is also
- 43:14different from other tumor types
- 43:16and with with regards to the.
- 43:20So cellular and extracellular
- 43:22domain of the receptor.
- 43:24Several studies have shown,
- 43:26including David Dream slap,
- 43:27that on these tumors often
- 43:29shut the extracellular domain,
- 43:31which is the the drug binding domain,
- 43:35to Susan Medwed binds to
- 43:37the extracellular domain.
- 43:38So once you lose that,
- 43:39you lose the therapeutic target.
- 43:41Yet most of the antibodies were
- 43:43used in technical lab to detect her.
- 43:45Two expression is actually
- 43:47against the intracellular domain.
- 43:49So are her two.
- 43:50Let me know.
- 43:50Staying may still be positive,
- 43:52and yet the tumor may not responded
- 43:56to treatment for that reason,
- 43:58so that's another important consideration,
- 44:01and here are some nice images from doctors,
- 44:06rim rim slab showing the differences.
- 44:10I intracellular domain was
- 44:12labeled with the CB11 antibody,
- 44:15which we use for awhile now.
- 44:17We we use EP3 currently which
- 44:18is also against the interests.
- 44:20The domain and the only antibody
- 44:24clone that targets the extracellular
- 44:26domain that at least I'm aware
- 44:28of is the SP3 antibody and so.
- 44:3288% of the tumors with a high
- 44:35intracellular domain had low
- 44:37extracellular domain labeling levels.
- 44:43Her two testing could also be expanded to
- 44:46other high grade under material carcinomas.
- 44:49There are several studies that just
- 44:52came out this year showing that her
- 44:54two positive ITI is highly associated
- 44:56with a P53 apparent Geno type,
- 45:00regardless of histologic classification.
- 45:02As many of you know, there is some.
- 45:06Uhm, interobserver variability and
- 45:10how these tumors are classified.
- 45:15So basically you could have a P53 aberrant
- 45:18tumor that based on other features
- 45:20may be called a clear cell carcinoma
- 45:22or a grade 3 endometrial carcinoma,
- 45:25and that would potentially make the patients
- 45:29ineligible for uneligible for the treatment.
- 45:32So there is there is a potential
- 45:34to expand the treatment for to
- 45:37include these tumors as well.
- 45:40And one of the studies showed that the
- 45:42correlation was even stronger between
- 45:44the her two status and the P53 mutation.
- 45:47Then her two status and serious sister type.
- 45:51And this was a one of our studies in
- 45:55collaboration with the University
- 45:56of Wisconsin,
- 45:57showing her two positive ITI in
- 45:59a clear soccer Sonoma.
- 46:04Similarly, in Carcinosarcoma's there are
- 46:06in vitro and in vivo studies showing.
- 46:11UMD at the targeted treatment may work.
- 46:15And in our study, we found that 12%
- 46:19of course in sarcomas are positive
- 46:23if you use the 2007 criteria,
- 46:26most of them are uterine her two
- 46:30positive ITI is much less common and
- 46:32high grade ovarian serous carcinomas,
- 46:34so 14% versus 7%.
- 46:36And most of the tumors that were
- 46:39hurt a positive had a serious
- 46:41or a mixed epithelial component.
- 46:45Heterogeneity similar to an immediate,
- 46:49serious carcinomas was also
- 46:50commonly seen in these tumors,
- 46:52and most of them had a positive
- 46:54ITI in the carcinoma component.
- 46:57Only one case had a two plus
- 46:59staining in the circular component,
- 47:01which is shown here on the upper right.
- 47:06So there is currently a clinical
- 47:09trial in Japan and the Japanese
- 47:12group already published data on.
- 47:15Compared to status and they found they
- 47:18actually compared the gastric criteria
- 47:20with the current breast criteria and
- 47:22they found 70% concordance between
- 47:25the two different scoring criteria,
- 47:27mostly due to the differences in lateral
- 47:32based, lateral membranous pattern.
- 47:37There are many.
- 47:40Tissue agnostic or tumor type agnostic
- 47:43clinical trials are available.
- 47:45Basket trials that may include all solid
- 47:48tumors with her two positive positive status.
- 47:51So what scoring criteria should we
- 47:53use for for these trials or what?
- 47:56What are those trials using one of
- 47:59them was recently published, so I.
- 48:02Went into the details and into the
- 48:05supplementary material to find out how
- 48:07was the her two status determined.
- 48:09This particular trial included
- 48:11two endometrial cancer.
- 48:13Is one of them was not tested,
- 48:15the other one was her 2/3 plus positive
- 48:18and the only comment they made on how
- 48:22the status was determined was that
- 48:25the heritage status was defined on
- 48:27the basis of local lab testing data
- 48:30and no further detail is provided.
- 48:33These are the currently ongoing
- 48:36trials for endometrial serous
- 48:38carcinomas and coarseness sarcomas.
- 48:41And I expect there will be many more.
- 48:44There are many more in the works and
- 48:47I think lastly, on the prognostic,
- 48:50prognostic,
- 48:51and predictive significance of her two
- 48:55status in breast cancer and gastric cancer.
- 48:58It's a known negative prognostic marker,
- 49:02and in breast cancer also her two
- 49:05positive ITI predicts a good response
- 49:08to other chemotherapeutic agents.
- 49:10Soum a large, collaborative study,
- 49:14also looked at the correlation
- 49:17between prognosis and her two
- 49:19status in endometrial cancer,
- 49:21and found that that is also true and,
- 49:24and the meteor serous carcinomas
- 49:26her two positive tumors have worse
- 49:29progression free and overall survival.
- 49:33So in summary, about 25 to 30% of
- 49:37endometrial serous carcinomas are her two
- 49:40positive to Tsumeb improves progression
- 49:43free and overall survival if added
- 49:47to the standard chemotherapy regimen.
- 49:51There are unique features of Hurtigruten
- 49:54expression and gene amplification,
- 49:55and the because of that.
- 50:00Speaker two testing and scoring
- 50:02algorithm was proposed based on the
- 50:062018 clinical trial enrollment data.
- 50:09There's also prognostic significance of
- 50:12her two status and potentially weakening.
- 50:18We can expand this a targeted therapy
- 50:21to other tumor types and also to early
- 50:25stage and a meteor service carcinoma.
- 50:27And I would like to acknowledge my colleagues
- 50:31and many of them helping me in pathology,
- 50:35especially pay hue and also
- 50:38in gynecological oncology, Dr.
- 50:40Santina and his lab and all the other
- 50:43wonderful gynecological oncologist
- 50:45gynecologist center in our group.
- 50:48So thank you very much.
- 50:49Period attention.
- 50:54That was wonderful and I don't see
- 50:58any questions in the chat yet.
- 51:01But I do have a couple of companies
- 51:05since her Tonio has is now embracing
- 51:10adenocarcinomas in multiple.
- 51:13Organ systems. Breast GY and ovary
- 51:18and Dmitry AM gastric colorectal.
- 51:23Uhm, why is it not used
- 51:27for lung adenocarcinomas?
- 51:30That's question number one and
- 51:32the question #2 is what about
- 51:35squamous cell carcinomas and
- 51:38number of those RP53 positive?
- 51:41The high grade ones
- 51:43you mean high grade serous
- 51:46carcinomas over the ovary.
- 51:48No, actually. My question is
- 51:51outside of that. You yeah.
- 51:53No I said no I I got.
- 51:54I got lost because I at the same
- 51:56time I was reading David Ramsey.
- 51:58Comments here he yeah I think for
- 52:02long I mean what I could tell you
- 52:04is probably, you know there's.
- 52:06I'm sure there's so many large
- 52:09studies on the molecular.
- 52:11Characteristics of lung cancers,
- 52:13and it's probably that that
- 52:15her two amplification is just
- 52:17not common among I don't know.
- 52:19I mean I that would be my guess
- 52:21that similar to other high
- 52:23grade tumors in the GI tract,
- 52:25I can speak for, you know,
- 52:26like a high grade serous
- 52:28carcinomas of the ovaries.
- 52:30As much as they are similar to
- 52:32endometrial serous carcinomas,
- 52:34the amplification hurt amplification and
- 52:36overexpression rate is much much lower,
- 52:39so it's really not a good good
- 52:41therapeutic target for those tumors.
- 52:44I can comment on that in long.
- 52:47There's hardly any amplification.
- 52:49There's some mutation for her too,
- 52:51but hardly any information.
- 52:52But in Italian that was
- 52:54just a terrific lecture.
- 52:55Thank you very much.
- 52:56Thank you David,
- 52:57but I do have a couple questions.
- 52:59The first one is about
- 53:01the more you look, the more you find
- 53:03that is that the more specimens that you
- 53:05looked at suggests that there are some
- 53:07input of heterogeneity that is and and we
- 53:10see there's some breast cancer as well.
- 53:11That is that if you look at more,
- 53:13there's some some breast cancers.
- 53:14Or someone had a genius heterogeneous,
- 53:16but the question is, does it affect outcome?
- 53:18That is, have you looked to see if
- 53:21when you find an increase in 10%
- 53:23because you look at more specimens,
- 53:25those patients actually respond
- 53:26to trust as a madman? Chemo?
- 53:28Yeah, that's that's one of the
- 53:30unanswered questions and and I
- 53:31don't have an answer to that.
- 53:33I all I can say is that it's been looked
- 53:36at in gastric cancer and apparently not.
- 53:38Too surprisingly,
- 53:39they don't respond that well.
- 53:41If every rate of her two positive,
- 53:44you know if they.
- 53:45Percent of tumor cells that are
- 53:46her two positive is lower.
- 53:47On the other hand.
- 53:49I'm, I know you're aware there is the
- 53:52antibody drug conjugates that actually
- 53:54may help overcome this problem,
- 53:56because once you know if you have,
- 53:59let's say a her two positive tumor
- 54:01cell cluster surrounded by all
- 54:03the her two negative tumor cells,
- 54:04but you're able to deliver that
- 54:06chemotherapeutic drug within
- 54:08the within the neighborhood,
- 54:09you know and and just bind to the
- 54:12receptor on the positive cells and then
- 54:14release the drug in the in the vicinity.
- 54:16That would also have this bystander.
- 54:19Chilling effect,
- 54:20so I think that that is potentially
- 54:23one way to to overcome this problem.
- 54:26For these tumors,
- 54:28yeah,
- 54:28and just in follow up related to
- 54:30that I was going to ask you about
- 54:32in her two or trustees map drugs
- 54:34taken and I I saw that there have
- 54:36been some beginning trials in
- 54:38and Dmitry AM in Destiny 3,
- 54:39which is a breast cancer trial of that drug.
- 54:41For the three plus breast cancer
- 54:43just reported on as positive.
- 54:44So some oncologists are saying that now we
- 54:47won't need fish anymore because anyone,
- 54:49that's.
- 54:49Even plus one positive or
- 54:51higher will get transcribed.
- 54:53Rusty can,
- 54:54and we probably will just test biopsy
- 54:57or some similar tests to have because
- 54:59you only need a low level to benefit.
- 55:02Are you seeing the same
- 55:03thing and endometrium?
- 55:04That is where the low levels
- 55:05benefit or did in the trials that
- 55:07have been done so far,
- 55:08I've only high levels been looked at.
- 55:10Uhm,
- 55:11the that the only trial that so
- 55:13far has been published is the one
- 55:16one I showed and I think there
- 55:18is others on ongoing trials that
- 55:21will include and her two,
- 55:23but I'm not entirely sure what the
- 55:26criteria for enrollment will be
- 55:28for those so so there there are no
- 55:31more data on that yet other than
- 55:33maybe you know some of those basket
- 55:36trials may have included tumors.
- 55:38That would fit into that category.
- 55:42So. So I have a question from Mary Robair UM.
- 55:48You attribute the difference between
- 55:51biopsy more like positive and resection
- 55:54to fixation alone or other factors
- 55:58and question number two is does the
- 56:02internal versus external domain issue
- 56:04apply to gastric and breast as well?
- 56:09First question, yes, that one of the
- 56:12possible explanations is fixation,
- 56:14as so there would be one argument
- 56:17to to do the testing on the biopsy.
- 56:20And just like in breast cancer,
- 56:22basically we could start the and
- 56:24that that's what I started doing.
- 56:26Starting the testing on the biopsy or
- 56:29creating and if it's negative then
- 56:31repeat the tests on the hysterectomy.
- 56:34The other potential explanation,
- 56:36in addition to fixation, could be a.
- 56:39More spatially heterogeneous sampling
- 56:42you know, like unlike breast cancer,
- 56:45where it's a directive,
- 56:46core biopsy or a gastric cancer,
- 56:49it's so directed. And the scopic biopsy.
- 56:51This is completely like a blinded biopsy,
- 56:54right?
- 56:54The gynecologist collects tissue from
- 56:58all potentially all parts of the,
- 57:01especially if it's a great time.
- 57:03It samples the very large areas
- 57:06of the endometrial lining,
- 57:07as opposed to if I select a.
- 57:10Block from this wreck to me that
- 57:12that is just that one spot in
- 57:14the on the heaters and exceller
- 57:17versus intracellular domain.
- 57:20From what I know, I think it's not that, uh?
- 57:24There is not such a large discrepancy
- 57:28in breast and gastric cancer.
- 57:30I think that's a more.
- 57:33Specific problem for for endometrial cancer.
- 57:37This extracellular domain shedding occurs
- 57:39more frequently in dimitriou cancer.
- 57:43And there is another question from Uma
- 57:47Krishnamoorthy. In your experience,
- 57:49what is the approximate percentage
- 57:51of caser with with heterogeneity?
- 57:55So in this study that we
- 57:58performed 30% overall.
- 58:00And among the positive cases more than 50%.
- 58:06Had heterogeneity and since then
- 58:08there there are other studies as
- 58:11well that confirmed a similarly
- 58:14high rate of heterogeneity.
- 58:16So that's I think in that regard
- 58:18it's more similar to gastric cancers.
- 58:23Then there is another question,
- 58:27MH446. It says what percentage of
- 58:30endometrial serous carcinomas are.
- 58:33I'd seen negative and fish
- 58:36positive and what is the mechanism
- 58:39so that would also be a good question
- 58:42and that's that's also one of the
- 58:45unanswered questions because based
- 58:47on the current algorithm we only do
- 58:49her two fish on the two plus is.
- 58:53We we don't do her two fish routinely on
- 58:57a 0 or one plus and and and on A3 plus.
- 59:01There are a few cases that we we
- 59:05subjected to fish that were part
- 59:06of a study and and we looked at
- 59:09those and and it it does occur I
- 59:12I can't remember a percentage.
- 59:13We didn't test a lot of cases
- 59:16but once nobody it happens and.
- 59:19I don't know.
- 59:20What the what the potential mechanism you
- 59:23know probably similar to to breast cancer?
- 59:26I mean, I think these are not,
- 59:27you know, tumor type specific.
- 59:29It may be that that they,
- 59:32they they protein is not expressed,
- 59:34you know.
- 59:35But but there is a there
- 59:37could be still amplification.
- 59:41OK, there is another one
- 59:43from Karen Finberg by fish.
- 59:46We assessed the her two gene nor
- 59:50other nearby gene on chromosome 17.
- 59:53And that's the question.
- 59:55Is it known?
- 59:56How much of chromosome 17 maybe Co
- 01:00:00amplified with her to a mutual carcinomas?
- 01:00:04And could this contribute to
- 01:00:07tumor aggressiveness and or
- 01:00:10response to targeted therapy?
- 01:00:13Yeah, I think this this has been raised
- 01:00:15also in breast cancer because there's a lot
- 01:00:18of other important genes on chromosome 17.
- 01:00:20Top 2P53 those all have been implicated
- 01:00:25in and cases where there is a.
- 01:00:31Chromosome 17 polysomy or gain
- 01:00:33of chromosome 17. Actually,
- 01:00:35I'm working on a paper right now on
- 01:00:38her two fish and related to, you know,
- 01:00:41to look at the specific characteristics
- 01:00:43of her two fish and and Co.
- 01:00:45Amplification is not that common.
- 01:00:48We had in our archives.
- 01:00:50We found about 15% rate of chromosome
- 01:00:5417 or polysomy in these tumors,
- 01:00:58or at least the chromosome
- 01:01:0017 centromeric gain. Uhm?
- 01:01:02But but clarification is actually
- 01:01:04not not that common.
- 01:01:06I think we had one case in
- 01:01:08which that that was present.
- 01:01:11And then finally, I'll recap where
- 01:01:14Doctor Morrow's comments Natalia.
- 01:01:16Thanks for the terrific review.
- 01:01:18As you know, Yale may have been the
- 01:01:21situation to have treated a patient
- 01:01:24with Herceptin for endometrial serous
- 01:01:27carcinoma Bay and Peter Schwartz.
- 01:01:30Her two positive year 2002
- 01:01:33bad win never reported it.
- 01:01:35Really interesting to see
- 01:01:37how this has evolved.
- 01:01:39Yeah, I think. I remember you
- 01:01:43told me that story before.
- 01:01:45I think this this is one of
- 01:01:47the important lessons from this
- 01:01:49from this work is that when we
- 01:01:52started I was still a resident.
- 01:01:54Actually when I started working
- 01:01:55on this and and I just didn't
- 01:01:57know which direction it will go.
- 01:01:59It took many many years for this to
- 01:02:03to come to fruition and and it was
- 01:02:07just really wonderful to see how this
- 01:02:09became a successful treatment option.
- 01:02:12Again, thanks to Doctor 17 and.
- 01:02:14They seem so.
- 01:02:18OK, it's a long journey.
- 01:02:20Yeah, excellent so.
- 01:02:23We can wrap it up now.
- 01:02:25Thank you so much Natalia.
- 01:02:27Thank you man bye bye.