Targeted Her2 Therapy and Her2 Testing in Endometrial Cancer: Current Status and Future Directions

November 04, 2021

Information

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.