"Stage IV Breast Cancer at Diagnosis: To operate or not: Swinging the Pendulum" and "WHO 2021 Classification of CNS Tumors - THE FIFTH - an update"

Transcript

• 00:00So I think we can get started.
• 00:03So hello everyone,
• 00:04welcome to one more YCC green Browns.
• 00:08I am Antonio Mora,
• 00:10chief of neurology and today is my
• 00:12pleasure to introduce our wonderful speakers,
• 00:15both of whom from our very own Cancer Center.
• 00:20The first speaker is Doctor Merrick,
• 00:22Goshen, who is a professor of
• 00:25surgery within oncology and Deputy
• 00:27Chief Medical Officer for surgical
• 00:29services at Smilow Cancer Hospital.
• 00:31Doctor Goshen earned his medical
• 00:33degree from Case Western Reserve
• 00:35University School of Medicine.
• 00:37And he also pursued an MBA at MIT.
• 00:42As well as a fellowship in breast surgical
• 00:44ecology at Northwestern Memorial Hospital,
• 00:47doctor Goshen is an innovator in
• 00:49tailoring surgery and therapy for
• 00:50women with early stage breast cancer.
• 00:52With funding support from the
• 00:54breast Cancer Research Foundation
• 00:56and National Institutes of Health.
• 00:58He is the principal investigator.
• 00:59Several phase two trials aiming to reduce
• 01:02the need for second surgeries or re
• 01:04excisions in women with breast cancer,
• 01:06one of which uses innovative image
• 01:09guided operating room capabilities to
• 01:11capture and remove all residual tumor
• 01:13utilizing MRI and mass spectrometry,
• 01:16which is used at Yale's hybrid
• 01:18operating room.
• 01:19Prior to joining nail,
• 01:21doctor Gosh spent 17 years in Boston
• 01:24at the Dana Farber Cancer Institute,
• 01:26where he was the inaugural and
• 01:29incumbent Dr Abdul Mohsin and Susannah
• 01:31out to hearing the distinguished
• 01:33chair in Surg conchology.
• 01:36He also served as the director
• 01:38of the Breast Surgical Quality
• 01:39Fellowship at the Dana Farber.
• 01:41And was an associate professor of
• 01:43surgery at Harvard Medical School.
• 01:45So without further ado.
• 01:47Doctor Goshen, the foresters.
• 01:50Thank
• 01:50you so much for that kind introduction
• 01:54and I'm excited to be here.
• 01:56I know we have one hour and we're
• 01:58going to try to go through two talks,
• 02:01so I will do my best to stay on time.
• 02:04And although you know in the
• 02:06introduction you talk about,
• 02:07you know, reducing the need for
• 02:09surgery and minimizing surgery.
• 02:11One interest of mine early on when
• 02:14I finished or was in training and
• 02:17fellowship was the role of surgery
• 02:19in stage four breast cancer.
• 02:21I'll kind of go through how the pendulum
• 02:24has really swung in actually two directions,
• 02:28so historically stage four breast
• 02:30cancer as a medium survival.
• 02:31This is really older data before more modern,
• 02:34targeted therapies of less than two years,
• 02:36and really treatment has been
• 02:38chemotherapy endocrine therapy more
• 02:40recently targeted or molecular therapy.
• 02:42There has been some radiation
• 02:44to sites of metastatic disease,
• 02:45and you know, interestingly,
• 02:47when people started looking at
• 02:49whether local regional therapy.
• 02:51Was being done.
• 02:52That number was actually fairly high,
• 02:5535 to 60% of women were undergoing
• 02:58local regional therapy in the United
• 03:00States when really it should have been
• 03:02reserved for palliation at the time.
• 03:04And then there was a question of whether
• 03:06there is any survival benefit in doing this.
• 03:08This is United States data,
• 03:10certainly most women fortunately present with
• 03:13localized or regional disease on stage four,
• 03:16breast cancer in the United States
• 03:18and this is very different when
• 03:19you look outside of EU.
• 03:21S.
• 03:21Is only about four to 6% of the population.
• 03:25You know,
• 03:26when I was taking my surgery boards,
• 03:28I would have really I I would have
• 03:30failed the room if I had suggested that
• 03:32we should do surgery in this stage.
• 03:34Four setting outside of palliation.
• 03:37It was generally accepted that local
• 03:39therapy did not prolong survival
• 03:41and there was some earlier data
• 03:43suggesting that there may be some
• 03:45stimulation of metastatic growth.
• 03:46However,
• 03:47we know that there are diseases
• 03:48in the stage for setting where
• 03:50resection of the primary and or
• 03:52metastatic tumor site could improve
• 03:54survival or does improve survival.
• 03:56For example, in colorectal disease,
• 03:58potentially with metastatic disease to
• 04:00the liver or in renal cell carcinoma,
• 04:03and there are good reasons
• 04:04to leave the primary alone,
• 04:06and there may be reasons to
• 04:07resect the primary tumor.
• 04:08For example,
• 04:09it is very easy to measure disease
• 04:11as opposed to getting scans when
• 04:14you leave the primary tumor alone.
• 04:16There is morbidity associated
• 04:18with resection in with even in
• 04:21a breast cancer surgery,
• 04:22certainly with mastectomy and more
• 04:25complex closures and reconstructions.
• 04:26With sometimes are required,
• 04:28there was some early data suggesting
• 04:31sources of cytokines or angiogenesis.
• 04:33Inhibitors which restrain growth
• 04:35could be released with metastasis.
• 04:37And really you know a question
• 04:39on whether there is a survival
• 04:41benefit in this setting or not.
• 04:43We did use surgery in the
• 04:45palliation of symptoms.
• 04:46Certainly fear of uncontrolled local disease.
• 04:49There was suggestion of reducing
• 04:51the shedding of metastatic cells
• 04:54and you know could it.
• 04:55Potentially if you respect the
• 04:57site provide more effective.
• 04:59Systemic therapy. Again,
• 05:01there was data and ovarian cancer,
• 05:04renal cell cancer and colorectal
• 05:06cancer setting about surgical debulking
• 05:09and surgical removal of disease,
• 05:11and again, this was work that I started
• 05:15about 2/2 and a half decades ago.
• 05:18So I say challenging the
• 05:19standard so Seema Khan,
• 05:21who was one of my attendings
• 05:23when I was a fellow,
• 05:25presented in 2002 in a in in a
• 05:29not a major surgical society or.
• 05:31On Koleji society was called
• 05:34Central Surgical Society,
• 05:35looking at the National Cancer Database
• 05:38for women with stage four disease.
• 05:41You know about 4% of patients in EU?
• 05:43S presented with stage four breast cancer.
• 05:45This is again in the 1990s median
• 05:47age or mean age of 62,
• 05:50which is really in line with our
• 05:52average age of breast cancer in
• 05:54the United States and you know,
• 05:55she looked at 16,000 women over a.
• 05:59I think it was a two or three
• 06:00year cohort period of time.
• 06:02And first you know the thing that
• 06:04was surprising to us and to her
• 06:05and to others was that almost 60%
• 06:07of women underwent local therapy.
• 06:10About 60% underwent mastectomy,
• 06:13about 40% underwent breast
• 06:15conservation and and you know,
• 06:18you can see what the negative
• 06:20margin rates were at the time.
• 06:23Not surprisingly,
• 06:24those that either did not undergo
• 06:26surgery or underwent mastectomy had
• 06:29larger burden of disease in terms of.
• 06:32Tumor size and you know she was
• 06:34the first to really present that.
• 06:36You know, if you didn't do surgery,
• 06:38Sir survival was twenty months.
• 06:40If he did,
• 06:41breast conservation was 27 months
• 06:43and if you did a mastectomy,
• 06:4532 months and again suggesting that
• 06:48potentially there is a survival
• 06:50benefit in the surgical cohort.
• 06:52You know those that had bone or soft
• 06:55tissue disease tended to do better.
• 06:57Certainly if you had fewer
• 06:58sites of metastatic disease,
• 06:59your outcomes were better giving chemo
• 07:03and or endocrine or combination of
• 07:06therapy ended up being of benefit and
• 07:08this is something that seem Doctor
• 07:10Khan has spent a lot of time on as
• 07:13well and we'll get to the modern
• 07:15era is on margin positive ITI and
• 07:18whether that would influence outcome.
• 07:21So independent predictors of survival.
• 07:23Or the use of systemic therapy?
• 07:24Certainly the location of metastatic disease.
• 07:26The burden of disease and the type
• 07:29of surgical resection that was done.
• 07:31And really for four or five years,
• 07:33this presented as central Surgical
• 07:35and published in surgery really didn't
• 07:38get much attention until 2006 to 2009.
• 07:41So guilty barbiere at MD Anderson decided
• 07:44to look at their stage four breast cancers.
• 07:47The mean Age was a little bit
• 07:49younger in their cohort.
• 07:50They were, you know,
• 07:52somewhat surprised at about.
• 07:5340% of their patients underwent surgery,
• 07:56have had breast conservation,
• 07:57have had mastectomies, and you know what?
• 08:00We would probably expect is
• 08:02that the patients were younger,
• 08:04less likely to have nodal involvement,
• 08:06fewer sites of metastatic disease
• 08:09in their cohort.
• 08:12And when they looked at their
• 08:14follow-up for 32 months,
• 08:16there was a trend towards better
• 08:18overall survival in the surgery group.
• 08:21And there was a benefit in terms of
• 08:25metastatic progression free survival.
• 08:27Then in the GPIO and there
• 08:29was an accompanying editorial
• 08:31by Monica Morrow and 2006,
• 08:34and I think it was something about this.
• 08:36The horse out of the barn.
• 08:37There were 300 patients
• 08:39with metastatic disease,
• 08:40with the Geneva Tumor Cancer
• 08:42Registry on the use of local
• 08:44therapy and again little over half
• 08:47the patients didn't have surgery,
• 08:49but 127 patients did.
• 08:51Most were mastectomies.
• 08:53They describe breast conservation as tumor,
• 08:55ectomy's negative margins and about half and.
• 08:59Nodal surgery in about 1/4 of patients,
• 09:02and this is just kind of a the diagram
• 09:05breaking that down in a schematic
• 09:08or graph form those that ended up
• 09:11undergoing surgery versus not were younger.
• 09:13Lower burden of disease in terms of
• 09:16the size of tumor and nodal disease,
• 09:19more likely again to have a single
• 09:21site of metastatic disease or less
• 09:24likely to have visceral metastasis
• 09:26more likely to undergo radiation.
• 09:29And then you can see what the
• 09:31use of chemotherapy and endocrine
• 09:32therapy was the same.
• 09:34And again, this is,
• 09:35you know,
• 09:35leads the thought of potential
• 09:37selection bias.
• 09:38If you were able to resect the
• 09:40tumor and get clear margins,
• 09:41there was a survival benefit as
• 09:44opposed to those that did not undergo
• 09:46surgery or that have positive margins.
• 09:49And then Fields Group looked at the
• 09:51wash U data over almost a decade,
• 09:54again about half of patients
• 09:56underwent surgery.
• 09:57This is a much longer median.
• 10:00Follow up of 142 months and again there was
• 10:03a survival benefit for surgery versus not.
• 10:06And there there is a theme in in.
• 10:08In all this there was a 250
• 10:10institution review over almost
• 10:13a two decade period of time.
• 10:15This was published in the Annals of Surgery,
• 10:17but Blanchard again.
• 10:19About 60% had surgery in the
• 10:22stage four setting and survival
• 10:25was 27 months versus 17 months.
• 10:28So, as I alluded to,
• 10:29there is selection bias, potentially
• 10:32younger woman with smaller tumors,
• 10:34less knodel involvement,
• 10:35fewer sites of metastatic disease,
• 10:37and this is kind of the differences
• 10:40between the studies from Seema Khan
• 10:42and Repeate and guilty Barbie era.
• 10:44And from the wash you and
• 10:46the the other data again.
• 10:48Younger women with smaller tumors,
• 10:50less nodal involvement,
• 10:51and fewer sites of metastatic
• 10:53disease had surgery.
• 10:55And certainly there have been a lot of
• 10:58attempts statistically and in terms
• 10:59of matching to be able to look at
• 11:02whether that difference continued or not.
• 11:06So this was a work that a
• 11:08previous resident of mine decided.
• 11:09Well,
• 11:10let's look at the Brigham and Farber and
• 11:12Mass general data and you know again,
• 11:14very similar to what everyone else did.
• 11:16You know we had a pretty small
• 11:18cohort of patients a little
• 11:20bit more modern era treatment.
• 11:21About 40% of our patients had
• 11:23surgery in the stage for setting,
• 11:25and I found that actually pretty
• 11:27surprising to see it was that high.
• 11:29But we were actually the first
• 11:31group to look at whether the
• 11:34timing of diagnosis or surgery.
• 11:36In relationship to the
• 11:37diagnosis of stage four,
• 11:39disease made a difference or not.
• 11:41About 25 out of those 61 patients had
• 11:45that surgery before stage 4 diagnosis.
• 11:47I'll go over why this is probably
• 11:50potentially important and 36
• 11:51after stage 4 diagnosis this is
• 11:53kind of hard to read, but again,
• 11:55those in the surgery group in terms
• 11:58of sites of metastatic disease
• 12:01very similar to previous studies
• 12:03with the surgery group having
• 12:05fewer sites of metastatic disease.
• 12:07Versus those that did not undergo surgery.
• 12:11And again, if you underwent surgery,
• 12:13you're more likely to get radiation therapy.
• 12:16So our median survival from the
• 12:19surgery group was 3.52 years
• 12:21and in the nose surgery group,
• 12:23just like everyone else.
• 12:242.36 years.
• 12:25However, the timing of diagnosis of
• 12:28stage four disease before after surgery,
• 12:31if it was done afterwards,
• 12:33that survival was four years
• 12:36versus before a 2.4 years.
• 12:38So you know,
• 12:39we you know our group looked into
• 12:41this and could this be an example
• 12:43of the Will Rogers phenomenon?
• 12:45Honestly two decades ago, if you ask me.
• 12:47But that was I didn't know the
• 12:50example that that Will Rogers uses,
• 12:52that when the Okies left the state of
• 12:54Oklahoma for the state of California,
• 12:56they raised the average IQ of both states.
• 12:59So I'll let you guys ponder
• 13:01that as we as we move on.
• 13:03So this was the first paper to suggest
• 13:06that the maybe it's there is no survival
• 13:08benefit in surgery and it's really the
• 13:10timing of surgery in relationship to
• 13:12the diagnosis of stage four disease.
• 13:15This shows the difference
• 13:16between surgery and not.
• 13:18But when we looked at the timing,
• 13:20that difference went away.
• 13:21So then I asked another colleague of
• 13:24mine that we recruited Laura Dominici.
• 13:26We looked at the NCCN database
• 13:28of stage four breast cancer.
• 13:29Again a little bit more modern,
• 13:31era 1000 patients,
• 13:33a much larger group.
• 13:35And then we did a match analysis
• 13:37of 236 non surgery patients to
• 13:4054 patients with that had surgery
• 13:42followed by drug therapy and again
• 13:45that survival benefit that was being
• 13:47seen in the surgery group versus
• 13:50non surgery actually disappeared.
• 13:52Survival is 3 1/2 versus 3.4 years.
• 13:55We matched her age,
• 13:56number of sites of metastatic disease,
• 13:58ER, her two sites of metastatic disease,
• 14:01and again I and my there was a very few
• 14:04of us who actually came out strongly
• 14:07against surgery in the stage for setting.
• 14:10And all I've been talking about is
• 14:13retrospective data, and obviously,
• 14:14you know with this you know
• 14:16anything in the world of oncology.
• 14:18Want prospective data?
• 14:19So the world of prospective data came
• 14:22from really a couple of brilliant folks.
• 14:25One is Raj Way bad way.
• 14:27Who's runs the breast service
• 14:30at Tata Memorial in Mumbai,
• 14:33India?
• 14:33They ran the first randomized trial of
• 14:37surgical removal of primary
• 14:40tumor with lymph node.
• 14:43Surgery in the metastatic setting there.
• 14:47Endpoints where primary endpoint was
• 14:49looking at removal of the primary
• 14:51tumor and actually nodes on overall
• 14:53survival and progression survival,
• 14:55and we're going to go over a couple of the
• 14:57randomized trials that have been done.
• 14:59That again, the Tata Group
• 15:01and Roger Roger Broadway,
• 15:02where there's a first looked at 350 patients.
• 15:05They were randomizing early to surgery,
• 15:09will go over to next to the
• 15:11the Turkish Medical Federation,
• 15:14which did drug therapy first,
• 15:15followed by surgery and finally.
• 15:17We're going to get to the E kog
• 15:19trial in the United States that
• 15:20I helped with with semakan drug
• 15:22therapy first followed by surgery.
• 15:24So the group in India looked at
• 15:26randomizing woman with stage four breast
• 15:29cancer to local regional therapy to none.
• 15:31They underwent local regional therapy
• 15:34and then if indicated anti estrogen
• 15:37therapy in the no local regional therapy,
• 15:39they were followed by when
• 15:41indicated anti estrogen therapy.
• 15:43Note it's important to know that there
• 15:45were in the time of her two positive.
• 15:48Breast cancer.
• 15:48None of the patients receive
• 15:50anti her two therapy,
• 15:52so that's a criticism of the trial.
• 15:54But again this was done.
• 15:55You know,
• 15:56deck started decades ago where you
• 15:58know anti her two therapy was just.
• 16:01You know getting approved in
• 16:02the United States and certainly
• 16:04in resource limited countries.
• 16:06It's not something that was,
• 16:08you know,
• 16:08automatically approved and paid for.
• 16:11This is the matching.
• 16:12They matched the you know their
• 16:14patient population very well and
• 16:16looking at overall survival.
• 16:18There was actually no difference
• 16:20between the two groups.
• 16:22They tried breaking it down
• 16:24by menopausal status numbers,
• 16:26the sites of metastatic disease,
• 16:27a number of sites of metastatic disease,
• 16:29like with that were done like
• 16:31the previous trials,
• 16:31and you can see really no difference.
• 16:35Interestingly,
• 16:35distant progression free survival
• 16:37was actually lower in the local
• 16:40regional therapy group as opposed
• 16:42to those that did not.
• 16:44And again,
• 16:45this is different than what will get to this.
• 16:47The Turkish and the US trial they
• 16:50were diagnosed with stage four breast
• 16:52cancer underwent surgery first,
• 16:54then followed by Agilent therapy.
• 16:58So Attila Saran,
• 16:59who's add Pittsburgh but helped run
• 17:01on behalf of the Turkish Federation
• 17:04of Society of Breast Disease.
• 17:06On randomized trial of evaluating
• 17:08resection of primary breast
• 17:09tumor with women with stage four,
• 17:12breast cancer,
• 17:13and these were actually simultaneous
• 17:15same day presentations at the
• 17:17San Antonio Breast Conference.
• 17:19Their early presentation in 2013
• 17:21is actually ends up being different
• 17:23than what they ended up publishing.
• 17:25Will spend a moment or two on that.
• 17:27Their primary goal is assessive.
• 17:29Early surgical treatment of the
• 17:31primary tumor and stage four
• 17:32disease effects overall survival.
• 17:33They also looked at progression
• 17:35free survival, quality, life,
• 17:37and morbidity different than the
• 17:39Tata group stage four breast cancer.
• 17:42That presentation was randomized
• 17:44as systemic therapy.
• 17:46Then local therapy for local progression
• 17:49versus initial local therapy.
• 17:51Uh,
• 17:52then a systemic therapy
• 17:54and then looking at overall survival
• 17:57chemotherapy was given to all patients
• 17:59either immediately or after randomization.
• 18:01All hormone receptor positive patients
• 18:04received anti estrogen therapy
• 18:06different than the Tata Group.
• 18:08The her two positive,
• 18:11overexpressed received trastuzumab therapy.
• 18:15Most patients if they underwent
• 18:18local therapy, underwent mastectomy.
• 18:20Radiation was given to some patients
• 18:23with with sites of metastatic disease.
• 18:26And early on, looking at the
• 18:28difference between surgery and those
• 18:30that just received systemic therapy,
• 18:32there was no statistical difference.
• 18:35Overall, when they broke it down by
• 18:39numbers of sites of metastatic disease,
• 18:41and if there was just a single site
• 18:44versus multiple sites in the Solitaire
• 18:46E or oligo metastatic setting,
• 18:48there was a suggestion,
• 18:50potentially of survival benefit
• 18:52and this is what they ended up
• 18:54presenting at San Antonio in 2013.
• 18:58This wasn't actually published
• 19:00until five or six years later,
• 19:02and we'll go over that.
• 19:03While the Tata group,
• 19:04you know,
• 19:05pretty rapidly published in Lancet on Koleji,
• 19:08so they had suggested the Atilius
• 19:10Group surrounds group in the Turkish
• 19:13Federation that there was no statistically
• 19:15difference or difference in overall
• 19:17survival survival in early follow-up.
• 19:20Potentially those with limited numbers
• 19:23of sites of metastatic disease,
• 19:25and I know that's of interest
• 19:27of people here at Yale and.
• 19:29Around the country of maybe not.
• 19:31Group behaves differently than
• 19:34others with metastatic breast cancer.
• 19:38These are the randomized trials
• 19:40that were or were underway,
• 19:43and their primary endpoints are either
• 19:45survival or time to progression.
• 19:47So we've seen what happened in India,
• 19:49what happened in Turkey?
• 19:50We're going to talk about the COG
• 19:53in the next one that will actually
• 19:55report out will be the Japanese
• 19:57jade COG 10710 seventeen trial.
• 20:00So this kind of circles back to you know.
• 20:03I think maybe if there's anyone who's in
• 20:05training that's watching is that you know,
• 20:07two decades ago I started as a
• 20:09fellow of SEMA Konzum and watched
• 20:11the work that she did in the central
• 20:13surgical challenging the standards
• 20:15of and providing local therapy.
• 20:17A suggestion that local therapy
• 20:19would be of survival.
• 20:20But then watching the retrospective data
• 20:23come out, then the prospective data,
• 20:25and then the usdata.
• 20:27So I was the KVB rap,
• 20:30which is now part of alliance.
• 20:32For E card 22108,
• 20:35this was presented at 2020 in San Antonio.
• 20:38The publication honestly will be coming out,
• 20:40hopefully in the next month,
• 20:41but until then you know it
• 20:45isn't published presented,
• 20:46but it will be published very soon,
• 20:49so we know that from the Tata Group
• 20:51that there was no survival with early
• 20:54local regional recurrence and then
• 20:56again I said that Alisa ran in 2018,
• 20:59presented that there was no
• 21:01difference also in.
• 21:03Come in local regional therapy in terms
• 21:06of survival but with longer follow-up.
• 21:09Their group actually suggested that
• 21:11there was an overall survival benefit.
• 21:13There is a lot of issues with
• 21:15this paper and publication and I,
• 21:18II and others wrote an editorial that
• 21:20was simultaneously published with this,
• 21:23but and we can discuss this in the
• 21:25in in the question answer session.
• 21:28But there was a suggestion that
• 21:29there was a survival benefit,
• 21:31so there's conflicting data equals 2108.
• 21:34Started in 2011 with its last
• 21:37patients enrolled in 2015 and
• 21:392013 because of slow accrual,
• 21:42they did amend their their overall
• 21:45goal and the and the randomization,
• 21:47but basically in EU,
• 21:49S or North America stage,
• 21:51four denovo breast cancer.
• 21:53Optimal systemic therapy including
• 21:55obviously anti her two therapy
• 21:57if there was no progression of
• 21:59distant disease followed by 4 to 8
• 22:02months of optimal systemic therapy.
• 22:03They either continued down
• 22:05the route of systemic.
• 22:06Therapy versus local early
• 22:08local regional therapy.
• 22:10And again, this is something that
• 22:12Doctor Khan focuses a lot on.
• 22:14Is the complete resection with free margins.
• 22:18Overall survival, just like I showed
• 22:20you with all the randomized trials.
• 22:22This is the breakdown in
• 22:25terms of the patient cohorts.
• 22:27For those that were registered,
• 22:29not randomized and randomized,
• 22:31again anti her two therapy was given
• 22:34when they were her two positive,
• 22:36certainly anti estrogen therapy
• 22:38when he R and or PR positive.
• 22:41Uhm, the dropout,
• 22:43which is really not surprising
• 22:45as those that had more,
• 22:47you know,
• 22:48advanced local disease was ended up
• 22:51being higher in the initial systemic
• 22:54therapy as opposed to or the group
• 22:57that was stable or responding.
• 22:59Uhm, median age a little bit
• 23:02younger than CMAS earlier study.
• 23:04Looking at,
• 23:05you know the NCDB database
• 23:07by about six or seven years.
• 23:09And then when you looked at
• 23:10those that were randomized,
• 23:11early local therapy 109 received surgery,
• 23:1687 achieved surgical free margins
• 23:19and and and local regional therapy
• 23:22was at 74 of those patients.
• 23:25The reasons why no surgery,
• 23:27some ended up refusing some progress,
• 23:30some was made by MD decision.
• 23:33Finally,
• 23:33we were able in the US to go back
• 23:36to what SEMA started in saying
• 23:38that there was a survival benefit.
• 23:40Now we come to the point of
• 23:42having randomized data from the
• 23:44US and suggested that there is no
• 23:46overall survival benefit for women
• 23:48with stage four breast cancer.
• 23:49This is with a median follow-up of
• 23:545353 months progression free survival.
• 23:57Similarly, no difference,
• 23:59something that you know we saw a
• 24:02suggestion of in the Tata Group.
• 24:05Is that potentially and there are
• 24:08certain subtypes of breast cancer that
• 24:10actually operating may actually be
• 24:12a more of a detriment to not operating,
• 24:15so it's not necessarily been equivalent,
• 24:16but potentially worse,
• 24:18and maybe that's seen in the
• 24:20triple negative breast cancer.
• 24:23One thing again that you know
• 24:25will be focused on a little bit
• 24:27in the paper is that there is
• 24:29some benefit in terms of local
• 24:31regional progression free survival.
• 24:33That's how useful that is of an
• 24:37endpoint is worth discussing.
• 24:40So kind of coming to conclusion is
• 24:42that early local therapy does not
• 24:45improve survival in patients with
• 24:47denovo metastatic breast cancer
• 24:49that there was actually a higher
• 24:52local regional progression when
• 24:54local regional therapy was used,
• 24:56the primary site. Again,
• 24:58there is a suggestion of progression free,
• 25:02you know, some local regional
• 25:05therapy response in the stage.
• 25:07Four breast cancer setting,
• 25:09and again the JAYCOB trial.
• 25:11Is still pending and at least in my,
• 25:14in my conclusions were that like in in
• 25:17almost two and a half decades, we went.
• 25:19The pendulum was swung from, you know,
• 25:22no surgery to surgery to maybe surgery or
• 25:25no surgery to hopefully now no surgery.
• 25:29You know, outside of palliation,
• 25:31although there is interest in,
• 25:34you know in the those with
• 25:36limited numbers of metastatic
• 25:37site or oligo metastatic disease.
• 25:39I don't think the randomized data from
• 25:41Tata or the Turkish group supports this
• 25:44and the card data that was presented
• 25:47ASCO doesn't support this either.
• 25:49Over the publication is still
• 25:50pending and once that's out then you
• 25:52guys can make your own judgment.
• 25:53So with that,
• 25:54I'd like to thank you for the provision
• 25:56of the podium and look forward to talking.
• 26:01Thank you very much, Mary.
• 26:03Uh, we have a few questions here,
• 26:07so for everyone, if you have questions,
• 26:09please post them in the chat.
• 26:11So let me read some of the questions here.
• 26:14A question from Doctor Caring, Addison.
• 26:19She points out that there is a
• 26:21national trend toward doing more
• 26:22local therapy for metastatic disease,
• 26:24which is calling a metastasis
• 26:27sectomy I guess.
• 26:29So, does this data provide some
• 26:30warning for adoption of this
• 26:32trend outside of research studies?
• 26:35Honestly, I think it it does,
• 26:37at least in breast cancer, that we really,
• 26:40you know, we may have an idea.
• 26:42We may have antidotes of when it works,
• 26:45and you know when you we looked
• 26:47at our data institutionally.
• 26:49Or many others did as well.
• 26:51You know you have to really be, you know.
• 26:55Careful for selection bias is
• 26:57that you know are unintended,
• 27:00but certainly part of this and I am really
• 27:02outside of the clinical trial or research.
• 27:05Sending as Doctor Edelson suggested.
• 27:08Really not a big fan of even
• 27:10certainly not local therapy,
• 27:12but even metastatic disease
• 27:14in that setting as well.
• 27:16And I know this is different than
• 27:18some other solid tumor types,
• 27:20but in the world of breast cancer,
• 27:23yeah, there was retrospective data.
• 27:25There was conflict on that,
• 27:26then we waited for prospective data.
• 27:28There was conflict on that on.
• 27:30Well it's not U S data or European data.
• 27:33Finally we get the usdata and we're,
• 27:35you know,
• 27:36on the border of getting the
• 27:39publication out on that as well.
• 27:41And then I thought.
• 27:43Another question from Doctor Peters.
• 27:46So did the EKACH trial allow
• 27:49any number of metastasis?
• 27:51It seems like the general
• 27:52thought was that this may be
• 27:54helpful in low volume disease, so
• 27:57it did allow for multiple
• 27:59sites of metastatic disease.
• 28:01I think the only real from what I
• 28:04remember and I actually enrolled a
• 28:06couple of patients to this trial.
• 28:09Patients that couldn't wear those with
• 28:12like leptomeningeal disease that were
• 28:14excluded and maybe a handful of others.
• 28:17And again, I think this points to the,
• 28:19you know is low volume or oligo metastatic
• 28:22disease different than those with
• 28:24higher volumes or burden of disease.
• 28:26And again a lot of people try to
• 28:28address those selection biases
• 28:30of like you know you know,
• 28:32is visceral Mets or lung Mets going to be
• 28:34different than soft tissue or bone Mets?
• 28:36I again outside of the research setting I am.
• 28:39Really cautious of this.
• 28:41I'm glad that in my two decades
• 28:44I've seen a a trend,
• 28:46hopefully away from from
• 28:47from local regional therapy.
• 28:50Thank you and Doctor David Rim.
• 28:54It's asking is it even possible to
• 28:57study cancer presented stage four,
• 28:59since in this modern era discovery
• 29:01of the cancer at stage 4 classifieds
• 29:03the patients as having received
• 29:05below is the standard of care.
• 29:09Any comment meaning
• 29:11maybe. I don't understand the question 100,
• 29:15so the. Bing diagnosis stage four is
• 29:19below the standard of care. Well, I mean,
• 29:21we're obviously in the United States I.
• 29:23I would say that you know,
• 29:24because we have such a well screened
• 29:26population that that number is
• 29:28relatively low, but it still is about,
• 29:30you know again, 4 to 6% depending
• 29:32on whether you look at Sierra,
• 29:33NCDB or whatever data set.
• 29:35But I really like thinking of things
• 29:38well outside of EU S borders and
• 29:40certainly in Sub Saharan Africa or
• 29:43Asia and many other parts of the world.
• 29:46You know there are a lot of women who
• 29:48are presenting with stage four breast
• 29:49cancer and are a lot more patients
• 29:52presenting with stage four breast cancer.
• 29:54And you know, should different
• 29:56options be considered in that setting?
• 29:59You know it was nice that at least and
• 30:01you know in the work on stage four,
• 30:03breast cancer and local regional therapy
• 30:06that we had counterparts in India in Turkey,
• 30:08in Japan and others that
• 30:10were looking at this.
• 30:11And it wasn't just run by EU
• 30:14S and Europeans in terms of.
• 30:16Helping us answer those questions.
• 30:19OK, and that well, how about the?
• 30:23Role of the Disney Cetera Ginnetti and
• 30:27the different phenotypes and molecular
• 30:30phenotypes and treatment available and how
• 30:33what does that do to despair? Diamond?
• 30:35In other words, I was wondering if you
• 30:38know if you have a great treatment,
• 30:40is it good to have surgery or not?
• 30:42Or maybe if you guys have a great
• 30:44treatment it doesn't matter? Yeah,
• 30:46so that's that's such a great question
• 30:48and you know you get those you know.
• 30:50You know, there's this young patient,
• 30:52you know she's got like.
• 30:54A couple of sites that maybe liver disease.
• 30:55You get anti her two therapy.
• 30:57Everything disappears.
• 30:58You know maybe she has a little bit
• 31:01of a lump or mass in the breast but
• 31:03you know you know you get the story.
• 31:05You know she has young kids
• 31:06and a family and you know,
• 31:07let's just, you know it's easy.
• 31:09Just take it out, you know I,
• 31:11I really think that's you know the you
• 31:14know she's going to likely do well anyways,
• 31:16whether I do the lumpectomy or mastectomy,
• 31:19remove the lymph nodes, yes or no.
• 31:21And again, there's this, you know, making.
• 31:24US or the patient feel better
• 31:27versus are we actually, you know,
• 31:30doing a benefit in terms of
• 31:31keeping them alive longer.
• 31:33And certainly you know,
• 31:34breast surgery may not be,
• 31:36you know, as morbid as you know,
• 31:37very large thoracic and
• 31:39intra abdominal surgeries,
• 31:40but you know in this society
• 31:42we put a lot of emphasis on on
• 31:44breasts in the breast cancer.
• 31:46And, you know, removal of the breast.
• 31:48And then the question becomes in the
• 31:50stage for setting if you do a mastectomy.
• 31:51How about doing reconstruction
• 31:52yes or no and kind of where?
• 31:54Where does that end?
• 31:55Or why don't you move the opposite?
• 31:57The rest as well, and you know,
• 31:58I've had those discussions
• 31:59time and time again,
• 32:00and you know,
• 32:01I would hope we're making some of these
• 32:03decisions based on data and the science,
• 32:05and not what like you know,
• 32:07feels good or or maybe the right
• 32:09thing to say at that moment.
• 32:11So I do think heterogeneity does
• 32:13make a difference,
• 32:14but I think it's probably
• 32:15going to do well regardless of
• 32:17what I do with my scalpel.
• 32:19Thank you and Doctor Lustberg is pointing
• 32:21out that they are very aggressive
• 32:23tumors that present biological stage
• 32:25for particularly in younger women.
• 32:27So it's not necessarily substandard care.
• 32:30This bad biology rim.
• 32:33That's great, that's a great comment.
• 32:35Yes, wonderful thank you so much.
• 32:37So I mean there's interest of time.
• 32:39We're going to move on to the
• 32:41next talk for the next talk.
• 32:44We have our very own doctor
• 32:47Anita Hutner Dr Hutner is an
• 32:49associate professor of pathology,
• 32:51who specialize in identifying
• 32:53diseases and cancers in the brain.
• 32:55She has received her medical degree from the
• 32:59University of Ehrlinger Nurburg in Germany.
• 33:01And a completely fellowship at Harvard
• 33:04Medical School at the Brig and and her
• 33:07residency here at the Ionia Haven Hospital.
• 33:09So in addition to her
• 33:12specialty in neuropathology,
• 33:13Dr Hutton has stated molecular
• 33:16diagnostic pathology,
• 33:17so in her research,
• 33:18Dr Hutner uses stem cells to try
• 33:20to recreate the brain disorders
• 33:22founding diseases like epilepsy and
• 33:24Alzheimer's disease and hopes to find
• 33:27better treatments for brain tumors.
• 33:28So today,
• 33:29Doctor Hutner will talk to
• 33:31us about a very important.
• 33:33Update in the WHL classification of
• 33:35brain tumors that will pretty much
• 33:38append the way we are calling these
• 33:40diseases and classifying disease and
• 33:42enrolling the patients in clinical trials.
• 33:45So we're very fortunate to have her
• 33:47here to educate us on that hardener.
• 33:52Thank you, Antonio.
• 33:53Thank you for this kind introduction.
• 33:56Thank you. It's a it's a real
• 33:58pleasure to be here and have the
• 34:00opportunity to share with you some
• 34:02insights into the upcoming 2021 W
• 34:062 classification of CNS tumors.
• 34:09It's now the 5th and I'll
• 34:12talk more about that.
• 34:15Uhm, in general, you might wonder, well,
• 34:18why shall we even deal with brain tumors?
• 34:21Yeah, they're relatively rare
• 34:23compared to other cancers,
• 34:26and when you look at the numbers in in
• 34:28a bit more detail, you realize that.
• 34:30Yes, well they are relatively
• 34:32rare compared to let's say breast,
• 34:35lung and other entities.
• 34:38UM, the outcome is rather devastating,
• 34:41so roughly estimated.
• 34:43We will find about 24,000
• 34:46patients with malignant glioma.
• 34:50The 85 year survival rate is rather low,
• 34:55it's 36% anti survivability
• 34:57rate for those two suffer.
• 35:00With a clear blastoma is really low,
• 35:03so it's it begs for innovation
• 35:06this entire field.
• 35:08The costs of treating patients
• 35:10with brain tumors or tremendous
• 35:13in in in simplified terms.
• 35:17But also we are illustrative,
• 35:18is this graph here.
• 35:20When you look at the survival rates,
• 35:23the five years or survival rates
• 35:25of children with leukemia.
• 35:27Right now, nine out of 10 surviving.
• 35:30Patients with breast cancer.
• 35:32Similarly,
• 35:32nine out of 10 survive when you
• 35:35look at patients with brain cancer.
• 35:37Now you're down to two per ten surviving.
• 35:41And then with glioblastoma,
• 35:43you're down to one pretend so you
• 35:46can see even in 2021 the field
• 35:50is begging for innovation and
• 35:53new approaches to handle this
• 35:56absolutely devastating disease.
• 35:59And so we this year there is a new W
• 36:02classification of brain tumors coming out,
• 36:07which is dramatically significantly
• 36:09different from before,
• 36:11and so I felt.
• 36:13Since we have a very large and active
• 36:15neuro clinical neuroscience community here,
• 36:17it would be good to discuss a few of
• 36:21those new changes because they will
• 36:24affect how we all practice and interact,
• 36:27and so for today I thought
• 36:29I'll show you a few.
• 36:31Some of the general changes
• 36:33and recommendations,
• 36:34then go into tumor specific
• 36:36changes and at the end I'd like
• 36:38to conclude with one of our own
• 36:41cases and methadone analysis.
• 36:43For brain tumors,
• 36:44which is now also recommended.
• 36:47And so.
• 36:47Why is it overall so important to
• 36:50accurately classify tumor samples well?
• 36:53The multiple aspects personalized,
• 36:57individualized patient care.
• 36:59It contributes to prognosis
• 37:02AIDS in therapeutic guidance.
• 37:04It's click current critical for
• 37:07clinical trial enrollment and
• 37:08also then we sent it for the
• 37:11interpretation of clinical trials data.
• 37:13The enrollment in experimental studies
• 37:15and here also data and analysis
• 37:19interpretation the evaluation of
• 37:22population based disease trends.
• 37:24Are aided by accurate classification
• 37:26system and also you know affected
• 37:29is allocation of resources by
• 37:31governments and health insurers
• 37:33to support health care and so.
• 37:36UW now publishes periodic revisions
• 37:40of tumor classifications,
• 37:42and these have therefore very diverse
• 37:44and important effects on many aspects
• 37:47actually of individual and population health,
• 37:50however,
• 37:51and David Luiz emphasize
• 37:52this at the last meeting.
• 37:54All classifications are somewhat imperfect.
• 37:59They are imperfect representations,
• 38:02and represent of.
• 38:04Come off in this state and
• 38:06the representative state of
• 38:08understanding at a particular time.
• 38:10And the interpretations.
• 38:12Of a limited number of experts and so.
• 38:17You see their limitations,
• 38:18their works in progress,
• 38:20yet they're still extremely needed.
• 38:26Just to shed light on the 5th.
• 38:28So the when you look at how
• 38:31the classification emerged,
• 38:32the first one was published in 17-9.
• 38:36The first edition then evolved over
• 38:38the years that the time gaps are
• 38:41at times quite considerable from
• 38:44the from 20 from 2007 to 2016 there
• 38:49was an almost 10 year time span,
• 38:52however the 2016.
• 38:54In addition, was a more or less a
• 38:58revised edition of the 4th edition,
• 39:01which received 2007 version,
• 39:03and here for the first time.
• 39:07Definitions were now based on
• 39:09the combination of morphologic
• 39:11and genetic characteristics.
• 39:13This was a huge shift in the field.
• 39:17And I feel that was celebrated by one.
• 39:21By some there's a paper in Kansas, L.
• 39:25Which caused the fall of the optical
• 39:28wall freedom from the tyranny of
• 39:30the microscope and the molecular
• 39:33changes stand could demonstrate this
• 39:37improves humor risk stratification.
• 39:41Uhm, the from 2016 to now to 2021.
• 39:46Again,
• 39:47you know time passed and but now with
• 39:52the advents in molecular technology.
• 39:55Information is gathered as lightspeed
• 39:58and so in order to bridge these gaps
• 40:03between WTO classifications, the.
• 40:07Consortium was formed.
• 40:09They see impact now consortium,
• 40:11which is a consortium to inform
• 40:14molecular and practical approaches
• 40:16to CNS tumor taxonomy.
• 40:18The goal here is to.
• 40:21Publish new developments in
• 40:24molecular diagnostics and inform
• 40:26the clinical world so this could
• 40:29be implemented along the way and
• 40:32there wouldn't be a long gap until
• 40:35new changes were implemented.
• 40:37If you wonder what the now stands for,
• 40:40it means not officially who,
• 40:42because this consortium was
• 40:44established in 2016 and basically
• 40:46the authors of all these C impact
• 40:48papers are also authors and editors
• 40:51of the new double classification.
• 40:53So it's a very.
• 40:54It's a very homogeneous group that works
• 40:56on this the the expert editorial group
• 41:00is composed of international group.
• 41:03Unfortunately the Blue Book
• 41:05is not yet published there.
• 41:07I was told by David Lewis there are
• 41:11production issues related to the pandemic.
• 41:14However,
• 41:15in the meantime I review paper,
• 41:19came out in neuro Oncology
• 41:21which is available and can be.
• 41:23Teen and so I quickly would like to go
• 41:26through a few general changes before I
• 41:28go into too much specific changes and.
• 41:33The significant change is really
• 41:37related to the report structure,
• 41:41and here we have now a so-called integrated
• 41:45histo molecular classification system.
• 41:49It's already in place at Yale,
• 41:51and this is what one of our reports looks
• 41:53like and so you have four layers there.
• 41:56Two is the histopathological diagnosis,
• 41:58which would be here.
• 41:59For example,
• 41:59glioblastoma layers 3 then defines the
• 42:04grade would be here for and then layer
• 42:084 forms the molecular information,
• 42:11which would be a list of molecular
• 42:14data here and in order to make sense
• 42:17out of this different components.
• 42:20A layer one is added which forms
• 42:24the integrated diagnosis and this
• 42:26is the combined tissue based
• 42:29histological and molecular diagnosis.
• 42:31And so this is continuously
• 42:33expanding with the addition of
• 42:35additional newer markers and the
• 42:37integrated diagnosis is really a
• 42:39collaborative, team based effort where we,
• 42:42as neuropathologists from surface as
• 42:45central role for the integration component.
• 42:49We closely work with neurosurgery,
• 42:51neurology, neuro oncology,
• 42:54genetics, and new radiology,
• 42:57and then integrate from
• 43:00this integrated diagnosis.
• 43:02Which then is used by neurooncology in
• 43:05radiation oncology foot for treatment.
• 43:08So it's a very intimately integrated process.
• 43:13A few words to just a few nomenclature
• 43:17issues, so when a diagnosis cannot
• 43:20be made and the term Nos is used,
• 43:25meaning non not otherwise specified,
• 43:27this just means that molecular
• 43:29information is not available and
• 43:31there could be multiple reasons
• 43:33it's either not available or not.
• 43:34The test was not performed or simply was
• 43:37not successful, whereas the NEC term.
• 43:42Not elsewhere classified,
• 43:44just indicates that the test
• 43:47was successfully performed.
• 43:48However, the test results simply
• 43:51do not fit into a known category,
• 43:55so further on.
• 43:57Now, in this new version,
• 43:59we're now distinguishing our
• 44:02grading from other classifications
• 44:04by adding the Hoos TNS grade,
• 44:07because this is meant to emphasize
• 44:10that the way the neuro Neuro.
• 44:13Who grades tumors is different from
• 44:15how it's done and you and your breast,
• 44:18for example.
• 44:20Further from the now we research,
• 44:24this might sound trivial using Arabic
• 44:27numerals instead of Roman numerals.
• 44:30And lastly,
• 44:31now is also grading within tumor types,
• 44:34and this is a bit more substantial.
• 44:36This is meant to provide more flexibility
• 44:39in using grade relative to tumor type.
• 44:42It should emphasize biological
• 44:44similarities within tumor types rather
• 44:47than just approximate clinical behavior,
• 44:49and it should.
• 44:50It conforms with who grading
• 44:52in non CNS tumor types.
• 44:53For example,
• 44:54we used to say astrocytoma IDH
• 44:58Mutant who's seen as great.
• 45:00Two or three or form when you have before,
• 45:05you could say, for example,
• 45:06I had a trim anaplastic
• 45:09astrocytoma who creates three.
• 45:11This is now obsolete.
• 45:13Now it's replaced and the
• 45:16nomenclature now would indicate
• 45:17that you have to say astrocytoma,
• 45:19IDH Mutant,
• 45:20who CNS great three.
• 45:23I think it will take a bit of time
• 45:25to get used to this overtime and the
• 45:28term glioblastoma now is exclusively.
• 45:31Served for the adult IDH wild type tumors,
• 45:35so the the stratification is really
• 45:39based on IDH status and so on.
• 45:43The humerus specific changes
• 45:44now go into this,
• 45:46so when you look at the 2016 WO list of
• 45:50tumors it has a wide range of entities.
• 45:53Terms like Mr Citic astrocytoma or here
• 45:56to use sarcoma epithelioid, do you blastoma?
• 46:00All these have been removed.
• 46:02Everything has been streamlined
• 46:05and reduced to three main groups,
• 46:08and these are the adult type diffuse gliomas,
• 46:11pediatric type diffuse, low grade glioma,
• 46:14Sandy Patrick type diffuse,
• 46:16high grade lumas.
• 46:18The pediatric type does not mean these
• 46:20are exclusively present in pediatric
• 46:22patients but they're often or more
• 46:25more readily seen in pediatric patients.
• 46:27We now when we look at this more
• 46:30closely so the astrocytoma now.
• 46:32We're talking now specifically
• 46:35about diffuse gliomas.
• 46:37There now is, it is the idea.
• 46:40Mutant status matters most,
• 46:42and the certification is based on
• 46:46astrocytoma IDH mutant and then the
• 46:49grading is based on grade 2-3 and
• 46:52four for the OLIGODENDROGLIOMAS.
• 46:54Again, IDH mutant status is very relevant.
• 46:58In addition to that,
• 47:00the 1P19 Q correlation status again,
• 47:04he DCNS grade goes up to two to three.
• 47:08And a glass stoma is exclusively
• 47:11reserved for IDH wild type tumors.
• 47:14And these are automatically
• 47:16who create 4 tumors.
• 47:17D pediatric type diffuse Low
• 47:20Bradley almost are now in.
• 47:23Now include diffuse astrocytomas
• 47:26with milk and milk LA mutations
• 47:30the angiocentric Luma.
• 47:33The polymorphous low grade
• 47:35neuroepithelial tumor of the young
• 47:37and then diffuse low grade lumas
• 47:39with MAP kinase alterations so you
• 47:41see it's very different group of
• 47:43tumors that's now front and center
• 47:45stage within a diffuse cleoma group,
• 47:48and then lastly high.
• 47:49Correctly,
• 47:50Omar Group includes H3K27 and altered 2 must,
• 47:56a new entity DH3G34 Mutant
• 47:59Group is now included.
• 48:02And also a new group deep diffuse
• 48:07pediatric type hydrate guma.
• 48:10Which is H3 wild type in wild type.
• 48:13Now with a high great great forward and
• 48:16nomenclature is part of it and then the
• 48:19last city infant type hemispherically
• 48:22Omaha for the adult type tumor tumors.
• 48:25There were also significant changes,
• 48:27so the diffusely infiltrative Astro
• 48:30City humor with an IDH mutation
• 48:34is morphologically in general well
• 48:37differentiated, lacks features of anaplasia.
• 48:39My target of activity is not detected
• 48:43or very low and what is absent and
• 48:46this is diagnostically relevant.
• 48:48Is microvascular proliferation and necrosis,
• 48:52and also there cannot be a city
• 48:55into a homozygous deletion?
• 48:57For the intermediate type here,
• 48:59formally called anaplastic as just cytoma,
• 49:02this is now the astrocytoma IDH
• 49:05mutant and now who CNS grade three.
• 49:09You have similar features except
• 49:11that now you find focalor dispersed.
• 49:14Anaplasia significant mitotic activity
• 49:17but still no faster proliferation,
• 49:20only crosses and no city can to a
• 49:24deletion rest for the highest grade now.
• 49:28Which is no longer called glioblastoma,
• 49:30but this is the astrocytoma IDH mutant.
• 49:35Suppose CNS great for you have features
• 49:39of a diffusely infiltrative Astro,
• 49:41static new class and with.
• 49:44And IDH mutation that exhibits
• 49:47also microvascular proliferation,
• 49:50necrosis,
• 49:50and in this case also sitting case
• 49:53IDK and to a homozygous deletion or
• 49:57any combination of these features.
• 49:59So overall. Do they drive home?
• 50:03Point is the diagnosis anaplastic
• 50:06astrocytoma IDH mutant and glioblastoma
• 50:09IDH mutant are no longer recommended
• 50:12and the city KN 2A and B homozygous
• 50:16deletions are molecular markers of whose
• 50:19in S grade 4 in an idea mutant astrocytoma.
• 50:25Uhm, the criteria for Clyde Blastoma now are
• 50:29limited to exclusively IDH wild type tumors.
• 50:34And here you find diffuse associated
• 50:38tumors with microvascular proliferation
• 50:40or in the past it used to be an end.
• 50:42Now it's just or you need
• 50:44one of those features,
• 50:45or you have a molecular defined tumor.
• 50:49Third promoter mutation,
• 50:51EGFR gene F receptor gene,
• 50:54and if.
• 50:55Amplification or plus 7 -- 10
• 50:58chromosome copy number changes.
• 51:02DIDID H1 type diffuse kioma with any of
• 51:05these features is called a glioblastoma.
• 51:07Who CNS Grade 4.
• 51:11So the question arises, how do you,
• 51:14you know, handle you plus two more now.
• 51:16So there are two options.
• 51:20And this is not necessarily trivial,
• 51:22so the case with diffuse kiyama without
• 51:26microvascular proliferation or necrosis.
• 51:28So without anaplastic features it is
• 51:31logically not really a hit glioblastoma,
• 51:35but it is a glioblastoma when it is IDH,
• 51:39wild type and displays each Fr amplification.
• 51:44Third promote imitation or plus 7 -- 10 E 10.
• 51:48Whereas when you have a true histological
• 51:51glioblastoma where you see morphologic
• 51:54features of anaplasia like Vasco preparation.
• 51:59Only crosses,
• 52:00it's not ugly blastoma.
• 52:02It's then a he still logically blows,
• 52:05not clear plus stoma with IDH
• 52:08mutation would then be an astrocytoma
• 52:11IDH mutant grade four so the
• 52:14term glioblastoma is not used its
• 52:17astrocytoma IDH mutant who created for.
• 52:22For the pediatric group, then we have
• 52:25the entities I already mentioned.
• 52:27I just wanted to point out the diffuse low
• 52:31grade leoma with the map kinase pathway
• 52:34alterations where you have several entities.
• 52:37Now within the FGF receptor category,
• 52:41where you have duplications mutations,
• 52:44be roughest involved or again into a D pad.
• 52:49Pediatric type diffuse tactically.
• 52:51Almost this is a relatively.
• 52:53Unusual entity in here.
• 52:55You have some involvement of
• 52:57PDGF receptor amplifications,
• 53:00or EGFR amplifications or milk.
• 53:05Others, when you then go beyond the
• 53:07diffuse gliomas, you look at Leo,
• 53:09neuronal, and neuronal tumors.
• 53:11I just want to point out there
• 53:13were few additional tumors added,
• 53:15like the high grade astrocytoma with
• 53:18pilot features within the glue,
• 53:20neuronal and neuronal tumors,
• 53:22and unusual tumor diffuse clonal
• 53:24tumor with oligo dentro cleoma like
• 53:26features and nuclear clusters.
• 53:28Myxoid Cleo neuronal tumors and the
• 53:32multinodular backlighting neuronal tumor.
• 53:34Uhm?
• 53:36Major changes were also seen
• 53:38added to the EPENDYMAL tumors.
• 53:40Appendable tumors are those with a
• 53:43relatively isomorphic appearance which
• 53:47form pseudorosettes around vasculature.
• 53:51They're linked to the ventricular
• 53:53system mostly,
• 53:54and so this was the original
• 53:57classification in 2016.
• 53:59Now this is abolished and the
• 54:02classification is now based on location
• 54:05Histology and genetic alterations.
• 54:08And here we have location based
• 54:12Supratentorial intro tutorial spinal and
• 54:15then lastly a few added two additional
• 54:18entities to MC so popular in Panama.
• 54:20And these soccer pending normal.
• 54:22And when we look at those.
• 54:24In in greater detail,
• 54:27the supratentorial ependymoma's used to
• 54:30be known with a real or fusion partner.
• 54:33This has been changed now the C 11 open
• 54:37reading frame 95 now is dedicated as
• 54:40CFTA and has multiple fusion partners.
• 54:43These are usually hemispheric extra
• 54:47ventricular tumors in adults and children,
• 54:51and another option is also.
• 54:54Yup, one fused to positive tumor.
• 54:58The interesting to introspect the
• 55:01info tutorial appending moments.
• 55:04Are the posterior fossa pantomima
• 55:06a Group A or B,
• 55:08and these are primarily in infants.
• 55:11Have an extremely poor prognosis.
• 55:13Unknown to have H3K27M metalation.
• 55:17Loss whereas here you have our attention
• 55:22of the HTK 27 M in the B once and
• 55:25they have a bit better prognosis.
• 55:27This panel Panama must show
• 55:30often mxi amplification.
• 55:32They are they're very malignant now.
• 55:36The mix of popular Panama was upgraded
• 55:38now to Grade 2 used to be grade one.
• 55:41There's no additional molecular
• 55:44data to change anything,
• 55:47and similarly for this update
• 55:49pending more marks stays the same,
• 55:51the embryonal tumors.
• 55:54I have seen also significant changes.
• 55:58These are as you can see in the image,
• 56:02very aggressive appearing blue cell
• 56:05tumors with high mitotic rate and here
• 56:09we have now molecular defined and
• 56:12histologically defined tumors in 2016.
• 56:15There were four.
• 56:17Subgroups and demolished the middle
• 56:21stomachs were stratified according
• 56:24to pathways which involved wind
• 56:27pathway Sonic hedgehog pathway and
• 56:30then non wind non Sonic hedgehog.
• 56:34The wind pathway.
• 56:37Middle of last time I had a
• 56:39relatively good prognosis,
• 56:40whereas the Sonic hedgehog
• 56:42activated ones with up TP with a
• 56:45P53 mutation in addition,
• 56:46had a very poor prognosis.
• 56:48Now in in 2021 the Sonic Hedgehog
• 56:53Pathway Group went from 2
• 56:55subgroups to four subgroups,
• 56:57so those on the editorial board that were
• 57:02splitters one rather than the lumpers,
• 57:05and so we have now more subgroups.
• 57:08Lastly, whenever you have MC involved or P53,
• 57:13these survival goes down the.
• 57:18The non wind non the groups
• 57:22three and four now went from.
• 57:26You know, to eight subgroups,
• 57:29which is now a significant
• 57:31almost hairsplitting.
• 57:35Attempt and you also have C or
• 57:37wherever you have mic involved.
• 57:39You have lower survival time.
• 57:41We will see whether this.
• 57:44Splitting major plus Thomas
• 57:46UP will hold over time.
• 57:49The molecular defined middle class Thomas,
• 57:53however, demonstrate distinct
• 57:55associations with morphologic patterns,
• 57:58and here for all wind tumors
• 58:00you see the classic type,
• 58:01which is a blue cell tumor.
• 58:04The Sonic Hedgehog group shows this
• 58:07decimal plastic nodular arrangement.
• 58:10And also you have a similar
• 58:13feature called in middle class.
• 58:15Tomorrow is extensive nodularity
• 58:17and the the group three and
• 58:20four are usually large cell,
• 58:22very anaplastic appearing middle blastomas.
• 58:26So for the middle class stoma.
• 58:27Overall it's more complex.
• 58:29Now it's more split.
• 58:33The tumor types I'm just pointing
• 58:36out a change in red in grading.
• 58:39Uhm, their overall to just
• 58:42summarize the 222 new entities.
• 58:46Within different subtypes,
• 58:47clue Mas que neuronal and ependymal.
• 58:50UM Brian has seen 4 sarcomas,
• 58:54so he added and there are several changes.
• 58:58I will not go through those just to see
• 59:02there is quite a bit of modification.
• 59:05Last feed I just wanted to make close with
• 59:08the case we had and we are out of time.
• 59:10Almost the methylome analysis
• 59:12for brain tumors.
• 59:14In 2018, this paper came out by
• 59:17the German group on David Capper,
• 59:20where Metalation based classification of
• 59:23central nervous system team was really dumb.
• 59:27Breakthrough in certain ways.
• 59:30The cancer methylome is really
• 59:32a combination of SOMATICALLY
• 59:34acquired in a metalation changes.
• 59:36And characteristics that reflect
• 59:38this cell of origin so you can
• 59:41trace the cell back to its origin.
• 59:44It also has been shown that this
• 59:46technology is highly robust and
• 59:48reproducible even when you use very
• 59:50small samples and you have only poor
• 59:53quality material and this profiles
• 59:55have been widely used to classify
• 59:57CNS tumors and this Disney plot here
• 01:00:00shows that there has been really a
• 01:00:03discovery of several new tumor entities.
• 01:00:06Secondly,
• 01:00:06it's very straightforward to use where
• 01:00:10you use a paraffin embedded section,
• 01:00:14microdissected,
• 01:00:14run the array,
• 01:00:16and then generate a report which
• 01:00:19is then based on this.
• 01:00:22And pattern here and the these
• 01:00:26new classification recommends
• 01:00:28DNA metalation studies done
• 01:00:32explicitly for several tumor types.
• 01:00:35For example,
• 01:00:35the pediatric high grade gliomas,
• 01:00:39the extra ventricular neurosci,
• 01:00:41Thomas Appending Momus,
• 01:00:42and also embryonal tumors.
• 01:00:44It's mandatory now for high grade
• 01:00:48astrocytomas with highlighted features,
• 01:00:50it's the only way to really
• 01:00:52diagnose this tumor.
• 01:00:53And for the diffuse general tumors with
• 01:00:56liquid entropy human like features,
• 01:00:58UM case election should follow cases
• 01:01:03with ambiguous tumor classification.
• 01:01:05Which are some I mentioned already.
• 01:01:08For example,
• 01:01:09in a young adult with a malignant
• 01:01:12IDH wild type glioma is suspicious.
• 01:01:15That should be looked at by methylome
• 01:01:19analysis diffuse wildtype lumas
• 01:01:21without necrosis and so forth.
• 01:01:24And brown tumors in general.
• 01:01:26Ependymoma as the higher grade
• 01:01:28many tumors will benefit from it,
• 01:01:30and patients with putative tumor syndromes.
• 01:01:33It also it aids in additional
• 01:01:36testing in complex cases,
• 01:01:38and there I wanted to briefly show
• 01:01:39one of the cases we had at Yale.
• 01:01:41We are metal lumen.
• 01:01:43Alesis actually resolved this case.
• 01:01:45So it was a 9 year old female
• 01:01:47with a very complex heterogeneous
• 01:01:50tumor with enhancement,
• 01:01:52cystic degeneration, midline shift.
• 01:01:56No one was sure was that this
• 01:01:58is on the benign side of things,
• 01:02:00or somewhat malignant and so
• 01:02:02biopsied and or a resection shows
• 01:02:05a very peculiar picture.
• 01:02:07Also,
• 01:02:07where we have fields with embryonal type
• 01:02:11morphology areas with pseudo rosette forming,
• 01:02:14this is almost Astro Astro blastoma
• 01:02:17like fields with sclerosis and there's
• 01:02:20more pleasure there is nothing.
• 01:02:22In our current WTO that would
• 01:02:26fit this features and so the the
• 01:02:30immunohistochemistry was not helpful
• 01:02:32at all. We ran I enormously wide
• 01:02:36piano or without any conclusion.
• 01:02:38UM, lastly sent it to end to end
• 01:02:44value for DNA metalation studies and
• 01:02:48here it came back to our surprise
• 01:02:52as a tumor which matches a neural
• 01:02:55epithelial tumor with Eminem,
• 01:02:58Eminem, one alteration.
• 01:02:59This was confirmed with a fish he choose.
• 01:03:04Helped us out and here we have
• 01:03:07now a probe that confirmed that
• 01:03:09the emanon arrangement is really,
• 01:03:13truly the driving factor here,
• 01:03:17and so the high grade new rapidly tumors
• 01:03:21M1 is defined as one rearrangement
• 01:03:24is a very new or relatively
• 01:03:27new entity recently described.
• 01:03:29It has several bank binding partners,
• 01:03:32including Band 2.
• 01:03:34Uhm it be metalation profiling shows it
• 01:03:38really splits off as a separate entity
• 01:03:43is distinctly different from others,
• 01:03:47so most of this high grades CNS.
• 01:03:50Peanuts are grouped clusters
• 01:03:52within the reference group.
• 01:03:55Here, 24% form 4 clusters,
• 01:03:58and the I mean one is one of them.
• 01:04:02And so in in general this.
• 01:04:05Worked a sort of false between Astroplus
• 01:04:09stoma, but also somewhat high grade.
• 01:04:12He was unsure morphologically
• 01:04:14what to do with it,
• 01:04:16but this now really helped us.
• 01:04:20You know,
• 01:04:21stratified this tumor,
• 01:04:22and so it was initially reported
• 01:04:25in in a minute you mop.
• 01:04:27In other tumors it has been seen in AML.
• 01:04:29It's actually it's improved survival,
• 01:04:33but I think there's not enough data to
• 01:04:37properly judge this rearrangement here.
• 01:04:39And so where do we go from here?
• 01:04:44Uhm,
• 01:04:44the goal is to build and expand
• 01:04:46on a molecular neuropathology
• 01:04:48service here at Yale.
• 01:04:50Embrace new developments.
• 01:04:54Embrace state of the art technology
• 01:04:57molecular markers and so forth
• 01:05:00to improve on the statistics.
• 01:05:02The image I showed you at the beginning
• 01:05:05of the talk and continue to work very
• 01:05:07closely with all our clinical partners.
• 01:05:09And here we are.
• 01:05:11I'd like to acknowledge and thank a wide
• 01:05:14range of colleagues from neurosurgery.
• 01:05:17Neurooncology my own group is
• 01:05:20fantastic group of neuropathologists
• 01:05:22Neuro radiology medical genetics.
• 01:05:24Molecular genetic pathology also again
• 01:05:27in my department radiation oncology
• 01:05:29and then many who work behind the
• 01:05:32scenes and help us along the way.
• 01:05:36And with that,
• 01:05:36thank you,
• 01:05:37I'm sorry I'll reign over.
• 01:05:41Thank you very much.
• 01:05:44Thank you very much. I need to.
• 01:05:46So I think we are running over time.
• 01:05:48So I think questions will need to
• 01:05:50be addressed through email to you.
• 01:05:52So I think this is fantastic and
• 01:05:56I think it is one more example of
• 01:05:58where the oncology field is heading.
• 01:06:00Usually bring tumors,
• 01:06:01lead the way in terms of
• 01:06:04incorporating molecular studies
• 01:06:06and then other diseases follow.
• 01:06:08So it seems like we're getting more
• 01:06:11complex and more sliced and if even.
• 01:06:14Rarer diseases so big challenges ahead,
• 01:06:19so thank everyone for attending and
• 01:06:21once again thank you for our wonderful
• 01:06:24speakers and I hope to see you next week.
• 01:06:27Our next grand rounds.
• 01:06:28Thank you very much.
• 01:06:30Bye bye.