Norbert & Suzanne Schnog Lecture/"The Evolving Landscape of Colorectal Cancer in 2022"

March 02, 2022

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Yale Cancer Center Grand Rounds | March 1, 2022

Presentation by: Dr. Cathy Eng

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00:0032 Cancer Center grain grand rounds.
00:03I'm making a guest appearance today
00:04and I can't say that it's wonderful
00:06to be a guest in introducing a very
00:09special speaker who is Doctor Kathy
00:11Yang and many of us know Doctor Ang
00:14who is very well known in the field of
00:18Colt GI Malignancies and Doctor Lang.
00:20Is the David Johnson chair and surgical
00:23and medical oncology, and she's Co.
00:25Leader of the GI Cancers research program.
00:28At Vanderbilt, she's also, I think Co.
00:30Director of the OR Director of the Young
00:33Adults Cancer Initiative and started at
00:35Vanderbilt about a couple years ago,
00:37so really has done phenomenally.
00:41Kathy received her MD from Hahnemann
00:43and then her residency in internal
00:45medicine at Russia and then did her
00:47fellowship in hematology oncology at
00:49the University of Chicago and then
00:51spent majority of her life at MD.
00:54Anderson focused on what is close to,
00:57I think several of our hearts in
00:58in focused on colorectal cancers,
01:00GI cancers and translational research and
01:03what impact can we do in in those fields.
01:07She also played important roles in
01:09faculty governance. I was excited to see.
01:11Kathy ticker roll in as in the
01:14faculty Senate,
01:15which often is an important piece
01:16and then move to Vanderbilt in 2019.
01:19Her interest has been in clinical
01:21trials and how can we define novel
01:24drugs for treatment of these cancers.
01:26And as I mentioned,
01:28is also beyond focus on the young adult
01:30colorectal cancer patients has also
01:32focused on role of immunotherapy in HP.
01:35Associated Cancers has published many,
01:37many papers on these fields
01:39and has led many trials.
01:41I'm not going to enumerate.
01:42All of the her leadership roles in
01:45the various national societies in
01:47ASCO ASCO GI E Cog and see I most
01:51recently that rang was chosen as the
01:53Vice chair of the swag GI Committee
01:56and NCI GI Steering Committee and also
01:58has focused on workforce shortages.
02:00So overall,
02:01what I would describe as not only
02:03a talented clinician,
02:04but also thinking about our field
02:06and oncology and the broader things
02:08that guide us.
02:09So really looking forward to her
02:12presentation today. Welcome, Kathy.
02:13You're only sorry this is virtual.
02:16Well, thank you so much and let me go
02:20ahead and share my screen. And. Sorry.
02:35OK, did did it come across OK?
02:38Perfect so today is March 1st,
02:41so it's colorectal Cancer Awareness Month,
02:43so I am delighted to participate in
02:47this session with all of you today.
02:49With so many familiar faces and
02:52thank you so much for inviting me.
02:55So we'll just be touching up on kind of the
02:59general field regarding colorectal cancer,
03:01since it seems appropriate for March
03:04colorectal Cancer Awareness Month.
03:06And these are the topics we'll be discussing.
03:12And these are my disclosures.
03:15So friendly reminder for those
03:17that are don't treat colorectal
03:19cancer in a regular basis.
03:21It is expected in 2022 that 151,000
03:24individuals will be diagnosed with
03:26this disease and about 45 thousand
03:28of those will be rectal carcinoma.
03:30It still remains the second leading
03:31cause of cancer death for men and
03:33women combined and the meeting age.
03:34As many of you are aware is
03:36usually in the late 60s,
03:37but I'm going to be touching upon
03:39that because of my own interest in
03:41early onset colorectal cancer and
03:43for as long as I've been in practice.
03:46Unfortunately,
03:46the five year survival for our stage
03:49four patient population has basically
03:51only changed from about 13 to 14%,
03:53and it looks closer now to 15%.
03:56Based upon these numbers.
04:01Friendly reminder as well for
04:02the majority of our patients.
04:04Unfortunately they do not have an
04:07inherited form of colorectal cancer
04:09such as Lynch syndrome or FAP.
04:11In the majority of cases are
04:13going to be sporadic and that's
04:16why this is very difficult.
04:19Cancer for us to tackle because I
04:22believe it's largely multifactorial.
04:24I'm not going to be touching
04:26upon the very basic information
04:27regarding chemotherapy because
04:29most of the literature nowadays
04:31is about molecular subsets,
04:33and I'll touch upon the more recent
04:35data on some of those subsets.
04:37But for us for any stage
04:404 surgically unresectable,
04:41patient or patient that is going
04:43to receive neoadjuvant therapy
04:45with metastatic disease prior
04:47to surgical resection,
04:48we often consider the use of systemic
04:50chemotherapy and the most common regimens,
04:52as many of you are familiar with.
04:54May include folfox or folfiri
04:55with the consideration of a
04:57targeted agents such as berbasis,
04:59ma'am or anti EGFR therapy
05:01such as PM AB or C tax map.
05:05If the patient is rest wild type.
05:07If the patients treatment naive if
05:09they don't have a right sided tumor,
05:11we may want to consider anti EGFR therapy,
05:13although that is not my personal preference.
05:15I tend to reserve it for further
05:18down the line and then full Fox
05:20Erie for a patient that is well
05:23with good performance status.
05:24Fair reasonable file with the high
05:26response rate of 65 to 78% and then
05:28of course we have our oral agents
05:30regorafenib and lonsurf that are
05:32currently FDA approved as single
05:35agents in the refractory setting
05:36and then last but not least,
05:38the rare subtypes currently.
05:40Our median survival for all stage four
05:43patients is roughly 32 to 34 months
05:45for the general patient population,
05:47but once again,
05:48right sided tumors do not appear
05:50to fear as well in regards
05:52to overall survival for our.
05:54Either Rasputin patients and
05:56then our right side of patients.
05:59And these are the molecular subsets that
06:02we've largely been focused on recently.
06:05Queiroz is the most common mutations.
06:07Majority of our patients,
06:08but we do like to take into account other
06:11rare RASK mutations such as N Rasen d'etre,
06:14and then we do have some
06:16other rare mutations,
06:16including MSI high,
06:18which will be discussing the BRAF mutation,
06:20which is less than 10% of our
06:23patient population with V600E.
06:24PIK 3 CA is being investigated,
06:27as in clinical trials and then.
06:30And then there's the end track fusion,
06:31which I will not be touching upon,
06:33because that's extremely rare
06:34and have yet to see a patient
06:36with the interact fusion.
06:38But I'm always curious when people tell
06:40me they've had one occasional patient,
06:42and that's less than 1% of all patients.
06:46So for all of our patients
06:48with metastatic disease,
06:49I'm going to be focusing on that in large
06:51part for this talk and then touching
06:53upon a little bit on early stage,
06:55colon and rectal if brief time.
06:57But next generation sequencing is extremely
06:59important for our patient population,
07:01and identifying once again those
07:03mutations that I mentioned.
07:05And these are some of the
07:07aspects will be touching upon.
07:08Once again, MSI Grass B RAF
07:11and her two amplification.
07:16For MSI high colorectal carcinoma patients,
07:19which represent less than 10%
07:20of our patient population.
07:23This is one of the most important
07:25studies to date for MSI high patients,
07:27and I'm sure many of you are familiar with
07:30the role of pembrolizumab in treatment.
07:33Naive MSI high colorectal carcinoma patients.
07:36This was basically a one to one
07:38randomization that has since been
07:40updated in regards to overall survival
07:43compared to standard chemotherapy,
07:45and in this case was two primary endpoints,
07:47PFS and OS, and the results were extremely
07:51impressive when they were originally.
07:54Presented and eventually published.
07:55And this is looking at the progression free
07:58survival for our MSI high treatment naive
08:01patients when receiving Pember Lizum app.
08:03This is single agent pembrolizumab.
08:05Now you may say that there's a crossover
08:08in about 1/3 of patients in those that
08:10did receive Pember Lizum app at 1st and
08:12did not appear to benefit from this drug.
08:14And unfortunately we don't have the exact
08:16etiology to account for this right now.
08:18But as you can see here,
08:19the PFS was twice as high for
08:22that versus standard chemotherapy
08:24for the majority of patients.
08:27And the OS has also been determined
08:30to be of significance in the sense
08:33that there was crossover loud.
08:35Once again, this is a Co primary endpoint,
08:37so 60% of patients were allowed to
08:40crossover to receive IO therapy,
08:42and so that that is obviously an issue when
08:44I'm looking at your statistical significance.
08:47The prespecified P value
08:49was supposed to be 0.0246,
08:51so they did not meet its pre
08:54specified value for OS,
08:56however.
08:56Obviously I would say we can clearly see
09:00that there was crossover 60% of patients,
09:02and that's likely accounted for
09:04this and also keeping in mind this
09:06is really considered the standard
09:08of care for these patients.
09:09Now what is the other 1/3 of patients that
09:12do not appear to benefit from IO therapy?
09:15Once again,
09:16we still have yet to understand why that is,
09:19and obviously it does bring to mind
09:21that is there a potential benefit for
09:24the consideration of chemotherapy,
09:25plus IO therapy?
09:27And that is an ongoing trial by the way.
09:31Looking at response rate,
09:32you can see here 44% versus 33% for
09:36pembrolizumab versus standard chemotherapy.
09:39But what is of great interest?
09:41I think for many of us is the fact
09:43that there may be some potential
09:45benefit for combination therapy.
09:47Now this is a single ARM study,
09:48Checkmate 142 looking at Nebo plus iffy.
09:53It was part of a large study
09:56that we're not comparative arms,
09:59but looking at various cohorts,
10:00and this was in the treatment
10:02naive setting here,
10:03primary endpoint was response and this was
10:06published by Heinz Josef Lenz last fall,
10:10and I told you the response rate was
10:1244% for single agent pembrolizumab.
10:14Keeping in mind this is once
10:15again a small study, 45 patients.
10:17This is not a phase three,
10:19but the response rate was 69% and
10:22as you can see across the board.
10:24Quite impressive response rates and they
10:27reported that the 24 month of OS was 79%,
10:31so it's actually quite impressive
10:33and obviously I think many of us
10:35look forward to learning more about
10:36the benefit of combination therapy
10:38and see if it is truly superior.
10:40But once again, Pember Lizum app has
10:43demonstrated this in a phase three trial.
10:46What are the ongoing trials?
10:48So there is a stage three trials called
10:52Atomic, which is folfox plus or minus 8 SO.
10:55And then, as I mentioned before,
10:56there is a combo study that
10:57was very slow to enrollment.
10:59Hopefully will it will finish
11:00enrollment at some point called commit.
11:02Looking at Folfox plus Bev.
11:04And then it has,
11:05oh there is a Merc platform study
11:07that is also new and ongoing as well.
11:10And in rectal cancer there's actually
11:12some very intriguing data regarding
11:13MSI high and that was just reported.
11:15So we'll touch upon that.
11:18So obviously the results from Pember
11:20Lism AB are quite impressive and
11:23and there was another pilot trial
11:25called the Niche trial looking at a
11:27very very small number of MSI high
11:29patients and looking at the role
11:31MSI and MSI stable patients looking
11:33at the role new Advent IO therapy
11:35in that setting and they noticed
11:37there was some significant benefit.
11:39So why not consider that in an MSI
11:42high rectal patient population
11:43and this trial was actually just
11:46presented by Doctor Loomis who is a.
11:48Fellow at Memorial Sloan Kettering under
11:51the guidance of my friend Andrea Sirsak.
11:54They're looking at the star lamat,
11:56so here locally advanced MSI high
11:58rectal cancer stage two stage three.
12:01They gave six months of Dystar lemon
12:03and then they wanted to look at
12:06basically their response by endoscopy
12:08as well as by imaging and the
12:11primary end point here is response.
12:12Now be results from this trial were
12:15so impressive that they decided to go
12:17ahead and provide the presentation on
12:19the 1st 11 out of 16 patients enrolled.
12:22The total number of patients expect.
12:25Roll and roll in. This trial is 30 patients.
12:28And here is what they call clinical
12:30complete response.
12:30Once again is the endoscopic CR
12:33plus the radiographic CR and they
12:36required all patients to have an MRI.
12:38And this was the patient population.
12:40Just to give you an idea real quick,
12:41I'm just going to touch up on the key points.
12:43A lot of patients were T3T4 a lot
12:46of patients were node positive.
12:47These were MSI high,
12:50but all were BRAF wild type.
12:53And this is the very early results.
12:55We do not have long term results,
12:57just early results of the 1st 11
12:59patients out of the 16 enrolled this
13:01far and they reported a complete CR.
13:04And in this study in fact they omitted
13:06the consideration of radiation and surgery.
13:08So do keep that in mind in this
13:11patient population.
13:12Obviously single institution study
13:14we need more follow up and I'd
13:16like to see this data validated
13:18now in Full disclosure.
13:19Kristen See Amber who I'm helping to mentor
13:21and I worked with her extensively on this.
13:23Protocol we had actually created this
13:27national trial supported by Ekaki,
13:29a 2201 looking at New Advent Niveau
13:32EP also in the MSI high patient
13:34population with the consideration of
13:36five by five radiation therapy and then
13:40also the consideration of sphincter
13:42preservation here primary endpoint was
13:44Patsy R because the findings from Asco
13:47GI from Doctor Loomis this trial is
13:49going to undergo some rapid amendment
13:52to maybe allow the consideration.
13:55Of not necessarily requiring 5 by 5
13:58radiation therapy unless there's bulky
14:01tumor and adenopathy and obviously
14:03once again it's very interesting
14:04'cause we actually recommended the
14:06consideration of making sphincter
14:08preservation as a primary endpoint.
14:10But when we originally wrote this trial,
14:12we were told that that was being too
14:14progressive and here we are today
14:16trying to amend this trial to keep up.
14:17But once again,
14:18this is a national trial and we
14:20will remain open and we hope to
14:22enroll these patients once again.
14:24Pilot study of roughly.
14:2631 patients as well.
14:29What about our Brafman patients?
14:31Well,
14:31for our MSI stable be wrapping in patients,
14:34it's very poor prognostic
14:36factor for these patients.
14:38It's less than 9% of our patient population.
14:40Unlike Melanoma,
14:41single agent Byref inhibitors
14:43have not been impressive with
14:45response rate of less than 5%,
14:46and we noted that there were basically
14:49escape mechanisms in colorectal cancer in
14:52comparison to the success that was seen
14:54in Melanoma with standard chemotherapy,
14:56the median overall survival
14:58is only 12 to 14 months.
15:00And So what can we do?
15:01How can we basically not only
15:03utilize our B RAF inhibitors?
15:06But how can we also consideration
15:08other downstream impact?
15:09And so here we have the combination.
15:12Basically with Ralph,
15:13Egypt are and then there was an
15:15attempt in combination with Mac.
15:17This was the B control,
15:19so the B control had a triplet versus the
15:22doublet versus standard chemotherapy.
15:24For patients that have received at
15:26least one prior line of therapy
15:28for B RAF meeting V.
15:30600.
15:30Mutation and the doublet was determined
15:32to be just as successful as the triplet,
15:35and this was FDA approved.
15:37This is the regimen called B raft OD,
15:40and it resulted in OS of nine point 3
15:42months versus standard chemotherapy.
15:44Now what's really interesting is
15:46they decided to examine that regimen
15:48because it seemed to be the most
15:49successful and try to move it up
15:51front to the treatment naive setting.
15:52And this is the anchor trial which was
15:55reported at ESMO and I show it here.
15:56'cause this has since been updated as well.
15:59At ESMO last year.
16:00And they reported a response rate
16:03of about 50%.
16:04However, the PFS was only about four months,
16:07and so that was clearly not a home
16:10run for a treatment naive patient.
16:13So at this year's Oscar GI just
16:15a couple weeks ago, Dan Morris,
16:17so I'm so very proud of.
16:18From MD Anderson has completed this
16:21pilot trial at MD Anderson looking at
16:23end crafted and so text amount so the
16:26beer F to V but in combination with
16:28immune checkpoint inhibition with
16:30nivolumab in this setting and this is
16:32in previously treated patients and the
16:34reason for that is because there appears
16:36to be a higher immune activation and
16:38higher team be in this patient population.
16:41And as you know some of the
16:42B RAF subtypes actually.
16:44Are very similar to this one.
16:46So more likely to respond to IO therapy,
16:49single institution study, small numbers,
16:51important to keep in mind.
16:54And here's the primary endpoint response,
16:56and these were the doses that
16:57were provided to these patients.
16:58Keeping in mind these patients need a
17:01better option as they just showed you,
17:03they don't do well with standard
17:05chemotherapy therapy,
17:05and even with RAF target therapy,
17:09they still need a better response.
17:12So once again,
17:14single institution very thought provoking.
17:17They report a response rate 50%
17:19so not much higher than what was
17:21already reported in the prior study.
17:23However,
17:23the PFS was a little bit higher at 7.4
17:26months, and the OS was 15.1 months.
17:29This is after a medium fault time
17:31of 16 months.
17:32Now these results were impressive
17:34enough that now this is going to
17:37be a national trial swab 2107 with
17:39a 2 to one randomization of the
17:42addition of BIOTHERAPY.
17:43At a study less than 75 patients,
17:46this should be opening up.
17:47This is March,
17:48so it should be opening up at
17:50the latter part of April and we
17:52are excited about this trial.
17:53It allows one to two prior lines of therapy,
17:56so that's in your previously
17:58treated brip patients.
17:59If you have any patient
18:01starting in the next two months,
18:02please consider this trial when
18:04it is open at time to activate
18:06it at your institution.
18:07Now there is a phase three trial
18:10that is ongoing for these patients
18:12and I also want to highlight this
18:15because it is the only phase three
18:17trial in treatment naive patients.
18:19So this is a one to one to one
18:25randomization of basically beer after V.
18:27So end carafe,
18:28and if the BRAF inhibitor plus the
18:30text map or that same combination
18:33be wrapped heavy plus folfox,
18:35they've actually decided not
18:36to proceed with full fury.
18:37That was part of the run in phase
18:39and so does now with Folfox.
18:41This phase three arm just opened
18:43about two weeks ago and then the
18:46control arm is standard chemotherapy,
18:48so this trial is largely being run
18:50in Europe and they're about 9 sites.
18:52The last time I checked in the United States,
18:54we are one of the sites that
18:55are participating in this trial.
18:56Once again,
18:57we really need to find an option
18:59for these patients with very
19:01poor prognosis otherwise,
19:02so please consider enrollment to this trial.
19:07I wanted to just briefly touch upon her too,
19:09'cause there's a lot of interest and direct.
19:11Can I know that many of you are
19:13familiar with direct can because it is
19:15proved in gastric and breast cancer,
19:17but her two positivity is extremely
19:20rare in colorectal cancer,
19:22unlike a gastric and breast cancer,
19:24it's about 4% of our patients,
19:27and once again it is required to be 3 plus
19:30by IHC or fish amplified and IHC 2 plus.
19:34So ongoing studies that I will
19:35not be touching upon 'cause they.
19:37Finished enrollment,
19:38but have not yet been reported yet.
19:40There's swag 1613,
19:41which is treasure map plus produce
19:43a map versus standard chemotherapy
19:46in the previously treated setting,
19:48and then the Mountaineer study was
19:50to catnip plus restitution amount.
19:53Now I'll just be touching on destiny
19:55because this was a recently updated as well.
19:58So Destiny is looking at an antibody
20:01drug conjugate,
20:02which is direct can and this trial
20:04it was extremely interesting for
20:06many of us in colorectal cancer
20:08because it's number one.
20:09It's a different type of drug and
20:11#2 they allowed patients that have
20:14had prior anti her two therapy.
20:16You'll see here they provided the
20:186.4 milligram per kilogram dose and I
20:20mention that because there's a second
20:22study that is also testing the dose.
20:23Currently that is open and this is
20:26at Q three weeks you'll see cohort.
20:29Today is your IHC 3 plus patient
20:32population or your fish positive
20:34cohort B is I see two plus and the
20:37cohort C is IHC one plus primary
20:40endpoint was response.
20:41'cause keeping in mind these
20:43are small patient population.
20:46And here focusing on Cohort 8,
20:48that's really where your focus should be.
20:5153 patients of those 53 patients,
20:5424 had a response,
20:55and these were heavily pretreated patients.
20:58If I recall correctly,
20:59the median line of therapies was free and
21:02and basically the response rate was 45%.
21:05So once again it can be provided
21:07to a patient.
21:09That's her two positive that
21:11that is naive to trust its map,
21:13or it can be provided to a patient that has.
21:16Had progression of disease which
21:18has treasuries map and this could
21:20be an option now very similar to
21:22the studies in breast and gastric.
21:24There is a known toxicity as
21:26many of you are aware,
21:27with interstitial lung disease,
21:28which is in less than 10%
21:30of the patient population,
21:31but something important to keep in mind.
21:35And then it wanted to touch upon Cara.
21:38So Karas mutation for us in colorectal cancer
21:43has been one of the most common mutations.
21:47Especially when you take into
21:49account your standard crass.
21:50But then you also have your address
21:51and then rest. Which means all
21:53these patients do not benefit.
21:55So that's about 30 to 60% of patients
21:57do not benefit from anti EGFR therapy.
21:59And then recently there's been some
22:02interest looking at drugs that
22:04are specific to the Cross G 12.
22:06The mutation now keeping in
22:07mind this is very, very rare.
22:09In colorectal cancer it's
22:11less than 5% of our patients,
22:13but it is a potential option
22:15now this has been reported,
22:18you probably seen the data already with long,
22:20much more impressive with lung and colon.
22:23Not so impressive as a single agent.
22:27Basically the response rate was
22:28about a little less than 10% and
22:31this was just published recently.
22:33So Teresa is the drug.
22:37Progression free survival was four months.
22:39The medium fall was after this.
22:41After meeting followed 11 months,
22:42the 12 month PFS was only 11% and
22:45now there are obviously looking
22:47at this drug in combination.
22:50So I I look forward to seeing
22:52some of that data.
22:54But I just want to show this,
22:55although not specific to colorectal cancer.
22:58Once again,
22:58this is at aggressive from another
23:01competing company and I wanted to show
23:04this because it was very impressive
23:06in regards to pancreatic cancer.
23:08Once again, the very small numbers,
23:10so I always.
23:11I'm always very hesitant when
23:13I see very early data.
23:15But basically to focus on the
23:18GI patient population and they
23:20reported that there was basically
23:22a response attend in 10 patients.
23:25Five out of those ten had a
23:27response with pancreatic cancer,
23:28which is unheard of as many
23:30can guess because once again,
23:32pancreatic cancer is still remains
23:34a challenge,
23:35and we don't have a lot of novel agents.
23:38This is once again G12C,
23:40which is not the most common RASC
23:42mutation in pancreatic cancer,
23:44but once again could be.
23:45Potentially beneficial,
23:46and then they are looking at it.
23:48Other malignancies very similar
23:49so that to the soeder as they are
23:52looking at it in combination as well.
23:55So just intriguing data from
23:56this year's Oscar GI.
24:00I did want to focus on the role of
24:03circulating tumor DNA, just very briefly,
24:05because there are two ongoing
24:07trials and early stage disease,
24:09and then there was this trial
24:11that was just presented at Asco
24:13GI from the Japanese group.
24:15Doctor Katata called Circulate Japan
24:17and I thought that this was a very very,
24:21very important study that should
24:24receive attention because it
24:26looked at basically all stages.
24:29Colon rectal cancer resectable stage
24:33four they basically obtained pre-op
24:35circulating tumor DNA using the
24:37signature platform and then they
24:39followed the patients at four weeks,
24:4112 weeks, 24 and 36 weeks,
24:43and so they provided their data
24:46regarding the 1st 1000 plus patients
24:47that have been enrolled this far in
24:50this trial and they've compiled it
24:51based upon these three ongoing studies.
24:53As you can see here.
24:56Like Vega Galaxy and Altair.
25:01And what it really shows basically where
25:04we think the field is obviously going.
25:07Here we have some information for
25:09stage one through stage four and and
25:11as you can see here at the disease
25:13free survival if you're circulating
25:15tumor and DNA remain negative with
25:18dramatically different from if you
25:20remained positive and this is at post-op
25:23when compared to baseline at 4 weeks.
25:27And then they continued to look
25:30at their sequential circulating
25:31tumor DNA at 4 weeks and 12 weeks.
25:33And as you can see here,
25:34obviously if it remain negative,
25:36that's a very positive benefit in
25:38regards to disease free survival.
25:40But if you went from negative to
25:42positive that changed your disease
25:43free survival from 98% to 63%.
25:46If you went from positive to negative,
25:49let's say with attachment chemotherapy
25:51that improved your disease free survival
25:53but positive to positive obviously
25:54was not a good prognostic indicator.
25:59And this is looking at the role
26:01of adjuvant chemotherapy here.
26:02If you have a positive circulating tumor DNA,
26:04so very intriguing data,
26:06and probably the largest data to date.
26:09So it's it's just important to note.
26:11And once again the purpose of this
26:13lecture today is kind of give you
26:15an idea of the existing interest
26:16on many of the studies that are
26:18ongoing in colorectal cancer,
26:20so I apologize I missed.
26:26I apologize. There it is.
26:29OK, I was on the right track.
26:30I thought I didn't include this slide so
26:32currently and as many of you that know me,
26:35I'm heavily involved in the NC
26:38cooperative groups with swag and ACOG,
26:40and especially with my role now on
26:42the GI Steering Committee and very
26:44supportive of cooperative group trials.
26:47So this is the COBRA trial looking
26:49specifically at stage 2 colon cancer.
26:51As many of you know,
26:52for stage 2 colon cancer,
26:54as long as I was in fellowship till now,
26:57it's always been a discussion with
26:58the patient about the role of.
26:59Management chemotherapy 'cause it's
27:01never been really well defined and has
27:04not been statistically significant
27:05thus far in any prospective trials.
27:07So here can you utilize the role of
27:10circulating tumor DNA and take some
27:12of this new science so they're using
27:15the Guardian platform and apply it?
27:17And so this is being led by Van Morris,
27:20who I mentioned to you earlier
27:22is running the be raft trial,
27:24looking at patients that are either
27:26just going to receive standard
27:28care with active surveillance.
27:29Or they have their circulating tumor DNA if
27:32there's no circulating tumor DNA detected,
27:35they just go on standard surveillance.
27:38If it is positive,
27:39then they will receive full Fox Orc
27:41pox and so this trial is ongoing.
27:43So if you have stage two,
27:46play patients with colon carcinoma,
27:48please consider enrolling to this trial.
27:52There's also the circulate US study,
27:54which will be led by Chris Lu
27:55and Arvind Dasari.
27:56Once again,
27:56my very close colleagues and I've
27:58had the pleasure of working with them
28:00and mentoring them over the years.
28:02And and now they have their own trial
28:05as well. For stage three patients.
28:08And here if you're circulating
28:09tumor DNA is detected,
28:11you would be randomized to folfox
28:13Erie versus standard capox or folfox.
28:16So this trial should open up any day.
28:18It's had an amendment even before
28:20it was opened,
28:20and that's resulted in a delay in.
28:22About a year.
28:25And other ongoing trial.
28:27So in Full disclosure I am the
28:30one of the national pies here in
28:32the United States. For fresco.
28:332 I just wanted to make sure to keep
28:36this on your radar because this trial
28:38has completed enrollment and well,
28:40hopefully we'll get some information
28:42regarding the results at some point soon,
28:44so we can determine if there
28:46is a benefit from this agent.
28:47This is an anti veg F agent as well and
28:51it was compared to placebo in patients
28:53that have been previously treated with.
28:56All standard chemotherapy,
28:57and they may have received
28:59regorafenib or lawn service,
29:00or the combination.
29:01Sorry,
29:02but exposed to both of them in the past,
29:04so it allowed all patients to participate in
29:07the reason I also wanted to demonstrate this.
29:11Show this to you is because in enrolled very
29:14quickly earlier than the expected time frame,
29:16and that's because it was such an unmet
29:19need for our pretreated metastatic
29:22colorectal carcinoma patients.
29:24There is only one phase,
29:26three ongoing trial at this time,
29:28which is an international trial.
29:30It's leap.
29:31It's based upon this very small
29:33study of originally 30 patients.
29:35They have this small phase two study of
29:3830 patients and they've now expanded it.
29:40Based upon these results.
29:41As you can see here,
29:43basically 22% with a short PFS of 2.3
29:46months and they've created this phase
29:49three trial that is ongoing looking
29:51at live at net plus pembrolizumab.
29:54So I'm trying to identify another
29:56potential option for patients and then
29:59then patients will be considered compared.
30:01Sorry to the standard of care
30:03of regorafenib or lawn service,
30:04so this is the only ongoing
30:06phase three trial.
30:07Currently enrolling and I'm sure it
30:09will also finish enrolling quickly.
30:11Hope I believe there's and hopefully
30:14another couple of other trials
30:16that are going to be open soon,
30:19but currently when I last checked,
30:21these were the only activated trials.
30:24And I wanted to touch on rectal cancer,
30:27'cause I think it's really important for
30:29people to see where the field is going
30:31and so traditionally for rectal cancer,
30:35we had always provided neoadjuvant
30:37chemotherapy with five,
30:38a few based treatment,
30:40and then proceeded to surgical
30:42resection with the Tammy and then
30:44followed by Advent chemotherapy.
30:46Whether it's five,
30:47a few based or oxaliplatin based,
30:49but the reality was that a fair number
30:52of patients were never receiving.
30:54Our Advent chemotherapy,
30:56either due to delays from surgical
30:59resection due to toxicities or wound
31:01healing issues or just lack of compliance
31:05in regards to their actual treatment.
31:08So what can we do to change this
31:10aspect and in Europe they just
31:11started looking at the sequence
31:13and then in the United States.
31:15We have followed suit and now it's
31:17called total neoadjuvant therapy.
31:18If you could potentially
31:20provide all your treatment,
31:21chemotherapy and your
31:23chemo radiation therapy.
31:24Up front before consideration of
31:26surgical resection or the reverse
31:29sequence where it chemo radiation
31:31therapy followed by chemotherapy,
31:33but I wanted to touch upon
31:35this trial because it's
31:36important that I do want to mention this
31:38and the other reason is that obviously,
31:41radiation therapy has known
31:43toxicities and for our patients.
31:46This is obviously an issue that
31:47we do want to take into account,
31:48so is there a way to reduce our
31:51toxicities and is there a way potentially
31:54to even avoid surgical resection?
31:56So this is Angelita Habr Gama,
31:59who at leave is in her late
32:0180s at at this point,
32:03and when she originally published
32:06on the consideration of just
32:09observing by close surveillance,
32:12those patients that had had a
32:14significant response to their treatment
32:17instead of proceeding with TMA,
32:19can you watch and wait?
32:21Basically do a watch and wait approach
32:23and watch them conservatively and when
32:25she originally brought up this concept?
32:27She herself as a surgeon.
32:28People thought there was this
32:30was this could not be possible.
32:32This data was not real.
32:35Why would a surgeon not offer a patient
32:38surgical resection with rectal cancer?
32:40And in fact, she appears to have caught up.
32:43Obviously she was way ahead of her
32:45time once again for this amazing idea.
32:47So now we have some very interesting data
32:51from the Memorial Sloan Kettering Group.
32:53They created the Oprah trial,
32:56the Oprah trial was a. Phase two study.
32:58I don't want to emphasize.
33:00This needs to be validated.
33:02This is a phase two study done
33:04that was completed at select sites.
33:06I think about 15 to 18 sites
33:09in low lying rectal tumors.
33:11Providing the patients either chemo
33:14radiation therapy followed by chemotherapy
33:17or induction chemotherapy followed
33:19by chemoradiation therapy and the
33:22patients were evaluated by endoscopy and MRI.
33:25If they had no complete response.
33:28Then they went on to total
33:31misso rectal excision,
33:32or they had clinical response.
33:35You could undergo watch and wait approach.
33:39And here you can see regardless of
33:41the sequence that you received,
33:43there was equivalent disease free survival.
33:46But he also noted, was those patients
33:49once again low lying tumors.
33:52Stage tumors stage three.
33:54If you received chemo radiation
33:56therapy first then followed by
33:59chemotherapy for systemic therapy,
34:01these patients appear to be more
34:03likely to have sphincter preservation
34:05and were more likely to undergo a
34:07watch and wait approach because
34:09of their degree of response.
34:11Now this is phase two.
34:13It is being.
34:16Expanded more, not the exact same way,
34:20but it is going to be a phase
34:22three trial led by Josh Smith.
34:24Also for Morris Sloan Kettering.
34:25For consideration of this watch
34:28and wait approach and once again
34:31we need to validate the data.
34:34Now they did update their
34:35data just so you are aware.
34:38At last year's ASCO and here's
34:40pictures of clinical complete
34:42response near complete response and
34:44incomplete complete response and the
34:46time frame of which they assessed.
34:48When the response.
34:49Sorry of the degree of response,
34:50was roughly 7 to 8 weeks.
34:53And here you can see when
34:55looking at organ preservation,
34:57obviously those that had a political
34:59complete response at three years
35:01that was 78% versus a near complete
35:04response at three years was 45%.
35:07So obviously there was possible there's
35:10possibility of a watch and wait
35:12approach for some of your patients.
35:14Whenever we have this opportunity,
35:16we review it with both our
35:18radiation oncologists,
35:19our surgical oncologists and our
35:20medical oncologists and really make
35:22this a multidisciplinary approach.
35:23Then discuss it at our
35:25multidisciplinary tumor board,
35:26and I obviously encourage
35:27everyone else to do the same.
35:29So very intriguing.
35:30Obviously we look forward
35:31to the phase three trial.
35:35And last but not least,
35:37I do want to touch pad on something
35:39very dear to me or early onset
35:41colorectal cancer patients,
35:42so this data is not new data.
35:44This is looking at the senior
35:47database from 1975 to 2010.
35:48It was originally published by
35:50Christina Bailey, who is actually
35:51now my colleague here at Vanderbilt.
35:53She wrote this when she was
35:54a fellow at MD Anderson,
35:55and as you can see here.
35:59As you can see here, there is an
36:02expected increase over the next decade
36:04for our young patients in Blues,
36:0620 to 34 years of age and
36:08red is 35 to 49 years of age.
36:11I'm sorry somebody has the wrong number.
36:13I apologize and rectal cancer also
36:16is supposed to be increased by the
36:20year 2030 by 124% in the very young.
36:22The 20 to 34 year age group.
36:27This obviously was recognized
36:29by patient advocates,
36:30patients and their providers as well,
36:32and this resulted in a change and
36:34I think as many of you are aware
36:37by the US preventive taskforce
36:39to reduce our screening age from
36:4150 years old to 45 years old,
36:43and so this is a new recommendation.
36:45Obviously if the patient is having symptoms
36:47and it's younger than 45 years of age,
36:50we would encourage screening immediately.
36:54But this is an issue you can see here.
36:57Trends in the United States looking at 2001
36:59through 2005 versus a decade later on.
37:02And you can see there's an increased
37:04incidence of young onset colorectal cancer,
37:06and especially in those states
37:08with higher incidence of obesity.
37:12This actually has been demonstrated
37:14as well in the nurses health study.
37:16Looking at your current BMI and
37:18your risk of colorectal cancer.
37:21And there's also been some interesting
37:22data looking at the role of
37:24antibiotic use and exposure and how
37:25it may impact the microbiome.
37:27This is one of roughly about three to four
37:30studies that have been published as of late.
37:32So intriguing data.
37:33Once again,
37:34we don't know the exact
37:36reason why our young adults,
37:37who the majority of them,
37:39have spontaneous colorectal cancer.
37:41They do not have Lynch syndrome or developing
37:44colorectal cancer at such an early age.
37:47So we had the honor of publishing a
37:50picture paper recently in Lansing
37:53Oncology looking at how to create
37:55a framework for these patients.
37:57As many of you know,
37:57I'm I've created this young Adult
38:00Cancer Center here at our institution,
38:02which is not just for colorectal
38:04cancer patients.
38:05It's for all young adult cancer
38:07patients between the ages of 20 and 45,
38:09and these are some of the aspects
38:10you really need to think about
38:12when you're seeing these patients.
38:13Fertility financial guidance,
38:15physical wealth beating being.
38:17Sorry.
38:19But other concerns obviously
38:22regarding job security,
38:25body image and just the fear of not
38:29knowing exactly how best to address this,
38:31because these individuals are very
38:33young and they're going through
38:35a very different aspect of their
38:38life versus our older median age
38:40patient of 67 years old.
38:41In addition, we you know,
38:44as you can guess,
38:45these patients face other concerns,
38:47especially regarding financial
38:48toxicities and and the the pressure
38:51that they feel because some of them
38:54obviously are still working and
38:56don't have financial independency.
38:59They're not financially independent,
39:01but they don't have to worry
39:03about the cost of care,
39:04and so these are important things
39:06to take into account for our
39:08young adult patient population.
39:09So here are my Co directors.
39:11I just wanted to highlight that
39:12Michael Byrne and Libby Davis.
39:14Michael Byrne is BMT,
39:16and Libby Davis in sarcoma.
39:18And this is just the information on
39:20our program and we're very grateful to
39:22have many involved in our group and
39:25provide resources for our patients.
39:26And this was actually one of my patients.
39:29She was 32.
39:32And you know,
39:32I love it when people say,
39:33well, you look too healthy.
39:34You can't have colorectal cancer.
39:36Well, she was training for a
39:38marathon and she was in great
39:40health but had bowel issues,
39:42probably for about 8 months.
39:44They kept in telling her
39:46that she had irritable bowel
39:48disease or it was hemorrhoids,
39:50or it's from her marathon training.
39:53And when I saw her she had about 50 to
39:5760% of her liver involved with tumor.
39:59Unfortunately, she as you can see here.
40:02She fought for with her basically
40:05was amazing individual thought
40:08her colorectal cancer.
40:11Lived with it for about five years
40:14and unfortunately passed away
40:16the latter part of last year,
40:17but during her time she made a
40:19huge effort to serve an advocacy
40:21groups and became a national patient
40:23advocate for the fight colorectal
40:25cancer program and that was actually
40:27a picture of her in Times Square and
40:30she used to run regularly these 5K
40:33events with her friends walk run.
40:36So in closing points,
40:37Please remember screening starts
40:39at the age of 45.
40:41Please continue to educate others
40:42about the signs and symptoms of
40:44colorectal cancer and recognize
40:45that these patients may need to be
40:47screened earlier than 45 if they have
40:49these symptoms that do not resolve,
40:51recognize the unmet needs are so
40:54psychosocial needs of our patients.
40:56Currently,
40:56most of the advances in colorectal
40:58cancer have largely been made in
41:01the rare molecular subtypes and
41:02for the majority of our patients.
41:04We still need novel agents
41:05and unfortunately for us.
41:06Colorectal cancer IO therapy has
41:08had limited efficacy excluding
41:10in MSI high patients.
41:12Next generation sequencing is always
41:13the standard of care for our patients,
41:15and I always,
41:16always,
41:16always try to enroll to a clinical trial
41:18whenever possible so we can obviously
41:21make greater treatment advances.
41:22So thank you so much for your
41:24attention and I would be happy
41:26to take any questions.
41:30Kathy, that was great.
41:31I didn't talk to you fast.
41:33No no, no no. It was perfect and
41:36it was incredibly informative
41:38and really just wonderful.
41:40I think Nita may have the first question.
41:48Thank you Kathy, and thanks Eric.
41:50I ask Doctor Wyner,
41:52mentioned really informative and and
41:54taking us through where the field is.
41:57Perhaps my first question to you is
41:59more around rectal cancer management.
42:02And as you mentioned,
42:03at the end of the hammer,
42:05gamedata and watchful waiting and I
42:08think the early trial on neoadjuvant.
42:10I think part of the worry there is are you?
42:12How are you all accounting in this
42:14you know is around this field where
42:17there's not only a biological?
42:18Implications, but.
42:20Quality of life implications.
42:22That is, do you miss the window on a
42:25curative approach without an ostomy and
42:27and and I wonder if that was considered,
42:30especially in that first trial,
42:31which I thought was.
42:34Interesting that people at
42:35Memorial agree to do that to
42:37put in Check Point early on.
42:39And because you may lose a window and I
42:41wonder where you think the field is on that.
42:43And then I have a bigger question.
42:45Perhaps around colon cancer,
42:47I think because number one in rectal cancer,
42:51you know as as I showed you,
42:53the incidence is expected to be
42:55quite higher over the next decade,
42:57especially for our young patients.
42:59So from my own personal experience,
43:02when I'm seeing these patients a lot of
43:04them are willing to take that risk because
43:06especially if they have a low lying tumor,
43:09they don't want to consider an APR,
43:12and so they're willing to consider that risk
43:15as long as they're being followed closely,
43:18and many of them are extremely compliant,
43:20then in that setting.
43:21So I think that in that case,
43:23as long as they have a good relationship
43:25with their surgical oncologist and
43:28medical oncologist, I think it's
43:30very reasonable to consider it in.
43:31In that setting, you know.
43:32Obviously what I didn't show you is that.
43:34No one really looked at the role of
43:36circulating tumor DNA in this setting, right?
43:38But in the phase three trial, that's I.
43:41I don't know, I presume won't be
43:43open for another 8 to 10 months.
43:45I hope they will also take that into account,
43:48and I think other trials are also
43:49trying to take that into account.
43:51And obviously 'cause that could impact
43:53our surveillance period as well.
43:55But I agree with you,
43:56you know,
43:57recurrent rectal cancer is one of the
43:59most challenging cancers because of the
44:02quality of life on patients because.
44:05Lost largely the involvement of the sacrum,
44:08when they have recurrent disease
44:10in the pain that means do.
44:12But I I it's very interesting when you talk
44:14to the national patient advocacy groups,
44:17you know,
44:17once you get a large number
44:19of them are younger patients,
44:20they are more than willing to take
44:22that risk to avoid the potential
44:24issues with bowel bowel issues to avoid
44:27even radiation therapy in the setting
44:29of the MSI high patient population
44:32because of toxicities as well.
44:34So they're really looking at quality of life.
44:37The majority of them,
44:38no,
44:38I think
44:39they're the ones that are low and you
44:41can avoid a stoma. They'll do it.
44:42I think the ones where the worry
44:44is is it's perhaps an LAR.
44:45And now you're dooming them
44:47to a recurrence and Eric will
44:49remember this in the late 90s.
44:51We were doing local excisions for T2T3,
44:53and then they were coming back with a APR.
44:56So I think that that perhaps is the part.
45:00That, I think would be a concern,
45:02and I think Brazilian data they
45:04follow their patients really closely,
45:06whereas we're not as as a
45:08coordinated system in America.
45:11And and you have a very valid point,
45:12but but patients are really motivated.
45:17Can I ask just a little question before
45:19you get to your big question needed?
45:20And my little question is.
45:23How do you you know?
45:24So I understand you follow people closely,
45:27but. How do you follow people closely?
45:31I mean you can't.
45:32You can't be biasing multiple
45:34little areas all the time,
45:36so you're following people closely with just,
45:40you know, some sort of scoping.
45:43You know, a low scoping procedure,
45:45correct? We kind of followed
45:46at our institution.
45:47We kind of followed the memorial
45:50data and have also done the
45:53regular intervals with endoscopy.
45:55Testing as well as diagnostic
45:58imaging with MRI.
46:00Yes Nita yeah no. I think
46:03Eric you hit the knee.
46:03I think who is examining
46:05and do they pay attention?
46:06I think that's the set.
46:07The second question perhaps is
46:09similar now that you know if you're
46:11looking at breast and standardization,
46:13I'd still sense that even though colorectal
46:16cancer is one of our most common cancers,
46:18there remains a gap in standardized
46:21testing and you just showed U.S.
46:23data of the 1% rule, right?
46:25The one person you know,
46:26the 3% hurt to the MSI.
46:28And how do we sort of work in
46:31national agencies in your role in?
46:33Starting to think about cancer and what
46:35should be the major things we test.
46:37I I still think it's a Wild West out there.
46:40If we ignore some of the top
46:42institutions you know when you
46:43get to the rest of the country
46:44I I would say that.
46:46From my experience thus far,
46:48I would say the majority of people
46:50do get tested for obviously rash.
46:52That has been the most common thing which,
46:53which obviously is extremely important.
46:55So then they can avoid
46:57anti EGFR therapy there.
46:58I fully agree with you though there
47:01are patients that still come to me
47:03that have never had the raft testing,
47:05which obviously is extremely important.
47:06They've never had MSI testing and
47:09you know I fully agree with you.
47:11I would just say that in every
47:14single lecture we give every single.
47:17Bit of publications that we can provide
47:19to individuals to educate others.
47:22We have to encourage that all patients need
47:25to be tested for molecular marker analysis.
47:28I mean, that is critical to their
47:31overall treatment and and you know
47:34it's it's so interesting when bearoff.
47:37So when Scott Kopetz originally
47:40talked about testing for BRAF,
47:42everybody thought he was crazy because
47:44it was such a rare patient population.
47:47And how we're going to get people to do that,
47:49but it's really as you know,
47:51it's a matter of education.
47:53And now it's it's.
47:54It's for the majority people.
47:56It is considered a standard of care.
47:57I would say a large number
47:59of people test for it now,
48:00but her two is still.
48:02It's still, you know,
48:03we're trying to get there,
48:05but her two is not commonly tested for,
48:08and Kathy does that affect treatment
48:10for stage one and stage two disease no?
48:13So, I mean, you're really talking
48:15about more advanced disease.
48:16We're testing is really.
48:17Critical, correct?
48:18Although obviously for MSI high we
48:21would encourage it in all stages.
48:23Yes, for largely metastatic
48:25disease 'cause we have not found
48:27benefit of these other targeted
48:29agents in early stage disease.
48:32We've tried.
48:34With anti EGFR therapy,
48:36we've tried with anti VEGF
48:38therapy and stage three,
48:40which was they were
48:41not successful studies.
48:43OK, so I'm going to ask a question.
48:47That you know, sort of a like big
48:50question about the future or the present.
48:53But if you had could do anything.
48:57And the goal is to reduce colon cancer
49:01deaths in the United States and beyond.
49:03And you have two interventions
49:06that you could use.
49:08What would you do?
49:10Two interventions or two interventions
49:12or two two? You know?
49:14What are the unmet needs so
49:16the two biggest unmet needs
49:18for colorectal cancer in 2022?
49:21I would say, well, the the number
49:23one needs still remains screening.
49:25I mean, in all fairness, we are still
49:27under screening in the United States.
49:30It's still I think it's like 78 percent is
49:33the best so so many people are being missed.
49:36And just because they don't
49:38want to be screened. Number 20.
49:41If I could do something
49:44and make it effective,
49:46I wish we could find some way to make IO
49:49therapy helpful in the majority of her MSI.
49:52Stable colorectal cancer patients.
49:54We appear to be at a standstill in regards
49:59to any potential combination thus far.
50:02It you know it has.
50:04It's worked well in other malignancies.
50:06Obviously, Upper GI, HTC Cholangio,
50:11and here we are still nowhere with it,
50:13really.
50:13In colorectal cancer,
50:14except the less than 5% with MSI HIGH.
50:17But screening I would rather prevent the
50:20colorectal cancer and not have to treat it.
50:23That would be my number one
50:24thing which I know sounds odd
50:25coming as a medical oncologist.
50:29Well look look, we all want to put
50:31ourselves out of work eventually
50:33and to what extent do health care
50:35disparities lay in tech excess
50:37debts in colorectal cancer?
50:41So obviously this isn't.
50:43This is an issue as you
50:46know in our clinical trials.
50:48As like many other clinical trials,
50:50especially though in colorectal cancer,
50:53the majority of patients that enroll in
50:55clinical trials are not our average patients,
50:5895% are of their Caucasian or white,
51:02and the majority of patients do not
51:04participate in clinical trials.
51:06I wish I could.
51:07So if the number if I could ask,
51:08have a number three, I would get,
51:10I would get more people to appreciate
51:13the importance of clinical trials
51:16and to help with enrollment,
51:17and allow us to be able to provide.
51:19The standard treatment arm in the
51:21community you know and and that
51:24way will help with enrollment,
51:25so that would be my number three thing,
51:27but in regards to diversity we are
51:31lacking in clinical trials completely,
51:34and a large number of the obviously
51:36the datasets that exist.
51:37So I love Andrea sirsak.
51:39She's a friend of mine memorial,
51:40but she just published a big publication
51:42looking at mutations at Memorial.
51:44It's one of the largest data sets,
51:46but yet 95% of her patients.
51:50Or white,
51:50and so it's not representative
51:52of the actual community.
51:53Nothing against her.
51:54It's the data she has,
51:55but that's the patient population
51:57that they have at Memorial.
52:00The problem, so we have a kitten
52:02question from Mary Kate Kelly,
52:03and that question is,
52:04there's a low fat diet or a
52:07vegetarian diet help decrease
52:08the chance of colorectal cancer.
52:11I would say definitely does not hurt.
52:13There's a lot of literature
52:15going back and forth.
52:17We're going in the diet.
52:17I think the majority of studies have shown.
52:20Obviously your tendency to
52:22obesity is is more of a concern.
52:27There was also a very very nice publication
52:29just recently from my colleague here,
52:31Martha Shrubsall and epidemiology looking at.
52:36Poly phenols, I believe.
52:39And the increased risk actually
52:42in the black patient population
52:45which was published just recently.
52:48And a related question just came in,
52:52which is in patients who
52:53have had colorectal cancer,
52:55and they say to you,
52:57what can I do to prevent a recurrence?
52:59Are there any data that would
53:02support lifestyle interventions
53:04such as exercise, diet,
53:06any any other sort of
53:09nutritional supplements,
53:11and finally, aspirin.
53:13Right, so there is data regarding aspirin
53:17that appears to be more beneficial in
53:20the PIK 3 CA mutation patient which
53:24is about 15 to 20% of our patients.
53:26Better baby aspirin seems to be fairly
53:29benign and potentially helpful.
53:30And then Jeff Meyer Heart has published
53:33before on the role of exercise as well.
53:36I would say all good healthy eating
53:39patterns and exercise obviously can't harm
53:42you and I would highly recommend them.
53:45And then there's been some.
53:48I would say those those the majority
53:50of the data.
53:53Alright, well, and and any data on vitamin D
53:59that is an ongoing trial being led
54:02by Kim Eing I think it is called
54:05forgot the name of the trial.
54:06I apologize, it is being run through the
54:09alliance and so they are looking at that.
54:12Alright, well I think that I think everyone
54:15got a tremendous amount out of this.
54:17Thank you so much for joining us all,
54:19be it from a distance we we look forward
54:22to having you here in person at some time.
54:25And please please give our best to all
54:28our friends at Vanderbilt and we really
54:31enjoyed having you thank you so much.
54:32Thank you so much. It's been my pleasure.
54:34It's been great thanks. Have a great day.