Therapeutic Advances

May 27, 2021

May 27, 2021 | Drs. Mehra Golshan, Michael DiGiovanna, Andrea Silber, and Dr. Maryam Lustberg

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00:00GAIL breast cancer CME series.
00:03Really excited and fortunate to have
00:06three phenomenal speakers in our medical
00:10oncology colleagues in this session.
00:13We're going to first start off
00:16with Doctor Maryam Lustberg,
00:18who is our incoming breast program director,
00:22packing her bags,
00:23and on our way from Ohio State to Yale
00:26in the in the next couple of weeks,
00:28she's going to be talking about a really,
00:31really interesting area area
00:33just so much excitement,
00:35change and controversy on when do we
00:38deescalate and when do we escalate
00:41for breast oncology therapies?
00:43Then we'll go to.
00:45Doctor Michael D.
00:46Geovanna is going to be discussing
00:48recent advances in systemic
00:50therapy for breast cancer,
00:51and you know each year whether it's at ASCO,
00:54ESMO or San Antonio.
00:55There's so many really exciting
00:57developments in drug therapy that
01:00come out and it'll be great to to
01:03hear about those and certainly last
01:06but not least is Doctor Andrea Silber
01:09discussing really super important topic
01:11of breast cancer epidemiology in 2021.
01:14Risk factors,
01:16and specifically in our vulnerable
01:19population.
01:20We're going to leave some time at
01:22the end to answer any questions,
01:24but please feel free to put in
01:27questions either into the chat box
01:29or to the question and answer box.
01:31It will try to answer some of those
01:34in real time and then at the end
01:36leave time for some discussion
01:38with our three esteemed colleagues.
01:41And with that,
01:42I'd like to turn the podium
01:44over to Doctor Doctor, Maryam,
01:46Lustberg, Deescalation,
01:47and escalation of breast cancer therapy.
01:50Current status.
01:50Thank you doctor Lester.
01:53Thank you Doctor Gosain and thank you
01:56to the participants for joining today.
01:59I'll start with sharing with you
02:01patient perspectives on the escalation
02:04of medical oncology therapies.
02:06This was a recent publication where
02:09patients and advocates were engaged on
02:12what they thought about the escalation
02:15trials and what were their some of their
02:19perceived barriers and facilitators.
02:21And in these discussions,
02:24it's interesting that up too close
02:26to half of patients expressed.
02:29Some unwillingness to participate in
02:31a deescalation medical oncology trial
02:34and some of it was actually centered
02:36around terminology they actually did
02:38not like the term deescalation and the
02:41most preferred terminology was actually
02:43the lowest effective chemotherapy goes.
02:46Listed here are some of the facilitators
02:50that patients expressed and a lot
02:52of this centered around the hope
02:54that deescalated therapy would
02:56have less physical side effects,
02:58less impact on day-to-day life,
03:01and less out of pocket expenses.
03:04The biggest barriers were related to
03:06fear that the cancer would come back,
03:08or that they would have decision,
03:10regret, and so this.
03:11These data highlight the importance of
03:14good patient and provider communication.
03:17Other standards continue to change,
03:19and breast cancer,
03:21and as we have mounting evidence
03:24for better deescalated therapies.
03:27Thankfully, due to ongoing clinical trials,
03:31so I will highlight in the next few
03:34slides some of the the the the the
03:36latest advances in the escalation
03:38in medical oncology.
03:40There are so many that I won't be
03:42able to highlight all of them but
03:44to to recap our goals and medical
03:46oncology and the escalation.
03:48The calls aren't you reduced
03:50chemotherapy use while still having
03:52the most effective regiment.
03:54Making regiments better tolerated,
03:55both acute and long term stamping
03:58therapies that are not shown to
04:01be effective in reducing costs.
04:03So starting with your positive disease.
04:06Most of you are familiar with the Taylor
04:09R ask RX perspective study using the
04:1221 gene expression assay or Oncotype DX.
04:16Which should that?
04:20Most patients with low required scores.
04:23There really was no improvement in
04:26outcomes by the addition of chemotherapy
04:28to standard of care and open therapy,
04:31and this has of course changed
04:34our standard of care care and has
04:38significantly reduced chemotherapy
04:40use in ER positive breast cancer.
04:44Going on to just kind of delving
04:46into the data a little bit more,
04:48the benefits of D escalation in the
04:52younger cohort where a little less clear
04:56based on the Taylor Taylor RX study Hall,
04:59and I think we can see here in those.
05:04In those patients who are 50 or younger
05:08between the required scores of 16 to 25.
05:11What the data was showing is that
05:13there was a lower at that rate do
05:16too with chemotherapy when it,
05:18when it preceded undergone therapy.
05:20So is this what is what is leading
05:24to this better outcome and this is
05:26continues to be widely debated.
05:28Is it ovarian suppression,
05:29effect of chemotherapy,
05:30or is it actually the cytotoxic
05:34effects of chemotherapy,
05:35and several models have been proposed and
05:39several perspective studies are.
05:41And to answer this question and
05:44different medical oncologists have
05:46very strong opinions about this
05:49that I'm sure you've heard about.
05:52So what about the escalation
05:54in ER positive node,
05:55positive disease and there is
05:58on your study was reported out
06:01in in the last San Antonio.
06:04And as you can see in this schema,
06:07those patients with up to three
06:10positive nodes with the crime scores
06:12of 0 to 25 were randomized to standard
06:15of care which was chemotherapy.
06:17Plus under compare P versus
06:20Anderson therapy alone.
06:21Those with high recurrence
06:23scores actually came up study.
06:25Receive standard of care chemotherapy.
06:28Close to 5000 patients were enrolled.
06:30And as you can see,
06:32there was no significant difference in
06:34invasive disease free survival with
06:37additional chemotherapy for those
06:38with requests for between zero to 25.
06:41After immediate follow up of five years,
06:43so this is obviously practice changing and.
06:49A wonderful set of data for us
06:51to reassure our patients with not
06:54positive disease with favorable
06:57features on gentleman profiling.
06:59But again, similar to the Taylor RX study,
07:03how we approach the younger cohort of
07:06patients is a little less clear in
07:10the in the study that premenopausal
07:13cohort appeared to have significant
07:16difference in outcomes when
07:18chemotherapy was used.
07:19And again whether this was due to the
07:23chemotherapy affect or to the effect
07:25of ovarian suppression from chemotherapy.
07:28These data are not going to
07:30answer that specific question.
07:31Although,
07:32interestingly,
07:32when we actually look at the
07:34type of endocrine therapy that
07:35was used in this study,
07:37only 16% and then they can therapy,
07:39arm actually had a variance.
07:40Regression therapy administered
07:42and only 3% in the chemotherapy
07:46arm had a variance oppression.
07:48Straight so so where do we go from here?
07:51How do we synthesize these data
07:53and how do we?
07:54How do we approach that younger
07:57patients with no positive disease?
07:59And I think the data are
08:02continuing to evolve,
08:03and it's important to also highlight
08:05some new data that represented
08:07also in the last time Junior
08:09breast meeting by Nadia Harbucks,
08:11Group of the ADAPT Study.
08:13And here they use dynamic K 67
08:18monitoring where those who actually
08:20had favorable K 67 numbers after three
08:24to four weeks of endocrine therapy,
08:27regardless of their age,
08:28even if they had low low
08:30nodal disease burden.
08:31Actually did fine without chemotherapy.
08:35So so.
08:35So there's this kind of adds to
08:37the body of data of if we have
08:41better biological predictors
08:42to be able to better pluck out,
08:44patients were at higher risk
08:46versus lower risk,
08:47can be better tailor our therapies
08:50in this endocrine responsive
08:52group that had this lower post
08:56Ki 67 levels after a short pre
08:59operative in therapy at the data
09:01I just showed you in the previous
09:03slide tend to do relatively well.
09:06Start a push.
09:07I I did a nice job summarizing
09:09these data as a discussion in
09:11the last thing Antonio,
09:13and as I mentioned,
09:14these data are continuing to evolve.
09:17What we know for sure is that we do need
09:20to take into account on anatomical risk,
09:23use some type of baseline
09:25gene expression profiling,
09:26whether it's Uncle Type DX,
09:28mammaprint and then whether we should
09:30also use some type of endocrine therapy
09:33response guided measurements I think.
09:36It remains to still be determined
09:39whether this is additive or superior.
09:42I don't think we can say for sure,
09:44but but the data are continuing to evolve
09:47pretty rapidly in the in this space,
09:49and I'm sure I'm giving this
09:51talk in two years.
09:52Will have additional data to share with
09:55you moving on to her two positive disease,
09:57a huge area of the escalation strategy
10:00has been with the use of anther
10:02site plans since her to direct the
10:05therapies carried cardio toxicity risk.
10:06And as you enter cyclins,
10:09there has been continued effort
10:11looking at whether we can safely
10:15eliminate anthracyclines in in
10:17her two positive therapies.
10:19So this was one of the first studies that
10:23showed that where non after after cycling,
10:28taxane plus Carbo regiment less stressed
10:31him out was compared to two AC TH.
10:34And other numerically the numbers favor
10:36that the answer cycling regimen there
10:38was actually no statistical difference
10:40in outcomes between the two groups,
10:43but certainly higher toxicity with
10:46increased cardiac toxicity as well as.
10:50Secondary malignancies with anthracite news.
10:53But this numerical difference still
10:56was unsettling for some oncologists,
10:58and I think many of us had continued to
11:01use anthracite playing for very high risk.
11:04Her two positive disease and inflammatory
11:07breast cancer and said that the
11:09after cycling news has persisted.
11:11But just in the last month the
11:13results of the perspective train
11:15two study were reported out.
11:17This was originally presented
11:19in the last ASKO,
11:21where a more modern regiment
11:23including for choosing map was used.
11:26And as you can see,
11:27there is absolutely no difference
11:29between the upper side pain and
11:30not after cycling group and no
11:32difference in overall survival.
11:33So I think additional reassuring
11:36data that answer cycling is can
11:38be deescalated and in the majority
11:41of our for two positive cases,
11:44what about staging won her two
11:46positive breast cancer?
11:47Obviously you know we used to use multi
11:50pomp chemotherapy for these tumors as well,
11:52But what if we use less than the APITI study,
11:55set the standard that using single agent
11:58taxing question has chosen not followed by.
12:00He requested to not lead to
12:03very highly effective outcomes,
12:05and it was certainly better tolerated
12:08than multi agent chemotherapy so so so
12:11it was a very reassuring results that
12:14continue to to persist as the data mature.
12:17Can we further deescalate this therapy
12:19and this was the attempt trial looking
12:22at what if we substituted the taxing
12:25percept in ARM with TDM one which tends
12:28to be better tolerated in some respects.
12:32I can have a little less neuropathy,
12:34not hair loss,
12:35and that time study showed that there was
12:37some similar efficacy between the two arms.
12:39However, to the surprise of some of the
12:42people who are looking at the data,
12:45it was not necessarily better
12:47tolerated and there was actually higher
12:49discontinuation rates in the TV on one arm.
12:52Which had led to the next,
12:53the escalation trial design account too,
12:56which is looking at a shorter to UTM one arm,
13:00not a whole year.
13:01And this is still in development,
13:04but certainly highlights for you another.
13:06Further attempt at Deescalating stage
13:09one her two positive chemotherapy.
13:11Many of you are familiar with the
13:13Compass study an I would like to
13:15just highlight that it's it's.
13:16It's a nice combination of both
13:18the escalation,
13:19an escalation of therapy where
13:21D escalating carboplatinum and.
13:23After cycling, but at the same time,
13:26given that we know that her two positive
13:29disease is at higher risk of CNS
13:31relapse for patients with residual disease,
13:34there is an opportunity to build on
13:36the data of the Katherine study and
13:38essentially add a small molecule
13:40inhibitor to catch them which has
13:42been shown to have great CNS activity
13:44that will show in a little bit.
13:47And we always need chemotherapy
13:49for her two positive disease.
13:50This area is rapidly changing
13:53and very exciting.
13:54I think there is an opportunity to
13:57potentially look at imaging biomarkers
13:59to identify patients who who are
14:01more likely to achieve PCR without
14:04chemotherapy with just the use of dual.
14:07Her two targeted therapy.
14:09So this was recently reported
14:11by Rosen Connelly and this this
14:14approach using PET imaging as a as a.
14:17Biomarker for picking the patients
14:19that can have a deescalated approach
14:22is actually going to be prospectively
14:24evaluated in any thoughts that
14:26they coming up.
14:27Keep an eye out on another presentation
14:30from Nadia hard working Group.
14:32Looking also at chemotherapy for you edge
14:35events coming up in the upcoming ASCO.
14:39Moving on to triple negative breast cancer.
14:41Certainly,
14:42given the more aggressive phenotype
14:44of triple negative disease,
14:45we've been much more cautious
14:47about the escalating therapies in
14:49triple negative breast cancer,
14:50but I would be remiss if I didn't
14:52mention that there's a body of
14:53work with tumor in simple,
14:55implicating lymphocytes as a
14:57measure of good prognosis,
14:59and this is something that
15:01can lead to potentially DFD.
15:02Escalated immunotherapy based treatments,
15:05or even elimination or chemotherapy.
15:08I will highlight one such study.
15:10Where stage one,
15:12triple negative breast cancers with
15:14high tells actually did did just as
15:18well with or without chemotherapy.
15:19Certainly a lot of ongoing,
15:21exciting,
15:21effective efforts are going on
15:23in the till space before we can
15:26safely deescalate therapy and
15:27triple negative breast cancer.
15:29But they are coming.
15:31An exciting abstract and presentation
15:33will be presented in this year's ASCO
15:36looking at part inhibitor alone as
15:39preoperative neoadjuvant chemotherapy
15:40and BRCA one and two tumors.
15:42This is without any chemotherapy
15:45patients with these types of tumors
15:47actually had pretty high on PCR rates,
15:49so these are exciting data that
15:52will be further represented in
15:55this coming as still coming up.
15:57So we talked a lot about Deescalation,
15:59but obviously.
16:00We need to just kind of touch on
16:02some of the escalation approaches.
16:05Certainly we've made a lot of progress,
16:07but we still have over 40,000
16:10individuals with breast cancer
16:11dying from advanced breast cancer,
16:14so it goes without saying that our current
16:17strip strategies have significant gaps.
16:20So one of the great successes of escalation,
16:23in my opinion,
16:24has been the the introduction of the CD.
16:2746 inhibitors 222 minus static breast cancer.
16:31That's, ER, positive that they have led
16:34to improved progression free survival.
16:36Anne continued more and more overall
16:38survival data are maturing and will
16:41be presented in this year's ASCO,
16:43so you can look at it as
16:46an escalation approach,
16:47but also deescalation approach because.
16:50What the data to show also is at work for
16:53a long time to initiation of chemotherapy
16:56in patients with metastatic breast cancer.
16:59What about escalating argument
17:00underground therapy in early stage?
17:02Breast cancer.
17:03Three studies have been reported out,
17:06but only monarchy with Emoci club has
17:10been shown to to to improve outcomes.
17:13I think the data are still maturing
17:17and I would say we are not ready
17:20too too too too too.
17:22Add city 46 inhibitors.
17:24Agile and therapy.
17:25At this point in time.
17:28And when you further inspect the data,
17:31that question has been why?
17:32Why has Monarch even the only positive study,
17:35while Penelope B and Palace were not an?
17:39There's a very nice presentation coming
17:41up in the next ******* looking at the
17:44composition of tumors that actually
17:45derive benefit and Penelope and they
17:47tend to be of the lumenal before iety,
17:50so I think kind of the biology
17:52of these chambers.
17:52Whether we can kind of phenotype,
17:54the tumors that are more likely to
17:56benefit from agile and taxi for 1600.
17:58Happy, I think it's the next step.
18:01Brain metastases are huge gap and
18:03we need to do better to catnap
18:06inverted climb with an important
18:08study and as the basis of adjutant
18:11to catnip that I mentioned in the
18:14in the compass study coming up.
18:16And I will wrap up with escalation of
18:21our preoperative chemotherapy regiments
18:24in triple negative breast cancer.
18:27Certainly we have approval for
18:29two checkpoint inhibitors in
18:31the metastatic setting,
18:33but what about in the pre operative setting?
18:35Again,
18:35Keynote 522 has been in the
18:37news quite a bit recently.
18:40The patients and in the intervention arm
18:43essentially got everything they had,
18:44carbo,
18:45they attacks all they got after cycling
18:47symbolism as well as a year of her
18:50Pember Lizum app after after surgery.
18:52So the kitchen sink was given and
18:56improved PCR rates in the intervention
18:59arm improved event free survival.
19:02With these data,
19:04Merck went to FDA ODAC an ask for approval
19:08of pembrolizumab for pre operative.
19:12Want to get chemotherapy and it was denied.
19:15Why was it denied?
19:17Really?
19:18The the Act committee wanted to
19:21see results of analysis for an even
19:25potentially the the final analysis.
19:27Analysis For results actually
19:29became available in May,
19:30and they were positive whether they're going
19:33to go back in after time .4 or wait until
19:36the final analysis remains to be seen.
19:38But generally I think most of us think
19:42that potential approval is getting close.
19:45I wanted to highlight an important
19:47abstract that you will hear about
19:49in the next ASCO coming up with our
19:52rule of Mob that Jeffrey Nova study,
19:54which did not throw the kitchen
19:56sink applications.
19:57There was no carbo.
19:58There wasn't a year of immunotherapy
20:01and they still had very remarkable results.
20:04So I think data are mounting that
20:07for appropriate.
20:07We can select the patients most
20:10likely to benefit from immunotherapy.
20:12This is something that potentially
20:15could help. Our patients.
20:17I'm gonna wrap up with a saying that won't
20:21have time to discuss in great length.
20:23Our escalation strategies and
20:25metastatic breast cancer,
20:26but a lot of exciting work is going
20:28on in this area and it will be a
20:31focus of our future discussions.
20:33So in conclusion,
20:34it's it's about right side therapy,
20:36not D, escalation or escalation.
20:39We have a way to go to achieve this
20:40for every individual diagnosed
20:42with breast Cancer Research,
20:43patient engagement,
20:44team science and collaborations
20:46are the path forward.
20:48Thank you so much for your attention.
20:51Thank you Doctor Lustberg that was
20:53really fantastic and I know I have
20:56a bunch of questions for you at the
20:58end and hopefully our audience,
21:00whether they're locally here in
21:03Connecticut or internationally,
21:04will put some questions in the
21:06question to answer a chat box for you.
21:09Next, we're going to move on
21:11to Doctor Michael D.
21:12Geovanna and discussing recent advances
21:15of systemic therapy for breast cancer.
21:20Thank you doctor Cubana.
21:57Sorry for the technical problems,
21:59thank you for having me and for all of
22:01the attendees being on the conference.
22:04I will hit some highlights and advances
22:06in therapy for each of the types of
22:09breast cancer and I'll start with her
22:11two positive breast cancer we now have.
22:14Eight different targeted drugs for
22:16treating her two positive breast cancer,
22:19so it's been wonderful progress
22:20in this field and of these eight,
22:22there's actually been five new FDA
22:25approvals in just the last two years.
22:27Those are the ones that I've
22:29highlighted in red here,
22:30and that does not even include FDA
22:32approvals for a biosimilars or
22:34subq preparations of some of these.
22:37So the first drug I'll mention is
22:40TDM one or trastuzumab in fanzine.
22:43This was first approved a number
22:44of years ago,
22:45as per the Amelia trial,
22:47showing that in second line therapy
22:49for her two positive metastatic disease TDM,
22:52one was superior to what was then most
22:55commonly used second line therapy of
22:57lapetina been capeside of been with improved
23:00progression free survival response rate,
23:02and overall survival,
23:03as well as less toxicity,
23:05and this became the standard second line.
23:08B for metastatic disease at that time,
23:10bumping the patent Open Cape,
23:11cited being to third line and
23:14then the other really important.
23:16Recent results using this drug
23:19were the results of the Catherine
23:21trial that looked at this drug in
23:23the post neoadjuvant setting in
23:25patients who had been treated in
23:27the neoadjuvant setting with trust
23:29using map based therapy and those
23:31who did not achieve a pathological
23:34complete response were randomized to
23:36standard of care which was to complete
23:38a year of the trustees and map.
23:40Or switching to TDM one instead,
23:43and there was quite remarkable results
23:46in terms of switching with almost a
23:4850% decrease in disease free survival
23:51and freedom from distant response and
23:54overall survival looking promising as well.
23:56Just in the past month,
23:58published online is an update of
24:02the Catherine trial with subgroup
24:04analysis and I'll just mention a
24:06couple of the important follow line
24:09subgroup analysis from this trial.
24:11One is that the improvement with
24:13the switch to TDM one came both in
24:16patients who were treated with an for
24:18cycling as well as those who were
24:20not treated with anthracyclines.
24:21It came even in patients with the
24:24very highest risk disease categories.
24:27The improvement was seen regardless
24:29of hormone receptor status,
24:31positive or negative,
24:33and in this trial,
24:35about 70 patients entered initially
24:39having clinical stage one disease
24:43and getting neoadjuvant therapy.
24:44An of those who entered the trial
24:47with clinical stage one disease
24:49and still had residual disease.
24:51Those who got switched to TDM
24:53one seemed to have a benefit,
24:55although it's small numbers and so
24:56we can't really pull statistics.
24:58But there were six disease free survival
25:02events in those that continued trastuzumab,
25:05and none in the arm that was switched to TDM.
25:08One and of these events,
25:11three of them were non CNS
25:13distant recurrences,
25:14two or CNS recurrences,
25:15and one was a contralateral breast cancer.
25:18So although small numbers it gives
25:20us pause to think about even using
25:23this strategy in patients who present
25:25with clinical stage one disease,
25:28and that's a controversial area
25:29whether to use this strategy or not.
25:34But the Catherine trial did set
25:35a new paradigm for treating
25:37her two positive disease,
25:39which is in general we could
25:41debate stage one disease,
25:43but in general patients with
25:44her two positive disease,
25:45now we think should get neoadjuvant therapy,
25:48because if they get a non path CR we
25:50can improve their long term outcome by
25:53switching to TDM one and this paradigm.
25:55Now we also apply to the triple
25:58negative subset because the create X
26:00trial showed that in triple negative
26:02patients who get neoadjuvant chemo.
26:04Therapy.
26:04Those who do not get a path CR and
26:07we now have a worse outcome can
26:09have their outcome improved by the
26:11use of edge of in Cape cited mean.
26:13So I think for both her two positive
26:15and triple negative disease we should
26:17always think about neoadjuvant
26:18therapy For these reasons,
26:19because in the post neoadjuvant
26:21setting we can improve long term
26:23outcome by intervening.
26:24For those who don't get a path CR.
26:29The next drug I wanted to
26:30talk about is to cotton.
26:31If so, this is a her two
26:34tyrosine kinase inhibitor.
26:35We now have three.
26:37Her two tyrosine kinase inhibitors
26:39to choose from and low to captain.
26:41If unlike the other two is highly
26:44selective just for her two without
26:47hitting the other members of
26:50the her two receptor family,
26:52you can see here that there's no
26:54activity against the EGF receptor.
26:56Let Patton in has an Nurettin.
26:58They both have equivalent activity
27:00against the EGF receptor interaction.
27:02If actually inhibits all of
27:04the receptors in this family.
27:07So the her two climb trial looked
27:11at the introduction of Takata nib in
27:14the metastatic setting for patients
27:16who had prior first line therapy with
27:19trastuzumab and second line therapy
27:21with TDM one an the really important
27:24part of this trial as Merriam has
27:26shown you is that this trial welcomed
27:29patients with brain metastases and
27:32not only treated brain metastases but
27:35even untreated or progressing brain.
27:37Test icees because the earlier
27:40phase trials with this drug showed
27:42good activity in the CNS,
27:44and so patients in this trial were
27:47randomized to therapy with trastuzumab in
27:50capeside of being with or without to continu.
27:54And in this trial,
27:56almost half of the patients entered
27:59with brain metastases.
28:01About 60% of them were
28:03treated brain metastases,
28:04but the rest were untreated
28:07or treated but progressing.
28:09And the overall population showed
28:12an improvement in progression
28:15free survival of 2.2 months.
28:17An improvement in overall survival
28:19of four and a half months.
28:20So this was an important trial showing
28:23an improvement in overall survival.
28:25And the response rate nearly
28:27doubled from 23% to 41%.
28:29An in patients with brain
28:32metastases who entered the trial,
28:34they achieved the same benefit
28:37of a 2.2% month improvement
28:39in progression free survival.
28:43Interestingly, the objective response
28:46in the brain metastases of patients
28:50who had active brain metastases by
28:53resist criteria were 47% versus 20%
28:56because we know Cape cited being also
28:58does cross the blood brain barrier.
29:00So remarkably, almost half of patients
29:03had objective response by recist
29:05criteria in their brain metastases
29:08that were active brain metastases.
29:10So this drug is quite active.
29:12In the CNS and this slide shows
29:15the CNS progression,
29:17free survival of the patients
29:19with brain metastases,
29:20and it improved by nearly six
29:23months from 4.2 months.
29:25Median progression free survival to
29:27almost 10 months and at one year 40%
29:30of the patients had not had brain
29:32progression in the experimental arm,
29:34whereas none of the patients in the
29:37standard arm still are without progression.
29:41And this show is in the
29:42patients with brain metastases.
29:43The overall survival,
29:45which was improved by six months
29:48from 12 months to 18 months,
29:50so really important results in the CNS.
29:52And because this is such a active
29:55drug and with these good results,
29:57it's now being tested in the second
30:00line in the her two climb 02 trial
30:03which is looking at second line T
30:06DM one versus T DM 1 + 2 cotton.
30:11The next drug I want to
30:13talk about is trastuzumab.
30:14Dear XD can this is another
30:16antibody drug conjugate like TDM
30:18one and the table on the right
30:21compares it to TDM one TDM.
30:23One has the payload being
30:25a tubulin inhibitor.
30:26This drug has a topoisomerase
30:28one inhibitor and this drug also
30:30has what's called a stand by a
30:33bystander effect because when the
30:35targeted drug when the payload
30:37is cleared from the antibody,
30:40it actually can diffuse.
30:41Through the membrane of the cell.
30:44So if there is heterogeneity of
30:46the her two expression in a tumor,
30:48you can get killing of cells that
30:50perhaps have lower levels of her two.
30:52By this bystander effect.
30:56And in phase one trials,
30:58this drug was extremely active in
31:00her two positive breast cancer and
31:02her two positive gastric cancer
31:04as well as even breast cancers
31:06that had lower levels of her two.
31:08Perhaps because of this bystander
31:10effect in cells that had heterogeneous
31:12levels of her two expression and
31:15in phase one trials overall 86% of
31:18subjects had at least some tumor shrinkage.
31:21And so the trial that got this drug,
31:23FDA approved was the destiny of 1 trial,
31:26which was a single arm phase,
31:27two trial and patients in the
31:30metastatic setting had to have prior
31:32trastuzumab an prior TDM one and 2/3
31:35of them also had prior per Susan Mab.
31:38Almost all of them had visceral metastases,
31:41and this was a fairly late line
31:43trial with the median number of
31:45lines of prior therapy being 6.
31:48And despite this being a Lateline
31:50trial once again,
31:51the activity was really dramatic
31:54with almost all patients having
31:56at least some shrinkage of their
31:59tumor by recist criteria,
32:01a 60% confirmed objective response rate,
32:04a Disease Control rate of 97%,
32:07an 11 out of 168 patients with complete
32:11responses in their metastatic disease.
32:13So an amazingly active drug,
32:15even in a very late line setting.
32:19Excuse me and and despite this
32:21being a Lateline setting,
32:22these were really durable responses
32:25as well with their median duration
32:28of response of almost 15 months
32:31and overall survival at one year
32:33still being 86% despite being
32:36six line therapy on average.
32:39The one huge caveat with this drug
32:41is to watch out for the side effect
32:44of interstitial lung disease,
32:46or pneumonitis,
32:47which occur din almost 1415% of
32:51patients an in two point 2% of patients.
32:54It was actually a fatal,
32:56so the one caveat with this drug
32:58is to be highly vision vigilant
33:00for any respiratory symptoms that
33:02could indicate pneumonitis.
33:04And because this drug is so active,
33:06it's being tested in a number
33:09of other settings now.
33:11We have accelerated approval based
33:12on the single ARM trial that I
33:15just showed you the destiny O2
33:17trial is the definitive trial.
33:19Comparing this drug to treatment of
33:20physicians choice in a phase three setting.
33:23With these options,
33:24the Destiny 03 is comparing
33:27this after first line therapy
33:29head to head against TDM one.
33:32So it's just using web
33:34touristy can versus TDM.
33:35One in second line.
33:36The Destiny 04 trial is looking at
33:39her two low breast cancer patients
33:41because I showed you in phase one.
33:43Trials responses in those patients.
33:45So this is just using map touristy can
33:48versus chemotherapy of physicians choice,
33:51and in Destiny 05 it's actually
33:53being compared to TDM one in the
33:55in the post neoadjuvant setting.
33:57As per the Catherine trial where
33:59patients who get into management
34:00therapy and have residual disease
34:02will be randomized to TDM one
34:04or try D'souza Mabdi rixty cat.
34:06So being tested in all of
34:09these different settings.
34:10Another her two targeting drug that was
34:13just recently approved is margetuximab,
34:16and this is actually a derivative of
34:19her of trastuzumab that has the FC
34:23Gamma portion replaced by another
34:26FC Gamma alteration that has a
34:28higher affinity for activating FC
34:31Gamma receptor and a lower affinity
34:33for inhibitory FC Gamma receptor.
34:36And this is based on the fact that
34:38we know that trastuzumab is not
34:40only a targeted signal transduction.
34:42Drug, but it is that immunotherapy as well.
34:45That does recruit the immune system,
34:47and so it was thought by making
34:50transducer maps more able to
34:52actively recruit the immune system.
34:54It may give it enhanced activity,
34:56and so this was tested in the Sophia trial,
35:00which was a phase three trial of
35:02transducer Med chemotherapy versus
35:04margetuximab plus chemotherapy
35:06in later line therapy,
35:08and there was a fairly small positive result.
35:11As you can see here in progression.
35:13Free survival improving by about two months,
35:16so not a huge result,
35:18but enough to get this drug FDA approved.
35:20So it's now part of our armamentarium
35:23and the final her two targeting
35:25drug recently approved is narrative,
35:27which was tested in the Nala trial and
35:29this was a trial of Neurontin and Capeside,
35:32it being versus LA patented capeside
35:34of being in patients who had at
35:36least two prior therapies for their
35:38metastatic her two positive disease
35:40and the new rotten if compared to
35:42La Pata nib did have an improved
35:44progression free survival.
35:45Overall response,
35:46and perhaps a little bit in overall survival.
35:49None of these patients had prior to continu,
35:52and so in the era now of using
35:55two continents,
35:55it will be difficult to know if there really
35:58is a place for new ratine in metastatic.
36:00Her two positive disease.
36:03And so,
36:04as I showed you,
36:05we now have many drugs to choose from.
36:07An I oppose this as a reasonable
36:10order sequence of therapy that
36:12we can use for her two positive
36:14metastatic disease patients.
36:16In the first line,
36:17therapy should have pertuzumab,
36:18trastuzumab,
36:19and taxane because of the remarkable
36:22overall survival benefit seen
36:24in the Cleopatra trial TDM,
36:26one is still considered the second line
36:28therapy as per the Amelia trial and
36:30we now can consider a third line therapy.
36:33Being just do some AB capeside it
36:35being into cotton if since we have
36:37seen an improvement in overall
36:38survival in the her two climb
36:40study and this is especially
36:41of course attractive for patients who
36:43may already have brain metastases from
36:45their her two positive disease and
36:47then perhaps enforced line therapy,
36:49we could use a trust.
36:50Susan abjure Exede can,
36:52although this may ultimately compete with
36:55the her two climb regimen for third line
36:57therapy and then in late line therapy,
36:59perhaps we might want to use margetuximab
37:02for the slight edge it might have over
37:04trust using map in the Wave line therapy.
37:06Moving on to triple negative breast cancer.
37:10We now have five or six targeted
37:12drugs that are approved for
37:14triple negative breast cancer.
37:17We have two park inhibitors are lab rib and
37:20no tell is operated as Merriam showed you,
37:23we now have two checkpoint inhibitors,
37:26anti PDL, one drugs at Season
37:2811 map and Pember Lism AB.
37:30We have an antibody drug conjugate
37:31and I kind of include carboplatin
37:33as a targeted therapy for triple
37:36negative breast cancer because if
37:38you remember from the TNT trial,
37:40particularly patients who had germline BRCA.
37:43Mutations.
37:43They had a remarkable high response
37:46rate to single agent carboplatin
37:48about a 60% response rate for germline
37:51carriers and that is applies to not
37:54only triple negative disease but any
37:56germ line BRCA mutation carriers.
37:59So in terms of immunotherapy,
38:02we have two positive results in
38:05the metastatic setting.
38:06I think the results aren't as
38:08enormously impressive as they are
38:10in some other types of cancer,
38:12like Melanoma or lung cancer,
38:15but they are positive results,
38:16and so we now have these that we
38:19can use in the IMPASSION 130 trial
38:22atisa lism AB versus placebo was
38:25added to nab paclitaxel,
38:27an in the PDL 1 positive patients.
38:30There was a two to three month
38:32improvement in progression Free Survival,
38:34a significant improvement in response rate,
38:36and if this holds up,
38:38but perhaps an impressive improvement
38:40in overall survival,
38:42the Keynote 355 was a similar
38:45trial using Pember Lizum app,
38:47and the chemotherapy might have
38:49been nap after taxol or path that
38:51axle or gem carbo in first line.
38:53Setting again and in those with
38:55the CPS score greater than 10%,
38:57an improvement in progression free
39:00survival of almost four months.
39:02And so we now have either of these
39:04drugs atisa lism AB or embolism
39:06AB for approval for PD L1 positive
39:08patients by the appropriate assay I
39:11might add in the first line setting
39:14with these chemotherapy agents
39:16there was another trial looking at
39:18a teasel is a map with paclitaxel,
39:21the impassioned 131 and interesting Lee.
39:24This was a flat out negative trial
39:26with no improvement in progression.
39:28Free survival,
39:28minimal improvement in response rate
39:31and no improvement in overall survival.
39:33And the only difference between this
39:35and the 130 child was a nap attack,
39:38slow versus paclitaxel.
39:40So we don't really understand why
39:42is this one negative?
39:44Is there a difference in the patient
39:46population that was enrolled?
39:48It's hard to see that on the
39:49surface it was first line.
39:51Triple negative patients.
39:52Is there truly some
39:54magical difference between
39:55Napa Taxol and path that axle?
39:57I suspect nabbed paclitaxel
39:58does have an edge on Paxil,
40:00but is it really so much of an edge
40:02that it would make this difference?
40:03Or is it just chance because the
40:06results with immunotherapy are
40:08not tremendously impressive?
40:10And is it possible that some
40:12private trials might look positive?
40:13Some might look at negative?
40:15We don't know the answer,
40:17but for now, if we use atezolizumab,
40:20we should use it with nab
40:21Papa Taxol and not paclitaxel.
40:26What about the use of immunotherapy in early
40:29stages of triple negative breast cancer?
40:32Miriam mentioned this child,
40:35the keynote 522 trial and the first
40:37interim analysis was published
40:39in the New England Journal,
40:41at which point 600 patients were
40:43enrolled and it showed an impressive
40:45difference in pathological complete
40:46response rate for the addition of
40:48Pember Lism AB to the kitchen sink,
40:50as Merriam explained with a 14% improvement
40:54in pathologic complete response rate.
40:56And we do know in this disease that
40:59pathologic complete response is a very
41:01strong predictor of long term outcome.
41:03And we know that the FDA in the
41:05past has said that they would
41:06consider drug approvals based on
41:08improvement in pathologic complete
41:10response for this type of disease.
41:16This is not yet approved,
41:17and as Marion mentioned in February,
41:22the pharmaceutical company actually
41:23asked the FDA to consider accelerated
41:26approval based on these early results.
41:29As she mentioned,
41:30there was an ODAC meeting in February
41:33and the Odacon the FDA decided at that
41:36time not yet to grant accelerated approval.
41:40Wanting further follow up and more
41:42endpoints that were still premature.
41:45In terms of event free survival
41:47and overall survival,
41:48and in fact at the time of this
41:50meeting the trial was up to over
41:521100 patients and the path CR rate
41:55delta was a little bit different than
41:57it was with the 1st 600 patients.
41:59There was a 7% difference at that time.
42:03The P value was still quite good,
42:05but be 'cause the statistics
42:08were allowing multiple analysis.
42:10Then in order to have a
42:12statistical significance though,
42:13there was very high stringency
42:14for what the P value would need to
42:16be an it actually didn't hit it.
42:18Yet at this point,
42:19and Merriam showed you that there
42:21is ongoing analysis and we might
42:23hear about this soon.
42:25But meanwhile we have to decide
42:26to do what to do with our triple
42:29negative patients who present,
42:31especially if there are high risk
42:33patients and I will tell you
42:36that for some young,
42:37very high risk multiple node positive
42:40patients who I have encountered a since
42:42the publication of the first data.
42:45I have used this regimen even though
42:46it is not FDA approved and we still
42:49don't know the long term outcome.
42:51I've had insurance companies
42:53agree to improve this approved.
42:55The immunotherapy on the basis
42:58of what data we have so far.
43:01It's not clear that we should all
43:03be doing this for every patient,
43:04but we have to discuss with
43:06the patient sitting before us.
43:08Whether we do this or not.
43:09And I will say that I've done it
43:10with a couple of patients so far.
43:14We now have an antibody drug
43:16conjugate for treating metastatic
43:17triple negative breast cancer.
43:18That's quite a good active drug.
43:20It's sacituzumab gobatti can
43:22the antigen is trope too,
43:24which is present on many breast cancers and
43:28the active moiety is a topa one inhibitor.
43:31It's actually SN 38,
43:33which is the business molecule,
43:35the active metabolite of Irene Attican.
43:38Ann, this was tested in the
43:40ascent trial versus treatment of
43:42chemotherapy of physicians choice,
43:44and this antibody, drug conjugate,
43:46was quite active with an improvement
43:48in progression free survival.
43:49A six month improvement in overall
43:51survival and of substantial
43:53improvement in the response rate.
43:55So this was approved for triple
43:56negative metastatic breast cancer.
43:58After two or more prior chemotherapies,
44:00and it's actually now being tested
44:02in hormone receptor positive as well.
44:04We are participating in that trial
44:05and I've had patients with hormone
44:07receptor positive disease in the trial.
44:09Had good responses as well.
44:11We often think of an antibody drug
44:14conjugate as a much more tolerable
44:17therapy than a naked chemotherapy,
44:19but actually I have to say this
44:22particular drug does have toxicities
44:24that are on par with chemotherapy,
44:26including neutropenia,
44:27nausea and vomiting,
44:29diarrhea, abdominal symptoms,
44:31complete alopecia, low blood counts,
44:35decreased appetite, and rash.
44:37So although it's a very
44:38active drug in a good drug,
44:40it doesn't seem in terms of toxicity.
44:42Would be a free ride
44:45compared to chemotherapy.
44:46And then finally,
44:47in the last few minutes I'll
44:49just a few words about hormone
44:51receptor positive disease.
44:52We now have five biological agents that we
44:55can combine with our endocrine therapies.
44:58The three CDK 46 inhibitors
45:01everolimus and alkalis sub alkalis,
45:03is active only in those tumors
45:06that have a PR 3 kinase mutation,
45:09which is about 40% of metastatic
45:11hormone receptor positive breast
45:12cancer in the solar one trial that was
45:15published almost two years ago now,
45:17which was a randomized phase
45:18three looking at full strength,
45:19with or without alkalis.
45:21If there was a significant improvement,
45:23progression free survival and response rate.
45:26So this is now considered standard
45:28therapy for patients in combination
45:30with focus strength to have
45:31a PR 3 kinase mutation.
45:33This can have some substantial
45:35toxicity as well, including diarrhea.
45:38Hyperglycemia that requires
45:40aggressive management,
45:41an erracht as well that can be
45:44prevented by using an antihistamine.
45:46We have the three CDK 46 inhibitors
45:50which have remarkable activity in the
45:53metastatic setting in first line,
45:56and says the second line nearly doubling
45:58response rate and nearly doubling
46:00progression free survival and in the
46:02metastatic setting they really all
46:04seem to have nearly identical activity.
46:06There's maybe a slight edge for
46:09abemaciclib in that it has a little
46:11bit of single agent activity,
46:13which the other two seem not to,
46:15and perhaps some potential to cross the CNS.
46:18Blood brain barrier and some CNS activity.
46:21But for the most part in the
46:23metastatic setting they seem to be
46:25extremely active and equally active.
46:27So as Miriam mentioned,
46:29the big question is will these
46:31be able to be moved into the early
46:34stage setting and she mentioned
46:35that we have one positive trial,
46:38the monarchy trial,
46:39which looked at very high risk patients
46:41with four or more nodes positive or
46:44one to three nodes positive and other
46:46high risk features and enrolled.
46:48Over 5000 patients and looked at
46:50the use of abemaciclib for two
46:53years with the edge of an enderman
46:55therapy versus not an this at early.
46:58At about a year and a half follow up as
47:00seems to be a positive trial so far in
47:03terms of reduction in distant relapse.
47:05Free survival.
47:08But as far as Marion mentioned,
47:10what we have looking at us in the face
47:13is two other early stage trials with
47:15palbociclib that seemed to be negative
47:18and so is there really a difference
47:20between abemaciclib in pablum?
47:22Albo psych lab?
47:23Is there a difference in the
47:25patient population?
47:25Is there some other explanation
47:27and we have an ongoing trial with
47:29Ribociclib which hasn't reported yet.
47:31Now the interesting thing is,
47:33these results are reported at
47:35different time points and there
47:37were different treatment durations.
47:39So in the Penelope B trial,
47:42which looked at patients who had
47:45residual disease after neoadjuvant therapy,
47:48this analysis is out at 43 months.
47:51And if you looked at the two year mark,
47:54there was a 4% difference in
47:57favor of the palbociclib,
47:59but that went down at three years,
48:02and at the four year follow-up Timepoint,
48:04essentially no difference between the arms.
48:06When we look at the monarchy
48:08with abemaciclib,
48:09which appears to be a positive trial so far.
48:11The treatment duration is 2 years,
48:13but the follow up so far is
48:15only 19 months and so it may be
48:18that we see some effect of these
48:20while the therapy is going on.
48:22But once the therapy is completed over time,
48:25the difference between the
48:26two arms might go away.
48:28So we need more study,
48:30more follow up and we need to
48:32see the results of the Natalie
48:34trial which is using recycled for
48:36three years in high risk disease.
48:38That's my last slide.
48:41One thing I wanted
48:42to say once again getting back to
48:44dealing with the person to sitting
48:45in front of you question arises.
48:47Should we act on this data with abemaciclib?
48:50It's not FDA approved.
48:51We really don't know if this is
48:54going to hold up in the long term,
48:56but I will tell you that I have brought
48:58this up sometimes with patients.
49:00So I recently had a patient who had
49:0312 nodes positive and was starting her
49:06regimen therapy and I discussed with
49:07her whether to add emoci clip because
49:09it's enormously high risk to have.
49:11Well, no, it's positive and I prescribed
49:13with Emoci clip for this woman.
49:15It would be covered by her insurance company.
49:18Again, we don't know if we should be
49:19doing this. We sometimes act early.
49:21We may be giving therapy that has toxicity
49:24that in the long run doesn't help,
49:26but I consider it in very high
49:28risk patients based on this data.
49:31So I stuck my neck out in a
49:33couple of areas there,
49:35but that's my last slide and I'll
49:36be happy to take any questions
49:38now or at the discussion time.
49:42Thank you Doctor Digiovanni,
49:44that was fantastic and there are questions
49:47that are trickling in and they both
49:49in the chat in question and answer.
49:52Certainly not last and least,
49:55but we have Professor Andreas Silvers.
49:58Gonna really give us a exciting
50:00update on breast cancer
50:01epidemiology for risk factors,
50:03especially in our vulnerable populations so.
50:06Thank you, Andrea.
50:15You're on mute still.
50:19Good afternoon,
50:20thank you for that introduction.
50:22It's my pleasure to present today
50:24and I will start out by describing
50:28the topography of breast cancer
50:30in 2021 and I reviewed current
50:33epidemiology and how we got here.
50:45Sure, but it's not advancing.
50:58It's my conflict of interest.
51:02And as you can see on this slide,
51:04breast cancer in the United
51:07States is extremely common.
51:08It's the most common cancer one season women.
51:12But it is not the most common
51:15cause of death that is lung cancer.
51:17You can compare the results of
51:21deaths that are anticipated in 2021
51:23for lung cancer, which is 100 and
51:2716,660. It's a very common
51:31tumor in elderly women.
51:337% of all breast cancers will
51:37appear in women over the age of 70.
51:43Just want to highlight a little
51:45bit that breast cancer is
51:47heterogeneous and there are multiple
51:50different tumor subtypes there.
51:51Subtypes within the subtypes
51:53such as Lumenal A and luminal B.
51:56The significance of this is going
51:58to be come clear when we talk about
52:02etiology and prevention and also keep
52:05in mind that breast cancer subtypes
52:08actually can change in up to 25%
52:11of patients when they metastasize.
52:14Their breast cancer has changed
52:16subtype and the most common change
52:19that one sees is going from lumenal,
52:22a two triple negative.
52:26And here's the breakdown of
52:28breast cancer by subtype,
52:30and you can see that lumenal a specifically,
52:34but hormone receptor positive breast cancer,
52:38is the most common type,
52:40regardless of age or race,
52:43and it's six times more common than
52:46the triple negative breast cancer.
52:50Let's move ahead and talk about risk factors.
52:53I think from my previous slide,
52:56you can tell one of the risk factors is
53:00being female and another is being older,
53:03but those are non modifiable risk factors.
53:07Personal history of invasive or non
53:10invasive breast cancer predisposes to both
53:14contralateral and ipsilateral primaries.
53:16Benign breast disease with atypia.
53:20Family history and this is regardless
53:22of whether there's a mutation
53:25for women with family history.
53:27Only 5 to 6% have identifiable mutations,
53:32and when you look at known
53:35mutations that comprises less than
53:3710% of all breast cancers.
53:39Breast density I will get into that
53:42a little more later in the talk,
53:45but let's talk about increased exposure to
53:48estrogen throughout the female lifetime,
53:51early menses.
53:53Menses now starts below the age
53:57of 11 in the United States.
53:59This was not true.
54:01A generation ago, delayed childbearing
54:03or no lipperhey late menopause.
54:07Menopause is occurring later now, it said.
54:10Between 50 and 51,
54:11that was not true.
54:13A generation ago,
54:14exogenous estrogen that has been
54:16given to women to help them through
54:20the menopause and that estrogen is
54:23more of a risk when it's combined
54:26with progestin and previous studies,
54:29it looks like the estrogen that's
54:31given as a single agent to women
54:34who have had hysterectomies is not
54:37as risky an transgender women.
54:40Due to increased exposure of estrogen.
54:45Moving along to radiation,
54:47that's radiation therapy,
54:48which is given to children or mantle
54:52radiation for Hodgkin's disease.
54:54Radiation therapy is the highest risk
54:57when it's given during adolescence,
55:00between age 10 to.
55:0214 When the breast is most
55:04actively proliferating,
55:07but there's also an increased
55:09risk from radiation exposure,
55:11either accidental,
55:12such as Chernobyl,
55:14or intentional such as warfare,
55:18and this also was shown to be
55:21most active for the adolescent
55:24girls and wasn't as seen to be a
55:27risk factor after the age of 45.
55:31Drinking alcohol.
55:32As little as one alcoholic beverage
55:36per day in several studies has
55:40shown a slightly increased risk of
55:44breast cancer and then obesity.
55:47Just wanted to highlight breast density.
55:50You can see here that there are some
55:54women who have extremely dense breasts,
55:57and for those women at level 4 that
56:02increases the odds ratio 6 fold.
56:05So that's a very very important risk factor.
56:10So much so that the Christmas
56:13study that comes out of Sweden.
56:16Actually use breast density to
56:19enroll women in their chemoprevention
56:22trial using tamoxifen.
56:27An risk factors vary by subtype.
56:31Greater parity was associated
56:32with a lower risk of hormone
56:35receptor positive breast cancer,
56:37but it is an increased risk for
56:40triple negative breast cancer.
56:42Breastfeeding can cut the risk for
56:45triple negative breast cancer by 50%.
56:47Well, that's not true for
56:50receptor positive breast cancer.
56:55So these two women on the cover
56:58of Good Housekeeping show.
56:59How are modern women are more likely to
57:03have risk factors for hormone receptor
57:06positive breast cancer by delaying
57:09childbearing having fewer children
57:12and those things increase the risk.
57:15As a matter of fact,
57:17breast cancer is more common in
57:20areas like the I-95 corridor,
57:24an in Marin County,
57:26not due to environment,
57:27but due to cluster of risk factor for the
57:31type of women that live in these areas,
57:34and modern women are taller.
57:36Bigger also are more likely
57:38to be diverse in this country,
57:41and these are reasons to increase
57:44the risk for breast cancer.
57:47Let's move ahead to looking
57:49at the rest of the world.
57:51Global incidence is increasing.
57:56And you can see that breast cancer is
57:58different in different types of countries.
58:01In highly developed countries,
58:02most women get breast cancer when they're
58:05older and less developed countries.
58:08That's the reverse,
58:09and it's thought to have to do
58:11with the wealthier countries
58:13having higher rates of obesity.
58:15But as you can imagine,
58:17the case fatality rate is lowest
58:20in highly developed countries,
58:22and this is even true in our own country.
58:26When you look at the case fatality
58:28rate in a state like Connecticut,
58:30which has the second highest
58:32rate of breast cancer,
58:34the case fatality rate is the lowest Ann.
58:39You compare that to some of our Southern
58:42states that may have lower incidence
58:46but higher case fatality rates,
58:49and this may have to do with insurance
58:52in these various states in our country.
58:56When we look at the nationality, the
58:59United States doesn't even make the top 15.
59:02Belgium is the number one.
59:06But when we look at Survival World wide,
59:09you can see a very different story.
59:12The five year survival in
59:15the United States is 95%.
59:18Compare that to what you see
59:20in South Africa and Mongolia.
59:25And survival rate in the United
59:27States does vary by subtype.
59:29The hormone receptor positive breast cancers.
59:33Looking at the most recent SEER
59:36data have an excellent prognosis
59:38and even the five year survival for
59:41the triple negatives when they are
59:44localized have a better prognosis
59:47than you see in other countries.
59:52But survival rates don't
59:53really tell the whole story.
59:56First of all, women being diagnosed with
60:00breast cancer today may have better outcomes.
01:00:04We'll see in the most recent SEER data,
01:00:07but diagnostics and treatments
01:00:09continue to improve overtime,
01:00:12and there's good access in highly developed
01:00:15countries and highly developed cities.
01:00:17When you look at some of the SEER data,
01:00:20but these numbers don't take
01:00:22everything into account.
01:00:24First of all,
01:00:25survival rates for hormone receptor
01:00:28positive breast cancer.
01:00:3050% of the patients that are going to
01:00:33relapse will relapse after five years.
01:00:35So the five year survival rate kind of
01:00:39skews things and some of the survival rates,
01:00:42although they may be due to stage,
01:00:45they may really have to do with
01:00:48overall health response,
01:00:50an access to treatment so different
01:00:53subtypes may predict timing of relapse.
01:00:57But there are so many other things I'm
01:00:59going to be a little controversial here
01:01:02and say geopolitics can determine outcome.
01:01:05Look at a situation in Puerto Rico
01:01:09during Hurricane Maria where it
01:01:12really decimated their health system.
01:01:14That does change screening.
01:01:16It does change treatment and
01:01:19it will change outcome.
01:01:21Let's take geopolitical changes
01:01:24in our own country.
01:01:26Let's look at the pandemic.
01:01:28For the pandemic may have changed
01:01:31patterns of screening change patterns
01:01:33of treatment and I hate to say it
01:01:36women have been known to increase their
01:01:40alcohol intake during the pandemic.
01:01:43Are we going to see changes in
01:01:47epidemiology due to the pandemic?
01:01:51So who are the most vulnerable
01:01:54that we see now?
01:01:56Black women, particularly younger women.
01:01:59They are more likely to be diagnosed
01:02:02with triple negative breast cancer
01:02:04and more likely to be diagnosed.
01:02:07Diagnosed at a younger age.
01:02:10Blacks are more likely to die
01:02:12of breast cancer at any age.
01:02:15They presented a later stage,
01:02:17but their insurance status is worse
01:02:20twice as likely to be uninsured.
01:02:24Well,
01:02:25immigrants from less developed
01:02:26nations we talked about what you
01:02:29see with global breast cancer
01:02:31and I'll talk a little bit about
01:02:33sexual minorities as well.
01:02:37The NCI talks about risks in terms
01:02:41of cancer health disparities,
01:02:43and you can see it.
01:02:44Top of this slide.
01:02:46Women who are African American have a
01:02:51higher risk of dying from breast cancer,
01:02:55but let's get into the various
01:02:57groups that are more likely to
01:03:00suffer cancer health disparities,
01:03:03and I think I'm going to describe for you
01:03:05how many of these apply to breast cancer.
01:03:09We already talked about women of
01:03:11color and breast cancer outcome,
01:03:14and women of different ancestry
01:03:17or recent immigrants made.
01:03:19We also have a higher risk of both getting
01:03:23breast cancer or particularly their outcomes.
01:03:27Individuals of lower socioeconomic
01:03:30status have decreased.
01:03:32Access to screening,
01:03:34decreased access to treatment.
01:03:36An also may have associated health
01:03:40problems that make treatment problematic.
01:03:43Well, individuals with disabilities
01:03:45are less likely to get screened,
01:03:48and that's been looked at.
01:03:49At Mammographic screening
01:03:52in wheelchair population.
01:03:55Again,
01:03:55individuals who have poor
01:03:58insurance coverage are less likely
01:04:01to get the best possible care.
01:04:03We talked about the rural areas
01:04:06in the United States in the South
01:04:09that those patients have worse
01:04:11insurance coverage and are less
01:04:14likely to have access to care.
01:04:16LGBT population.
01:04:17LGBT women are less likely to
01:04:22get screened and also have.
01:04:26Some of the estrogen during lifetime risk
01:04:30factors that would increase their risk.
01:04:34We talked about immigrants,
01:04:37refugees,
01:04:38and the elderly who are more
01:04:41likely to get breast cancer.
01:04:45So breast cancer rates are declining
01:04:47in our country and this is due to
01:04:50diagnostic advances and some of the
01:04:52things that Mariam and Mike talked about.
01:04:55But risk factors have been identified and
01:04:58they really vary depending on the subtype.
01:05:02There are certain regions in the world,
01:05:04but in our own country that
01:05:06are increased risk for adverse
01:05:08outcomes and special populations.
01:05:11In the United States are disproportionately
01:05:14vulnerable to adverse outcomes.
01:05:17It will require an enormous
01:05:20collaborative effort not only on
01:05:23the part of the medical community,
01:05:25but on the part of all citizens to
01:05:28transform cancer care for all people.
01:05:31Regardless of their race,
01:05:33ethnicity, immigration status,
01:05:36age, gender,
01:05:37sexual orientation or socioeconomic status,
01:05:42one of the biggest risk factors
01:05:44for breast cancer is the
01:05:46communities that people grew up in.
01:05:51And thank you for your attention,
01:05:53and I always like to mention those
01:05:55that I seen with breast cancer or
01:05:58have been affected by the disease.
01:06:04Thank you doctor.
01:06:06So that was fantastic and you know,
01:06:09thank you for all three of
01:06:11our speakers for you know,
01:06:12three really phenomenal presentations
01:06:14that you know show the breadth
01:06:17of the care and services that
01:06:18we provide here at Yale.
01:06:20But more importantly,
01:06:21you know the the options and
01:06:23therapies that are available to
01:06:25women and some of the challenges
01:06:27that we have moving forward in
01:06:29terms of not only screening but
01:06:32treatment of our more vulnerable.
01:06:35Populations there were a couple of
01:06:36questions in the chat box and hopefully
01:06:39others will come in in the question
01:06:41and answer until we get some more.
01:06:42I wanted to start with a question
01:06:45to for Doctor Lustberg and the
01:06:47others on D escalation of therapy,
01:06:49and I guess how do you approach that
01:06:53question to patients when you're,
01:06:55you know, trying to offer a trial?
01:06:57That's going to do less rather than more,
01:06:59especially for that anxious
01:07:01patient who's you know,
01:07:02main concern is living and survival and.
01:07:05I'm not necessarily trying to sell
01:07:08that trial to them on deescalation,
01:07:11but kind of.
01:07:12How do you make them feel comfortable
01:07:14moving forward down that route?
01:07:16Yeah,
01:07:17that's a great question.
01:07:18Doctor goes on, I think.
01:07:19I think it takes a lot of open communication,
01:07:24listening understanding their fears,
01:07:26goals of care, but also spending
01:07:30time laying out the rationale.
01:07:33I like to say these trials were conceived
01:07:35by the best minds in breast cancer,
01:07:38essentially synthesizing all the
01:07:40best data that we have to date.
01:07:43And here's why.
01:07:44We're thinking that more is not
01:07:46necessarily more so it does take more time.
01:07:50But I think I tend to use that
01:07:52as an educational opportunity,
01:07:54and certainly if they don't feel comfortable,
01:07:57that's their choice.
01:07:59But I think regardless,
01:08:01I think it opens up the dialogue for
01:08:04potentially an additional trials down
01:08:05the road just to get them comfortable
01:08:08about the clinical trial process,
01:08:10how these concepts are vetted so
01:08:14carefully and that we would never.
01:08:17Consciously give a therapy
01:08:18that is known to be so far.
01:08:22Angel yeah. In a safer,
01:08:26vulnerable population.
01:08:27So many women have to work
01:08:29and have to take care of their
01:08:32families during treatment.
01:08:34And it's not a choice.
01:08:37And if we can deescalate it can
01:08:40be the difference between being
01:08:42unemployed and maybe losing housing
01:08:45and losing ability to take care
01:08:48of the rest of their life so
01:08:51they can be attractive. Slowly.
01:08:57There is a question in the chat box
01:08:59from Carolyn Friedman and maybe Andrew.
01:09:01You want to tackle this first and then
01:09:04the other is why are dense breast
01:09:06dense breasted women still getting
01:09:08yearly mammograms and nothing else?
01:09:10And maybe a little bit about
01:09:11the difference between kinetic
01:09:13and maybe some other states.
01:09:15I'm, well, Connecticut was one of the
01:09:19first states to pass a wonderful law
01:09:22mandating that women are identified
01:09:25as having dense breasts and making
01:09:28sure that there is insurance
01:09:31coverage for additional testing
01:09:34either an ultrasound or an MRI.
01:09:39An Carolyn, you bring up a great point.
01:09:42Many states have signed on to this.
01:09:45But not all States and you ask a question.
01:09:51I think it's a matter of priorities.
01:09:54Connecticut has been very good
01:09:56in terms of advocacy,
01:09:58and there was a tremendous advocate
01:10:01who got this through after her own
01:10:05experience of having a mammographic
01:10:08le undetectable tumor.
01:10:10That was an advanced cancer.
01:10:15Thank you Andrea. A question for.
01:10:18Michael, I'm here Chesapeake early on,
01:10:22about two years ago it posed a question
01:10:24in an editorial where to platinum
01:10:27salts it in triple negative breast
01:10:30cancer in the neoadjuvant setting.
01:10:32You know, have things changed,
01:10:34or is it still something that were?
01:10:37You know struggling through case by
01:10:39case and differences maybe between
01:10:42bracca specific T NBC versus sporadic.
01:10:47It's a good question and we still
01:10:49do struggle with it an it's we it.
01:10:51I think it's fair to say it's
01:10:53still not standard of care.
01:10:55There are a number of trials that that
01:10:57have shown that when it's incorporated
01:10:59into the neoadjuvant setting,
01:11:01it improves the pathological
01:11:02complete response rate.
01:11:04So if you are of the mind that the goal
01:11:06of treating early stage triple negative
01:11:09breast cancer is to maximize the triple,
01:11:11the maximized,
01:11:12the pathological complete response
01:11:14rate because we know those patients
01:11:16are the best to be cured.
01:11:18Then it's reasonable to
01:11:20consider incorporating it.
01:11:21One might not think it's
01:11:23worth incorporating it in a
01:11:25relatively lower anatomical risk,
01:11:28so maybe a stage one patient or,
01:11:31and as you said,
01:11:33we know from the metastatic
01:11:35setting with the TNT trial that the
01:11:37response rate for BRCA germline
01:11:39mutation carriers is quite high,
01:11:41so it may be worth incorporating
01:11:43it in that standpoint,
01:11:45although there was an early
01:11:47stage trial that compared.
01:11:49Yes,
01:11:49this Platten to standard chemotherapy
01:11:51and it wasn't much of a difference in
01:11:53terms of pathological complete response.
01:11:55For just just that comparison.
01:11:58So it's still a question that's up
01:12:00in the air whether to incorporate
01:12:02it into the early stage.
01:12:07There's a probably a question maybe
01:12:09for Andrew, but also others in the
01:12:11chat box from our fellow Angelique.
01:12:13Has there been any reduction of
01:12:16the disparities in outcomes between
01:12:18minority races and white women in
01:12:20the last two or three decades?
01:12:22And maybe expanding on some of the exciting
01:12:25work and research that you've been?
01:12:27An advocacy that you've been
01:12:29doing here here at home?
01:12:32I'm. We do a lot better in Connecticut
01:12:35than in rest of the country.
01:12:38Some of the disparities in terms of outcomes,
01:12:43certainly in terms of
01:12:45screening and access to care,
01:12:47are better in this state than many others,
01:12:50but there is still a huge disparity.
01:12:54Partially because white women are
01:12:58doing better, which it increases.
01:13:02But the difference between races and I think.
01:13:08You know, we've got a long way to go.
01:13:14There is a question in the chat box
01:13:17from Professor Rim and Merriam.
01:13:19Do you want to 'cause I can't even
01:13:22pronounce half the drugs that you guys
01:13:24can put out the transducer map I get,
01:13:26but the others are tougher.
01:13:29Yeah, it's great.
01:13:30Great question, so I think I
01:13:32think what you're pointing at is,
01:13:34I think our our poor man's definition
01:13:37of what's triple negative and
01:13:39what's to her two positive.
01:13:42I think it's going to change a lot
01:13:43in the coming years because of these
01:13:46antibody drug conjugate therapies.
01:13:50Drugs like this have shown to have
01:13:53remarkable activity even in what we would
01:13:55consider normally hurting negative,
01:13:57but just a little bit of
01:13:59her to her too low signal.
01:14:02Is associated with significant outcomes.
01:14:04So I do agree with you Doctor Ram that I,
01:14:09I suspect, as these trials are finalized,
01:14:13I think we will be looking at
01:14:15different standards or care
01:14:16for this purchase subgroup.
01:14:18And for those who couldn't see the question,
01:14:20it will is will trousers some outdoor
01:14:23teak sent he can make all low.
01:14:25Her two patients targets
01:14:26for this sort of therapy.
01:14:28And will this change the
01:14:30triple negative category so?
01:14:33So, so it's like, yeah, I think
01:14:35obviously we need to wait for additional.
01:14:38You know, phase three data for that category,
01:14:41but so far the results are very,
01:14:44very promising. I think there may
01:14:48be additional Adcs that maybe safer.
01:14:52But with this particular drug,
01:14:54the higher, higher risk of interstitial
01:14:56lung disease is a concern.
01:14:58But but, but I, I really think
01:15:00we're going to have a lot more.
01:15:02ABC's in the next few years,
01:15:05and they seem to be very
01:15:07effective class of drugs.
01:15:09So maybe a question for all three of you.
01:15:13You know, I guess, how do you you
01:15:15know in your leadership positions and
01:15:17when you go to advocate for these
01:15:19drug therapy trials to be developed,
01:15:21you know how do you convince drug
01:15:24companies and pharmaceuticals to
01:15:26deescalate when so much of their work
01:15:29is based on giving more so that they
01:15:31can make more money for themselves and
01:15:34their shareholders and that kind of that.
01:15:38Challenge that you know that we all we all
01:15:41face in in in this in these discussions.
01:15:48No simple answer, I'm sure. I
01:15:49think there is such a mark.
01:15:52I live in a market because
01:15:54these are human lives,
01:15:55but there there there is so much need.
01:15:59For additional therapeutic that
01:16:00sadly there is a market to have
01:16:02new drugs that address things.
01:16:04But one thing if we were talking
01:16:06about the business model of things
01:16:08is what happens in breast cancer?
01:16:09Is if an agent is shown to be effective
01:16:12in the metastatic setting then we move
01:16:14it forward to the earlier stages.
01:16:16Untested and early state setting.
01:16:17So just take the CD 46 inhibitors
01:16:20or even even some of these Adcs.
01:16:23I think the market will expand
01:16:24and they will be tested in these
01:16:27earlier stage cancers with the
01:16:29goal of improving outcomes so.
01:16:31I don't, I think they'll do fine.
01:16:33I think they'll be OK.
01:16:35And I guess I would add the drug
01:16:37looks the best when it has the best
01:16:38outcome and the drugs have the best
01:16:40outcome when they are used in the
01:16:42population for which they there
01:16:43is really the benefit for them.
01:16:47And I was going to say,
01:16:48with respect to disparities,
01:16:51that if more people who had chronic
01:16:55conditions from different backgrounds
01:16:58were in the clinical trials,
01:17:02they would better be able to evaluate
01:17:05is more better for everyone.
01:17:07What happens with the diabetic obese patient?
01:17:10Maybe more isn't better for them,
01:17:13and because so many of these
01:17:16patients are excluded from trials.
01:17:18We're able to say more,
01:17:20maybe better for the healthy,
01:17:23wealthy and wise patients,
01:17:26but not necessarily for other patients.
01:17:32And maybe that points to the kind
01:17:33of the low resource countries,
01:17:35because a lot of this has been focused on,
01:17:37you know, discussions,
01:17:38and what happens here in the
01:17:39United States and you know,
01:17:41many of the audience you know are
01:17:43what may be potentially calling
01:17:45in or watching from overseas
01:17:47and a low resource settings.
01:17:50And you know some of the challenges
01:17:52they may face not having the
01:17:54access of the same drug therapies
01:17:56that we do here in the US.
01:18:01Yeah, so the the World Health
01:18:03Organization has launched a new
01:18:05global Breast health initiative,
01:18:08and there are actually looking
01:18:10for interested members to apply
01:18:13to be part of these committees.
01:18:15Looking at different pillars
01:18:17and that includes diagnostics.
01:18:20That's one area where if you can't even
01:18:22determine her two results reliably,
01:18:25you know how can you even
01:18:26determined a good therapies.
01:18:27So there's a. There's a pillar.
01:18:29Focus on Diagnostics,
01:18:30an access to therapeutic.
01:18:32Supportive care and symptom management.
01:18:34So I think there are some exciting
01:18:37developments in diagnostics so
01:18:39that we can at least have a better
01:18:42understanding of the subtype of breast
01:18:44cancer and then further working with
01:18:47pharma companies to form collaboration.
01:18:49So so for those who are interested
01:18:52WHO is now accepting applications
01:18:54to these committees,
01:18:55and if you need if you want to be in touch,
01:18:57I'm happy to put you in touch.
01:19:00I'm also encouraged at Yale seeing
01:19:03younger physicians who are very,
01:19:06very interested in lower resource
01:19:10nations an in devoting their academic
01:19:14careers to finding some solutions.
01:19:20Excellent and any parting words.
01:19:23Merriam, Andrea, Michael.
01:19:28I just wanted to thank Doctor
01:19:31Gauchan for organizing the series
01:19:33of best breast care is really,
01:19:35truly multidisciplinary and I think Next
01:19:40up will be radiation oncology, correct?
01:19:43And I'll say that you asked about the
01:19:45difficulty of getting patients on
01:19:46some of our other clinical trials,
01:19:48and I'll say clinical trials
01:19:49is also the best care.
01:19:52Absolutely.
01:19:54And I was just going to conclude by
01:19:56saying I'm lucky to be able to work with
01:19:59the colleagues that I can because we
01:20:01really do have a breadth of experience.
01:20:03And thank you very much for having me here.
01:20:07Thank you everyone and would like to
01:20:09thank all the participants you know,
01:20:11calling either from the office
01:20:12next door or from overseas.
01:20:14This is a lot of fun. Thanks so much.