Emerging Strategies in Breast Cancer Treatment and Care

October 20, 2022

October 19, 2022

Presentations by: Michael DiGiovanna, MD, PhD, Rachel Greenup, MD, MPH, Christin A. Knowlton, MD, MA, John Lewin, MD, and Haripriya Ayyala, MD

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00:00Yes.
00:03So targeting her 2IN breast cancer
00:06has resulted in markedly improved
00:08results in treating this disease.
00:11And as this slide shows,
00:12there are now eight her two targeting
00:15drugs that are FDA approved not including
00:18biosimilars or subcube preparations
00:19and most with indications in multiple
00:22settings and six new drug or disease
00:25setting approvals just since 2019.
00:28In this talk, I'd like to focus on
00:31recent results with the antibody drug
00:34conjugate trastuzumab Durex tecan.
00:36Include with my personal thoughts about
00:40application of this particular drug in
00:43phase one studies trastuzumab dierickx
00:46tecan had remarkable activity not only
00:49in her two positive breast cancer.
00:52But as shown here also another her
00:54two positive tumor types and in
00:56breast cancer that was assayed as
00:58her two IHC one plus and two plus
01:01that were called her two low.
01:03I'll return to this group
01:05in just a few moments.
01:07Getting back to her two
01:09positive breast cancer,
01:10the destiny breast 01 trial was
01:12a single arm phase two trial of
01:15trastuzumab Durex tcan for her two
01:17positive metastatic breast cancer.
01:19All patients had prior treatment.
01:21With trastuzumab and TDM,
01:23one and 2/3 had prior treatment.
01:26With pertuzumab,
01:26the median number of prior lines of
01:29therapy in the metastatic setting was six,
01:32and 92% had visceral metastases.
01:37The results showed again remarkable
01:40activity in this or two positive
01:44population with a confirmed
01:46objective response rate of 60.9%,
01:48some complete responses and a Disease
01:52Control rate of an astounding 97.3%.
01:55In this heavily pretreated population,
01:59the median progression free survival
02:02was 16.4 months and the median
02:04overall survival has not been reached.
02:07At the time of the initial publication,
02:09the median duration of response
02:11was 14.8 months and again in a
02:15very heavily pretreated population.
02:17So the results of this trial led to
02:20FDA accelerated approval of this agent
02:22in December of 2019 for patients with
02:25her two positive metastatic breast cancer.
02:28Following two or more anti
02:31her two based regiments.
02:33The destiny breast 03 study was
02:35a randomized phase three trial
02:37of trastuzumab dierickx team can
02:40versus TDM one for patients with
02:42metastatic her two positive breast
02:45cancer with prior trastuzumab and
02:47and taxane treatment and this once
02:50again showed superior progression
02:52free survival and overall response
02:55benefit across all subgroups.
02:57The confirmed response rates were
03:00almost 80% for trastuzumab Drex Tcan.
03:04Versus 43.2% for TDM one and this
03:07trial led to full FDA approval of
03:10this agent in May of this year.
03:14Phase One expansion result.
03:18Showing here, Debbie one,
03:19that there was remarkably high
03:21response rates for patients with
03:23tumors that were her two negative,
03:25but IHC one plus or two plus.
03:29This led to a randomized phase three
03:32study in this 1 + 2 plus population
03:35destiny breast O four of trastuzumab DirectX,
03:38tecan versus chemotherapy treatment
03:41of physician's choice.
03:42Patients could have had one or two
03:45prior lines of chemotherapy for
03:47recurrence or or recurrence within
03:48six months of adjuvant chemotherapy.
03:51This study enrolled 557 patients
03:54of which 88% were hormone receptor
03:57positive but considered endocrine
03:59therapy refractory.
04:00And 70 to 80% of the patients also
04:02had a prior CDK 46 inhibitor.
04:06The results showed markedly
04:08improved progression free survival
04:11for trustees mapped DXT can,
04:13compared with chemotherapy,
04:14a physician's choice in the
04:17hormone receptor positive group
04:19and similarly in all patients.
04:21Overall survival as well was improved
04:25in both groups by over six months
04:29and confirmed objective response
04:31rates were remarkably higher for
04:33trastuzumab DirectX tcan in both
04:35hormone receptor positive and hormone
04:37receptor negative patients as shown
04:39here as were the clinical benefit
04:42rates and the duration of response.
04:45So this these remarkable results in
04:48what we're conventionally her two
04:50negative metastatic breast cancer.
04:51Patients suggests that it takes
04:54very little her to expression for
04:56on tumor cells for this drug to
04:59have activity against a tumor.
05:01And based on the results of this trial,
05:03in August of this year the FDA
05:06approved a new indication for
05:08trastuzumab direct can for patients
05:10with what has now been termed quote
05:14her too low metastatic breast cancer.
05:17So I would like to share my thoughts
05:19and concerns about the omission from
05:21these studies and an omission from
05:23the FDA approval of patients who
05:25have tumors that are hurt to IHC 0.
05:29So first, regarding the technique of IHC,
05:33this is not a quantitative assay,
05:36but rather a qualitative test best
05:38at detecting the presence or absence
05:40of an antigen under the conditions of
05:42the essay and the tissue preparation.
05:45It might be considered at best
05:47semi quantitative and conventional.
05:49IHC is subjective as it's interpreted
05:52by the reader's eye.
05:53There are technologies to adapt
05:56immunodetection of antigens and
05:58tissue for quantitation,
05:59including one termed Aqua developed by
06:02my Yale colleague David Rim and Bob Camp,
06:05but these are generally not used
06:07in routine clinical practice.
06:09It just so happens that with
06:11her two immunohistochemistry,
06:13strong staining in formal and fixed
06:15paraffin embedded tissue correlates very
06:18well with her two gene amplification
06:20and performs well at identifying
06:22a tumor that is biologically.
06:24Driven by her,
06:25too.
06:27These original results by
06:29Dennis Slayman and colleagues,
06:31reported in science in 1989,
06:34compare for five different tumors.
06:36Her two gene content by Southern blot,
06:39her 2M RNA expression by northern blot,
06:43and protein expression by Western blot,
06:45which is what I want you to focus on,
06:48and immunohistochemical staining.
06:49And you can see that even the tumor
06:52here with the weakest or almost absent
06:56immunohistochemical staining in the 4th lane.
06:58That lacks her two gene amplification
07:00and has low levels of her 2M RNA.
07:03Clearly has her two protein
07:05detectable by Western blot.
07:07And I want to make the point that her
07:10two IHC result of zero in formalin
07:13fixed paraffin embedded tissue is
07:16not necessarily her too low null.
07:18And I suspect that there are
07:21really likely no breast tumors
07:23that are completely her to null.
07:25So what we've learned is that her
07:28two positive breast cancer expresses
07:30about 2,000,000 molecules per cell,
07:33and that level is about 100 times the
07:35normal level of her two expression,
07:38which is in the range of about
07:3920,000 molecules of her two per cell.
07:43So rather than refer to breast cancer as
07:46her two positive versus her two negative,
07:49a more appropriate description in
07:51my opinion is her two overexpressing
07:53versus her two normal.
07:58Never intending to be quantitative,
08:01Mike Press suggested the well known
08:03scoring system for her two IHC which is
08:06shown here which was designed to allow
08:08routine testing in pathology labs giving
08:11their ability to swing distinguish.
08:13Her two driven her two overexpressing
08:16breast tumors from all the others and
08:19it turned out that high level protein
08:21over expression by IHC most of the time
08:24correlated with her two gene amplification.
08:27And pathologists could relatively easily
08:29identify tumors with overexpression.
08:34David Rimm has found in the
08:36publication shown here that even
08:38experienced pathologists don't have
08:40a high level of agreement on scoring
08:42for breast cancers that are not,
08:45frankly her, too positive.
08:47In this publication,
08:48he showed that data from the College
08:51of American Pathologists surveys
08:52on a series of about 1400 breast
08:55cancer cases showed that 19% of the
08:58cases generate results with less
09:00than or equal to 70% concordance
09:02for her two IHC 0 versus 1 plus.
09:06And in another series of 170 Yale
09:09Cancer Center cases that was
09:11distributed to 18 pathologists,
09:13there was only 26% concordance
09:16between IHC Zero and one plus.
09:22In another study, David Rimm's
09:23group used his Aqua method of
09:26quantitative immunofluorescence to
09:28develop conditions that could more
09:31quantitatively measure levels of her
09:332IN non overexpressing breast tumors.
09:36And this plot shows quantitation
09:38of her two levels in cases that
09:41are IHC 3 plus shown in Green,
09:442 plus shown in black,
09:46one plus shown in red,
09:49and zero is shown in blue.
09:51And you can see that her two protein
09:54was detected in all of these cases,
09:57and within the limit of linearity
09:59of this particular assay,
10:01cases that were called by
10:03pathologists 2 + 1 plus or zero
10:06are fairly randomly distributed.
10:08Doctor Rimm suspects that there may
10:10be a small percentage of cases,
10:12not more than 10%,
10:14that may truly have undetectable
10:16levels of her two.
10:17But I actually remain unconvinced
10:19so far that there are any truly
10:23her two negative breast cancers.
10:25Two studies looked at whether there
10:28are actually clinical differences
10:29in breast cancer behavior between
10:31tumors that are her 20 or those
10:33that are being called her too
10:35low one plus or two plus.
10:37The first study from Canada looked
10:39at 319 cases and suggested that
10:42her 20 cases compared to 1 pluses
10:45and two pluses were actually
10:47more likely to be high grade,
10:49have lower ER histo score,
10:52be less likely to be PCR positive.
10:54Be more likely to be triple negative
10:57and have worse overall survival,
10:59which is actually counterintuitive
11:00to the known association of her
11:03two with more aggressive disease.
11:05However,
11:05a larger study from Dana Farber
11:08with over 5000 cases showed that
11:10although once again her two
11:12zeros seem to be less likely to
11:15be hormone receptor positive,
11:17they actually showed no difference
11:19in disease free survival,
11:20distant disease free survival,
11:22overall survival or pathologic
11:24complete response rates for those
11:27who got neoadjuvant chemotherapy.
11:28And that suggested that her
11:30two low breast cancer is not a
11:33distinct biological subtype.
11:36Finally, the Daisy study actually
11:39examined the activity of trastuzumab
11:42direkt can in all breast cancer
11:44subtypes with three cohorts shown here.
11:47Cohort 1 being conventionally
11:49hurt you positive patients,
11:51Cohort 2 being IHC one plus
11:53or two plus fish negative,
11:56what we now call her too low and cohort
11:593 being actually her 20 cases and
12:03responses were seen in 33% of the 72.
12:06Were too low cases, but also in 30.6% of
12:11the 30s of the 36 her two IHC 0 cases.
12:16So while the IH2 IHC 0 cases were slightly
12:20numerically less and the numbers are small,
12:22this study certainly supports activity
12:25of this agent in her 20 cases.
12:30So to summarize, I think I've discussed
12:33that IHC is not a quantitative assay,
12:37that pathologists have difficulty
12:39in distinguishing between her
12:41two one plus and 0 cases,
12:43that her two can certainly
12:45be measured in IHC 0 cases,
12:47that her two IHC breast cancers behave
12:50similarly to quote her two low cases,
12:53and that in the Daisy trial
12:55there was activity of trastuzumab
12:57dierickx tikan in her two.
12:590 cases that is with the
13:01small number of cases tested,
13:04really not very different from the
13:06activity seen in quote her two low cases.
13:09So I reiterate that her two IHC 0
13:12is not necessarily her to null and
13:15I suspect that no breast cancer
13:18is completely her to know.
13:20And it's clear that what we would
13:23consider normal levels of her two
13:26expression can confer sensitivity
13:27to trastuzumab direkt CAD.
13:29So I want to state that I think we
13:32know that there is her two expressed
13:34and there is her two normal.
13:37But I don't feel that we know for
13:39certain that there is any other
13:41category but besides those two categories.
13:43And so I make somewhat of a
13:45provocative statement,
13:46but I think I prefer I would propose
13:49that perhaps we should not be excluding
13:51her 20 IHC patients from potentially
13:54benefiting from trastuzumab dierickx T
13:56can I note that this would be off label?
13:59Use,
14:00but I think scientifically and
14:02with support from the Daisy trial,
14:04we could consider this agent
14:05for patients with her two zeros
14:08that otherwise don't have any
14:09other good treatments for them.
14:13That's my last slide.
14:17Thank you, doctor Digiovanna.
14:19That was a fantastic real overview
14:22of the evolving definition
14:24of her too and positivity.
14:26I'm sure that'll create some provocative
14:29hopefully questions in the chat box.
14:31And also later in the panel session,
14:36we're going to move on to
14:38Doctor Rachel Greenup,
14:38who's our chief of breast surgery
14:41here at Yale Department of
14:42Surgery and Associate Professor
14:44of surgery I'm talking about.
14:46Dates and breast cancer surgery.
14:47Thank you, Doctor Greenup.
14:54My name is Ray.
14:55Give me one second.
14:57I just have to.
15:01Re share.
15:10Can you see that? OK, great.
15:14Thank you for having me.
15:16So I'm Rachel greenup.
15:17I'm a associate professor of breast surgery.
15:20I've been at Yale about a year and a half,
15:22and I'm excited to be
15:24here with you all tonight.
15:26So I often start with this slide because
15:29one of our favorite things about breast
15:32cancer surgery is seeing the incredible
15:34strides we've made in practicing.
15:36And by reducing what we do unnecessarily
15:39and seeing how it improves patient outcomes.
15:42So we stopped doing radical
15:45mastectomies in the 1990s,
15:47early 2000s,
15:48when we learned that lumpectomy with
15:50radiation was equally effective.
15:52And you can see this picture here,
15:54this old black and white photo
15:56of this woman who's really had
15:58extensive surgery with resection
15:59of her pectoralis muscle.
16:01It's so rare for us to need to
16:03do such extensive treatment in
16:062022. I don't think the slides
16:08are forwarding yet, seeing that.
16:11We're still on the updates and breast cancer.
16:15And that's happening. Let me.
16:20Let's try this again. Can you see that?
16:24We're looking at the Milan one trial. Yeah.
16:26OK. Sorry about that. Thank you.
16:29More recently we've been able to reduce
16:32the number of axillary lymph node
16:34dissections and significantly reduce the
16:36rates of lymphedema in women who have
16:39small amounts of node positive disease.
16:41We have good 10 year data suggesting
16:45that older women with favorable
16:48hormone receptor positive breast
16:50tumors can safely forgo radiation.
16:53We have good data to suggest that many
16:55women with hormone receptor positive
16:57breast cancer have little benefit.
16:59From chemotherapy above and
17:01beyond endocrine therapy.
17:03And we have ongoing national and
17:05international trials of of which
17:07doctor Golshan is very much involved
17:10looking at women with low grade or
17:13low risk ductal carcinoma insight
17:15two who can forego usual care
17:17for active surveillance and this
17:19is a comment trial which we are
17:22currently enrolling at at Yale.
17:24So many of our patients come to us
17:26with a breast cancer that was diagnosed
17:28on screening imaging and you can
17:30see here a traditional diagnostic
17:32mammogram with a correlating ultrasound
17:34showing a biopsy proven breast cancer.
17:37And I'm going to start with breast cancer
17:39screening even though Doctor Lewis here,
17:41I'll be brief.
17:42There's been a lot of opinions over
17:44several years and as a group we are
17:48generally recommending screening
17:49starting at 40 on an annual basis,
17:52we more recently.
17:54In our American Society of Breast
17:57surgeons community,
17:58there has been formal guidelines that
18:00came forward in 2019 suggesting that
18:03women over 25 should undergo formal
18:05risk assessment for breast cancer
18:07based on personal and family history
18:09and that they were also eligible
18:12for consideration of screening.
18:14In addition,
18:15these guidelines were really
18:17valuable for practicing surgeons
18:18and that they included potential
18:21recommendations for supplemental imaging,
18:23including 3D mammography.
18:25MRI and or screening ultrasound
18:28for which yells very well known.
18:32When we meet our patients with
18:33a breast cancer diagnosis,
18:35many of them have options for
18:37surgery and this is a black and white
18:40illustration demonstrating an A
18:41simplest form of breast conservation
18:44with lumpectomy versus mastectomy.
18:46When we talk about breast conservation,
18:48that typically includes language of
18:50lumpectomy followed by radiation.
18:52But more recently we have identified
18:54a subset of lower risk patients for
18:56which radiation may not be necessary.
18:59We always defer that decision to
19:02our radiation colleagues.
19:03And we typically require support
19:05from our radiologist either through
19:08wire localized lumpectomy to mark the
19:11spot on mammogram or in modern day
19:14through localizing devices we have
19:17instrumented and operationalized tag
19:19localization across our smilo sites.
19:22And the data is suggesting that
19:24use of these smaller implantable
19:25devices that are removed at the
19:27time of lumpectomy improve comfort
19:29for patients and are associated
19:31with higher patient satisfaction
19:32scores with reduced rates of margin
19:36positivity and smaller resections
19:39of removed breast volume.
19:41I think it's worth discussing all
19:43the controversy around margins.
19:45This really hit the late press even in 2019,
19:502020.
19:50And this was based on the fact that
19:52re excision rates historically
19:54were really high ranging from 15
19:56to 25% and many of women who went
19:58back for second
19:59surgery had close but negative margins,
20:01meaning the second surgery did not
20:04identify identify residual disease.
20:06So there was a clear lack of consensus
20:08about what was enough and there was
20:10wide variation in clinical practice.
20:11Across the country. Doctor Moran,
20:14who leads our breast radiation oncology
20:17program was really critical in taking
20:19the lead on bringing together experts
20:21from a multidisciplinary perspective.
20:23They reviewed 33 men and 33 studies in a
20:27meta analysis including over 28,000 patients.
20:29And what they found was that certainly
20:32positive margins did definitely increase
20:34the risk of in breast recurrence.
20:36However, no tumor on ink for
20:39invasive ductal cancer was considered
20:41considered a negative margin and that.
20:44Age Histology size did not impact these
20:47findings and no amount of added radiation or
20:51chemotherapy could overcome good surgery.
20:54And Doctor Moran,
20:55in a partnership with many colleagues
20:58from across the country in both
21:01surgery and radiation also replicated
21:03this process for DCIS,
21:05which was really practice changing.
21:07And when we estimated the number of
21:09surgeries that it saved per year,
21:11it was about 25,000.
21:15Additional research that came out
21:17of Yale looking at margin was the
21:19landmark trial by Doctor Ennis Chappar.
21:21This was a randomized clinical trial,
21:23small numbers,
21:24yet it was one of the few local
21:26regional trials done in breast
21:28cancer for quite some time.
21:30And women were randomized to either
21:33having margins resected according
21:35to the discretion of the surgeon or
21:37routine cavity shave margins and it
21:39clearly reduced the rate of margin
21:42positivity and the need for re excision
21:44by about half and again practice.
21:46Changing for our surgical community.
21:49When we talk about mastectomy,
21:50we talk about removing the breast tissue.
21:52This can be done with or without
21:54reconstruction and we have wonderful
21:56plastic surgery colleagues that can
21:58offer either implant based and or
22:00autologous tissue reconstruction.
22:02And you'll hear from Doctor Ayalla
22:04later in our session,
22:06we know that there's been an increasing
22:08rates of contralateral prophylactic
22:10mastectomy or double mastectomy
22:12and that these rates have tripled
22:14in the last 40 years.
22:16I show this picture always of Angelina
22:18Jolie because she has a known Braca 1
22:20mutation and came out publicly talking
22:22about her choice for double mastectomy.
22:24Yet she's at incredibly high risk,
22:27as are our other hereditary
22:30cancer populations.
22:31But this data is really reflecting average
22:34risk women who don't have a high risk
22:37of developing cancer on the other side.
22:39We know that when women have their
22:42unaffected breast removed and have
22:44no hereditary Cancer syndrome,
22:45removal of the healthy breast does
22:47not add oncologic or survival benefit
22:49and is unfortunately associated
22:51with a small increased risk of
22:54surgical complications.
22:55But we do know many of our patients
22:57choose double mastectomy for the
22:59benefit of reduced surveillance,
23:01improved symmetry and Peace of Mind.
23:03And so again,
23:05our association of Breast surgery
23:07came forward in 2016 with a consensus.
23:09Statement saying that we should consider
23:12double mastectomy but not recommend it.
23:16We are increasingly doing
23:17a greater number of ******
23:19sparing mastectomies.
23:19We need to think about distance
23:21of the tumor from the ****** the
23:23skin quality, the tumor side.
23:25Increasingly we're realizing that
23:26even BRCA mutation carriers can
23:28safely have this operation done and
23:30the improved aesthetics for some
23:32women really helps them make it
23:34difficult choice for risk reduction.
23:38A little bit of a plug for our program,
23:40we're ready to launch a home recovery
23:43after mastectomy program at Yale.
23:44And this is really for a very select
23:47group of patients who live near the
23:49hospital who want to go home for
23:51recovery and who have a a safety
23:53net or support system with family,
23:56friends and a visiting home nurse.
23:58And we're excited to launch that program
24:01to again improve patient experience
24:03and choice of how they recover after
24:06such a life changing operation.
24:08When we think about managing
24:09lymph nodes in the axilla,
24:10we have good data from almost a decade ago,
24:13the Acas Oxy 11 trial that showed
24:15that women have a small amount
24:17of nodal positivity do not need
24:18a full lymph node dissection.
24:20We can rely on systemic therapy and
24:23radiation to sterilize remaining nodes.
24:26And we have a long-awaited data coming soon,
24:29hopefully from the Alliance 11202
24:31trials suggesting that women who have
24:34upfront biopsy proven nodal disease,
24:36who go on to have chemotherapy.
24:39And convert either to node negative
24:41or node positive may be able to rely
24:44on radiation further deescalating the
24:46need for completion lymphadenectomy.
24:50Lastly, I'd like to talk
24:52about genetic testing.
24:54We had clear NCCN guidelines around
24:57who was eligible for and covered for,
25:00from an insurance perspective,
25:02hereditary cancer screening.
25:04This study by Peter Beija was the
25:07first to suggest that we were probably
25:09missing a large group of women who
25:12did not meet our historic criteria,
25:14who then went on to have positive
25:16test results and again this prompted.
25:19Changes in our American Society
25:21of Breast surgeons guidelines for
25:23hereditary breast cancer testing
25:25really endorsing that any patient
25:28with a known breast cancer should be
25:30offered a genetic testing and that
25:33genetic counseling and potential
25:35testing should be made available.
25:38Finally,
25:38we have long-awaited data again from
25:41the ECOG 2108 trial suggesting that
25:44removal of the primary breast tumor
25:46in women with metastatic disease
25:48does not improve overall survival.
25:50This was a study by Seema Khan
25:52and Doctor Golshan was also very
25:55involved in this national discussion.
25:57They looked at a secondary outcomes
25:59of chest wall disease and patient
26:01quality of life.
26:02Women went on to have breast
26:04conservation or mastectomy with
26:06negative margins and systemic.
26:08Treatment at the discretion
26:09of their treating team.
26:11And essentially we found
26:12that local regional therapy,
26:13including surgery and radiation
26:15did not extend survival in
26:17women who were diagnosed with
26:19newly metastatic breast cancer,
26:21but it did have some improvements
26:23on controlling disease and
26:25disease progression locally.
26:27So that's a whirlwind tour on
26:29updates and breast cancer surgery.
26:30I'd be happy to take any questions
26:32and thanks for joining us.
26:35Thank you. Doctor Greenup having you
26:37here lead our breast surgical program
26:39is just absolutely fantastic and all
26:41the work that you've done whether it's
26:44in the home recovery from mastectomy
26:46and others is so welcome here.
26:50We're going to move on to doctor
26:52Kristen Knowlton.
26:52Doctor Kristen Olson is one
26:54of our radiation oncologist.
26:55She's also the director of our
26:58Smilo site and Hampden and also our
27:01NA PVC lead and director here at
27:05our Yale New Haven Hospital site.
27:08She'll be discussing a radiation oncology.
27:14Great. Thank you.
27:15Are you able to see my screen?
27:17Not yet. OK, all right.
27:22OK. Here we go. How about now?
27:25Yes. OK. All right.
27:27So hi, I'm Kristen knolton.
27:30Thank you for the introduction.
27:31And this is our updates in radiation
27:35oncology from the Smilow Breast Center.
27:38So the Smilo network, as we all know,
27:41the Smilow cancer hospital, Yale,
27:43New Haven Health Network spans quite
27:46a bit of Connecticut and radiation
27:49is offered at Rennich Trumbull.
27:51We have Derby where,
27:53well that is under Griffin Hospital.
27:56The physicians who treat patients in the
27:59radiation oncology Department are Yale
28:01physicians from our department, Hamden,
28:04New Haven, Guildford and Waterford.
28:07And each site has a representative
28:10from what we call the breast team
28:12and which means that that person
28:15specializes in Breast Cancer Care,
28:17attends tumor boards,
28:19attends our weekly Recology Center,
28:21radiation oncology.
28:22Eating and breast chart rounds as well.
28:24And all of the sites within
28:27the Smilow Cancer Hospital,
28:28Yale New Haven Health system have
28:30apex accreditation that stands for
28:33accreditation programs for excellence.
28:35And that's under the auspices of Astro,
28:38which is essentially the premier radiation
28:40oncology society in the United States.
28:43And one could also argue globally,
28:45except for Derby,
28:46but Derby does also have great accreditation
28:50from the American College of Radiology.
28:53So all sites that shows that we
28:55have no clear concrete evidence
28:57that we are providing high quality
29:00patient centered care at all sites.
29:03So the breast team is led
29:05by Doctor Marina Mina Moran,
29:07she's a professor in our department.
29:08She's obviously chief of our
29:11breast cancer radiation oncology
29:12group and she's also vice chair
29:15of the NCCN Breast Cancer panel.
29:17And under her leadership the
29:19Breast team practices high quality
29:22evidence based Breast Cancer Care.
29:24And what that really means is that
29:27we we strive to always provide
29:29care that is supported by high
29:31quality data with meaningful.
29:33Follow up.
29:34Also the rest team participates in
29:36clinical trials often in conjunction
29:39with our medical oncology and
29:41surgical oncology colleagues.
29:43We hold weekly disease site
29:45specific chart rounds.
29:46We've adopted systemwide planning
29:48goals and objectives and the point
29:51of this team approach is that to
29:53that to ensure that when patients
29:54go to any site where we offer
29:57radiation oncology within the smilow
29:59cancer hospital system that the
30:01patient will get similar care.
30:03I do want to go back to this disease.
30:05Site specific chart rounds specifically to.
30:08So in radiation oncology,
30:11it's mandated that all radiation
30:14plans get reviewed by your
30:16peers and it happens weekly.
30:19And in our department,
30:20we used to do all sites together.
30:23But under me and his leadership,
30:24we started to have breast cancer
30:27disease teams chart rounds on our own,
30:29separate from the rest of the
30:30group so that we could really
30:32concentrate and delve in deeply
30:33into the breast cancer cases.
30:35And she really was ahead of the curve
30:37when we started that seven years ago
30:39and we were the first disease team in
30:41our department to do that subsequently.
30:43Now the Gu team and the
30:45thoracic team are doing
30:46that. So I chose thinking
30:48about our talk today,
30:50I chose to concentrate on our
30:52commitment to de escalation of care,
30:54which is certainly an important emerging
30:57strategy in breast cancer treatment.
30:59And specifically I chose to concentrate
31:02on our clinical trial participation
31:05because I do believe that our departments
31:08clinical trial participation really
31:10shows our commitment to embracing
31:12and helping move forward escalation
31:15of care and what I mean by that.
31:17Is either decreasing the dose
31:20or the number of fractions,
31:22or maybe even omitting radiation completely,
31:26but aiming to decrease toxicity
31:29essentially while keeping
31:31outcomes the same or even better.
31:34So an important trial that
31:37recently closed at our institution,
31:39but we was open and we enrolled
31:41a large number of patients.
31:42It's called the idea study and it
31:45stands for individualized decisions
31:46for endocrine therapy alone.
31:48And the Pi locally was Doctor Moran
31:51and this will piggyback a little bit
31:54on Doctor Greenup's discussion where
31:57she mentioned the CLG B9343 study.
32:00So that study was a well done phase three.
32:03This trial with over 12 years of
32:06median follow-up that has shown us
32:09that patients over 70 with a tumor 2
32:12centimeters or less estrogen receptor
32:14positive excised with negative
32:17margins and negative nodes either
32:20clinically or surgically tested.
32:22Those patients if they take endocrine
32:24therapy they can do very well
32:27and radiation therapy can safely
32:28be withheld in that group.
32:30So the idea trial,
32:32the goal is to expand on that.
32:35We start looking at younger ages,
32:3650 to 69,
32:38but this is a single ARM cohort study.
32:41So it's not a randomized trial,
32:42it's a single ARM cohort study
32:44to start exploring this.
32:46So it's similar at you know
32:48hormonal receptor positive,
32:50margins negative,
32:51no negative.
32:52These patients because they're younger do
32:54need to have some sort of axillary staging,
32:57Sentinel node biopsy or axillary
32:59dissection and in order to ensure
33:02that it's a favorable cancer that.
33:05Ideally we'll behave well.
33:06The Oncotype recurrence score
33:08must be less than or equal to 18.
33:10So these patients were enrolled on
33:11the single ARM cohort study and they
33:14did not receive radiation therapy.
33:15They had their lumpectomy with their
33:18axillary staging and five years of
33:20endocrine therapy and surveillance.
33:22And the primary objective is looking
33:24at local regional recurrence.
33:26And here we have our secondary
33:28objectives looking at the rates of
33:30salvage mastectomy and also to see as
33:32local regional recurrence associated
33:34with endocrine therapy compliance.
33:36So this trial is maturing now.
33:39It's closed as we said and
33:41now the data is gathering.
33:44Also at our at Yale,
33:45we we're offering the fabric trial
33:47that closed even more recently and
33:49as we could see a pair fabric stands
33:52for study of radiation fractionation
33:54on patient outcomes after breast
33:56reconstruction for invasive breast cancer.
33:59Although ironically the people,
34:00the physicians could have stage zero
34:02but they do put invasive cancer in the trial.
34:05So the question that this is trying
34:07to answer is can we decrease the
34:09treatment time IE the number of
34:11fractions for these patients
34:13and possibly the toxicity.
34:15For patients who require postmastectomy
34:17radiation therapy in the setting of
34:20implant based reconstruction and I
34:21highlighted this to let us know that
34:24what that patients had to undergo
34:26immediate reconstruction meaning
34:27the placement of a tissue expander
34:30or an implant either at the time
34:33of mastectomy or within 30 days.
34:35So and we see they could have stage zero
34:38through stage 3 invasive breast cancer.
34:40Yeah, it was could be ER positive or not,
34:43chemo or not.
34:44It was very open but the two arms are
34:48arm two is our standard treatment
34:51which is 25 fractions for these
34:53patients to great per fraction.
34:55And the experimental arm is looking
34:58at hypofractionation cutting
34:59down the number of treatments.
35:01And in intact breast cancer cases
35:03we've seen that this can be very
35:06successful in actually with as
35:07far as controlling the disease
35:09locally and also has less toxicity.
35:11So the goal in this trial is to
35:13say hey well this also hold up.
35:15In the setting of an implant or a tissue
35:17expander to be exchanged to an implant.
35:20So the objectives for this trial
35:22were looking at physical well-being
35:23of the patients and patient recorded
35:26outcomes using the fact be instrument
35:28and here's some other patient recorded
35:30outcomes that will be looked.
35:31They were looking at pain,
35:32our mobility,
35:33lymphedema and of course we want to
35:35look at the clinical outcomes too,
35:37recurrence,
35:38breast cancer specific survival
35:39and interestingly this also wanted
35:42to see was there a difference in
35:44the two fractionations.
35:45As far as rare radiation oncology,
35:48radiation therapy side effects such as
35:50brachial plexopathy or secondary malignancy.
35:55Now we're getting to
35:56trials that that are open.
35:58So we have open now at Yale at
36:01essentially all I think of all the sites,
36:04the MA 39 trial also called the Taylor RT,
36:07I'm the local Pi for this trial and here
36:09we see the name a randomized trial of
36:12regional radiotherapy and biomarker low.
36:15Low risk node positive and T3N0
36:17breast cancer. That's a mouthful,
36:19but that's the official title and the
36:21question that this is looking to answer is.
36:24Can we withhold regional nodal
36:26radiation therapy in patients with
36:29low volume nodal disease who have a
36:32favorable breast cancer IE hormonal
36:34receptor positive and Oncotype
36:36score of less than or equal to 25.
36:39And so yes,
36:40here we see down here PCP one or two
36:42with low volume nodal disease and
36:44the definition of what low volume
36:47nodal disease is changes depending
36:49on whether axillary dissection was
36:51performed or Sentinel lymph node biopsy.
36:54Only was performed.
36:55We see here the Oncotype score.
36:57The patients could not have
36:59chemotherapy before the surgery,
37:01but it is allowed after the surgery.
37:03And however, when COVID came around,
37:06they changed it to allow some limited,
37:08they should say neoadjuvant endocrine
37:10therapy allowed because as we know
37:13during COVID some patients were placed
37:15on endocrine therapy as a placeholder.
37:17So here we see our primary
37:19objectives in in May 39,
37:21it's to compare breast cancer recurrence
37:23free interval and our secondary
37:25objectives are all our usual suspects,
37:28disease free survival,
37:29breast cancer specific survival,
37:31overall survival, local recurrence,
37:34local regional recurrence,
37:36free interval.
37:37They're also looking at ARM
37:40volume and motility,
37:41still looking at really at
37:43lymphedema and there are some
37:44quality of life questionnaires and
37:46here we see the randomization.
37:48So arm one, arm two is our standard arm.
37:52So if someone had lumpectomy standardly
37:54they were and they have regional notes,
37:57they have nodal involvement.
37:59Standard arm is whole breast to
38:01radiation therapy plus regional nodal
38:04RT or in the postmastectomy setting
38:06chest wall and regional nodal RT.
38:09So the experimental arm that the patients
38:12can be randomized to would be following
38:15lumpectomy just the whole breast
38:17irradiation therapy and not including the.
38:20Total fields of the patient had a step,
38:23they'd be randomized to no
38:24radiation therapy and of course
38:26then we'll be following them.
38:27But as mentioned,
38:28this trial remains open and patients
38:30can enroll through our department.
38:33And now we are opening this trial soon,
38:36Deborah de escalation of breast
38:39radiation and RGB R007 and this
38:42piggybacks off of the first trial
38:44I talked about the idea trial,
38:46I remember that's the one where that
38:49was that was going to be looking at
38:52the withholding radiation therapy
38:54for stage one cancers ages 50 to 69,
38:57no nodal involvement,
38:58ER positive Oncotype less than
39:0118 that was a cohort study.
39:03And the patients of course had
39:05to go on endocrine therapy.
39:06So now this is pushing that forward
39:08even further to get even more
39:10high quality evidence to say hey,
39:13can we withhold radiation therapy in this
39:15setting and this is a phase three trial.
39:17So here we see that see
39:19its patients with a T1.
39:20So we know that means 2 centimeters or
39:23less and 0 hormonal receptor positive.
39:25Her two negative Oncotype recurrence
39:27score less than 18 just like the idea
39:30trial the ages, well here you're allowed.
39:32It's a little bit more with the ages,
39:35but the whole point is to expand the ages.
39:40And so we're randomizing to arm one,
39:43which is the standard arm,
39:45which would be radiation therapy
39:47to the breast plus endocrine
39:49therapy or our experimental arm,
39:52no radiation therapy plus endocrine therapy.
39:55So while patients of all ages
39:57are really allowed to enroll,
39:58the point of this is really
40:00to start expanding this out to
40:02patients that are younger. Umm.
40:04OK. All right.
40:05So thank you.
40:10Thank you, Doctor Knowlton.
40:11A lot of great trials that have been
40:14run at Yale and are currently open and
40:17accruing your work and your team with
40:19Doctor Moran has been really fantastic.
40:22We're moving on to Doctor John Lewin,
40:25who's our chief of breast imaging.
40:28And the Espi president coming to talk
40:31about some of the latest in in in,
40:33in breast imaging available not
40:35only at Yale but potentially
40:36around the country as well.
40:38So, Doctor Lewin, the floor is yours.
40:42Thank you. Can you see my
40:46screen? Yeah, of course.
40:50So let me go to presentation mode.
40:54Alright, so thank you. So yeah,
40:57I want to talk about what's new in breast
41:02imaging and as Doctor Goldstein said,
41:04not just the Yale but everywhere because
41:06it's kind of interesting to know what's
41:08going on that's imaging effects everybody
41:10whether in primary care or in surgery.
41:14So here having just run a
41:16meeting on breast imaging,
41:18the Society of Breast Imaging
41:19meeting here are the hot topics,
41:21so as with the rest of the world.
41:23AI is a hot topic and the
41:26question is will mammograms be
41:28read by a computer in five years?
41:30And the answer is maybe.
41:33That's what we said five years ago,
41:35so it's not at all clear.
41:37The it's very easy to make a nice
41:40paper using AI to read mammograms,
41:42but now that they're starting
41:44to be implemented in clinics,
41:46we're finding railroad real world results
41:48aren't quite what we'd hoped they would be.
41:51So it's going to be a while before we let
41:53the computers read screening mammograms
41:55even without human intervention.
41:57But almost certainly in five years,
41:59AI will be used as a second read
42:02in most cases.
42:04Now the sad thing is,
42:05we know from history it will mostly depend
42:07on if there's a payment for the act.
42:08That's what happened with the
42:09predecessor of AI,
42:10which was called Computer aided diagnosis.
42:13It took off only because it was paid
42:15for and it really didn't work that well.
42:17And eventually Medicare said, well,
42:19we're not going to pay for this anymore.
42:20It doesn't actually work.
42:21But the same thing will happen with AI.
42:23If we can prove that it has merit
42:26enough and it gets paid for,
42:27it will take off.
42:29But that there's no question AI is
42:31going to have everything to do with
42:34every part of medicine and certainly
42:36radiology and certainly breast imaging.
42:38Contrast enhanced mammography is
42:40a big deal in meetings and it's
42:43a large area of research.
42:45But clinical adoption has been slow
42:47because there is no billing code.
42:49So it's just like with AI,
42:51if we can't get paid for it,
42:52it's very hard to get places to buy
42:55it when it was conceived and invented.
42:59It was about 20 years ago.
43:00The idea was that it would save money
43:02and we would all be capitated back then.
43:05For those of you who are old
43:06enough to remember,
43:06we were all told that
43:08capitation was the future.
43:10Well,
43:10that really never happened.
43:12And so the fact that it's low-cost
43:14now was actually slowing its adoption,
43:16but you'll see that it's a
43:19pretty good modality.
43:20And the thing that's a big source of top of
43:23discussion in our world is labor shortage.
43:26So there's a shortage of technologists
43:29all over the country and certainly Yale.
43:32And so if you have trouble getting
43:34them mammogram scheduled,
43:36that is why this happened,
43:37because of the pandemic and
43:40just overall great resignation.
43:42Certain number of texts decided
43:44they had enough and now
43:46we're training new tax breast
43:48radiologists are also in great.
43:50Short supply all over the country.
43:54And the last thing that is.
43:58A hot topic in breast imaging is how
44:00we screen and especially screening
44:01high risk women and then something
44:03called personalized screening and
44:05that's what I'm going to talk about.
44:07So screening, just review,
44:09mammography has been proven to reduce
44:11breast cancer mortality by seven of
44:13eight randomized clinical trials.
44:15So that's the highest level
44:16of proof you can have.
44:18The eighth trial was the Canadian trial,
44:20which was full of problems and
44:22actually one nice session and this
44:24year's meeting had to do with people
44:27coming forward who are in the Canadian
44:29trial in the 1980s and admitting that
44:32they did not randomize the patients.
44:34Did that have a much impact on anything?
44:37No.
44:37But it's interesting because it
44:39was clear from the data that they
44:41could not have actually randomized
44:42patients in that trial.
44:44The next big thing that is now absolutely
44:46standard of care is tomosynthesis.
44:49This evolved from the development
44:51of digital mammography.
44:53About 20 years ago and then
44:55Thomason says got approved shortly
44:57thereafter and now Thompson.
44:59This is basically the standard
45:01anywhere in a large city.
45:03There's still places that only do
45:052D mammography but Tommy was really
45:08become the basis so Thomas since this
45:10definitely find some cancers that
45:12are not visible on 2D mammography
45:15and all mammal Yale is done with
45:18tomosynthesis even if it's on the mobile van.
45:21And the other thing which I'm sure
45:23which I'm sure almost all of you are
45:26familiar with is supplemental ultrasound,
45:27also called screening ultrasound and this
45:30is used for women with dense breast tissue.
45:33So dense breast tissue hides
45:35cancers on mammography,
45:36and it also increases the risk
45:38of breast cancer somewhat.
45:39But it's really the fact that the
45:41dense tissue can hide a cancer.
45:43That has been the push for
45:45supplemental ultrasound and the
45:47movement started in Connecticut.
45:49Screening ultrasound had been done in
45:51New York at boutique practices around the
45:54country and most probably in some Manhattan.
45:57But the movement to screen all
45:59women with dense breast tissue with
46:02ultrasound started in Connecticut.
46:03And it's really taken off.
46:06And again,
46:06a lot of it is economics.
46:08In much of the country you would have to pay
46:10for your own chain out of your deductible.
46:12But in Connecticut it is covered and the
46:16most patient can pay under law is $20.
46:20So what again is,
46:22is dense breast tissue,
46:24well here is a classic slide
46:26that I guarantee you many of
46:29your patients are familiar with.
46:31So on the left is the rest that is
46:33mostly made of fat and in on the
46:35Mammo report we would say that the
46:37breast tissue is almost half that is.
46:39Really worded,
46:40I would say the best issue is best issue.
46:44Even if there's even no lines like
46:46you see here, it still makes milk,
46:47it still has breast elements,
46:49and it can still get breast cancer.
46:51But that's the wording they chose to use.
46:53And then the next one up is called
46:56scattered fibroglandular tissue tissue,
46:57and it looks something like that,
46:59where there's more black than white.
47:02This may not be nowadays.
47:04It's a little less dense when you see it
47:06on digital mammography with processing.
47:08But then the next heterogeneous,
47:10where it's denser but there's still at
47:12least 25% of the tissue is not dense
47:16and then extremely dense and you can
47:18see it would be hard to see a cancer.
47:21And because cancers are white,
47:22in the middle of all that white tissue
47:25and your patients can go online and go to
47:29densebreast-info.org formally are you dense?
47:33What's the name of that website?
47:34And certainly in Connecticut,
47:37everybody knows about presidents.
47:39So here's an old example of
47:41just what the problem is.
47:43So here is a digital mammogram
47:45where there is a cancer and when
47:47you when I should listen.
47:52Eatings the audience is like, well,
47:54it must be right here, but in fact it
47:56was found because it was palpable.
47:59But it was also visible in Old Town and
48:01was enrolled into my first digital.
48:04Contrast tomography trial and it's
48:07right there shows not only how
48:09tricky it is to find breast cancers
48:11and dense tissue but also how well
48:14certain other modalities can work.
48:16So that's why our supplemental and.
48:19Incomes. So in retrospect,
48:22you can see the cancers here,
48:23but you would never be able to
48:25pick that out and on this slide
48:26to zillions of people, no one.
48:30So. I risk screening,
48:33which is different than supplemental
48:34screening is what I want to talk about.
48:36The additional screening for patients
48:38who are at high risk and typically
48:40that's due to family history.
48:42So the biggest risk factors
48:44for breast cancer are gender.
48:46If you're familiar with
48:47higher risk and then age,
48:49as you get older, your risk goes up.
48:50But aside from those,
48:53family history is.
48:55The risk factor that is most you utilized
48:59to determine your risk gene mutations
49:01is another source of high risk force.
49:04The bracket one and bracket 2 carriers
49:06are at very high risk as you all know,
49:09but now there are many other mutations,
49:11there's check too is a common one that we
49:14screen typically high risk patients for so.
49:20The other thing that can cause
49:21you to be high risk is if you had
49:23a previous biopsy with what we
49:24would consider a high risk lesion,
49:25atypical ductal hyperplasia,
49:27fibular carcinoma insight two
49:28these are benign lesions.
49:30But they confer an increased risk for the
49:33rest of your life of three to four times.
49:35So if you have any risk at all and
49:37you multiply by three to four times,
49:38you end up high risk.
49:40And the other thing is a history of
49:43mental radiation between puberty and age 30.
49:45It's interesting that you can radiate
49:47women after age 30 and not really
49:49increase the risk for breast cancer,
49:50but between puberty and 30.
49:53A dose of radiation used to treat
49:57cancer is a high risk factor.
49:59Personal history of breast cancer makes
50:01you more likely to get another breast cancer,
50:03and that one's a little controversial whether
50:06we should do high risk screening for those.
50:08So the guidelines for high risk screening?
50:12Are as follows the most followed guidelines
50:14from the American Cancer Society.
50:16And this is where that 20 to
50:1825% lifetime risk comes.
50:20So you calculate the risk
50:22using one of the models,
50:24and if it's above 20%,
50:26then the Marion County Society would
50:28recommend that you consider screening with
50:31MRI as well as mammography starting at 30.
50:34News from for as long as
50:35they're in good health.
50:36Now, this is a lifetime risk.
50:37So you you really interpret this that
50:40you continue until their lifetime
50:41risk falls below that 20% range.
50:44But it's not for everybody.
50:46There's downsides to high
50:48risk screening with MRI,
50:49and I'll show you some of those,
50:51but keep in mind that 2025% lifetime
50:54risk based on family history and
50:56genetics or mental radiation
50:57or if you have leaf framing,
50:59which puts you at a very high risk.
51:01Now we've talked about the
51:03American collector.
51:04We talked about the American
51:05College radiology and the American
51:06Society breast surgeons.
51:07They have similar recommendations
51:08to American Society,
51:09but they also include high risk
51:11screening for women who have a
51:13personal history of breast cancer,
51:14especially if they're young and
51:16they have dense breast tissue.
51:20What do we use for risk models?
51:21If you see risk models in
51:23your radiology report,
51:24you want to know where they come from.
51:26Well, the oldest model is the
51:27Gale model and that was what was
51:29used for all the tamoxifen trials.
51:31It is primarily focused on
51:35environmental and hormonal. Actors.
51:37It has a family history factor,
51:39but it's very coarse.
51:41It's it's oh, basically.
51:42The backup pro and Klaus and Myriad models
51:45predict the risk of having a PRC mutation,
51:48but they do not predict predict
51:50your overall cancer risk.
51:51The one we use for determining high risk
51:53screening is the tire cusick model,
51:54which is also called Ibis.
51:56And it uses multiple factors,
51:58and the latest version,
51:59which is version 8,
52:00includes breast density.
52:01It has a much more complete family
52:04history than the GAIL model.
52:06It comes with outputs that are five
52:08year lifetime and we use lifetime to
52:11decide whether people should have an MRI.
52:13Excuse me?
52:14And the reason is because we're
52:17trying to gear these toward young
52:19women where we have the greatest
52:21chance of having a positive impact,
52:23saving as many years of life as possible.
52:27The only genes in the model
52:28of BRACA one and two.
52:29So it doesn't include all the other genes,
52:31which is a little problematic because
52:33now many of our patients have genetic
52:35panels that show they have mutations
52:37in other genes that confer risk.
52:40And you cannot have had a personal
52:41history of breast cancer.
52:42It does not take that into account.
52:46So what do you do if you are at high risk?
52:50Well, as I said, we do annual MRI and that
52:53has to be performed with Ivy contrast.
52:55There's no utility to
52:56ordering a non contrast MRI.
52:57The patient is months MRI
52:59but they don't want contrast.
53:01Then it's useless. First demography.
53:04We do non contrast them right
53:06only to evaluate implants.
53:07We do that very rarely these days.
53:09Elenium contrast is now very safe.
53:11It does this thing called NSF where it was.
53:15Horrible disease,
53:16but the contrast agent that caused that
53:19is off the market and the point where
53:21we don't even do routine crap testing.
53:23So.
53:26The other so you know for that FF.
53:28So that really saves a lot of work.
53:29You don't have to worry about getting
53:32pre MRI creatinine deposition of
53:34gallium you've probably heard about.
53:35They could see it in people's brains
53:37who have had multiple MRI with contrast
53:40that has been essentially eliminated by
53:42changing to macrocyclic from linear agents.
53:44So with MI,
53:45you also should have annual mammography
53:48because in studies you find about 9% more
53:51cancers if you add the mammogram for the MRI.
53:53So by far if somebody says
53:55I only want one of these,
53:56then they should have the MRI.
53:58It's quite far the better test.
54:00But if you want to have the best screening,
54:01it's MRI plus mammography.
54:03And typically the mammography is
54:05there just like calcifications,
54:07which can be a sign of TCS.
54:09And if you're going to have MRI,
54:11there's no benefit to adding screening
54:13ultrasound every study has shown.
54:17So what does it look like if
54:18you have a screening cancer?
54:20Well, here's one that's about 8 millimeters
54:23and they certainly can come smaller
54:26at three and four millimeter cancers,
54:28but this is the perfect example.
54:32It's a patient with very
54:33low background enhancement,
54:34a single lesion that's obvious to everybody,
54:36even without the green circle.
54:38In fact, she'd had a screening mammogram
54:40the year before and it wasn't there, so.
54:43If you knew a little bit spiculated,
54:46it's a little subtle,
54:47but to us that little tiny
54:49bump there means speculation.
54:53This one's trickier.
54:54This one's Oval and smooth.
54:56And in fact, this one turned
54:57out to be a fibroadenomas.
54:59So it's not that everything
55:01that lights up is a cancer.
55:03So the case I showed, of course.
55:04Great if everything looked like that,
55:06but it doesn't always.
55:08So you will have probably benign.
55:11Comes from these,
55:11so we give you an assessment of probably
55:13benign and we recommend a follow up MRI.
55:16We recommend the targeted ultrasound.
55:17We cannot always tell a
55:19benign from malignant lesion.
55:20We have the capability to
55:22biopsy under Mr Guidance.
55:26The other thing that is sort of the
55:28equivalent of dense breast tissue but
55:30for MRI is background enhancement.
55:32So if the normal tissue lights up like this,
55:34and especially if it lights up with a bunch
55:36of blobs that are a little bigger than this,
55:38which is not uncommon,
55:39it could potentially provide a cancer.
55:42Even on this pattern,
55:43we would be able to see a cancer,
55:45but we're not going to see
55:47as many as we see if that.
55:50Especially DCIS is what we would lose.
55:53So how does DCIS typically present?
55:57So it can present as a thing
55:58called non mass enhancement.
56:00So you see a report and it
56:01says there's mass enhancement.
56:03We're saying,
56:03well it could be DCIS,
56:05but it's more likely normal and we
56:07have to decide we biopsy this or not.
56:10We know that neither one of these is
56:11likely to be an invasive cancer and
56:13in fact we know that both of them are
56:16more likely normal tissue than DCS.
56:17But if we want to make sure we catch dsas,
56:20we. We have to have a threshold.
56:23When do we biopsy, when do we not?
56:27So those are kind of the things that
56:29might help you interpret the reports you get.
56:32So how good are each of these tests?
56:34Well, when you add tomography.
56:38For the first thousand patients in the
56:40first screening round, I know that well.
56:42First of all know that typical
56:44screening mammography practice,
56:45we will find 2 to 4 cancers per thousand.
56:48The yearly incidence of cancer is around
56:50two to three in screening age patients.
56:53But not everybody shows
56:54up absolutely every year.
56:55So it tends to be a yield of about four.
56:58Adding tomosynthesis in the early studies
57:00showed about one to two additional cancers.
57:03Often these were low grade cancers
57:05which was a little bit disappointing.
57:07Ultrasound.
57:07Was better.
57:08So adding supplemental ultrasound is
57:11better than just doing tomosynthesis.
57:13Three to four additional cancers,
57:16almost all invasive and not all low grade.
57:18There were some high grade cancers for sure.
57:20Contracts that enhanced mammography
57:22and screening studies is a big jump
57:24because you're giving contrast.
57:26So the studies that were done
57:28showed eleven additional cancers,
57:30but the one that really drives
57:31everything is that if you do MRI,
57:33you find 14 additional cancers.
57:36So what does that really mean?
57:37But first of all,
57:38where does that really come from?
57:39So that 14 number comes from a study
57:42called the acronym 6666 trial.
57:44And for that trial you did not
57:46have to be high risk,
57:48you only had to have dense
57:49breast tissue 2800 subjects,
57:51they had mammography with
57:53or without tomosynthesis.
57:55And then for three years in a row they
57:57also had supplemental ultrasound.
57:59That's where they found about four
58:01cancers per thousand extra just
58:03on ultrasound.
58:04Pretty good yield,
58:05do you think you found everything?
58:06But then after three rounds of that day,
58:09they decided to do one round
58:10of MRI and lo and behold,
58:11there were 14 cancers per thousand
58:13that had been lurking there that were
58:16not found by mammography and Epstein.
58:18So what does that mean?
58:19Are we finding additional cancers
58:20that never would have been found?
58:22No. We're finding cancers earlier.
58:24So it's moving the detection point earlier.
58:28So that you're finding hopefully
58:30the same cancers earlier.
58:31We do not want to find 14
58:33cancers per thousand every year.
58:34That means we're over diagnosing,
58:36we're finding too many cancers,
58:37but that's not what happens.
58:38You find the 14 cancer.
58:42Number and the point is
58:44we're finding them earlier.
58:45So if you screen with MRI,
58:46you'll find smaller cancers
58:48and the cancers will all be.
58:50Of all different types as far as aggression.
58:53So they have to be aggressive enough
58:55that they make their own blood
58:57vessels in order to show up on MRI.
58:59So it's not prone to over
59:01diagnosis the way, for example,
59:03tomosynthesis seemed to be a little bit.
59:06So that's the feature.
59:07The feature is called personalized
59:09screening and in personalized screening,
59:10which we are not doing at this point,
59:11but we will be.
59:14As things progressed over
59:15the next five years,
59:16each patient will get screened
59:17based on their own risk factors.
59:19That has to mean that some get more
59:22screening and others get less.
59:23Doesn't do any good if we
59:24just screen everybody more.
59:25So it'll affect how often we
59:27say they should be screened
59:28and what modalities we use.
59:30We will use the standard risk
59:31factors that I mentioned,
59:32family history, etcetera.
59:33But also we can use AI to analyze
59:36the pattern on their mammogram.
59:39And it's been shown that with AI you can
59:43predict their short term risk very well.
59:46I'm more than just looking
59:47at density as we looked at,
59:49but if you look at the actual pattern,
59:50somehow the computer can tell
59:53what their short term risk is.
59:54So you might ask well how and they
59:56realized we really don't know.
59:58But if you're looking at short term risk,
01:00:01but you're really looking at not so
01:00:02much as risk but early detection.
01:00:04So in my opinion they're seeing
01:00:06early signs of cancer,
01:00:08not super specifically,
01:00:09but enough that if you take those
01:00:12patients where they say hey,
01:00:14this looks like there's going to be a
01:00:15cancer here and you do MRI on them.
01:00:17Find that it's the best predictor
01:00:19of short-term risk,
01:00:20so it's better than the entire music model.
01:00:24And that is what's going.
01:00:26So that's what we have to look forward to.
01:00:28But here's where we are today.
01:00:30Screening Murphy is still the
01:00:32only tool that was validated
01:00:33using trials with mortalities and
01:00:35endpoint and it's still the mainstay
01:00:37of breast cancer screening.
01:00:38But we know it's far from perfect.
01:00:40Ultrasound definitely finds
01:00:42additional cancers and dense breasts.
01:00:44And while we don't have a mortality
01:00:46based trial to prove that it saves lives,
01:00:48clearly we're finding cancers
01:00:49that would have kept growing,
01:00:51would have been found later with
01:00:53only mammography, understand.
01:00:54MRI is our most sensitive test,
01:00:57but it's also our most expensive
01:00:59and it also has this reputation of
01:01:01having false positives, which it does.
01:01:03But we've come to where we can manage those.
01:01:06We know where our threshold
01:01:07should be and we can do biopsies.
01:01:10And the key to optimizing screening
01:01:11in the future will be matching
01:01:13every patient to the best tests
01:01:15and interval for her.
01:01:17And AI will very likely play a role,
01:01:19which means mammography will very
01:01:21likely play a role because it's from
01:01:23the mammogram that we use the AI to
01:01:25determine risk. So again,
01:01:26a whirlwind tour of what's going
01:01:29on in breast imaging. So thank you.
01:01:33Thank you, doctor Lewin.
01:01:35That was really comprehensive
01:01:36and so much going on in the
01:01:38world of breast imaging.
01:01:39Last but not least,
01:01:40we have a doctor, Ayela,
01:01:42who's our newest faculty member,
01:01:43joining us from Memorial Sloan Kettering.
01:01:45Umm talking about advances in
01:01:49breast reconstruction.
01:01:50We're really excited to have
01:01:52a talented microvascular
01:01:53surgeon like you here at Yale.
01:01:55Thank you.
01:01:59Thank you for the introduction.
01:02:00Can you see my screen?
01:02:03Yes, awesome.
01:02:07All right. Well, good evening, everyone.
01:02:09This is a homestretch.
01:02:10Thank you for the introduction
01:02:12and for the invitation.
01:02:13So for the next 10 minutes or so,
01:02:14I'll be talking about strategies and
01:02:18comprehensive breast reconstruction.
01:02:20So we'll briefly discuss the background,
01:02:22why do we choose reconstruction,
01:02:24some options after both breast conservation
01:02:27and mastectomy surgery and a couple
01:02:30of new directions that we hope to be
01:02:32exploring at Yale for our patients.
01:02:34That it's been almost 25 years since the
01:02:37government has mandated healthcare payer
01:02:38coverage for all breast reconstruction,
01:02:41including contralateral procedures to
01:02:42achieve symmetry and any treatment
01:02:45after sequella of mastectomy.
01:02:47However, they're really still continues
01:02:48to be less than a 50% rate of women
01:02:51who are seeking breast reconstruction.
01:02:53And upon additional surveys
01:02:54of these patients,
01:02:55we have found that common reasons
01:02:57not to choose reconstruction are to
01:02:59avoid additional surgery belief that
01:03:01reconstruction is either not important
01:03:03or not available or potentially.
01:03:05A fear of breast implants,
01:03:06especially surrounding the
01:03:08current media state.
01:03:10We have found over and over
01:03:12that patients who do undergo
01:03:13reconstructive procedures have very
01:03:14high rate of satisfaction and very,
01:03:16very good and improved quality of life.
01:03:19And reconstruction is we can
01:03:21be performed concurrently with
01:03:22both breast conservation methods
01:03:24as well as after mastectomy.
01:03:26And it's important to note for our
01:03:29patients that reconstruction is
01:03:30safe and it does not affect the
01:03:32risk of local disease recurrence.
01:03:34And we think about uncle plastic surgery.
01:03:35This is very advantageous in many respects,
01:03:37and there's tons of literature and
01:03:39numerous algorithms to help us decide
01:03:42the optimal incisions and resection patterns.
01:03:44But I think it's simplest to tell
01:03:46patients that large breasts generally
01:03:48undergo therapeutic reduction.
01:03:49Small breasts with small masses undergo
01:03:52tissue rearrangement with a lift,
01:03:54and small breasts with a large
01:03:57mass may need volume replacement
01:03:59in the form of a local tissue flap.
01:04:02So here's a schematic of an oncoplastic
01:04:04reduction for a larger breast.
01:04:06We usually use this incision pattern,
01:04:08the the wise pattern and this is a
01:04:11patient who had a upper outer tumor
01:04:13for resection and we approached
01:04:15this using again that traditional
01:04:17wise pattern incision.
01:04:18We were able to reduce and lift
01:04:20the breast after the tumor was
01:04:22removed and she here she is postop,
01:04:24good contour, good symmetry.
01:04:27Small breasted patients who are losing
01:04:29a significant amount of their volume
01:04:32may need replacement with tissue.
01:04:34Often we take this from the back.
01:04:36So for example,
01:04:37this woman had a upper intermedial
01:04:39quadrant tumor and would have definitely
01:04:42had an aesthetic contour deformity.
01:04:44It doesn't have quite enough tissue
01:04:45to rearrange and she definitely
01:04:47does not lean a lift,
01:04:48nor does she want to be smaller.
01:04:50So the plan is to replace this volume with
01:04:52a thoracodorsal artery perforator flap,
01:04:55taking just the skin and the fat.
01:04:57Of the back and sparing the muscle.
01:05:00And this is her post-op healed good contour,
01:05:02no volume loss.
01:05:06So options after mastectomy,
01:05:07there are two traditional arms we know about.
01:05:09Of course for total breast volume
01:05:11replacement implant or autologous based.
01:05:13We decide on the best arm together with
01:05:16the patient after discussing her unique
01:05:18goals and values and certain specific
01:05:21factors such as plans for radiation.
01:05:23Implants are still the most popular choice.
01:05:26A certain subset of patients,
01:05:28small breasted minimal tosis,
01:05:29can have an implant placed
01:05:31directly at the time of mastectomy,
01:05:33but it is still definitely more common
01:05:34for this to be done in two stages.
01:05:36This allows the mastectomy skin
01:05:38to heal and in cases of limited
01:05:40skin will allow us to expand the
01:05:42pocket to the desired volume.
01:05:43The prosthetics have traditionally
01:05:45been placed underneath them also,
01:05:47but now there's a large movement to
01:05:48place them above the muscle and these
01:05:50implants of course include silicone
01:05:52or saline still in the market.
01:05:56The pros of course is you
01:05:58have one operative site,
01:05:59you're only operating on the chest.
01:06:01Compared to the autologous group,
01:06:03it is a reduced operative time and
01:06:05there is more rapid post-op recovery.
01:06:07But the cons is we're doing unilateral
01:06:10reconstruction is very difficult to obtain
01:06:12symmetry to the contralateral breast.
01:06:14The patient does have to
01:06:15come back very frequently,
01:06:16sometimes over the course of several
01:06:18months for tissue expansion visits,
01:06:20and they do require at least two operations
01:06:23to achieve reconstructive completion.
01:06:25With radiation there is potential
01:06:27for increasing complications and
01:06:29sometimes in very thin patients who
01:06:31have low BMI and we are putting
01:06:33the implant above the muscle,
01:06:35the implants can be visible,
01:06:36palpable or you can see rippling.
01:06:40Natalie, this option,
01:06:41great options for patients who want
01:06:43their own tissue natural appearance
01:06:44and feel often are very good options
01:06:46in unilaterally constructions to match
01:06:48the tosis of the contralateral breast.
01:06:50And I think this is usually the
01:06:52better option in the setting of
01:06:54radiation or very large skin deficits.
01:06:56However,
01:06:56it does require an experienced microsurgeon
01:06:58and we're operating on two sets of body.
01:07:00So this does necessitate a longer operative
01:07:04time and a longer recovery upfront.
01:07:07So there's a lot of discussion about
01:07:09the optimal timing of reconstruction.
01:07:11Immediate reconstruction is
01:07:12definitely always preferred,
01:07:13so patients do not have to wake up flat.
01:07:15But a lot of plastic surgeons are
01:07:17wary of the effects of radiation
01:07:19on their final reconstruction,
01:07:21whether that is an implant or
01:07:23if it is a flap.
01:07:24And we've also found that patients
01:07:26can be very overwhelmed with their
01:07:27recent cancer diagnosis and they want
01:07:29to defer thinking about their choice
01:07:31of final reconstruction until all of
01:07:32their adjuvant therapy can be completed.
01:07:36So we find that we can mitigate all
01:07:38of these concerns by placing a tissue
01:07:39expander at the time of mastectomy
01:07:41to maintain the breast pocket,
01:07:43make sure that the patient does wake
01:07:44up with some sort of breast mound.
01:07:46And then we have the patient
01:07:48complete their cancer treatment
01:07:49including adjuvant radiation,
01:07:50chemo,
01:07:50whatever is needed with the expander
01:07:52in place the entire time.
01:07:54And then in these cases it's preferred
01:07:56that the tissue expander should be placed
01:07:58in the pre pectoral plane above the muscle,
01:08:00avoid the morbidity of
01:08:02elevating the pectoralis muscle.
01:08:03It allows much faster, much more comfortable.
01:08:05Extension for the patient so
01:08:07they can be fully expanded,
01:08:08healed,
01:08:08go on to adjuvant therapy more quickly.
01:08:11And then on the patient's own timeline,
01:08:13the expander can be exchanged electively,
01:08:15so patients have time to discuss again,
01:08:17choose if they want to continue and replace
01:08:20this expander with a permanent implant,
01:08:23or at this point they can remove the
01:08:25prosthesis and put in their own tissue.
01:08:27This patient shown here,
01:08:28she underwent expander placement,
01:08:30fully expanded in a few weeks,
01:08:31completed all of her radiation
01:08:33and then came back,
01:08:34I believe six months later
01:08:37for autologous reconstruction.
01:08:38So we figured out a really good way to use
01:08:41our own tissue to create
01:08:42healthy warm breasts,
01:08:43restoring blood flow in and
01:08:44out of this new breast mound.
01:08:46And we tell patients that they're
01:08:47going to feel like a breast,
01:08:49which is true to others,
01:08:50but not necessarily the patient.
01:08:51Often patients are very disconcerted
01:08:53with the numb feeling in their chest.
01:08:55So now we're working on strategies
01:08:57to improve sensory recovery after
01:08:59mastectomy concurrently with
01:09:01autologous tissue reconstruction.
01:09:02I really like the way one
01:09:03of my partners put it.
01:09:04We have to hook up the plumbing
01:09:07and the electricity to make
01:09:09the reconstruction complete.
01:09:10So to offer truly comprehensive
01:09:12breast reconstruction,
01:09:13we must be able to also offer options
01:09:16to prevent and treat sequella of
01:09:18axillary dissections under radiation.
01:09:20As we know,
01:09:21lymphedema is very devastating to
01:09:22patients quality of life and we have
01:09:24not yet found a curative treatment.
01:09:26We do offer hope to offer preventative
01:09:28options such as immediate lymphatic
01:09:29reconstruction or also known as
01:09:31lympha at the time of the axillary
01:09:34dissection and we can utilize reverse
01:09:36lymphatic mapping to identify which
01:09:38nodes are important for armed drainage.
01:09:40For patients who already develop
01:09:42develop any sort of lymphedema,
01:09:44they do have patent lymphatic
01:09:45channels in their arm.
01:09:46We can bypass these scarred lymphatics
01:09:49with serial lymphatic ovular anastomosis.
01:09:51This is a really easy outpatient procedure.
01:09:54And for those who are a little
01:09:55bit more advanced,
01:09:56I have no channels left in their arm.
01:09:57Lymph node transplant can often be performed.
01:10:00So we use the omentum as a good donor
01:10:03side to prevent donor site lymphedema.
01:10:05But with the use of referral synthetic
01:10:08mapping we can also take select
01:10:10groin lymphatics along with the
01:10:12abdominal flap for whole holistic
01:10:14breast and axillary reconstruction.
01:10:16So very grateful to join Yale,
01:10:18be a part of this multidisciplinary
01:10:19team focused on cancer eradication
01:10:21and really improvement of quality
01:10:22of life for our patients.
01:10:24So thanks for the opportunity to
01:10:25discuss our approach to comprehensive
01:10:27breast reconstruction tonight.
01:10:29Thank you, Doctor Ayala. Wow.
01:10:31Thank you, everyone for, you know,
01:10:345 phenomenal presentations
01:10:36and the audience for sticking
01:10:40with us through this evening.
01:10:42There are a couple of questions that
01:10:44actually came in through the chat,
01:10:45not sure they can actually
01:10:46be seen by the audience.
01:10:47I'm going to ask our panel.