Quite a long session and we, we should start now.
And the first speaker is Audit Kata Person, uh, everybody knows her,
she's coming from Israel and she cannot come in person.
Therefore, we will have audit.
Online and she will bring a Her presentation about radiotherapy
updates and the Cinderella project.
Please order it. Thank you very much for the kind introduction
and thank you very much for inviting me.
As indicated, I will speak about radiation therapy updates,
and I'm very happy that I'm not overlapping with the great updates that Nicola
Rocco said before in his presentation, and I will also update about the
Cinderella project.
So I have no financial disclosure, but I am a radiation oncologist in what is known
as a surgeon's grade meeting.
I must say that I'm very flattered that I was invited to speak in this meeting because the UK
team is leading most of the changes and improvement in breast radiation therapy.
And including about radiation-related side effects and patient reported outcomes and of
course we have our EO leader, uh, former president Anna Kirby,
which is local from London.
Um, I do not have nice surgical videos in my presentation, but I hope I'll keep you
interested and of course, uh, the Cinderella trial is supported by the EU.
So breast cancer treatment in general for early and metastatic setting is constantly
changing, highlighting the importance of disease biology,
tumour genome, immunity combined with classical pathological and clinical features and
patient related factors and us as local regional therapists,
surgery and radiation.
Those both local regional therapy underwent significant changes in concepts and
technique, and you heard all about this in the sessions today.
I was privileged to be to be able to listen to the session.
Both are highly dependent on expertise, and this is why I find the London press meeting so
important. But even though treatment and is constantly
changing, the benefit of radiation therapy is quite consistent,
and you can see that nicely over the years.
Radiation improves local regional tumour control.
For all breast cancer patients, for all patients, it decreases breast
cancer related mortality in node positive patients and in some high
risk node negative as well and also after breast conservation therapy,
so we need to keep that in mind.
But the proportional benefit of radiation in decreasing local regional recurrences is
reported between 50 to 85% reduction in recurrence, but the absolute
benefit is related to the risk of recurrence. So in low risk patients there is barely any
benefit from adding radiation therapy and in high.
Risk patient, there is a high benefit from adding radiation therapy,
and this is per individual case because it depends on multiple factors that interplay with
each other, and we know a lot about disparity of care.
So a patient that is at low risk can become a high risk if she's not getting good care,
and I recommend to read the recent Las commission.
Uh, that was published in The Lancet about breast cancer care and disparity.
So what are the options about low risk and the small benefit of radiation,
if any, we have current option, either a mission of radiation or partial breasting
radiation, both options we have level one evidence, I would say we have ongoing trial and
we have some population that we have missing information.
With regards to a mission of radiation, I would say it's a shared decision with the patient
because radiation in those patients does not have a survival benefit,
but we see significantly high rate of local recurrence in those patients,
so you have to share with the patient.
We, you spoke about aesthetic outcome and side effects of radiation.
Obviously this is the best way to go to reduce side effects is not to give the treatment,
but we know from the CLGB and the recently published update of the prime 2 trial,
and I used the San Antonio slide and not from the New England Journal publication because you
can see how the A local recurrences deviate across the years.
There is a high risk of local recurrence, especially in those patients who will live
longer than 5 years. So you need to discuss this with the patient.
We have recently published two really nice studies, the Lumina cohort and the
ID study.
Uh, both are even earlier age compared to the prime 2 and the CLGB
trial, and they're using concept of, of biology and clinical pathological factor and
also the oncotype recurrence score, but we need to remember that those patients were only.
Follow up for 5 years.
We don't know what will happen in 10 years and we have from the prime to long follow up
according to the ER receptor even in patients who had high ER receptor,
we did see high local recurrence rates. So this is a shared decision with the patient.
How about partial breast radiation? Is less radiation or less volume of radiation
more? For partial breast, we have different types of
partial breast intraoperative can be done at time of primary surgery or after brachytherapy,
the same concept, or external beam after final pathology.
The key to success of selecting those patients who are eligible for partial breast irradiation
is a go again to select the truly low risk patient, and we learned that.
From the EO trial from the intraoperative, when they chose according to AO guidelines for
partial breast, they had a lot of local recurrences when they looked at the very low
risk, uh, there was a very low local recurrence maybe in those patients you can even omit
radiation. You should also select the technique because
different techniques have different volumes of radiation and this can be significant for local
recurrence as well and you need to select the adequate dose fractionation and volumes because
it significantly.
for toxicity, and we learned that from the rapid trial partial breast
irradiation twice daily, more toxicity from partial breast compared to whole breast
irradiation. Something went wrong there with the partial
breast. So again this is Charlotte Cos and as
she indicated here, breast radiation therapy, less is more.
So the key to success is selecting the low risk. You can see that from the import low trial a UK
leaded trial about partial breast, the partial.
The group had similar oncological outcomes and less toxicity,
and this is what we want to achieve when we radiate the patient.
So it's highly important to choose the correct technique, irradiate.
I recommend to irradiate when you have the final pathology and you truly select the low
risk patient. You should also select the adequate dose and
fractionations and volume as I indicated before and again a UK led trial,
the fast forward, you can use 5 fraction for partial breast radiation.
You don't need all the protracted fractionation.
Patient can come to the uh radiation only 5 times.
So we went on to the current option ongoing trial, so many low risk,
including an omission of radiation, and what we need to remember and do better in clinic is we
have missing information about the lobola group.
We just recently submitted a paper with the CC think tank,
a group focusing on what we miss in a local regional therapy for lobular carcinoma.
The NRG NSABP B51 was presented in San Antonio.
Is this the new low risk group for de-escalation of local regional,
especially local regional radiation?
In this trial, they took a clinical T1 up to T3N1 patient.
Those who had complete response, nodal response in after primary systemic therapy
were randomised either to get no radiation therapy to the regional node versus regional
node radiation. And if you look closely at what they did.
In the trial, they also de-escalated additional factors of local regional therapy,
including omitting the chest wall radiation in those who underwent a mastectomy,
and some of the patients underwent only sentinel lymph node dissection,
so they were also randomised for omission of regional no radiation.
And what reported in San Antonio that they reported the local
regional and the regional recurrences and when we look at the 5 year outcome,
you can either be pessimistic or optimistic because it was presented in an
optimistic way. Overall they had a total of 15 events.
Which is extremely low or very low for 5 years, but if you're pessimistic,
you can see that all the regional recurrences, 100% of the regional recurrences
occurred in the no regional no radiation. So we,
we should think about that.
So pessimistic or optimistic or maybe realistic, this is David Dudwell.
He's from Oxford University, one of the smartest persons,
and of course oncologist I know, and he said in the San Antonio presentation he's Stood up
and said 5 years is too short follow up for radiation because radiation is a long term
investment and the benefit mostly in survival from radiation is seen at 15 years and we know
that from the Oxford meta-analysis CBC TCG.
And they also the EBCTCG recently published in uh their uh
meta-analysis about regional node radiation in early breast cancer,
so this is a higher group of patients.
And they divided the trials according to older trials and new trials
after '89 and you can see here that regional
node irradiation provides a benefit for regional benefit in and
also uh. In mortality, reduced mortality, and as I
indicated before, the benefit increases according to the risk,
and they also found a benefit in patients who were pathological node negative
getting regional node radiation, and we need to explore that more to understand which path.
we're talking because we don't want to radiate all those no negative patients,
and this is most of the cases here were in addition to axial lymph node dissection.
So I think we should think very wisely how to de-escalate therapy
when we analyse these data.
So, as I indicated, the proportional and the absolute benefit are important,
and there is a delicate balance uh that can be changed due to poor management and radiation
therapy like any breast cancer meet uh. Treatment is based on
multidisciplinarity and interdisciplinarity expertise, and I heard some excellent
talks today.
I support these expertise because we need expertise in surgery and radiation,
and we can do differently. We can, we can succeed differently according to
the indication if we choose the correct indication, the correct volume of radiation
dose and fractionation.
The radiation technique and if we perform quality assurance and peer review,
there are a lot of publication about that.
So radiation therapy is no longer just to to put the fields on and you can
nicely see here. The dosimetric map of irradiating a breast,
you can irradiate half the patient or only the breast, and this is the same prescribed dose
and it aims for the same volume. So it's highly important how you perform the
radiation. So I'm going to the next topic, the Cinderella
project. And this is a local regional project that is
led by MJ Cardoso from Lisbon. She's a breast surgeon,
and this is an example for how a dream come true because MJ is working on
this project for, I think, over a decade, and the challenge is that 1/3 of breast cancer
patients suffer from suboptimal or and poor aesthetic outcome after surgery with or without
radiation. And the patients for the same breast cancer
stage are often given different uh options to choose from,
uh, and the sequencing of either systemic therapy, local regional therapy,
different surgeries, it's always confusing for the patient.
And there are various reasons for poor aesthetic outcomes,
whether it's associated with the patient, with the treatment,
or with the surgical and radiation expertise and type of therapy that was applied.
And even though you discussed earlier today, proms, etc.
there are no actual validated tools to evaluate these aesthetic outcomes.
Most centres do not assess aesthetic outcomes, do not perform photographic documentation
prior to surgery and after surgery, no problems, and Those who do those take
the extra mile often do not use the information they gather to improve the service,
so we have a lot of missing data about that, and the aesthetic outcomes even might not
reflect patient satisfaction with the aesthetic outcomes, actual aesthetic.
Outcomes of physician assessment.
So how can we communicate all this information prior to surgery?
How can we tell the patient about the complications and watch how she might look?
How do we improve the informed consent process?
How can we improve patient satisfaction even if the aesthetic outcome is not that good?
So this is often the procedure that is done in most centres.
The patient is meeting the doctor. They decide,
and, and, and they discuss different type of surgical and local regional therapies.
She meets the nurse, she gets information, and then she goes into the internet or talk to her
friends. And I don't know about in the UK, but I know in
the US and in Israel many patients come to us and ask,
I will undergo mastectomy and reconstruction even if she's eligible for breast conservation
and ask for either augmentation or even risk reducing mastectomy and think she will look
fabulous. And then comes the treatment and they're
disappointed and uh.
They, they feel pain, discomfort, they have poor quality of life,
and we can blame the radiation therapy, but sometimes it's not only the radiation therapy,
sometimes we see these patients even when they come for us for assessment prior to radiation,
and we have multiple factors that contribute to this.
So the Cinderella project is actually an international consortium supported by the EU
and it aims to provide an AI, artificial intelligence based solution to all
those challenges.
We are developing an AI app for patient.
We have inside the app validated information including videos including text,
and the patient can read as much as they want and access the app as much as they want and the
different information is according to different levels according to what the patient wants to
know. And the app is aimed to predict the aesthetic
result of an individual patient, and it is based on the,
on a large database that was years of work of MJ and her colleagues,
uh, if you know the BCCT programme, so they have a huge database.
So, um, what the clinical trial is all about, and I'm not familiar that there are any
clinical trials validating in the app, so the clinical trial that we're doing with the
Cinderella trial is validating the app in improving the decision
making process and patient.
Satisfaction with surgery.
So this is a multi-center prospective randomised trial comparing
the decision about the surgery and local regional therapy and the match expectations
in a conventional method like the MD and. Nurses that explained to the patient or what
was done in the department compared to the Cinderella app and the app and the AI team
is working to improve the app itself according to the input from the trial.
So if you want to read the protocol, it's available in class one we published it last
year. And we are here.
We already uh recruited half the patients, which I think it's a great achievement for a
local regional trial with an app because we know that it's often very difficult.
So we hope to provide you with uh at least initial outcomes in the
coming months.
So I would like to thank the Cinderella team and look it up on the website.
We're planning free webinars of the Cinderella Consortium also about AI,
about patients input, and about aesthetic outcome after breast surgery.
Thank you very much and I want to thank Marlon uh for inviting me and all the effort and
my apologies for not being there with you.
Thank you. So
thanks for it. uh, great presentation as usual.
Since you're online, we'll take one question for it because that way she can then she's free
to do what she wants. Is there anything burning that the audience
wants to ask with regards to local regional treatment, radiation therapy?
All right, thank you for the excellent presentation.
Uh, I have only one question.
The impact of the boost, uh, in breast conserving surgery.
How do you see it?
This is an excellent question because the boost is in my view,
horrible. It increases the toxicity of radiation and
fibrosis, I think approximately doubles or triples in some patients if you plan it
incorrectly. I will speak about it tomorrow.
A little bit, but what you see in recent trials of radiation therapy like in the
Danish breast cancer and also in the, in the trials by uh the UK
uh the fast fast forward trial.
Most patients don't need a boost. It's between 15% to 20% of the patients need a
boost. It's no longer like the URTC trial that after
the URTC publication, I think 99% had a boost, so we should
rethink who we need to boost because it causes significant toxicity.
Excellent question.
Or at one, so you. All right, one more question.
From fast forward, are you guys seeing more local fibrosis or any kind of toxicity locally
related to radiation therapy?
So, and now, now we already have uh more than 2 years after fast
forward and we recently encountered a little bit late in duration in
patients uh so we. are reevaluating if it's only our
impression or it's associated with the protocol, but this was not reported in the
in the study itself.
The study had they recently reported the longer follow up in one of the
meetings, but they had a median of 6 years, so it might be due to our planning or just a
coincidence.
So thank you so much. All right.
We'll move on to the next presentation by Maggie Banis Palichowski,
who's going to talk to us about de-escalation of treatment in all the fields,
surgery, chemotherapy, and radiation therapy.
Thank you so much and thank you so much for having me here.
Uh, I am a gynaecologist and I know this is quite unusual for many of you,
but in Germany, most breast surgeons are, uh, gynaecologists and we also do systemic therapy
and a lot of breast diagnostics.
Uh, I will be talking about the escalation of therapy and many thanks to Orri who already
covered in a wonderful way most of the important radiotherapy topics so I'll be
concentrating on, uh, surgery and chemotherapy and let us start with local regional treatment.
As you know, in the last two decades we have seen a remarkable de-escalation when it comes
to the margins. We've come from 10 millimetres and then 5
millimetres, then 2, and right now most of the national guidelines do endorse either no
or 1 millimetre.
Right now we are talking more about sparing healthy tissue because if you look at this
tumour on the right side you will see that the tumour has been removed with 1 millimetre in
all directions, but you see that the large proportion of the specimen is actually healthy
tissue that we have we could have spared, and this relation of the tumour tissue to the
removed tissue is usually referred to as a resection ratio.
And resection ratio means that we are aiming at removing the tumour centrally in the specimen
with the exception of oncoplastic procedures of course where we sometimes aim at removing a
very large portion of the breast, um, but in case of resection ratio,
most of the currently ongoing studies are including this,
um, uh, this, uh, resection ratio as one of the end points.
So when we're talking about different localization techniques,
uh, we also look not only at the on.
At the margins or uh resection uh re-excision rates but also a resection ratios in many
countries the standard is still the wire guidance, but as you know there are also many
types of markers that allow for a probe guided detection during the surgery,
and we can also visualise the tracer different tracers are available or a technique that I,
I personally like a lot we can do in ultrasound to visualise the tumour but right.
We don't have much data that compare all these techniques, and the largest study worldwide
that is ongoing is the Melody trial.
We have already enrolled more than 2000 patients.
We will be looking at margins. We will be looking at re-excision rates,
but resection ratio is also one of the end points, and the study has been initiated by two
study groups, the EU Beast Study Group, and also the very active British study group I run
it. And I'm very happy that many esteemed UK
colleagues uh are on the team. Our chair Ashkhari,
but also Rajiv Dave, James Harvey, and Yazan Masan is the head of the UK steering committee.
So if you are, um, um, interested in joining UK has just opened some study sites,
uh, but many are to follow. Please contact Yazan.
Recently in the breast there has been a very interesting special issue on the de-escalation,
and we're actually wondering whether we might be seeing at least in some settings,
either a de-escalation or maybe an escalation in disguise because while we are allowing
obviously many patients to receive breast conserving surgery due to the updated margin
guidelines, many of our patients are. Receiving a mastectomy and this um a proportion
of patients is actually increasing either with an uh reconstruction or without we have seen
already from the United States that the proportion of patients opting for a mastectomy
or also a bilateral mastectomy is increasing and we've also seen this trend from Canada and
from other countries. So just something to think about um for you.
When we are talking about de-escalation in the surgical setting,
obviously, a potential dream might be to omit surgery at all,
and maybe in the future, the first setting where we will be able to do this will be in
patients who are excellent responders to new adjuvant chemo.
Because every time we perform a surgery in a patient who received new adjuvan chemotherapy
and we are informed by the pathologist that the patient had pathological complete response,
obviously we're asking ourselves ourselves if the surgery was maybe an overtreatment.
Unfortunately, the imaging is not good enough, so sometimes we see patients who uh still have
a residual tumour upon ultrasound or MRI, but the pathologists describe uh dead tumour cells,
pathological complete response, but also we can see the opposite patients where we can identify
no residual disease upon imaging, uh, but they have quite a lot of residual invasive disease.
So right now we cannot omit um at least an intervention and there was a very interesting
trial, the responder trial led by Ukhail from Heidelberg in Germany called um a Responder
trial. The colleagues explored a very interesting uh
concept. Patients received new adjuvant chemotherapy,
then they received a vacuum assisted biopsy, and you have heard about this concept in the
wonderful presentation by Nicola today, um, and then all the patients received surgery.
And the colleagues were wondering that uh if maybe if the vacuum assisted biopsy can
reliable reliably predict PCR we might actually omit the surgery.
Unfortunately in this German trial, the false negative rate was quite high,
so uh we did not um incorporate this concept to the guidelines,
but there is a follow up trial coming uh where we will focus on uh patients that are better
selected for this intervention and maybe we will be able to show that the false negative
rate can be lowered.
Our colleagues from the United States, as you have heard before,
has already gone one step further.
In the study led by Doctor Ker from the United States, um,
they performed vacuum assisted biopsy after new treatment, and if this vacuum assisted biopsy
showed PCR, they um omitted breast breast surgery at all.
But, and this is very important to know the patients received radiation therapy.
Right now we have 3 year follow up data and there have been uh no invasive breast relapses,
very, uh very um uh good result but a short follow up.
And there is also a study that is exploring a different, um,
sorry, a different uh side of the same coin.
namely the Descartes trial.
Here the colleagues are exploring if patients receiving breast conserving surgery and
reaching a PCR might forgo radiation therapy at all.
So I'm wondering right now if maybe in a couple of years we will be able to forego both
interventions, but right now we do not have enough data to support this.
Um, concluding for local regional therapy, we have already seen a massive de-escalation when
it comes to the margins. Current trials are going to clarify which
localization techniques are best to spare healthy tissue,
and for omitting surgery completely, we need more data and specifically we need more follow
up time. So now let us look at the systemic therapy and
uh since the talk is very short, I will just focus on the HER2 positive breast cancer.
And as you know, uh 20-30 years ago, the HER2 positive breast cancer was actually the entity
that was most difficult to treat young patients not responding to chemotherapy and dying quite
quickly. There has been a very interesting session by
the ESMO last year called HER2 positive breast cancer from no hope to good prognosis in 20
years because there has been a remarkable development when it comes to to positive breast
cancer, and this is based on the introduction of targeted drugs.
Our monoclonal antibodies justtuzumab, then antibody drug conjugates and um
lately also the throzin kinase inhibitors and due to these drugs we are able to cure
many patients and obviously the question comes to mind when can we go chemo free,
when can we omit chemotherapy completely if we have such an abundance of targeted and very
modern drugs. There is already a de-escalation happening.
We cannot forego chemotherapy completely in the standard of care in the clinical setting,
but this is the algorithm from the AGO Breast committee that is very,
uh, similar to the ESMO guidelines.
And as you can see in patients with very small tumours, CT1 N0,
uh, after the surgery, if the pathologist confirms T1N0 status,
these patients received a very short chemotherapy, 12 weeks,
just Paclitaxel.
Uh, this is a very well tolerated regimen, just one cytotoxicic drug,
and just tuzumab for one year. So there is already the escalation happening.
But we would obviously like to see other trials that are looking at chemo-free options,
and one of these trials was Fer gain from Spain, uh, presented last,
uh, last year at the San Antonio breast conference, and so these patients had all had 2
positive breast cancer and they were randomised.
Some of them received classical poly chemotherapy in the new adjuvant setting with
two antibodies, our current standard of care.
The second arm received 1st 2 cycles of a cream of free regimen,
just to zoo up protozumab and endocrine therapy if they had hormone receptors at the tumours.
After two cycles, they performed PET CT to see if the tumour is responding well to treatment.
In 80% of the patients, this was the case, and these patients proceeded to receive further
chemo-free regimen, antibodies plus minus endocrine therapy,
and after the surgery, this is very important.
If they reached PCR after chemo-free regimen, they did not receive any chemo at all.
Proceeded to receive antibodies but nothing else.
And now we have already 3 year follow up data for these patients.
As I said, in 80% of the patients there was an excellent response based on the PET CT after 2
cycles, and these patients reached PCR in 38% of cases,
which is quite nice when you consider that these patients did not receive any chemotherapy
before surgery. So now I'm showing you the data for the
survival. Patients who reached PCR after the chemo-free
regimen have an excellent prognosis. There was just one invasive recurrence,
um, but patients who did not reach PCR, they received chemotherapy in the post adjuvant
setting after the surgery.
The survival. Was slightly worse so we're waiting for more
study data and for more clinical trials, uh, but and this is my personal conviction,
uh, I'm sure that in a couple of years we will be looking at very effective chemo free regimen,
um, and that was it for you. Thank you very much for listening.
I'm very much looking forward to discussing these topics afterwards with you.
Thank you, Maggie for this excellent overview and we go further to the next presentation.
Connie Leo, uh, breast surgeon from Switzerland, Baden, and she will
present uh de-escalation in the axilla.
Thank you very much.
Thank you very much to the organisers for the invitation.
I'm very honoured to talk to you about de-escalation in axillary surgery.
These are my disclosures.
The presentation will cover two topics. I will talk about axillary surgery in the
upfront surgical setting, and I will also talk about axillary surgery in the post neoadjuvant
setting because there are a lot of things going on.
And in the end, I try to give you an algorithm that depicts the situation that we have now in
2024.
But first I will start with some facts.
Axillary lymph node dissection does not improve outcome, but it increases morbidity,
especially on mobility.
Axillary surgery has therefore no therapeutic rationale, but it serves as a staging
procedure and also to inform adjuvant treatment plans.
However, the increasing role of biology over anatomy in systemic treatment decisions renders
axillary interventions less important.
And given the widespread use of genomic essays, there is less need for axillary surgery to
guide systemic therapy.
And last but not least, axillary recurrences are rare.
So if we consider this, it is clear that the importance of axillary dissection is rapidly
dwindling. Axillary staging has been
evolving from has been evolving
from performing traditional axillary lymph node dissection starting in the 1970s,
1980s, 1990s to performing sentinel lymph node biopsy from the early 2000s to
omitting any type of axillary surgery in selected patients nowadays.
So I want want to briefly talk about the highlighted studies here,
and I also want to explain the situation in the post-net chemotherapy setting because here's a
lot of research activity going on.
In case of a positive sentinel lymph node.
There used to be axillary completion axillary lymph node dissection up to the year 2010,
2011 when the first data from the Z11 trial were reported.
In this trial, patients that had tumours less than 5 centimetres,
tumours that were.
Negative upon clinical evaluation and patients that decided for breast conserving surgery and
had adjuvant radiotherapy scheduled.
If these patients had 1 to 2 positive sentinel nodes, they were randomised either to receive
completion axillary lymph node dissection or no axillary lymph node dissection.
There was no difference in 10 year overall survival and in 10 year disease free survival
between the groups, and also there were very low axillary recurrence rates,
so this was a practise changing trial, but Sorry.
I don't think this is the last version of my presentation I sent you,
but it doesn't matter.
So it was a practise changing trial, but there were some limitations to the Z-11.
There were no data on patients with mastectomy, no data on patients with extra nodal
involvement, and also there were a lot of different irradiation protocols involved.
However, the validation studies that have been performed so far have not only confirmed the
results but also broadened the inclusion criteria, and I want to shortly introduce you
to the Cenoak trial, a very well designed trial with a large sample size.
That was published just recently this year in the New England Journal of Medicine.
The primary endpoint of this trial was recurrence free survival at 5 years,
and you can see that there was no difference between the sentinel node biopsy only group and
the completion axillary dissection group.
The trial included more than 2500 patients.
And also they included important subgroups like patients that underwent mastectomy,
patients with sentinel nodes that had extracapsular extension,
patients with larger than 5 centimetre tumours, and also they included men.
However, fortunately unfortunately, only 10 men were enrolled in this trial.
Now the subgroup analysis of all these groups also showed that sentinel lymph node biopsy
only was not worse than axillary lymph node dissection.
So the Senomak trial adds robust evidence that we really can avoid completion axillary lymph
node dissection in patients with 1 to 2 positive sentinel nodes.
Now what about complete omission of axillary surgery in clinical node negative patients?
The choosing wisely recommendations from the SSO advise against routine sentinel node biopsy
in patients 70 years and older when they have small tumours,
hormone receptor positive, HER2 negative, and this was based on data from the CAGB 9343
trial. Now one can ask, does anyone with early stage
clinically no negative disease benefit from axillary surgery?
And there are some studies going on currently that try to answer this question,
and I want to just comment briefly on the data from from the sound trial that also
tries to answer this question.
This was a large prospective randomised trial with more than 1400 patients of all ages.
The patients had tumours of up to 2 centimetres in size.
They didn't have axillary node involvement upon clinical examination,
and, and this is important, it was mandatory that they had a preoperative axillary
ultrasound with no lymph node involvement.
All patients had planned breast conserving surgery and radiation therapy,
and they were randomised and either got sentinel node biopsy or no axillary surgery.
And as you can see here, distant disease-free survival.
It was not different between the groups and also overall survival was not different and it
was an excellent rate with 98.2% versus 98.4% at five years.
Now the majority of patients were postmenopausal and also had hormone receptor
positive HER2 negative breast cancer.
So the sound trial safely supports strongly the safety of omitting
axillary surgery in this older patient population with small hormone receptor positive
breast cancers. Now let's switch gears a little bit and um look
at axillary surgery after neoadjuvant chemotherapy.
We have robust evidence that um We can avoid that
we can omit completion axillary lymph node dissection in patients that start with a
positive axilla, get neoadjuvant chemotherapy, and then have a conversion to a node negative
situation. There are different studies conducted.
And they all used different or they used different axillary staging procedures,
and I just want to mention the TAD, the targeted axillary dissection.
This is a technique where upon biopsy of the lymph node,
the positive node gets marked with a clip or with a radioactive seed,
and then if the patient converts to a node negative situation,
only this clipped node together the sentinel nodes gets removed.
And with the evidence that was gathered from these studies,
one can say that it is safe to omit axillary surgery, completion axillary surgery in
patients that convert to a negative situation after chemotherapy.
Now, this is different if there is residual nodal disease after neoadjuvant chemotherapy.
Here, the studies are still ongoing and we have three trials going on right now.
This is the Texas trial, the Alliance A 011 202 trial, and the Spanish ANAT trial.
All trials include patients that have residual nodal disease after neoadjuvant chemotherapy.
All trials compare classical axillary dissection to axillary radiation therapy
either after a sentinel node biopsy only or in case of the tax.
Trial after a procedure that is called targeted axillary surgery and that
consists of a sentinel node biopsy of removing the clipped node and also of removing
suspicious nodes that might be in the axilla.
However, we await the results in 2030 and up to then, outside of clinical
trials. Axillary dissection remains the standard of
care in patients with residual nodal disease after neoR1 chemotherapy.
I just want to briefly mention the Exana trial by the EU Breast Group.
A large study has already enrolled more than 5800 patients.
In this prospective multicenter cohort study, they want to evaluate different surgical
methods of axillary staging in the context of neoadjuvant chemotherapy.
Now this is my last but one slide.
This is an algorithm that depicts the situation of axillary surgery in 2024,
and I just try to very briefly walk you through.
In the situation of upfront surgery, we have a patient with a negative lymph node status
evaluated upon clinical examination, but also axillary ultrasound.
And if this patient has low risk features, she's postmenopausal,
small cancer, hormone receptor positive, she can omit sentinel node biopsy.
Otherwise she gets sentinel lymph node biopsy, and if there are 1 or 2 macro metastasis that's
sufficient, one does not complete axillary dissection.
However, if there are 3 or more positive sentinel nodes,
one has to consider completion axillary lymph node dissection.
Now in the case of upfront surgery with a positive lymph node status,
the patient has to undergo axillary lymph node dissection.
A portion of the Texas trial is currently being investigating this situation as well,
and it might be possible that we also can de-escalate in this situation in the future,
but the data for that are not here yet.
Now in the neoadjuvant setting, we have to consider the lymph node status pre-neoadjuvant
chemotherapy and post neoadjuvant chemotherapy.
A patient starting with a negative axilla, she gets sent in a lymph node biopsy.
A patient that has a positive axilla that converts to a clinical node negative situation
after the neoadjuvant chemotherapy, she is the ideal candidate for targeted axillary
dissection. However, if upon histological examination there
is residual nodal disease in these patients, they have to undergo completion axillary lymph
node dissection. And if there is no conversion to a negative
axilla, if she stays positive, she has to get axillary no dissection from uh
to begin with. Now I have 2 take home messages.
Only few indications for complete axillary clearance remain.
That is the clinical node positive patient in upfront surgery and residual nodal disease
after neoadjuvant chemotherapy, and this is also inflammatory breast cancer.
I didn't allude to that, but this is a special entity, and I just want to mention it here.
And take home message number 2 results of ongoing trials may further limit the
indications for axillary surgery.
Thank you very much for your attention.
Thank you. Excellent presentation as usual.
We have our next speaker who's going to talk to us on the treatment of breast cancer and
special groups in the extreme of ages, uh, and pregnancy, so it's a lot in 10 minutes.
Uh, Alessandra De Scalzi.
Hi to everyone, good afternoon.
Thank you for inviting me. For me it's thrilling to be here.
I'm so honoured.
um, and today I come from Milan and I'm a breast surgeon.
So, uh, today I treat the breast cancer in special groups extreme of age
and pregnancy.
I have to run faster because we have to say a lot about this theme and we,
we start to define what are the extremes of age.
Age is considered an important prognostic factor in breast cancer patients,
and as we know, uh diagnosis at a very young age is independently related with the
worst outcome.
According to United States National Cancer, median age,
the diagnosis is 63 years old, but how we could define extreme of
ages. There are a lot of difference between clinical
trials and we don't have a unique response.
Uh, so there are no data to support screening of symptomatic women younger than 30.
And I've tried to analyse them to those large studies.
A considering woman before 14 years old passing through there for screening,
it's evident if that woman had a high cholera rates
of uh recola and a very high rates of false positive result.
In the second study that I considered in the same population,
uh, We can affirm that the The arm of
a symptomatic woman uh undergone to mammography
doesn't give us any cancer, fortunately.
So at the opposite extreme in the elderly population, a huge study considered the
screening by decade of age.
In this case, in this case, obviously sensitivity and specificity increase with age,
but we have another point to consider the benefit of the screen this population,
and this is depends on the life expectancy of this population.
tumour biology, is it a different disease?
If we see a US National Cancer database which
compares tumour biology between those two extremities of
age, it's quite evident that younger woman has higher tumour
grade, more triple negative, more H2 positive.
But the stage of presentation is almost the same with a lot of
metastasis presentation in both of those two populations.
Um, I present a study conducted in our institute in Millena which
compare in premenopausal woman, the very young to the less young.
This is not polite, but uh. So, before 35 years
old, we have a higher key is 67, higher tumour grade,
and so all those data are significant uh impressive.
According to high percentage percentage of an endocrine cancer
and age diagnosis, also in young population, mutations are more diffuse.
But let's have a look.
Let's have a look about the surgical approach.
Um, in the past decade, as said before, there have been marked
trends of mastectomy, and it's quite impressive to see that the greatest
increase are seen in women with small tumour and also in
situ disease.
According with the uh the increase of mastectomy, also the
contralateral prophylactic mastectomy increase.
Um, age was the most significant factor related to increased
ochondrallate mastectomy.
Obviously, has increased the rate of mastectomy, increased also the rate of reconstruction both
in in young population but also in a population above 65
years old. As I said before,
uh, we have to choose wisely when to perform a sentinel lymph node biopsy
in 170 years age with early breast cancer.
OK, about systemic therapy, chemo, uh, are used in younger
women more often than in women above 75, and, um,
such decisions are often made by based on age, cancer stage,
patient uh performance status, and comorbidity, and this is quite evident
also adjuvant chemo.
I used uh more in younger women, but important data that today I was
delighted to underline is that PCR is the same.
In fact Uh, fewer elderly women receive chemo for their breast cancer,
and when they are prescribed systemic therapy, they are often given non-cardiotoxic
regimens, but also elderly patients had a similar and substantial
clinical benefit from new adjuvant chemo.
Just to remember, uh, there is a high recommendation discussion about fertility in
the younger population when we give chemo.
About radiation therapy, I think everything is said.
I just want to remember this CLGB study which allows us to
omit safely radiation in population over 17 years old.
Uh, and also the prime 2 study which confirmed the data of the previous study.
Trying to, to have some outcomes, OK.
Young women are at increased risk for developing more aggressive subtype of breast
cancer. The effect of age on survival of women with
early breast cancer seems to be vary by cancer subtype.
and uh luminal tumour seems to be particularly
particularly pronouncetic in human with luminal breast cancer.
Maybe you for long natural history.
I for me it just a question. OK.
Um, local recurrence free survival rate in breast cancer patients is
based on patient age.
Younger patients develop both types of recurrence more frequently than the older.
And, and this is um Something to um
Underline.
I try to have some disclosure.
The extreme of age are usually not included in clinical trials.
So often we see undertreatment or overtreatment of this population.
Breast cancer diagnosis at the extreme of age differs in clinical pathological
characteristics. This difference, in addition to patient
comorbidities, expected lifespan, impact treatment recommendation,
and patient choice.
Outcomes differ between those diagnosed at the extreme of age,
likely do a combination of those above factors.
An assessment of tumour biology and physiological age should be used to make
treatment recommendation.
Special consideration of genetic testing, fertility preservation,
a survivorship should not be overlooked in the young.
OK, I'm late.
Uh, the last minority of today is pregnancy.
In fact, the manager of breast cancer during pregnancy fortunately is a
rare condition, but we don't have any clinical trials for obvious reasons.
Um, and we have to look to the last year consensus of ESO
to understand how to treat this patient.
The first line imaging modality, uh, is for sure breast ultrasound.
Mammography could be performed in a single projection, and the breast MRI should be
avoided because gadolinium passed a cephalic barrier.
Um, systemic staging for early breast cancer could be just an
X-ray and an abdominal ultrasound and if
available, a body MRI, well, body MRI is recommended.
But, um, trying to, to speak about chemo and surgery, pregnant patients must receive
the treatment as similar as possible to no pregnant patients.
Why? Because chemo, uh, to guarantee overall
survival, chemo is contraindicated in the first semesters of gestation
and we uh have to avoid immunotherapy.
On the opposite side, surgery could be done with breast conservative or
mastectomy and sentinel lymph node biopsy can be carried out.
Obviously, if uh we perform a mastectomy, we reduce the problem of
postoperative radiation therapy.
Because when indicated, it could be done post-operative with the pelvic
shield, but when it's possible, it's preferred to postpone until the delivery.
So, disclosure, the over lack of high-level evidence around this topic is huge.
Decision making about obstructive management and oncological treatment in pregnancy should
be carried out in a specialised centre.
59:56.159 --> 01:00:01.570 From the second trimester, chemo is considered as relatively safe.
01:00:02.080 --> 01:00:06.459 Breast conservative and mastectomy are both viable strategy.
01:00:06.760 --> 01:00:08.810 Thank you for your attention.
01:00:12.600 --> 01:00:15.750 Thank you, Alessandra, for the next excellent talk.
01:00:16.120 --> 01:00:22.979 Uh, we got our further to Viripati um she
01:00:22.979 --> 01:00:24.899 will. Yeah.
01:00:27.340 --> 01:00:33.760 Oh, I didn't know. OK, we have to change something.
01:00:35.179 --> 01:00:39.909 Um, we, we go to the next lecture now from Cicero Urban.
01:00:40.159 --> 01:00:44.679 He will speak about ethical considerations in risk inducing surgery.
01:00:45.679 --> 01:00:48.469 Sorry guys, that's me and no Star Wars.
01:00:48.939 --> 01:00:53.020 It was an amazing, uh, present lecture wasn't it?
01:00:53.360 --> 01:00:56.800 But now we would talk. I will be the good guy now.
01:00:56.879 --> 01:01:00.790 I will try to talk about good things that you should do in your practise.
01:01:01.239 --> 01:01:03.770 So ethical considerations and risk reduction surgery.
01:01:03.879 --> 01:01:07.050 I don't have conflict of interest here to disclosure.
01:01:08.219 --> 01:01:13.739 And let's consider this case a young woman, this is a real case,
01:01:13.879 --> 01:01:18.879 real life, 20 years old, deeply affected by her mother's death from breast cancer at the age of
01:01:18.879 --> 01:01:19.899 38.
01:01:20.280 --> 01:01:25.370 All genetic tests were negative after concealing an explanation still wants risk
01:01:25.370 --> 01:01:26.870 reduction mastectomy.
01:01:27.239 --> 01:01:31.679 What would you do? Mastectomy, bilateral mastectomy in this
01:01:31.679 --> 01:01:34.310 patient. Noesis's tests were negative.
01:01:34.520 --> 01:01:37.790 And what if she has breast cancer?
01:01:38.000 --> 01:01:40.070 Something changed to you? Well.
01:01:41.050 --> 01:01:47.689 Uh, why are these so many unnecessary mastectomy to reduce risk and.
01:01:49.780 --> 01:01:53.100 When are they really necessary? That's the question.
01:01:53.949 --> 01:01:56.060 Well, I love this answer.
01:01:56.399 --> 01:02:03.120 drastic surgical solutions have become socially acceptable and even glamorous approach.
01:02:03.850 --> 01:02:06.879 Well, is this the Angelina Jolie effect?
01:02:07.969 --> 01:02:12.639 It's a big no here. It's not the only explanation to this
01:02:12.639 --> 01:02:19.239 phenomenon. It is a phenomenal event for from
01:02:19.239 --> 01:02:23.010 us as doctors. It is due to the making effect.
01:02:23.120 --> 01:02:27.399 Mein was a journalist from the 19th century, um.
01:02:28.389 --> 01:02:34.040 He said for every complex problem, there is a clear, simple,
01:02:34.070 --> 01:02:35.540 and wrong answer.
01:02:36.469 --> 01:02:43.439 So let's ask, let's go to the good answer to our patients to the best option,
01:02:43.870 --> 01:02:47.830 not to the bad options, as we are discussing this morning.
01:02:47.949 --> 01:02:52.360 So in summary, uh, ethics before technique, this is my first point here.
01:02:52.949 --> 01:02:57.229 Then I will show you a very practical approach using.
01:02:58.360 --> 01:03:05.000 4 tools in clinical ethics decision model and a controversial choices in a controversial world
01:03:05.000 --> 01:03:08.709 and some at least good news well.
01:03:09.649 --> 01:03:11.300 Ethics before technique.
01:03:11.770 --> 01:03:12.899 What is ethics?
01:03:13.330 --> 01:03:16.370 Ethics is the best way to do something.
01:03:17.919 --> 01:03:23.020 It is the right way to do something or both? I think they are both a combination of both.
01:03:23.070 --> 01:03:24.780 Well, uh.
01:03:26.610 --> 01:03:28.120 What is the best for the patient?
01:03:28.370 --> 01:03:30.879 What is the best for the system?
01:03:31.209 --> 01:03:34.409 What is the best for the surgeon?
01:03:35.270 --> 01:03:38.939 In the ideal world we should have a convergence of values,
01:03:39.500 --> 01:03:45.219 but what happens in the real world we have conversions and divergence.
01:03:47.709 --> 01:03:52.590 Why it matters here because besides the number of risk reduction,
01:03:52.830 --> 01:03:58.870 prevention of deaths and techniques, there are patients risk perception about the quality of
01:03:58.870 --> 01:04:01.550 life and her autonomy.
01:04:03.020 --> 01:04:09.929 Why in particular should risk reduction mastectomy be seen more as an ethical concern
01:04:09.929 --> 01:04:15.969 than a strictive medical question because it is a risky condition because we have genetic
01:04:15.969 --> 01:04:21.360 exceptionalism because breast is not thyroid and breast is not thyroid,
01:04:21.419 --> 01:04:22.919 it's not an ordinary.
01:04:23.129 --> 01:04:29.689 We have a very difficult approach with the breast when we just let this out.
01:04:30.280 --> 01:04:34.040 Very practical clinical ethics approach for risk reduction mastectomy.
01:04:34.060 --> 01:04:36.250 I invite you to read this book. It's fantastic.
01:04:36.350 --> 01:04:39.879 It's very fast, fantastic in in a flight you can wait.
01:04:40.850 --> 01:04:43.679 Four tools. First, medical medication,
01:04:43.969 --> 01:04:48.219 preference of patients, contextual uh features and quality of life.
01:04:50.219 --> 01:04:54.060 Medical indication is very easy to us. What, what are medical indications?
01:04:54.100 --> 01:04:59.209 The facts, interpretation about patients' physical and psychological condition to provide
01:04:59.209 --> 01:05:02.689 a reasonable basis for clinical judiment.
01:05:03.020 --> 01:05:08.489 We have lots of data about risk reduction mastectomy, about contralateral mastectomy.
01:05:08.550 --> 01:05:12.139 We all know the best indication for each patient.
01:05:12.669 --> 01:05:18.260 This is very clear in the literature we know that we have uh complications in contralateral
01:05:18.260 --> 01:05:21.899 mastectomy. These complications can delay the adjuvant
01:05:21.899 --> 01:05:27.780 treat treatment, so it is worse for the patient when when we go to contralateral breast to do
01:05:27.780 --> 01:05:30.659 mastectomy when she has to do.
01:05:31.820 --> 01:05:33.250 Uh chemotherapy.
01:05:34.179 --> 01:05:38.790 So we are not doing the best and we all know, at least in oncology,
01:05:39.040 --> 01:05:45.959 that doing systemic therapy we can reduce the risk of contralateral cancer so no way
01:05:45.959 --> 01:05:52.629 to do contralateral mastectomy there is no data sufficient to do a good indication so it's not
01:05:52.800 --> 01:05:57.679 clinically indicate for most of cases that most patients that come to us.
01:05:58.159 --> 01:06:02.830 Asking to this preference of patients autonomy is a very important tool.
01:06:02.959 --> 01:06:04.949 It's it's very important.
01:06:05.239 --> 01:06:11.719 This is an issue in Apex and in general all persons have fundamental right to control their
01:06:11.719 --> 01:06:16.389 body, but we see the world not as it is but as we are.
01:06:17.449 --> 01:06:19.439 Words have power.
01:06:19.689 --> 01:06:21.560 Watch with this.
01:06:21.790 --> 01:06:27.320 Watch out, prevent prophylactic mastectomy, preventive mastectomy.
01:06:27.489 --> 01:06:30.199 These are a disaster. This is a risk reduction,
01:06:30.250 --> 01:06:36.209 mastectomy, a risk reduction in mastectomy, mastectomy, mastectomy is a mutilation.
01:06:37.939 --> 01:06:39.659 It's a it is a mutilation.
01:06:40.310 --> 01:06:46.679 This should be we should say to our patients what they wanted if she wanted a mutilation,
01:06:46.729 --> 01:06:53.530 OK, but this mutilation, uh, we have a cause for this mation to be good for her quality
01:06:53.530 --> 01:06:58.370 of life. Risks of genomic tests are psycho social or
01:06:58.370 --> 01:06:59.620 greater than medical.
01:07:00.250 --> 01:07:01.570 It's a huge problem.
01:07:02.300 --> 01:07:05.139 When you go to pharmacy and do a genetic test in Brazil,
01:07:05.149 --> 01:07:06.419 it's not possible to do it.
01:07:06.620 --> 01:07:09.209 I know that some countries you have it available.
01:07:09.500 --> 01:07:12.790 This is a disaster because patient received the, the, the,
01:07:12.800 --> 01:07:16.489 the test and she don't know what she's gonna do with this,
01:07:16.500 --> 01:07:17.770 uh, uh, result.
01:07:19.070 --> 01:07:24.010 And our genetics so.
01:07:25.040 --> 01:07:27.860 A risky condition is not a disease.
01:07:28.739 --> 01:07:31.129 Genetics there are.
01:07:32.280 --> 01:07:38.399 Something that I want to show you people overestimate the impact of genes and.
01:07:40.790 --> 01:07:47.510 30 to 40% of women in the United States consider contralateral prophylactic mastectomy,
01:07:47.709 --> 01:07:53.379 so psychological cultural facts we know that this is not a disease.
01:07:53.709 --> 01:07:59.399 This is more a psychological disease than a real disease in our practise.
01:07:59.629 --> 01:08:05.379 Our societies adverse to uh uh to this kind of risks well.
01:08:06.739 --> 01:08:11.520 Uh, and the presence of children impacts the decision.
01:08:11.610 --> 01:08:18.149 Costs contralateral prophylactic mastectomy has additional costs for our health
01:08:18.149 --> 01:08:25.080 system, and besides age, the attention, immediate breast reconstruction
01:08:25.080 --> 01:08:29.240 is the most important factor in contralateral mastectomies.
01:08:29.899 --> 01:08:34.299 This was what what we were discussing about the influence of doctors.
01:08:34.459 --> 01:08:39.779 More the doctor have influenced less contralateral mastectomy,
01:08:39.819 --> 01:08:44.470 more patient has influenced more contralateral prophylactic mastectomy.
01:08:45.100 --> 01:08:48.490 Controversial choices in a controversial work to finish,
01:08:49.089 --> 01:08:54.140 uh. These are not good indications for
01:08:54.140 --> 01:08:58.750 contralateral mastectomy or to bilateral mastectomy to limit surveillance,
01:08:59.040 --> 01:09:01.959 to improve symmetry, to manage risk aversion.
01:09:03.168 --> 01:09:05.358 Mastectomy is not psychotherapy.
01:09:06.149 --> 01:09:09.359 Is a mutilation Some good news.
01:09:10.289 --> 01:09:14.068 We are reducing contralateral indications.
01:09:14.409 --> 01:09:19.979 We are reducing contralateral bilateral and bilateral mastectomies unnecessary in practise.
01:09:20.249 --> 01:09:23.778 So the Angelina Jolie effect is going down. It's good.
01:09:23.849 --> 01:09:25.449 It's a good new and.
01:09:26.609 --> 01:09:30.569 Patients that should do or can do hereditary breast cancer,
01:09:30.620 --> 01:09:36.419 selected cases of familial breast cancers, CSO radiation therapy,
01:09:36.810 --> 01:09:40.529 no BRCA gene carriers, but with a strong family history.
01:09:40.620 --> 01:09:47.330 So this is, these are cases that we should do we should offer to patients contralateral or
01:09:47.330 --> 01:09:48.700 bilateral mastectomy.
01:09:48.930 --> 01:09:52.729 My final message impact of the availability improving.
01:09:52.839 --> 01:09:58.560 The quality of reconstruction is increasing the indications for unnecessary mastectomies.
01:09:59.029 --> 01:10:05.430 However, has not been studied until now, but it is some of the causes contralateral risk
01:10:05.430 --> 01:10:11.830 reduction mastectomy has complications, add costs, and may be higher than the expected
01:10:11.830 --> 01:10:13.140 positive effects.
01:10:13.509 --> 01:10:17.979 The indication must take into account the oncological reconcilitative psychological
01:10:17.979 --> 01:10:19.069 aspects and.
01:10:19.560 --> 01:10:24.000 These 4 tools are very useful in our practise for our our.
01:10:24.689 --> 01:10:27.890 Decisions in, in, in uh in clinical.
01:10:29.529 --> 01:10:34.220 Medicine is a is a science of uncertainty and an art of probability.
01:10:34.450 --> 01:10:37.890 Risk reduction of mastectomy is an indication of probability.
01:10:38.580 --> 01:10:42.640 And an art of uncertainty, so thank you so much.
01:10:42.890 --> 01:10:45.680 Sorry I, I should go because my flight is.
01:10:47.680 --> 01:10:53.330 And thank you so much for the opportunity to be with you here in this great meeting.
01:10:54.470 --> 01:10:57.029 Thank you, Jero and safe flight to Cape Town.
01:10:57.629 --> 01:11:01.419 So our next speaker is a colleague and a dear friend, uh,
01:11:01.629 --> 01:11:05.979 Vishak at the party who's going to talk to us about managing familial breast cancer risk in
01:11:05.979 --> 01:11:07.419 non-mutation carriers.
01:11:13.060 --> 01:11:16.729 Thank you so much for the kind invitation, particularly to Marlene.
01:11:16.930 --> 01:11:22.160 It's great to be here amongst colleagues and friends, particularly at your 10th anniversary.
01:11:22.529 --> 01:11:25.979 Only two talks keeping you from dinner, so we've drawn a short straw,
01:11:26.049 --> 01:11:30.839 I think, but Cicero has very kindly set the scene very nicely for my talk.
01:11:31.250 --> 01:11:32.839 So here are some of my disclosures.
01:11:34.879 --> 01:11:40.060 So I'm going to try and articulate some of the nuances in managing familial risk in
01:11:40.060 --> 01:11:41.390 non-mutation carriers.
01:11:42.250 --> 01:11:49.180 C is very eloquently described the nuances of managing risks in mutation carriers,
01:11:49.220 --> 01:11:51.370 so I won't go into that too much.
01:11:52.259 --> 01:11:56.899 Probably a good place for us to start is to remind ourselves that actually most cancers
01:11:56.899 --> 01:12:01.890 that we see are still sporadic, so they are not caused by a heritable high risk gene mutation.
01:12:02.140 --> 01:12:05.569 In fact, it's usually caused by a combination of environmental,
01:12:05.779 --> 01:12:09.680 hormonal and genetic factors. So what does the landscape look like?
01:12:09.859 --> 01:12:13.250 Well, actually 90% of breast cancers are sporadic, as I said,
01:12:13.459 --> 01:12:18.649 so we are really only talking about 10% of the population that might carry a genetic
01:12:18.649 --> 01:12:19.819 susceptibility.
01:12:20.160 --> 01:12:25.350 Within that 10% group, if you undertake genetic testing, essentially you're only able to
01:12:25.350 --> 01:12:32.350 identify a high risk penetrant gene alteration or a pathogenic variant in approximately 20% of
01:12:32.350 --> 01:12:36.129 those patients. So you're still left with a significant volume
01:12:36.129 --> 01:12:42.459 of patients that have come to clinic seeking genetic risk assessment that walk away without
01:12:42.459 --> 01:12:47.540 a specific yes yes or no answer, particularly that 70% group.
01:12:49.750 --> 01:12:55.410 So you must think what have we been doing in genetics for for for the last few years if we
01:12:55.410 --> 01:13:01.399 can't even articulate what the risk is in that 70% group that seek genetic risk assessment.
01:13:01.609 --> 01:13:08.319 We have been busy, I assure you, um, so since the discovery of hereditary breast
01:13:08.319 --> 01:13:12.850 cancer as a syndromic condition in the early 1880s, a huge.
01:13:13.310 --> 01:13:16.399 have been made, particularly in technology and the speed of sequencing.
01:13:16.509 --> 01:13:22.069 So initially we used to use Sanga sequencing, but some clever individuals then discovered the
01:13:22.069 --> 01:13:28.009 BRCA1 and BRCA2 genes, which gave us something really concrete to hang on to and to test
01:13:28.319 --> 01:13:34.229 followed that by the Lynch syndrome gene discovery which took us into the colorectal
01:13:34.229 --> 01:13:36.549 setting, but clearly not.
01:13:36.970 --> 01:13:41.759 Uh, a space for for today, and Cicero has uh very quickly mentioned some of the,
01:13:41.770 --> 01:13:46.720 the non-BRCA high risk gene, um, syndromic conditions, CAD syndrome,
01:13:46.729 --> 01:13:51.399 um, and hereditary diffuse gastric cancer and Pertz Jager syndrome as well.
01:13:52.879 --> 01:13:58.149 So yeah, as I say, we have been busy, but more recently we've also got some new kids on the
01:13:58.149 --> 01:14:01.109 block. So check 2, although we knew about it,
01:14:01.169 --> 01:14:07.509 we probably weren't clever enough to decipher the complete risk landscape within the
01:14:07.509 --> 01:14:12.069 CE2 gene and in fact ATM as well, and I'll tell you a little bit more about that.
01:14:12.689 --> 01:14:18.299 For many, many years you probably heard people say there must be a BRCA 3 out there,
01:14:18.359 --> 01:14:24.419 and I, and I reckon that was probably PA B2, so we actually have 3 high risk,
01:14:24.529 --> 01:14:31.330 highly penetrant breast cancer predisposition genes now that we can test and clinically
01:14:31.330 --> 01:14:34.589 action. Angelina Jolie, very familiar to this audience,
01:14:34.720 --> 01:14:41.520 but has caused us um a huge increase in volume um in referrals and um individuals seeking
01:14:41.520 --> 01:14:47.160 genetic risk assessment, um, with a reminder that actually 90% of them actually don't need
01:14:47.160 --> 01:14:50.569 it. The 100,000 genomes project in this country
01:14:50.569 --> 01:14:55.770 actually posed us a big challenge in terms of mobilising genomics outside our specialty to
01:14:55.770 --> 01:15:01.640 really embed testing within the oncology setting, and we are really working hard to do
01:15:01.640 --> 01:15:04.240 that. But more recently you've got newer genes coming
01:15:04.240 --> 01:15:09.930 onto the sceneA1, BRI one, and we really need to understand a little bit more about them.
01:15:10.810 --> 01:15:17.140 So what does this in summary, um, you know, what does the risk landscape within uh genetics
01:15:17.140 --> 01:15:20.259 look like? Well, we've got some gene variants that greatly
01:15:20.259 --> 01:15:26.770 increase risk, so we've talked about BRCA1 and BRCA2, up to 70-75% lifetime risks of breast
01:15:26.770 --> 01:15:31.589 cancer for an unaffected woman, but these are rare, they're rare in the population,
01:15:31.819 --> 01:15:34.259 and they only cause a small proportion of cancers.
01:15:34.339 --> 01:15:36.020 It's really important to remember that.
01:15:36.859 --> 01:15:41.229 There's some gene variants that will increase risk but in a polygenic way,
01:15:41.379 --> 01:15:46.740 and you will need a large volume of those to actually meet the threshold that might be BRCA
01:15:46.740 --> 01:15:49.859 equivalent. So you might see a large proportion of women
01:15:49.859 --> 01:15:53.620 test a large proportion of women. They probably won't reach the threshold of some
01:15:53.620 --> 01:15:59.645 of the BRCA gene carriers and really. We're then starting to think about some of the
01:15:59.645 --> 01:16:02.294 more common variants that we all carry.
01:16:02.685 --> 01:16:05.564 These are widely, widely seen within the genome.
01:16:05.805 --> 01:16:11.194 They confer low penetrance and low risk, and you would need a lot more of these to actually
01:16:11.194 --> 01:16:16.595 clinically action them in terms of any additional screening or surgical interventions.
01:16:17.285 --> 01:16:20.955 They do have a place, however, in stratifying breast screening,
01:16:20.964 --> 01:16:25.444 and that's probably a talk for 2025 LBM maybe.
01:16:26.259 --> 01:16:31.339 So let's remind ourselves what these families with syndromic breast cancer susceptibility are
01:16:31.339 --> 01:16:33.970 grappling with. It's not just breast cancer.
01:16:34.140 --> 01:16:37.830 They have a whole host of risks, both malignant and benign,
01:16:38.100 --> 01:16:39.410 that they need to think about.
01:16:39.740 --> 01:16:44.540 So when you have someone in front of you with one of these high risk gene pathogenic variants,
01:16:44.660 --> 01:16:49.899 I think it might be useful to remember some of the other factors and some of the other risks
01:16:49.899 --> 01:16:54.259 that we will have counselled them about, but they also need to consider.
01:16:56.109 --> 01:17:02.000 So really, um, this, this group with these high risk gene alterations are tip of the iceberg.
01:17:02.189 --> 01:17:06.720 Um, they're rare, they're high risk, but we can do something about them and we know how to do
01:17:06.720 --> 01:17:11.950 it quite well. The bottom of the iceberg is is probably where
01:17:11.950 --> 01:17:15.250 some of the nuances lie at the moment in terms of, you know,
01:17:15.390 --> 01:17:21.060 what is the role of things like family history, what is the role of tumour histology in women
01:17:21.060 --> 01:17:25.470 who carry more of the moderate risk penetrance genes such as ATM check 2,
01:17:25.750 --> 01:17:31.975 RAD 51 CD and then the. Huge amount of women who possibly might do a
01:17:31.975 --> 01:17:38.055 direct consumer test that looks at hundreds of single nucleotide polymorphisms and come away
01:17:38.055 --> 01:17:42.754 with it quite anxious into your clinics asking for risk reduction or increased surveillance,
01:17:43.524 --> 01:17:48.935 and we really actually need to think about what right interventions we ought to offer them.
01:17:50.109 --> 01:17:56.930 So, um, breast cancer risk lots of modifiable and non-modifiable risk factors that are not
01:17:56.930 --> 01:17:59.979 new to the audience, so one might question, well, um,
01:17:59.990 --> 01:18:02.339 you know, what is the benefit of genetic testing really,
01:18:02.509 --> 01:18:03.540 why should we do it?
01:18:03.790 --> 01:18:06.310 Um, it is beneficial, it's useful because um.
01:18:06.634 --> 01:18:12.104 If we identify a pathogenic variant, we can identify the cause of the disease in that woman
01:18:12.395 --> 01:18:18.714 and offer predictive genetic testing to her at-ris relatives and do some risk reducing
01:18:18.714 --> 01:18:22.825 interventions, either screening or risk reducing mastectomy reconstruction.
01:18:23.370 --> 01:18:27.200 If she's going through cancer treatment, she can use this information to make treatment
01:18:27.200 --> 01:18:32.930 decisions such as the use of PARP inhibitors. And um we've already talked about prevention um
01:18:32.930 --> 01:18:37.419 through surgery, screening, but also chemo prevention uh in gene specific scenarios.
01:18:37.770 --> 01:18:43.330 There's a huge relief from uncertainty. And we can't we can't really underestimate that.
01:18:43.390 --> 01:18:48.089 These families have been living with a lot of questions, a lot of fear and anxiety,
01:18:48.330 --> 01:18:51.919 with a high cancer burden generation on generation.
01:18:52.129 --> 01:18:56.149 And once you find that reason, sometimes it's a huge relief for them.
01:18:57.500 --> 01:19:01.000 Other young couples may use this information to make reproductive choices,
01:19:01.009 --> 01:19:05.410 such as accessing prenatal testing or pre-implantation genetic testing through
01:19:05.410 --> 01:19:07.080 IVF-based embryo screening.
01:19:08.000 --> 01:19:13.200 Despite genetic testing though, um, we know that we're not going to identify a pathogenic
01:19:13.200 --> 01:19:14.750 variant in a lot of families.
01:19:15.080 --> 01:19:18.120 So what about them? Why, why have we failed to do that?
01:19:18.240 --> 01:19:21.060 Well, actually you might not have tested the right genes at all.
01:19:21.399 --> 01:19:25.680 Um, it might be a completely acquired susceptibility and they didn't need genetic
01:19:25.680 --> 01:19:32.399 testing, or the uh techniques used in the laboratory might um fail to detect a pathogenic
01:19:32.399 --> 01:19:35.600 variant or a pathogenic mutation, even if it's there in the genome.
01:19:36.000 --> 01:19:39.419 And that still happens despite all our advances in knowledge.
01:19:40.189 --> 01:19:45.180 We might not have identified all the genes that we need to that account for hereditary breast
01:19:45.180 --> 01:19:50.819 cancer susceptibility and last but not least, perhaps we really need to sit back and think
01:19:50.819 --> 01:19:56.609 about um the the importance of multifactorial and polygenic risk in this space.
01:19:57.830 --> 01:20:03.509 So when we're thinking about women, sorry, uh, when we're thinking about unaffected women um
01:20:03.509 --> 01:20:09.580 who have completed a uh a genetic test, that could be single gene or panel test,
01:20:09.830 --> 01:20:15.640 um, if they are found to have a high. Risk gene mutations such as in BRCAPal B2,
01:20:15.870 --> 01:20:18.419 you do not need to quantify their risk further.
01:20:18.669 --> 01:20:23.600 We are really good at knowing what those risks are lifetime and age related,
01:20:23.790 --> 01:20:27.549 so please just ask us or we can we can help you decipher that.
01:20:28.229 --> 01:20:31.729 But in the group of women that have access to genetic testing,
01:20:31.899 --> 01:20:38.209 um, have a family history, and we do not identify a single known pathogenic variant.
01:20:38.379 --> 01:20:43.379 Those are the ones that actually may benefit from the use of digital risk assessment tools
01:20:43.379 --> 01:20:45.379 such as Tyrausic or Cris.
01:20:45.819 --> 01:20:51.259 Um, and I've just put a table there to to give you a little bit of um an idea as to how they
01:20:51.259 --> 01:20:52.979 vary. So you can see actually that.
01:20:53.060 --> 01:20:57.979 Can takes into account lifestyle factors such as the use of the pill,
01:20:58.330 --> 01:21:01.240 age of menopause, but also alcohol use.
01:21:01.609 --> 01:21:08.330 And if any of you have used can risk, if you input the volume of alcohol that an
01:21:08.330 --> 01:21:13.810 unaffected woman in her thirties consumes today, and that might be a high volume perhaps and you
01:21:13.810 --> 01:21:17.720 change that to no how alcohol at all, it's hugely.
01:21:19.490 --> 01:21:24.879 Influences that risk output, so it's really important to actually know the nuances of the
01:21:24.879 --> 01:21:30.959 tool you're using because that decision may actually be based on a very small um.
01:21:31.919 --> 01:21:35.370 Window of lifestyle factors that might change in the future,
01:21:35.640 --> 01:21:40.109 but once that surgical intervention is done, then you probably can't take that back.
01:21:40.680 --> 01:21:47.209 The other thing to remember is some of these tools such as Tyra Cusick are only account for
01:21:47.209 --> 01:21:54.080 BRCA1 and BRCA2, whereas actually the cans model now accounts for much more more genes
01:21:54.080 --> 01:21:55.229 than that and it's just there.
01:21:57.040 --> 01:22:01.220 So Should we just forget about family history?
01:22:01.700 --> 01:22:04.649 You know I've just said we're really great at genetic testing.
01:22:04.819 --> 01:22:06.299 We've got digital tools.
01:22:06.770 --> 01:22:10.549 Should we just use these all the time and not worry about family history?
01:22:10.620 --> 01:22:16.500 Well, I'm hoping to prove you wrong, but actually before me this amazing group Renaattal
01:22:16.500 --> 01:22:21.740 in 2018 already did that work for us, and you'll see that they had two groups.
01:22:22.339 --> 01:22:26.484 They looked at the risk, the cumulative. 10 year absolute risk for developing
01:22:26.484 --> 01:22:33.354 contralateral breast cancer by age to family history in a group of women who had gene
01:22:33.354 --> 01:22:37.944 negative test results compared to women who hadn't undertaken genetic testing,
01:22:37.984 --> 01:22:43.015 didn't have a family history, and even after a gene negative panel test result,
01:22:43.225 --> 01:22:48.584 those with a significant family history continued to have a slightly higher increased
01:22:48.584 --> 01:22:50.975 risk of developing contralateral breast cancer.
01:22:51.720 --> 01:22:56.120 So family history actually is still useful, um, although it might seem quite dated.
01:22:57.140 --> 01:23:01.700 And what about the risk for women who have already had breast cancer,
01:23:01.770 --> 01:23:03.720 and I know you've been talking a lot about that.
01:23:04.009 --> 01:23:07.209 Um, again, if they're carrying a known pathogenic variant,
01:23:07.220 --> 01:23:12.770 the graph on the right shows you that they have increased lifetime risks of a second breast
01:23:12.770 --> 01:23:17.379 primary cancer, and that probably. Need a lot of discussion,
01:23:17.629 --> 01:23:21.339 but actually if they do not carry a high risk known pathogenic gene variant,
01:23:21.629 --> 01:23:23.939 then that risk is substantially much lower.
01:23:24.790 --> 01:23:30.629 It's still not the same as the general population, so that's why we actually say all
01:23:30.629 --> 01:23:33.950 these discussions are quite nuanced, as the previous speakers have alluded to.
01:23:34.640 --> 01:23:38.830 The story never stops at numbers, does it, and this audience will know that,
01:23:39.100 --> 01:23:43.109 and there's so many factors that women have to grapple with when they're making these
01:23:43.109 --> 01:23:46.629 decisions. Some of them will force them to pause that
01:23:46.629 --> 01:23:49.169 decision, whereas others will force them into that decision,
01:23:49.299 --> 01:23:52.830 and it's just about maybe thinking about why they're making that decision.
01:23:53.299 --> 01:23:58.859 At that time point and we use Maslow Maslow's hierarchy of needs quite a lot actually in the
01:23:58.859 --> 01:24:04.020 genetic counselling clinic in asking them why they're making that decision and what it's
01:24:04.020 --> 01:24:05.609 going to give back to them.
01:24:06.100 --> 01:24:09.419 I is it a safety need? Is it love and belonging,
01:24:09.459 --> 01:24:11.149 such as relationship issues.
01:24:12.270 --> 01:24:18.100 Um, so, uh, I hope I'm convincing you slowly but surely that examining the genetic code is
01:24:18.100 --> 01:24:22.060 complex and the microscope has become exponentially more powerful,
01:24:22.100 --> 01:24:26.290 which is great news, but actually it's also become cheaper,
01:24:26.540 --> 01:24:28.339 which gives us the challenge of.
01:24:28.875 --> 01:24:31.785 what we um we get out of this microscope.
01:24:32.075 --> 01:24:37.345 So I'm going to take you through a scenario where um so here's a gene gene panel um
01:24:37.515 --> 01:24:40.785 commercially available, um, most of you will be familiar with it,
01:24:40.825 --> 01:24:44.415 and any of you um can order it for any of your breast cancer patients.
01:24:45.270 --> 01:24:48.819 Um, you might look at it and not question it at all, but actually,
01:24:48.890 --> 01:24:53.330 if I were to tell you that only the genes highlighted in blue have a clear association in
01:24:53.330 --> 01:24:59.939 breast cancer susceptibility, whereas the ones in yellow only have a proposed association and
01:24:59.939 --> 01:25:04.810 require further evidence, whereas the ones in pink actually have no definitive association,
01:25:05.089 --> 01:25:07.540 perhaps you might think differently in ordering that test.
01:25:08.399 --> 01:25:13.879 And um this landscape is really evolving and it's really important to keep up to date with
01:25:13.879 --> 01:25:17.399 the evidence that um comes, comes from genomic testing.
01:25:18.200 --> 01:25:25.160 This is a prime example of that in that in 2006 there was a couple of papers that were quite
01:25:25.160 --> 01:25:29.270 convincing that BIP1 was a breast cancer susceptibility gene,
01:25:29.430 --> 01:25:32.109 and a lot of us started waving our hands in the air going,
01:25:32.240 --> 01:25:37.919 ah, this must be the answer to all the hundreds of families on my follow up list that I haven't
01:25:37.919 --> 01:25:40.560 found a gene gene cause in.
01:25:41.040 --> 01:25:45.729 But actually, you know, fast forward a few years and in 2016 we had a much bigger,
01:25:45.799 --> 01:25:50.839 larger study cos we were doing a lot more testing and actually now we're fairly convinced
01:25:50.839 --> 01:25:55.830 that BRIC one is not a breast cancer susceptibility um gene at all.
01:25:56.100 --> 01:26:00.819 Um, so I hope this, this is just showing you the nuances of that and um giving you some
01:26:00.819 --> 01:26:05.529 caution in terms of the panel tests that you order and perhaps um some questions to leave
01:26:05.529 --> 01:26:11.209 you with in terms of, um, you know, asking yourselves um whether the genes that um you're
01:26:11.209 --> 01:26:14.569 testing for in your patients, you know, is the natural history of those genes.
01:26:15.975 --> 01:26:21.254 Are we able to decipher the tumour spectrum if they're found to have a pathogenic variant in
01:26:21.254 --> 01:26:23.694 it? What are the lifetime cancer risks, because if
01:26:23.694 --> 01:26:27.575 we can't articulate some of this to our patients, it's particularly it's probably not
01:26:27.575 --> 01:26:33.095 very useful and if and when to intervene if you were to find something significant.
01:26:33.959 --> 01:26:37.740 So variant interpretation is definitely a science but also an art,
01:26:37.910 --> 01:26:42.229 um, and it's really important to think about the the laboratory you use,
01:26:42.310 --> 01:26:44.020 whether it's a accredited.
01:26:44.310 --> 01:26:46.270 Have you got the right variant in the right gene?
01:26:46.430 --> 01:26:48.020 Is it actually disease causing?
01:26:48.310 --> 01:26:49.939 Does it explain the phenotype?
01:26:50.180 --> 01:26:54.830 And actually, is it an incidental finding? Perhaps you have a group of patients that come
01:26:54.830 --> 01:26:59.470 to you that are not asking that question at all. Do you actually give them the choice and ask
01:26:59.470 --> 01:27:02.229 them. Do you actually want to know whether this is
01:27:02.229 --> 01:27:05.419 familial or genetic, or do we just assume that everyone does?
01:27:06.200 --> 01:27:11.879 Um, so I just my last slide, and I, I really like this quote from from this lady who had a
01:27:11.879 --> 01:27:18.279 direct to consumer test, um, a huge panel test of over 200 genes which found almost 50
01:27:18.279 --> 01:27:24.359 variants of uncertain significance, um, and obviously you know there was a lot of.
01:27:24.819 --> 01:27:29.290 Articles in the press about it at that time, and she says the stakes are very high.
01:27:29.580 --> 01:27:34.979 You have inherently nuanced and confusing tests and widespread ordering and interpretation by
01:27:34.979 --> 01:27:37.490 doctors who aren't really equipped to do so.
01:27:37.819 --> 01:27:41.890 The situation is ripe for overinterpretation and misinterpretation.
01:27:42.229 --> 01:27:44.490 Patients need to be prepared for ambiguities.
01:27:44.700 --> 01:27:46.089 Typically they are not.
01:27:46.379 --> 01:27:51.459 And when they say doctors, I include ourselves in it because we don't have all the answers
01:27:51.459 --> 01:27:55.870 either. Um, so I hope I've convinced you that actually,
01:27:55.879 --> 01:28:00.359 um, genetic testing is useful, uh, but it's, uh, both a science and an art,
01:28:00.399 --> 01:28:03.229 and we need to do it carefully for our patients. Thank you so much.
01:28:08.200 --> 01:28:12.049 Thank you, Vishaka for the very comprehensive lecture.
01:28:12.529 --> 01:28:18.790 Uh, we come now to the last not least, uh, presentation of this evening.
01:28:19.569 --> 01:28:23.720 I want to induct Chi Reeves from Oxford.
01:28:23.930 --> 01:28:28.359 She will discuss with us the impact of lifestyle on cancer development.
01:28:29.950 --> 01:28:31.740 And it's my mic on yet.
01:28:32.410 --> 01:28:37.700 Uh, unlike everybody else here today, it seems I'm, I'm not a surgeon or an oncologist,
01:28:37.859 --> 01:28:42.299 but my background is actually in cancer epidemiology, and what I've been asked to do is
01:28:42.299 --> 01:28:46.180 to give a very brief overview this afternoon of the role of lifestyle.
01:28:46.439 --> 01:28:49.899 Factors in the development of breast cancer.
01:28:50.560 --> 01:28:54.049 Somebody actually did suggest before the session that because I'm probably the only
01:28:54.049 --> 01:28:58.279 epidemiologist here, I could probably get away with saying anything and nobody would know
01:28:58.279 --> 01:29:02.560 whether it was the truth, but I am actually going to try and stick to the truth today.
01:29:03.140 --> 01:29:06.609 OK, there's my uh disclosures. I have no conflicts of interest.
01:29:06.979 --> 01:29:12.459 Um, so yeah, so the topic of lifestyle factors and breast cancer is very hard to deal with in
01:29:12.459 --> 01:29:18.899 10 minutes, um, and it won't come as a surprise to this audience to know that almost all of the
01:29:18.899 --> 01:29:23.620 factors that we know about the modifiable risk factors for breast cancer are in some way
01:29:23.620 --> 01:29:27.435 related to to sex hormones and. For purposes of this talk,
01:29:27.515 --> 01:29:31.024 I've tried to group them into these four broad categories.
01:29:31.314 --> 01:29:35.674 So first of all, we have risk factors that really relate to endogenous hormones.
01:29:35.794 --> 01:29:39.185 So by this I mean things relating to reproductive history,
01:29:39.955 --> 01:29:41.544 breastfeeding, for example.
01:29:41.875 --> 01:29:47.035 Then we have exogenous hormones, and the two main ones here are things like hormonal
01:29:47.035 --> 01:29:49.575 contraceptives and HRT use.
01:29:50.290 --> 01:29:54.870 Then we've got a whole set of risk factors which look like there's something else but are
01:29:54.870 --> 01:29:57.910 actually just really acting through sex hormones.
01:29:57.990 --> 01:30:03.220 So things like adipocity uh and probably alcohol we can include in that as well.
01:30:04.209 --> 01:30:06.669 And the last group, which is really a sort of catch-all group,
01:30:06.680 --> 01:30:11.359 and I'll just touch on this at the end, is you know all of the other factors that have been
01:30:11.359 --> 01:30:14.910 hypothesised to be associated with breast cancer risk.
01:30:15.160 --> 01:30:20.560 But in this group, you know, I include all of those where actually the causation is not so
01:30:20.560 --> 01:30:23.870 well established, the magnitude of the effects are not so clear,
01:30:24.479 --> 01:30:27.149 and certainly we don't really understand the mechanisms.
01:30:27.689 --> 01:30:32.839 So first of all then I'm going to start with probably the best known risk factor for breast
01:30:32.839 --> 01:30:35.700 cancer. You might not consider it a lifestyle choice,
01:30:35.759 --> 01:30:39.830 you know how many children you have, but it is at least modifiable,
01:30:40.040 --> 01:30:42.740 and this is one of the oldest known risk factors for breast cancer,
01:30:42.799 --> 01:30:48.589 and this dates back to the 1950s when people did studies of nuns and realised that they A
01:30:48.589 --> 01:30:54.240 higher risk of breast cancer than other women because of course they were niperous and
01:30:54.240 --> 01:30:57.379 actually parity has a dual effect on breast cancer risk.
01:30:57.560 --> 01:31:02.549 In the short term it increases risk up to about 5 to 9 years from the birth,
01:31:02.740 --> 01:31:06.189 but in the longer term, and that's what's important for absolute risk,
01:31:06.399 --> 01:31:08.919 it actually offers quite substantial protection.
01:31:09.229 --> 01:31:13.569 And the earlier you have your children, the better the protective effect.
01:31:13.859 --> 01:31:17.649 And if you look at what this means in terms of patterns of childbearing,
01:31:17.859 --> 01:31:21.540 you can see here that the best thing that a woman could do from the point of view of breast
01:31:21.540 --> 01:31:26.979 cancer risk is to have her children, you know, starting quite early in life and to have as
01:31:26.979 --> 01:31:29.660 many children as possible. Obviously I'm not advocating.
01:31:29.839 --> 01:31:36.589 In any way, you can if you want, but obviously that's what my
01:31:36.589 --> 01:31:39.180 parents' generation that was much more typical.
01:31:39.990 --> 01:31:44.919 However, as women start their families later in life and they perhaps don't have so many
01:31:44.919 --> 01:31:50.399 children, this protective effect is greatly diminished and in fact in women who are
01:31:50.450 --> 01:31:55.600 Starting their families in their 30s and certainly in their mid-30s,
01:31:55.759 --> 01:32:00.399 they're actually at increased risk compared to women who don't have children because they've
01:32:00.399 --> 01:32:05.640 only got the short-term increase in risk and they've not yet seen the long term reduction
01:32:05.640 --> 01:32:10.509 and may never see that reduction during their lifetime because that takes about 20 years to
01:32:10.509 --> 01:32:13.660 appear. And obviously the problem here is that trends
01:32:13.660 --> 01:32:17.009 in reproductive factors are definitely going in this direction.
01:32:17.379 --> 01:32:20.419 So unless we can mitigate in some way again, you know,
01:32:20.899 --> 01:32:25.540 against this, it's almost certain that breast cancer rates are going to carry on increasing.
01:32:25.830 --> 01:32:30.609 I should say that among Paris women there is an additional benefit of breastfeeding.
01:32:30.819 --> 01:32:35.140 It's not large. It's only about 4% additional reduction for
01:32:35.140 --> 01:32:40.140 every 12 months spent breastfeeding, and as you know, in the UK that's quite a lot of
01:32:40.140 --> 01:32:42.700 breastfeeding. You know, women in the UK tend not to
01:32:42.700 --> 01:32:46.549 breastfeed for very long, so they won't be realising that benefit.
01:32:47.259 --> 01:32:53.620 So that's the endogenous hormones. If we turn to Exogenous hormones and actually
01:32:53.620 --> 01:32:57.950 one of the main types of exogenous hormones that almost all women will will use at some
01:32:57.950 --> 01:33:01.629 point in their lives, and that's um hormonal contraception.
01:33:02.439 --> 01:33:06.200 This was actually a very controversial issue back in the mid 1990s,
01:33:06.240 --> 01:33:09.149 and it wasn't clear what effect it would have, if any,
01:33:09.439 --> 01:33:14.520 on breast cancer risk, and there was a very large meta-analysis that was published in The
01:33:14.520 --> 01:33:19.549 Lancet in 1996, bringing together the worldwide evidence.
01:33:19.919 --> 01:33:24.535 At that time it was largely on use of combined oral contraceptives because that Where most of
01:33:24.535 --> 01:33:29.575 the data were, and what this showed was that certainly while women were taking oral
01:33:29.575 --> 01:33:32.935 contraceptives they were at a slight increased risk of breast cancer,
01:33:33.134 --> 01:33:39.975 about 20 to 30%, but once they stopped taking contraceptives, this actually went down quite
01:33:39.975 --> 01:33:45.685 quickly and by about 10 years after stopping, they were no longer at any increased risk.
01:33:46.129 --> 01:33:52.759 And in fact, we did a study quite recently. It was published last year looking at more
01:33:52.759 --> 01:33:57.529 contemporary hormonal contraceptives because obviously things have moved on now.
01:33:57.979 --> 01:34:03.500 We don't just have combined oral contraceptives, we have progestogen only contraceptives,
01:34:03.620 --> 01:34:08.620 both oral and in. Form of implants and IUDs and interestingly we
01:34:08.620 --> 01:34:13.979 actually found that all of these types of hormonal contraceptives had an almost identical
01:34:13.979 --> 01:34:19.330 effect and the overall relative risk from this report, which was based on primary care data
01:34:19.330 --> 01:34:23.850 was actually about 25% increase, so again, very similar to this.
01:34:24.379 --> 01:34:27.729 And although this this might look like a a bad news story,
01:34:27.859 --> 01:34:33.259 it's actually fairly reassuring because what we know is that this is a transient increase in
01:34:33.259 --> 01:34:36.500 risk. It occurs at a time when women are in their
01:34:36.500 --> 01:34:38.100 early reproductive lives.
01:34:38.810 --> 01:34:41.419 Their background risks of breast cancer are pretty low,
01:34:41.709 --> 01:34:46.180 so it's not going to translate into huge absolute increases in breast cancer.
01:34:46.589 --> 01:34:51.649 Also, when you set it against the really quite substantial benefits of oral contraceptive use
01:34:51.649 --> 01:34:56.020 on things like ovarian and endometrial cancer, then certainly,
01:34:56.149 --> 01:35:02.669 you know, the net effect of contraceptives is actually to the good in terms of female cancers.
01:35:03.589 --> 01:35:09.299 Unfortunately, the same is not true for HRT use, and this is obviously very,
01:35:09.470 --> 01:35:15.950 very topical and the best evidence to date on the effects of HRT use and breast
01:35:15.950 --> 01:35:19.459 cancer come from this Lancet paper.
01:35:19.660 --> 01:35:26.330 Published back in 2019 and this again was a meta-analysis of around 24
01:35:26.330 --> 01:35:33.089 prospective studies which looked at HRT use at recruitment, followed women up to see
01:35:33.490 --> 01:35:35.799 what their risks of breast cancer were.
01:35:36.109 --> 01:35:42.060 And what it showed, I think quite clearly is that while women are taking HRT you can see
01:35:42.060 --> 01:35:47.569 that whether they take oestrogen only HRT or whether they take combined preparations,
01:35:47.859 --> 01:35:50.009 there is clearly an increase in risk.
01:35:50.299 --> 01:35:54.850 There's a very elegant dose response here in terms of duration effect.
01:35:54.859 --> 01:36:01.100 It gets bigger with increasing duration, and it is much bigger for combined preparations than
01:36:01.100 --> 01:36:05.205 for oestrogen. So addition of progestogen does seem to have a
01:36:05.205 --> 01:36:06.595 big impact on risk.
01:36:06.924 --> 01:36:11.725 But what was really important about this report was that it showed that it's not only a problem
01:36:11.725 --> 01:36:18.645 in current users that once women stop taking HRT, there is a small residual effect and
01:36:18.645 --> 01:36:22.345 certainly at least at least up until 10 years after stopping,
01:36:22.604 --> 01:36:26.955 we see an increased risk, particularly in long duration users.
01:36:27.970 --> 01:36:33.879 And what this meant was, you know, this new information on past use meant that when we
01:36:33.879 --> 01:36:38.390 looked at the effects on absolute risk of breast cancer,
01:36:38.720 --> 01:36:43.439 these were actually double what we previously thought because now we had a persistence of
01:36:43.439 --> 01:36:48.830 effect going into ages when the background risk of breast cancer becomes even more appreciable.
01:36:49.129 --> 01:36:55.509 So you can see here that if you look at you starting at age 50 for around 5 to 9 years,
01:36:56.080 --> 01:36:58.759 that should be. 5 to 9 years, which is actually a typical
01:36:58.759 --> 01:36:59.839 pattern of use.
01:37:00.129 --> 01:37:06.089 If you look at the cumulative risk from 50 to 70, you might expect to get about 1 extra
01:37:06.089 --> 01:37:12.290 breast cancer per 100 users of oestrogen only, but if you're talking about continuous combined
01:37:12.290 --> 01:37:17.520 preparations, which are the most commonly used ones, this rises to about 1 extra breast cancer
01:37:17.520 --> 01:37:18.959 per 25 users.
01:37:19.450 --> 01:37:25.049 So obviously for HRT use, the picture is very different from oral contraceptives.
01:37:26.979 --> 01:37:30.600 So turning then to the more sort of conventional what people tend to think of sort
01:37:30.600 --> 01:37:35.310 of lifestyle factors, and the first of these is is adult adiposity,
01:37:35.359 --> 01:37:39.120 and I've specified adult adiposity here because you'll see later,
01:37:39.220 --> 01:37:42.080 it's very different when we talk about childhood adiposity.
01:37:42.479 --> 01:37:47.109 And this has long been known that if you look at, and these are data from the Women's study
01:37:47.109 --> 01:37:53.870 here, you can see increasing BMI measured in middle age is strongly associated with
01:37:53.870 --> 01:37:56.399 increasing risk of breast cancer.
01:37:56.750 --> 01:38:02.430 And actually if you look at this relationship separately for hormone sensitive or ER positive
01:38:02.430 --> 01:38:08.910 cancers and ER negative cancers, you can see that the effect is really confined to ER
01:38:08.910 --> 01:38:10.020 positive disease.
01:38:10.270 --> 01:38:13.984 And this of course. Fits with everything we know about the effects
01:38:13.984 --> 01:38:18.455 of adiposity on breast cancer because after the menopause in particular,
01:38:18.944 --> 01:38:25.055 adipose tissue is the main source of oestrogen and so it fits the more adipose tissue women
01:38:25.055 --> 01:38:30.055 have, the higher their circulating oestrogen levels and therefore the greater their risk,
01:38:30.424 --> 01:38:35.504 particularly of ER positive disease. And there's certainly a lot of evidence now to
01:38:35.504 --> 01:38:39.424 support the idea that this is really mediated by oestrogen.
01:38:41.439 --> 01:38:47.359 So then turning to the other major um lifestyle factor that's often mentioned in the context of
01:38:47.359 --> 01:38:49.620 breast cancer risk, and that's alcohol.
01:38:50.149 --> 01:38:55.390 And you can see here again, this is very well established, very consistent from numerous
01:38:55.390 --> 01:38:58.060 studies. This is data from the many women's study
01:38:58.430 --> 01:39:01.089 showing that it doesn't matter what type of alcohol you drink,
01:39:01.640 --> 01:39:04.509 the risk increases, even at quite moderate levels, you know,
01:39:04.589 --> 01:39:08.990 this isn't excessive alcohol intake. This is well within recommended limits for
01:39:08.990 --> 01:39:12.270 women. Um, and this translates into an increase in
01:39:12.270 --> 01:39:16.859 risk of about 10 to 12% for each additional daily drink.
01:39:17.390 --> 01:39:22.020 Um, and again, it's thought that this may be mediated by hormones.
01:39:22.060 --> 01:39:27.529 You can see here that if you look at this relationship separately for ER positive disease
01:39:27.529 --> 01:39:31.609 and ER negative disease, it's very clear for ER positive disease.
01:39:32.020 --> 01:39:35.370 Haven't really been able to show a clear effect of ER negative disease,
01:39:35.540 --> 01:39:37.649 but the confidence intervals are quite wide.
01:39:38.149 --> 01:39:41.979 But what we do know from observational data and from intervention studies.
01:39:42.069 --> 01:39:47.330 Is that certainly women who have higher alcohol intakes tend to have higher levels of certain
01:39:47.330 --> 01:39:53.680 sex hormones, not just oestrogen but testosterone, perhaps lower SHPG levels,
01:39:53.979 --> 01:39:57.410 so they have higher levels of free testosterone, free estradiol,
01:39:58.459 --> 01:40:05.459 and so it may be that this again is at least in part mediated by the effect of alcohol on
01:40:05.459 --> 01:40:06.470 sex hormones.
01:40:08.540 --> 01:40:13.629 So this brings me to the last group, which is this kind of catch-all group of all the other
01:40:13.629 --> 01:40:18.339 things that have been sort of associated with breast cancer over the years,
01:40:18.689 --> 01:40:22.549 and I include here things like diet. There's lots of dietary factors other than
01:40:22.549 --> 01:40:29.189 alcohol, shift work, you know, in Denmark, women were being compensated if they'd
01:40:29.189 --> 01:40:32.700 been shift shift workers and they developed breast cancer.
01:40:33.629 --> 01:40:39.520 Also physical activity and early life body size, and the only one that I really want to show
01:40:39.520 --> 01:40:45.270 results for here because it's certainly the most substantial and I think probably the most
01:40:45.270 --> 01:40:50.720 interesting, and that's the effect of early life body size on on breast cancer risk and
01:40:50.720 --> 01:40:55.799 this is a paper taken from the. Women's study and this is looking at relative
01:40:55.799 --> 01:41:01.870 body size at age 10 and subsequent risk of breast cancer and you can see here that unlike
01:41:01.870 --> 01:41:06.189 all of the other risk factors, you've got an inverse association,
01:41:06.200 --> 01:41:11.240 firstly, quite substantial here. So this is women who reported being plumper
01:41:11.240 --> 01:41:12.970 than their peers.
01:41:14.200 --> 01:41:21.200 They have and this is the average body size in terms of BMI when when we looked at that
01:41:21.200 --> 01:41:26.240 in a subsample, and you can see there's a very clear decrease in risk with increasing body
01:41:26.240 --> 01:41:31.399 size at age 10, but the effect seems to be almost identical for ER positive and ER
01:41:31.399 --> 01:41:34.109 negative disease. And so whatever's going on here,
01:41:34.160 --> 01:41:37.629 it's probably not mediated by sex hormones. We don't know what it is.
01:41:37.680 --> 01:41:40.839 It's very poorly understood, but of course it's very.
01:41:40.982 --> 01:41:45.612 It is important that we do understand it because we can't advocate that children should
01:41:45.612 --> 01:41:49.323 put on weight in order to prevent breast cancer later in life.
01:41:49.652 --> 01:41:54.203 In terms of the other risk factors, physical activity was mentioned earlier on today.
01:41:54.453 --> 01:41:57.962 It has been consistently associated with a decreased risk,
01:41:58.212 --> 01:42:01.462 but of course it's also really strongly related to BMI.
01:42:01.812 --> 01:42:06.842 So it's not entirely clear how much of an independent effect physical activity has,
01:42:07.203 --> 01:42:10.295 you know, once you take Account of the fact that the more active you are,
01:42:10.545 --> 01:42:14.465 the lower your BMI, and hence we already know you're going to have a lower risk of breast
01:42:14.465 --> 01:42:19.295 cancer and certainly physical activity itself hasn't been associated with hormone levels.
01:42:20.226 --> 01:42:25.255 Lastly, in terms of these other risk factors, much of the work that we've been doing
01:42:26.025 --> 01:42:31.226 relatively recently on shift work and diet, haven't seen any really good evidence that any
01:42:31.226 --> 01:42:34.786 of those are really convincing risk factors for breast cancer.
01:42:35.250 --> 01:42:39.759 And this is my last slide here, and this is really just trying to pull all of these things
01:42:39.759 --> 01:42:46.629 together and also put them in context because I often hear people talk about HRT and say,
01:42:46.839 --> 01:42:50.990 oh, but the effects are negligible compared to adiposity and alcohol.
01:42:51.600 --> 01:42:56.359 And actually this is an attempt to try and give you an indication of the relative magnitude of
01:42:56.359 --> 01:42:59.520 these effects and obviously they change over time some of them,
01:42:59.640 --> 01:43:03.666 so I've chosen. Put approximate relative risks associated with
01:43:03.666 --> 01:43:08.186 each of these things in middle age. So thinking about what is its effect on women
01:43:08.186 --> 01:43:12.375 in their 50s and 60s when breast cancer is actually becoming quite common.
01:43:12.706 --> 01:43:17.775 You can see here that being nulierous compared to having two children in your 20s,
01:43:17.786 --> 01:43:20.346 probably increases your risk by about 20%.
01:43:20.936 --> 01:43:24.985 Drinking 2 drinks a day compared to being a non-drinker, slightly higher,
01:43:25.025 --> 01:43:30.562 25. Being obese compared to being a desirable BMI,
01:43:30.881 --> 01:43:36.731 much higher 50%, but actually by far the biggest risk factor in this group of modifiable
01:43:36.731 --> 01:43:41.521 risk factors is HRTU. So use for 5 to 9 years,
01:43:42.131 --> 01:43:45.722 continuous combined, will give you a relative risk of about 2.
01:43:45.932 --> 01:43:50.762 So it's putting you at the same risk roughly as someone with a first degree relative.
01:43:51.350 --> 01:43:54.790 So hopefully that gives you an indication um of, you know,
01:43:55.140 --> 01:43:59.640 the importance of some of these things. Obviously it's very difficult to summarise this
01:43:59.640 --> 01:44:01.890 in 10 minutes. It's a bit of a whistle stop tour,
01:44:02.120 --> 01:44:04.720 but um I'll certainly be very happy to take any questions.
01:44:10.129 --> 01:44:13.859 So as you can see, we are running over, and we don't want to keep you from dinner,
01:44:13.939 --> 01:44:17.660 so unless someone has any burning questions, one question.
01:44:19.819 --> 01:44:21.169 There's one burning question there.
01:44:22.629 --> 01:44:25.819 This is for the whole panel. Hi, I'm Mau Mai from Southampton.
01:44:26.160 --> 01:44:32.629 I just wanted to ask, what's the approach, uh, for of surgery in a lactating
01:44:32.629 --> 01:44:35.069 breast? Uh, what is the experience?
01:44:35.509 --> 01:44:40.100 Do you get the patient to stop breastfeeding and do you do reconstructions?
01:44:42.379 --> 01:44:46.149 to answer. You were talking about the press.
01:44:48.060 --> 01:44:51.459 It depends on the subtype of tumour.
01:44:52.370 --> 01:44:59.169 In fact, uh, uh, if, uh, uh, the tumour is hormonal, the woman cannot be,
01:44:59.259 --> 01:45:02.459 uh, be have have breastfeeding.
01:45:06.200 --> 01:45:10.000 So you always get the patient to stop breastfeeding before operating.
01:45:11.040 --> 01:45:15.970 OK, OK, so tumour occurring during breastfeeding, yeah,
01:45:16.450 --> 01:45:21.689 uh, we stop, uh, we, we stop breastfeeding, then we operate and then,
01:45:21.750 --> 01:45:25.740 uh, it's over. OK.
01:45:25.959 --> 01:45:31.359 Thank you. Thank you to all the panellists for a lovely
01:45:31.359 --> 01:45:34.390 session, and we'll see you all at dinner.
01:45:34.720 --> 01:45:35.470 Thank you very much.