Transcript for:
50th Webinar on Triple Negative Breast Cancer

foreign function is working okay because somebody is raising their hand I think yeah that's good yeah but I need to check that because usually people will start oh the pattern of the chat is okay uh can you use the chat are you I don't use the chat yeah yeah that's Luna first to start that's fine and there's some other people are using the chat already so good evening everybody and it's number 50 today so this is the 50th webinar uh yeah you have your own uh with us today so we have great talks this is triple negative breast cancer so to be heavier on oncology and pathology the webinar today compared to the usual surgical webinars we have the three great speakers um for the panelists and of course we have the lovely Ricardo Pardo with us today again and because they will do immediate translation to Spanish so if you want to listen to the talks in Spanish you there's this little Globe press on the group and choose the cheese the Spanish Channel if you want in English you can just go on the English Channel uh the three speakers one is on pathology from the states one is from Jordan and one on with aesthetic triple negative breast cancer from Antonio he's from Sweden and we have The Usual Suspects we have Andreas today and Peter Barry today and we have also the new addition that lovely another soundtrack from Serbia so we'll have we'll start the webinar uh if you have any question please put it on the Q a section so we can answer the questions for you later uh today during the webinar if you want to have any chat use the chat function we can see that's quite a few messages already on the chat function so let's start with the first talk and we have Prof Mohammed bazuki from the states to give us an overview about pathology of triple negative breast cancer Muhammad the next 15-20 minutes are yours okay good afternoon everyone it is 12 o'clock at Buffalo New York right now so I'm going to share my screen perfect so this will be a pathology of the treble negative breast cancer and this is the Roswell Park Cancer Institute Institute here at Buffalo New York it is not cold yet but the treble negative baristic answer definition is breast cancer negative for ER PR and her2 and I can say any ballistic cancer could be triple negative then I can stop the lecture here but I think if I do that nobody will invite me anymore so I have to go through this if you look at the normal breast terminal duct globular units and the ducts of the breast two layers of the lining gear the inner or the luminal cells or epithelial cells and the outer myoepithelial cell layers so cancer usually could arise from both of those layers the luminal and the basal layer when you look at the classification the molecular classification of breast cancer which didn't find its way to the clinical practice yet but we have the basal-like molecular subtype which are usually high grade tumors and associated in some fraction of cases would be RCA mutation and those tumors are mostly ER negative B or negative and they have two negative but they have expressing more other genes and more other immunoprofile and this is the main subject I'm going to talk about today the basal like breast cancer and we have other types molecular types the normal breast like those are usually typically also triple negative breast cancer in addition to the Claudine law and a molecular epocrine type of breast cancers when at the morphologic level when you look at the triple negative ballistic answers those are we can divide them into two categories according to the grid of the tumor so have the triple negative high grade tumors and the triple negative low-grid ones and the high grade ones those are mainly the invasive carcinoma of no special type those are as I said expressed more in the brca mutated patients and usually mute have mutation of the tb53g in addition to this type and we have the metablastic carcinoma and I'm going to talk about this and the epocrine carcinomas which are triple negative but they are usually expressed an androgen receptors and we have what is was called the medullary carcinoma now this classification has been dropped from the whoo classification and now they are called NST as the other duct carcines the low grade ones those are mainly the adenoid cystic carcinomas secretory carcinomas and the low-grid adenos type of the metablastic carcinomos and those are very rare so when we talk we'll talk about the basal breast basal-like breast cancer those are tumors which usually Express the basal epithelium and demonstrate a low expiration as I said of the genes of the ER and the her2 related genes and most of those cases 80 percent are triple negative but they do Express the egfr and the cytokeratin five six High molecular with cytokeratin and the most of the triple negative breast cancers are basal-like and the reverse is also is true and in for the clinical presentation 6 to 27 percent of the breast cancers are based alike depending on where you read and those a good fraction of those patients about one-fifth of the patients present at younger age group less than 40 years and we often have an aggressive course and poor prognosis at the gross those tumors usually are well circumscribed and also could be lobulated at the periphery here lobulation and they have Geographic gross necrosis is common in these tumors at the microscopic pathology What's called the invasive carcinoma NST with medullary features or medullary carcinoma and as I said this terminology we don't like this anymore and we include all those groups under the NST or no special type and usually they have solid architecture no tubule formation they are high grade high proliferative rate Ki 67 greater than 90 percent in most of those cases and the high cell density with the scant stroma and pushing borders and they have lymphocytic infiltration at the tumor Edge as we'll speak about and usually have Geographic or Central necrosis no much dcis on those tumors very rarely to see the dcis so this is at the H and E staining here so you have the very high grid nuclear features multiple mitosis prominent nucleoli no dcis you may find mitosis you will find necrosis in these tumors more caption of another case here necrosis here in the center lymphocytic infiltration at the periphery very high nuclear grade prominent nucleoli a lot of mitotic figures and those tumors usually as I said high grade high nothing grids more pictures here to show you the geographic necrosis in this basal-like breast cancers and this is here to show you the lymphocytic infiltration you think it is like intro memory lymph node or something like that in the breast and by definition those are Erp or and have two negative and the ki67 is very high greater than 90 percent in most of those cases so the immuno profile of those by definition triple negative PRP or her2 and positive for the high molecular weight and basal cytokeratins ck5 ck56 CK 14 17 egfr and these two markers are breast markers and they are very good markers and this the newly introduced one the trp S1 present positive in 86 percent of the triple negative ballistic Cancers and the geta 3 another breast marker we used a lot and it is in 70 of those tumors and the others are could be positive in these tumors the p63 the smooth muscle acting and the S100 among others so this is the picture and in my practice usually we apply one or at least or more of those markers to know it is a carcinoma so we do the ck5 or ck56 the egfr ck14 CK 17 14 and 16 are basal markers and usually you will find at least one of those positive in these tubes so the molecular pathology I think we touch it on those and the high degree of genetic and stability in those tumors heterogeneity of the gene could be numbers alterations and about 20 percent highly expressed the genes of the basal epithelium and demonstrate low expression of the ER and the her2 related genes the tb53 gene is mutated in up to 87 percent of the cases among other genes like the P10 retinoplastoma ones and others other histologic types of tribal negative breast cancer other than the basal Lake we have the metablastic carcinomas the adenoid cystic carcinomas the secretory carcinomas and the tribal negative tumors of luminal Androgen receptor type so the metablastic carcinoma a heterogeneous group of invasive carcinomas and we have classification of this year the list of classification the low-grade adenoscommas carcinomas and the fibromatosis like metabolastic carcinomas those are usually low grade with good prognosis and other high grade ones the spindle circarcinomas the squamous cell carcinoma is not of primary skin origin the metabolastic carcinomas with heterologous mesenchymal differentiation and the mixed metabolastic carcinates so the amino histochemistry profile of the metablastic carcinomas we use a panel of the immunohistochemistry to differentiate those tumors from other mimickers they are positive for the keratins ae1 A3 Bank keratin 34 beta E12 ck5614 p63 among others basal markers and the negative for the cd34 Desmond and the smooth muscle myosin heavy chains this is a caption here for the metabolastic carcinomas and this is if you have the dcis in this tumor so this is most will will confirm this is the metablastic carcinoma rather than sarcoma or metastatic tumor from somewhere else this is the spindle cell type high grade spindle cells and when you put markers like the ck14 it is both the focally boosted in some of those cells the second low grade one uh triple negative breast cancer is the secretory carcinoma very rare tumor occurs in adolescence and partially circumscribed with three main histologic types the solid the microcystic and the tubular types the new plastic cells are uniform round or polygonal finally granular and the cytoplasm has this is xenophilic light secretions and very characteristic for these tumors this Fusion Gene n-track etv6 translocation 12-15 this is here a microscopic picture of the secretory carcinomas with the characteristic secretion cytoplasmic secretion of this light blue uh secretion because of that the name is secretory carcinum the other low-grade treble negative breast cancer is the adenoid cystic carcinoma again one of those rare cancer in the breast 0.1 to one percent of the breast cancers and low aggressive malignant potential and they have my epithelial differentiation as we expect and exhibit the tubular trabecular solid crib reform and most probably mixed types of those and the calibriform is the most classic type and these tumors again is characterized by the Meb and if 1B translocation 6 9. and this is a characteristic morphology of those the crib reform pattern of those and sometimes the differential diagnosis here is the dcis you look at this you see the forming you think it is dcis then you go and it is not that high grade dcis then you go to do the markers it is triple negative breast cancer in most of the cases then let us talk about about the tumor infiltrating lymphocytes it tells this is most probably or most commonly in the basal-like type and as a Pathologists who have recommendations for assessing details in the breast cancer so it is evaluated for the stromal components so we see the percentage of the the Tells to the stroma of the tumor and evaluated at the borders of the invasive Cancers and we exclude the cells outside the tumor border and around the dcis and around the normal lobules and we count in this the lymphocytes and the plasma cells and we exclude neutrophils in this calculation so we have to examine those on full sections or preferred other over biopsies and we use the average tails in the tumor area and don't focus on hot spots to get the accurate estimation of this and the number of cells correlate with the pathologic response of the new adjuvant therapy and the new formal recommendations for the clinically relative tells threshold is it 50 20 percent one percent we don't know so far then we will talk briefly about the pdl1 and I think Antonio's will talk about the the scoring system of the pdl1 and the breast cancer so the bdl1 on the tumor cells when combined to its ligand on the immune service causes inhibition of the immune response and the breasted tumors that have the bdl1 tindu to have high numbers of cells the majority are of treble negative breasticances and the tumors arising in the brca mutation those are the brca1 mainly not drca2 is involved with the brca1 is involved with the DNA repair cell regulation cell cycle regulation transitional regulation and the chromatin moduling and the loss of the brca1 will lead to deficiency in the repair of the breaks of the double stranded DNA and 75 percent of all tumors developing in brca1 germline mutations are triple negative breast cancers so how about the residual cancer burden after the new adjuvant chemotherapy how we do that many systems we use and the parameters required to calculate this mainly the we have to submit the entire area of the tumor bit we have to measure the tumor Dimensions at least the two dimensions and we have to know the percentage of the tumor cells in the malignant cells invasive and inside to components in the tumor bed and the number of the positive lymph nodes and the largest dimension of the nodal metastasis most of the systems rely on those variables in addition to other variables for other systems and here for example this is from the MD Anderson website here this is the the brown coloration is the tumor bed and the blue dots are the tumors so for this is perfect here the tumor dimensions are exactly correlate with the tumor bed and in this here for example the tumor cells are less than the tumor bed size and so on so use these two Dimensions to calculate the the burden of the tumor after the new adjuvant chemotherapy and we have charts for this to know the percentage we don't count cells but for example if something like that scattered cells or grouped scattered cells you call for example this is one percent something like that like 10 percent and so on this is like 50 percent of the tumor to the bed area then we use many systems as I said but we use in our practice the MD Anderson uh equation so here we plot the tumor area the dimensions we bloated the the percentage of the invasive carcinoma and the website will subtract the dcis from this and from the calculations we can get the tumor burden or the residual cancer building assessment and for the pathologist on the call here so the new adjuvant therapy we use this for the endocrine or the chemotherapy before the Excision and to use the prefix little y to is added when assessing for the after the new adjuvant chemotherapy and the cellularities estimated by determining the overall cancer cellularity the insight and The Envision then the softwares will subtract the dcis from this and if we have only lymphobascular space Invasion so we use this as the percentage of the tumor in the in this area and if cases with previous metastasis before the treatment induced will stay as stage four even if complete response happens and the largest continuous Focus we use this to assign the PN in the lymph node and the fossil of the carcinoma if we have like therapy related change in between the fossil of carcinoma usually we add all this for the size to assess this but if you have intervening normal tissue of lymph nodes usually we subtract this so we use the largest contiguous Focus only we don't add the first side the isolated tumor cells are not included in any staging so it will be n0 but we calculate these two to calcul to take into consideration for the residual cancer burden if we have isolated tumor cells if no residual carcinoma in the breast or in the lymph nodes then the cap summary not to be used for remote so it is recommended to repeat the Erp or and the her2 for the invasive carcinoma of triple negative after the treatment I don't know what others do but we do repeat those after the treatment about the distant metastasis in patients with the residual disease after the new adjuvant chemotherapy the factors with associated with increase the chance of developing distant metastasis or the positive pathological infinite status and the lymphobascular space Invasion and the other factors here the increase the clinical stage the increasing in order stage and the multi-focality of the tumor and extra nodal extension so key pathologic features the triple negative is a heterogeneous and encompasses several histogic types the basal-like metablastic adenoid cystic epocrine and secretory carcinomas are commonly treble negative breast cancers we do immunohistochemistry to just first of all to know this is a cancer to start with usually we do the uh basal markers and the high molecular weight ck5 or ck56 Celine Gene 14 and egfr and the tumors arising in the brca germoline mutations carriers are enriched with the basal-like phenotype and details although providing useful prognostic information like the analytic reproducibility among others Among Us and that's all I have thank you very much that's perfect talk it's been that's a great talk up to the point addressing all different aspects of triple negative breast cancer thank you for that lovely talk from the Suki now we have one of the oncologists in Jordan and she's going to talk about adjuvant and new adjuvant treatments so now are you online I am online I'm just trying to share my screen that's great so the next 15-20 minutes are all yours that's great thank you just give me a second to go into zoom and to where come on yeah there it is so let's see there you go and my screen is sharing now that's perfect yeah we have this need to make it a full slide okay great so thank you yes and for another great webinar and uh having great colleagues to share and learn from uh first before any further scientific discussion congratulations on your golden anniversary and best wishes for a diamond anniversary hopefully uh with more and more success so and without further uh delay I will be discussing approach for triple negative breast cancer focusing on why neural is important what are the recent updates in your adjuvant approach its implication for adjuvant treatment and unique subsets especially the bracha positive subset and let's see why new adjuvant approach is important you know um a decade ago up until a decade ago whenever I give this talk and I have a special passion for new advent therapy in every aspect it's intuitive it makes sense to see the response of the tumor before you remove it and it was not until the FDL admit analysis of 12 randomized trials more than 12 000 patients demonstrated that there is no question that among patients whose tumors achieve a complete path response there is improved event-free survival and overall survival our goal for treating our patients as you can see huge difference for those who can whose tumors achieved a complete pasty are as opposed to less than PCR in response to new adjuvant therapies so PCR it's good news and that's by itself is a good reason to give new eye driven therapy another thing we learned from that meta-analysis is that triple negative breast cancer responds to chemotherapy indeed better than any other subset it is an aggressive tumor associated with a worse prognosis as compared to other subtitles but if you look here complete path response in that of the meta-analysis was the highest for connected breast cancer except if you use 32 targeted syrup you for two positive breast cancer and not only that we learned the group from MD Anderson developing what's called residual cancer burden uh which corresponds to that humor cellularity and size after treatment with new adjuvant therapy together with nodal size and the number of involved lymph nodes all together put in an equation to calculate what's called residual cancer burden and we did learn that triple negative breast cancer patients with tumors achieving rcb0 which is complete pass CR or RCP one which is isolated tumor cells tend to do very well and much better than those who achieve RCB two or three as you can see those with rcb0 and one do great and those with less than that need help so you definitely need to give it to learn which patient is yours well what can you do to improve pasty also your patients because path CR is excellent in use to patients with triple negative breast cancer well we now almost two decades we have learned that the frequency and intensity of chemotherapy people tend to forget that chemotherapy does work with the uh hype of new biologic and immune therapies available but really chemotherapy does work and as I showed you in the FDL admit analysis more than one-third one out of three of your patients with triple negative breast cancer will achieve complete pass CR and you can improve if you use those dense treatment every two weeks as the LGB trial examined the efficacy of sequential every few weeks or sequential every two weeks or concurrent and what they found is that the hazard ratio for overall survival is actually 0.69 30 reduction in recurrence and mortality if you use the dose dense approach every two weeks now it's been two decades and we tend to forget this fact and indeed the ecog trial uh almost a decade later did confirm that Weekly packlet Excel as opposed to every three weeks so it's actually actually it is considered those dance because it's given on weekly basis uh those dents is given usually every two weeks but weekly back to LIT Excel or those then speculative Excel is associated with literally the same reduction in the risk of death 0.69 mortality and disease-free survival Improvement 30 reduction risk of death and recurrence using weekly partly tax cell as opposed to every three weeks and finally the meta-analysis from the early release cancer trials group more than six trials more than 14 000 patients treated on every two versus every three week schedule and as you can see there is an absolute Improvement of three percent and recurrence and mortality so those dense approach is one of the approaches that can increase complete CR and those intensity matters and then yes as you can see in mult across multiple trials complete past CR for new adjuvant chemotherapy is at best between one-third and 40 percent and whether you add Platinum in the European continent or in North America there is a 15 to 20 percent increase in complete pass CR and yes the event-free survival was not improved in the North American trial but it was improved in the German trial and that was the case in another trial called brightness trial so to me there is no question that adding Platinum increases past CR there is a question about long-term benefit however a meta-analysis looking at all three trials that address the question of adding platinum in the new adjuvant setting did demonstrate a significant Improvement both in progression-free survival and positive impact on overall survival so the Platinum Saga to me is settled in favor of using platinum in the new adjuven setting last year the group from Tata Memorial interestingly looked at platinum in the new adjuven setting according to Age and what they found is that among the patients younger than age 50 there was a 20 increase in pass CR without much impact among the patients with older than 50. and indeed among the patients younger than 50 there was an absolute Improvement in both event research and overall survival only adding into the evidence in favor of using platinum in the new adjuven setting so Platinum incorporation matters and now we are in the era of checkpoint Inhibitors you know checkpoint Inhibitors now are being used everywhere so we might as well examine their efficacy and triple negative the challenging subset of breast cancer and we have a plethora of Trials but the only pivotal trial that led to the incorporation of temporalism up in the new adjuvant therapy of tribal negative early breast cancer patients um examine the efficacy of an optimal backbone of chemotherapy a carbo Platinum with paclitaxel followed for four cycle followed by adriomycin cyclophosphamide for four Cycles as you can see here with or without capitalism given eight Cycles before surgery and nine after so you this particular trial looked at new adjufant adjuvant use of temporalism which is very important and most of you remember had heard or at least read in the news because this was all over the news adding temporalism up to the optimal chemotherapy backbone increased complete path response by 13.5 percent that was attenuated to an only nine percent with further follow-up but it did translate to Improvement in event-free survival significant Improvement of more than six percent reduction in the risk of recurrence which is quite impressive however as you can see here the separation of the curves is quite obvious favoring the addition of temporalismab in the new adjuvant setting of course no pain no gain as you can see here a significant proportion one in five of your patients will develop some endocrine disorder usually hyper hyperthyroidism or adrenal dysfunction in addition to skin reactions and minute but significant number of immune related toxicity most important up to 20 of your patients will have long-term adrenal sorry thyroid dysfunction um so we are not smart enough to identify those nine percent or even more who could benefit from temporalism because the benefit was independent of PD L1 expression but it does work other trials tried to examine the effective immune therapy in the new adjuvant setting the Eyes by trial gave only new adjuvant with impact on PCR not on event-free Survival we've seen keynote trial increasing post both PCR and event 3 survival unfortunately in passion 31 missed the target of event-free survival but did indeed the addition of atheism have improved path response by an impressive 16 complete pass CR it only this in this table it was not reported but indeed it was reported last year and the event-free survival was not improved unfortunately when atheism map was added in the new advent setting and having said that the impression of 30 in the adjuvenating also did not improve eventually survival for the triple negative subset the neo-trap trial also tried to omit the anthracycline backbone and did not succeed in improving either PCR or event-free survival finally a very interesting trial please keep in mind use a German Trail use the new adjuvant door volume up pdl1 inhibitor only in the new adjuven setting and indeed it succeeded in improving PCR and event-free survival with eight Cycles in the new adjuvant setting so those dense approach adding Platinum adding immune therapy centralized map improved the new art driven settings still we have patients who cannot achieve a PCR the tumor not a cheap PCR what can we do and indeed it's very important now to use um new adjuvant approach not only because it helps understand what to do for the patient but also because it informs your decisions after the Japanese create x-trial now almost six years have reported that among patients who do not whose tumors do not achieve a complete pass CR giving a cycles of Cape cytopene does improve both event-free survival and overall survival and if you look at the benefit it's mostly driven by the subset with triple negative breast cancer and indeed it was independent of the companion chemotherapy of 5fu or Texan and if you look here you can see among the triple negative breast cancer subset in the createx trial a dramatic Improvement in overall survival and recurrence free survival indeed concordant with the subset analysis for benefit for triple negative breast cancer from Cape cyta bean from the Phenix trial and MD Anderson travels so we the Spanish group try to replicate create X trial unfortunately not demonstrating Cape cyta Bean benefit for those patients whether it's dual disease triple negative breast cancer but you can see the outcome for the overall survival in the Spanish Trail is far better than the create extra speaking for a different patient population included and the Spanish Trail demonstrated benefits for carboplatinum in the non-basal triple negative breast cancer identified by immunohistochemistry not Pam 50. so we try to build on the createx trial and use platinum everybody knows Platinum is an adjective connective breast cancer so let's use platinum for Advent therapy for those who do not whose tumors do not achieve a complete path response and guess what when comparing Platinum residual disease versus capsicle it was quite disappointing without actually any benefit for platinum above Cape cyta Bean if anything the benefit was in favor of cape citibin for the non-basal subgroup identified by Pam 50. so it looks like non-basal subgroup identified by 1050 or immunosti could benefit from Cape cycle but the problem is most residual Tropic breast cancers are based alike they're not non-basal-like they have much worse prognosis so what can we do number one we need to identify the basal subgroup and let me tell you immunohistochemistry or pathology or band 50 they only share 13 Concordance so identifying these are subgroup requires one language unification probably plan 50 is the most objective way and as you can see here in the same subset where they travel the authors try to identify the basal triple negative among 120 patients when they looked at core basal identified by histopathology as opposed to the other groups the outcome was not different but when they looked at 1050 basil against all other subgroups the outcome is much worse for the bazel subgroup so ninety percent of the tumors that are residual after triple negative breast cancer new hydrogen therapy heart targetable mutation and the mutation that we are all aware of is the bracha library mutation and in the Olympia trial they try investigators try to address that high risk subgroup with bracawan or bracha 2 mutation receiving new argument therapy having residual Disease by giving them 300 milligram twice annual twice daily for one year as opposed to Placebo and guess what there was a remarkable Improvement in invasive disease-free survival of eight percent that's 8.8 percent almost nine percent absolute Improvement in invasive disease free survival which is quite remarkable and particularly driven by distant relapse with significant impact on overall survival so you are talking for the first time on 40 reduction in the risk of death by one year of elaborative targeted therapy for those high risk patients and indeed elaborative reduced even CNS recurrence a challenge we always face with patients who preparing the breast cancer and as you can see all patients did derive benefit independent of the use of platinum therapy independent of the bracha mutation even hormone receptor status for the substitute patients with her more receptor positive disease and as you can see here yes event-free survival was improved by capitalism up but if you notice the question would be should we use olapreb or pembrolisumab in the adverbal setting and indeed there is no question or Labyrinth is indicated because it does improve overall survival yes there is Improvement in event-free Survival by embolism but if you look here PCR whether you achieve PCR by with or without temporalism of the impact is excellent the outcome is good if you do not if your patient does not if your patient's tumor does not achieve complete pass CR the outcome with residual diseases better if they have received temporalism up the question is should they receive a neoadjuvant or adjuvant probably adjuvant is not the one that's doing the trick the reason I'm speculating is that we have seen similar impacts in the German trial using the value map only in the new adjuven setting and as you can see here those who do not achieve a complete path CR tend to do much better than those who achieve a complete than those who do not achieve it and do not receive durable Maps speaking for a role so checkpoint Inhibitors in the new adjuvant setting rather than in the adventure I mean the positive impact on those who do not achieve a complete pass CR so patients who achieve a complete best CR and they have only a T1 T2 tumor probably they do not need checkpoint Inhibitors but those who have residual disease we don't know if two point Inhibitors will compensate for that but so far if they start on chemicalism they have to continue um we have three years to address the role of campsite I mean in the presence of pembrulous maps work trial and we have the brave trial as well um most likely pdl1 testing is not the one to decide on using Pembroke lesma because benefit was independent of pdl1 positivity still patience to the pdl1 positive tumors tend to do far better than those with pdl1 negative tumors the benefit the magnitude benefit is higher for ptl1 positive tumors we need probably more than just a checkpoint inhibitor for those who have residual disease so to conclude neoadvant therapy standard of care vertical negative breast cancer patients with at least 1.5 centimeter tumor on Imaging the recommendation is for those dance or weekly treatment with carboplatinum especially if they are younger patients with temporalism up until we identify a targetable subpopulation post new argument therapy I like to call it the more refined approach immune confusion era there is limited data about the role of capsider being when you are using temporalism ABS still I consider it standard of care hola prep is definitely indicated for patients with bracha mutation um the value of post-operative checkpoint Inhibitors is still unclear unless you start with premab in the new adjuvant setting as I mentioned Atheism in the adjuvant setting did not improve outcome and finally Whenever there is a clinical trial patients with tripling the breast cancer need to be enrolled because they that keeps informing our clinical decision to help our patients and with this I conclude and thank you for listening that's great talk thank you is enough for the comprehensive talk things were easier and simpler in the past was only chemotherapy or no chemotherapy are getting more and more complicated now it's great there's more than 600 people online for people I can see that some people are putting their questions on the chat function we will miss the questions on the chat function uh so Bibiana for example if you put your question on the Q a section there's a q a section if you put all the questions there we'll go through those after when we go on the discussion and for people that join blade if you go on the English Channel if you want to hear the talks in English but if you want to hear them in Spanish then we have the lovely Ricardo Pardo with us today so he's doing an immediate translation to Spanish can I quickly comment on a couple of questions just in case I'm not with you um for you for treating triple negative breast cancer in the during pregnancy it depends on which trimester of course surgery is your recommended modality unless it's really locally Advanced I would do new adjuvant anthracycles if it's locally Advanced if it's not locally Advanced I start by surgery you can deliver anthracite lens during pregnancy and you know Dr dusuki mentioned that they check the hormone receptor status afternoon Advent therapy yes and let me tell you if it changed that the Golden Rule post new adjuvant treatment if the hormone receptor status becomes positive great I will give the patient the benefit of Doubt and treat accordingly but the rule is if the patient starts with hormone receptor positive or hair to positive tumor you treat as such even if it becomes triple negative after surgery because you want to give them the benefit of Doubt so after triple negative breast cancer treatment if that tumor becomes ER positive I will use hormonal therapy here to positive I'll use targetable therapy are the questions I've seen here in the Q a um you can type the answers also while we do the last talk okay that's that's great but now we have Antonio's and until he's going to talk about metastatic breast cancer and he's one of the oncologists and he said he's one of the surgeons he's one of the oncologists in Sweden so Antonio it's great to have you with us today uh thank you thank you so much let's see and you see my screen yes great so thank you for the invitation I will talk about triple negative breast cancer metastatic disease and how we can treat the disease I will start with some epidemiology on the admined need about how we're going to treat this uh these patients on the left side of the slide you can see population based study from Sweden with a median survival in patients with metastatic negatives can say compared to hormone septopositive breast cancer and you can see the median survival of about 10 months quite depressive a number and then it becomes 37 months for Quality positive and then on the right side you can see um a population based study from sorry from France where we have a real world evidence database called The Asthma and you can see depending on the the year of diagonals is how it looks like with the median over survival and what we can see is that there is no difference if we take from uh 2008 to 2016 we can see median overall survival of 14 months and we we used to see an improvement in in metastatic setting in other subtypes but in triple negative we are a little bit behind and this is because we didn't have so many alternatives for treatment we had only chemotherapy we have now some new treatment approaches as perpenders second Inhibitors with chemotherapy and to um antibody there are conjugates that we're going to discuss today and we're going to try to get an algorithm how we can treat our patient now so at the end of my presentation we're going to have an algorithm on that and I'm going to explain step by step how how we are thinking cancer colleges so we're going to have different treatment lines first line second third and so on and then a preferred option and end Alternatives so let's start with the first line which is the the first treatment when we have a patient with a newly diagnosed metastatic negative breast cancer the preferred option if we have the possibility and a predictive biomarker with the pdl1 which is positive we can give immunotherapy in terms of federalism up or artesialism with chemotherapy I will talk more about that we can say that we have chemotherapy of course some monotherapy or combination if we don't have the the positivity of pdl1 to to be able to give immunotherapy and if we have a patient without pdl1 positivity and with a game line brca mutation we have the possibility to give perp inhibitors so let's see the evidence behind this first step these are the three the three trials behind the evidence about checkpoint Inhibitors as fast line treatment the metastatic negative breast cancer the first one was the impression 113 napakli taxi was a chemotherapy randomized trial plus minus atasalismob the difference in OS in our survival was 7.5 months in favor of of the addition of a resolution map but only for patients with pbl1 at least one percent in immune cells using a specific clone for pdl1 on the body called SP 142 and this is something that we need to think when we choose the treatment so this is why I give this kind of of detail then we had a negative trial the impression 131 which was a bit more the same but instead of non-parkly tax cell we used packletax cell and it was a negative prior so no no improvement when you give this combination quite surprising and then the keynote 355 with chemotherapy three different Alternatives packletox and napolitaxel or chiroplating with Kim cyta beam uh plus minus pembrolizumab with an improvement improvement AOS of about seven months it was the same as such as religion map but only for patients with tumors with combined positive score a kind of pdl1 positivity again of at least 10 with another club called 22 C3 okay so in this uh quite simplistic way I can I will try to explain this different loans and and how we get the different pdl1 positivities so you can see that we have let's see if I can yes the large cells here are tumor cells and the small cells are immune cells okay and you can see that we have we can have a one and himself supposedly and in order to be able to give a casualism map we look after staining with a specific loan we look at the email sense only and if we have at least one percent positivity we can give the medication in terms of the primary remark we are using the CPS score which is not really the same we are looking on the whole section we are counting all the cells and the positivity and then we divide it with a number of viable two motions so it's not really the same and why this is important well it has clinical implications and pdl1 in general it's not something that we as on qualities are also Keen about because we do not think that it this is a good biomarker for the first when when we need to decide if we're going to do the analysis on primary metastatic Collision it's not so easy to decide because we know that there might be discordant results so positive that can become negative and a negative can become positive so it might be so that we need to consider maybe to to do in both the analysis and then we have also seen that it depends on what clone you are using the result you get and if you're going to get the efficacy of the treatment so you cannot use the CPS core and then just give a tesolism up and and expect to to take the advantage of this medication there is a risk that this kind of positivity is not the one that uh is a driver for for the for the medication so you need to use the specific loan for the specific treatment uh and having said that it means that you might need to do both the clothes at the same patient or the same tumor because we have seen that there is a discordance between between these clones so you might have a negative let's say tumor in terms of pdl1 enamel cells and you are not able to give a resolution map but you might have a positivity in CTS core and you will be able to give them release mode so we need to analyze both so what about the evidence behind hemotherapy we have few studies that are dedicated to triple negative breast cancer in this setting metastatic setting using conventional chemotherapy but from the studies that we have we know that it's it's not that intentional survival to give a combination of of drugs in in chemotherapy so we prefer sequencing chemotherapy the only Advantage you gain with the combination is that you gain more responses but not bad apfs not better OS if you would like to give a combination it's better to give a platinum based combination compared to other trial that we used to discuss when we talk about uh you know chemotherapy and metastatic people negative disc cancer is the TNT trial uh quite easy trial in terms of of the design first line statement randomized to the set axle or cargo plot what we saw in this trial is that chiroplatin seems to be better in patients with germline maybe a cementation you can see here the responses for the whole population pretty much the same if we go to game line mutations mutated patients we see more responses when we give caroplatin compared to those attacks what we also saw in this trial was that if we use the gene expression profiling and divide the the negative disease to base alike and node base alike we can see that Carl blackin seems to do wash in non-basa like too much so those attacks seems to be better there another aspect to think about is that a rebooting which is a medication that we used to use later in the treatment lines is slightly better in terms of survival compared to other Alternatives in later lines so this also uh this was something that we are using when that we are deciding about the chip so what about patients with germline mutation in this situation the game line appears imitation can be used as predicted by a marker or a type of Target therapy called parbohibitors and we have two perp Inhibitors that we can use the first one is the second one is and you have to quite identical trials behind this recommendation the olympiads where patients were randomized to olaparib or chemotherapy different types of chemotherapy and the bracha trial we startomization between chemotherapy what we saw was any problem Improvement in progression fee survival about three months that's not so great but okay but we couldn't see a difference in OS but in general giving power prohibitors is a better alternative if we have to decide between chemo and perp Inhibitors because it's better tolerated fewer side effects and better quality of life so if we have to choose between these two we used to choose a public invitation so let's go to the second line here we have again chemotherapy that we use we have perp Inhibitors if we have not used this before and in order to think about other Alternatives here I need to present the headline as well so the classic headline for now is two different antibody that are conjugates such as and chemotherapy of course we can use and it might be so that we can move up the drag conjugates to Second Line some instances for instance it will have a recurrence within 12 months uh after the new ads when rather than chemotherapy then we can move up the mongolite come to second line so these two drugs uh is is the future of our our trading strategy of course and the present of course but refutes as well um uses uh so the antibody stratoism up here and with a Linker you have eight molecules of chemotherapy the payload is the DxD lyrics inhibitor and this combination or this drug is quite effective in her to positive disease and these also quite effective in what we call have to low disease so we can have a low as you can see here we can see the frequency of different side effects and what I would like to stress out here is the somewhat high risk for interstitial lung disease and this is let's say the the only toxicity that we need to be worried about with these medicines everything else is is easy to to manage and then we have the substitute remember viteka which is an antibody I guess trop2 receptor with a Linker binds to pay another payload called sm38 which is again Auto position and this is for now available for patients with negative response and as you can see here what we see in the toxicity profile is more or less Akinator so this has a trial behind the evidence we have our Central was a trial dedicated to the United Wisconsin uh they gave us versus different type of chemotherapy and what we saw was an improvement apfs but most important and it proven the OS is arrival with a median of 5.4 months Improvement in the destiny best zero four trial this was not a dedicated triple negative it was dedicated to her to low disease so we had a sub set of patients with triple negative 58 patients and we saw an improvement in both PFS and Os with the translation model of second compared to chemotherapy so the first trial is dedicated triple negative response the second one is the triple negative was a subset was a stratification fact right in the ascent trial what we saw was that we had 55 patients with using this medication as a second line with a progression of disease or recurrence of disease within 12 months after asthma treatment and what we saw was a clear Improvement in both BFS and Os with this medication compared to King effect so this is the reason why we can't use this medication second and what we have in later lines so pretty much the same I would say that if we have nothing using one of the previous lines we can use this later so this is the algorithm based on the evidence so far and what about the future well one aspect to consider is that we need to be better on how we're going to treat our patient with SQL Inhibitors with immunotherapy we need to find a better biomarker compared to pdl1 we need also to consider again are going to do with our head to low disease because this is something new for us oncologist so we need to think about our treatments we need to incorporate the new treatments that are dedicated to this disease and see how we're going to do compare with other treatments for tip negative disease all this evidence is from randomized trials but we need to think that this is a quite well you know well-defined population and when we as clinicians starting using our medications we are using two patients that are less controlled than those in in clinical trials so we need to think that we need to have their world evidence showing the effectiveness of these medications in real world practice and we are expecting to see more uh new drugs in this drug class of antibody drug conjugates more against tropical um acceptor for instance is one medication that we already have some clinical trials that are ongoing and I think that this will again change the clinical practice for in favor of our patients so thank you so much lovely talk Antonio's and many thanks for sharing all that with us uh shall we stop sharing screen and we have quite a few questions about 20 Questions online uh and uh I don't know if Santa is can join us or not yet so we have I am still with you that's great so we have also NADA with us and we have Andrea Peter and I think uh I don't want to ask to start the discussion with a question to Sana am I correcting saying that mother yes yes uh since Sana needs to run maybe soon I wanted to ask from the surgical perspective because I'm sure that there are many surgeons here with us today based on uh your experience and based on current recommendations what would you do what would your cutoff be to go for surgery up front and to or to go to a new Agilent therapy of course we're talking about no negative patients with small rumors we know that we would give new Divine therapy for large tumors than two centimeters but what about tumors like 10 millimeters 15 what what would you suggest oh thank you for this question you know despite the fact I have great passion for the argument therapy up to 1.5 centimeter uh even you know some could disagree 1.5 less than two centimeter I'm willing to go for upfront surgery and if that tumor really turns to be less than T1 or less you know meaning less than two centimeters I would give adjuvant therapy TC by four or something like that and that's it so less than two centimeters most guidelines say up to 1.5 centimeter but for me I would go up to two centimeters I'm okay with surgery up front because this sorry does this include also high risk tumors yes yes because more most of the new adjuvant trials you are we discussed for example the checkpoint Inhibitors they used a t1c meaning you know like more than 15 millimeter or T2 tumors more than two centimeters so if I want to be liberal I go up to two centimeters if I want to be strict everybody would decide would agree 15 millimeter tumor deserves upfront surgery for me up to two centimeters I'm okay with surgery up front and decide accordingly for what to do after I think if we ask that question to 10 different sessions everybody will give you a different take on it yeah but you know I mean because the treatment is quite toxic and the benefit has been proven for more than 15 millimeter strictly more not positive derived more relative and absolute benefit so practically speaking it's okay to go to upfront surgery for those with up to 15 millimeter even two centimeter um tumors to surgery the t1c discussion even if you look at the guidelines if you look at the associated breast surgery guidelines if you look at the nccm guidelines if you look at it German guidelines they call all t1c you can start with either or but I guess somebody's putting his hand up and he wants to talk about that Andreas Vision we're all very interesting and stimulating dogs I I will joke uh predominantly with Antonis because I'll say that we learned a lot of new words today but uh my my doing with regards to choosing to go foreign there are two things that we need to take into consideration I usually say that uh the the sequence of treatments results in modification of certain outcomes but also results to the uh additional remission of toxicities and and the one that gets to pay to pay the bill metaphorically speaking in the end is the patient meaning that uh we need to be very clear with one's goals and expectations so the choice of the cutoff uh regardless of oncological outcomes sometimes once the decision for that came of the chemotherapy is needed in this patient has been made uh is something that needs to include the parameters of surgery because while there is global agreement on that the cutoff between a T1 and the t2 are the two centimeters not all breasts are conservable with a T1 tumor in this sense and one's wish for surgical de-escalation has to be put into the equation so it is kind of a of a surgical decision as well and the denominator should be the combination of optimal outcomes in all Fields but minimization of toxicity as well the other thing that may be a concern and this is a discussion that we often have in Sweden Antonis is uh is very well versed in that is that we need to take into account that a well-known Factor we know we know that surgery cannot affect survival so type of surgery does not affect the survival but there is a type of surgery that affects survival and this is bad surgery followed by complications so if you have a patient where you would plan a more extensive procedure because a breast is not conservable this needs I see Peter nodding gear this is this is something that needs to be put into the equation because a mastectomy with a reconstruction for example that may risk delayed in systemic therapies will worsen the survival so the I think that the equation is quite quite multi-parametric in the sense since I get to be a panelist I want to ask a question with regards to new argument chemotherapy and this is for Sana and Antonis so my my question is with regards to what is the perceived expected or actual benefit of the new adjuvant chemotherapy approach for less aggressive variants of triple negative breast cancer so do we treat them the same um I'm gonna start uh first then I'll take the prerogative of ladies first you know um unfortunately for the triple negative breast cancer patients they were included as long some we haven't selected patients we haven't been actually smart enough to select subsets of propagated breast cancer and as you know the lemon sub-classification for triple negative breast cancer taught us there is at least four or five subtypes with different response to different classes of treatment but unfortunately when it comes to the trials currently we have discussed chemotherapy checkpoint Inhibitors we haven't been smart enough to select the less aggressive out we know some of the middle early subtypes are good some of the tubular subtitles are excellent but unfortunately whatever applies for the global triple negative breast cancer patients applies to them so in short answer we haven't been treating them any different from other uh you know more aggressive triple negative breast cancer patients let's hear from Antonius also what's his take on this then I have a question for Muhammad if that's okay Antonio what's your take on that also um yes I agree the problem here is a lack of evidence uh if we try to look at the evidence with new Ultraman chemotherapy for this low-grade triple negative breast cancer you can see that there is a way lower PCR uh but it's only some case series some small uh institutional studies we need more evidence at the same time we know that we give treatments that are quite uh they're quite difficult for the patients so we need to be smarter here and we need to consider that when we decide so the cutoffs we're saying is more about the you know the real deep negative response when we we get to the low grade we need to be smarter and we need to reconsider that and I agree with that and remember us surgeons sorry NADA and Peter and Andreas and Ricardo we're lazy people we get the Radiologists to show us where the problem is we get the pathologist to tell us what is the problem we get our encourages to challenge the problem biology can't just take a clip out so please please please sergeants here remember to put a like Eclipse there's nothing like a command call in the area where the tumor is if you get stuck with chemotherapy and you also Mark the axilla and you're still talking about evidence about subtypes do we didn't do we need evidence to give them the chemotherapy or do we need evidence not to give them the argument chemotherapy I'll be very uncomfortable keep starting with the azurement for a metaplastic or foreign I think those patients needs to have surgery first they look completely different they behave completely different not every triple negative is a triple negative Muhammad do triple negatives so you will see the pathology when they have the biopsy you'll see the pathology when they have the chemotherapy those different subtypes of of triple negatives like apocline meta plastic adenoid cystic if they give them a chemotherapy do they have differently do they respond differently yeah definitely thank you for the question definitely they will you know and the lower grid groups from my experience those respond poorly for this so this the the basal like or the high grade once they respond better and and this is published everywhere so yes the question is yes and also people are asking about lymphocytic infiltration and other features that you see in in high grade triple negative stances is that something that we need to take more note of in future I think in the future yes but if you ask about the present and the best we don't take this into consideration that that much it is at at this moment it is at the research level only you know we don't subtype those cells except at the research we don't even at our institution don't even mention the tales right now so maybe a few of us will do that but I I don't I don't know the clinical application of this and also let's go back to Peter we haven't heard Peter at all we're talking only about the breasts we're not talking much about the axillary the axilla is very important in the triple negatives isn't it Peter indeed um and we know that if there's a differential response what there usually is actually tends to respond better and more completely than the primary um in other subtypes but also triple negative and we know that residual disease in the exiller is is a very bad agnostic Factor as well and if you put it into the RCB equation it actually increases your RCB quite significantly especially if you've got more than one node um with residual disease can I make a couple of points here's on before that so firstly I would Echo what Andres said and also remember in the under 50 age group we have some reasonable evidence that if you delay systemic therapy in that in that younger population they have worse outcomes overall it's just everything else being equal so you know maybe in the younger patients where breast conservation is more complex as Andreas outline and you may get delays this should be a red flag and I think that they're the patients we should sway maybe for the 15 millimeters and above to go down the neiladuate path um the other thing I just mentioned is I think we we just had a very brief word about converting to ER positive and I think the way we should think about it I'm very um Keen to hear what Muhammad would say about this but I think the residual cancer and we look at receptors it's really about selection of the subpopulation because in we see in many so-called triple negatives you know maybe one percent ER positivity and it's still obviously defined as triple negative so any hour of three with the all red score um and and maybe that you know the ER positive uh you know sub kernel population is being selected out after residual you know with chemotherapy site I don't think it's changing receptor status maybe it's a semantic issue but it's more of a selection issue and then I agree with what Sana and others have said that you should then obviously use that treatment so I think it's just emphasized look at the receptors when there's residual disease now may I ask Muhammad it's very interesting you say that you do receptors at the end may I ask the others who does receptors repeat receptance after chemotherapy so NADA do you repeat the receptors where you work a few if somebody has a incomplete response to new adjuvant chemotherapy you have to positive or triple negative to repeat The receptors of the final pathology yes yes usually we routinely repeated receptors if there is a residual tumor what about Peter and Andreas yeah and sorry I'll start maybe um yes in the primary and and very importantly if there's residual nodal disease repeated in the node as well because you know you have to always question why why if there's a greater node or residual burden than say in the primary or there isn't residual nodal disease I think we need to question that in every instance and and again The receptors may be the answer it may be heterogeneous heterogeneous disease and uh it may not be what we think it is so in that case repeated on the Note as well what about what about you Andreas yeah we we look into that afterwards we looked at that afterwards and we're starting in our MDT to put triple negative not writing them that's triple negative so there's a her two negative completely zero there's half plus one have two plus two and fish negative yeah is anybody starting to put in their entity as this negative about their two plus one or two plus two and fish negative and will that change adult equal change anything currently but that might change things in the future uh any comments on that from anybody yes I will add on this you know because now it is when you test and this is one of the easy research you study to do just to collect the cases before and after and see how how much of those are converted or switch it from a negative to positive but the question is more than that and many factors many pre-analytic factors that what is colognes used how we interpret this uh before and those tumors all of us here knows the breast cancer is a heterogeneous disease so if you test more you will find more discrepancy and what is that called ischemic time how how much time used before we we put this biopsy and the or the specimen in the formally all those factors taken into consideration but now the Hot Topic is that just we analyze the her2 is positive negative equivalent then the equivocal we do the fish or this dish or any incito hybridization testing then becomes positive or negative so those cases now are talking about those the one plus the two pluses which are negative by the incito hybridization are those low hair to low category and if you do this discrepancy that the the number will be very huge or we presented this at the U.S cab last year the number maybe like around 30 40 percent and because in the in the in the current today's and in the older days when we interpreted the her2 we say it is negative we didn't be attention is it one plus or complete negative and all this stuff so this is a new era now where we're heading toward this and we have to to look carefully what is negative is negative is it really zero is it one plus is it two plus then it becomes negative after that by the ish so this is the questions we have to answer by the research and the biology and the other thing is that if you go back to the axilla so if the axilla was positive then you'd on stage then you do a Target dissection if it's negative we usually put them in the in a trial if it's possible it should treat what about an axillary that is negative to begin with you do a sentence with biopsy and you find the T that a node for example that had the complete response to chemotherapy what will you do Andreas what would you do what do you want to know I know I need to know what you do only well I think we we should give feedback to our Radiologists firstly that they've missed a uh node if we if we do a system on ultrasound so I think it's a good lesson uh it's all it's all knowledge isn't it and it's actually good it's positive knowledge in the situation you've described because there's no residual disease and you know that there's many you know PCR in the node so that's actually positive if you like so despite the fact that despite the fact that you may have under treated the patient I'm going to say under treatment but they may not have got to say Pembroke because you thought they were you know uh and zero so um you know then they've got not the treatment you would generally give if you knew it was not positive it's a pretty rare occurrence though I would say but what will you do to the axilla Peter oh uh if it's PCR in with the Sentinel node yeah I will do nothing more well well I mean you could argue because you know it was initially positive that the clinical oncologists will probably at this point in time still say will irradiate the axilla yeah um uh plus or minus just chest wall or breast because uh you know they currently treat on the initial disease extent not on the final disease extent and until we have the alliance trials in and the uh b-51 uh in the CBP b-51 we we have to treat those yeah is that yes well the other thing is of course ethnic and other trials uh such as that as well yeah is that what will you do Andreas so the the I I think that what one does in a situation like that is uh quite a unanimous um decision so to say my uh thing the thing that I would like to lift is the scarcity of evidence uh and so I think that this one of the reasons that this webinar is particularly useful for surgeons is that we we have the the opportunity to expose ourselves to a different way of data interpretation because we as surgeons are not only lazy we are also impatient so we had a very extensive drop down of randomized control trials and evidence stemming from that and how this is utilized in clinical practice we on the other hand tend to do first and the First Data produced is what we have done since we did it and we liked it and we think it works we do not go back to do a randomized control trial that we would need to do so we are kind of bound by a trend that we want to think works the reason that I am commenting on that is that I am among the ones that are very open and quite certain about the future reality that some of uh the pre-treated breast cancers especially they are negative hair to positive ones and the triple negative ones will not need surgery in the future and we will be able to go fishing sometimes instead of operating on them however current so we we have the exceptional responders trial that is a phase to study a small data set but still it looks how it looks we have good collaborative efforts suggesting that you could detect that in the setting of uh radiologic PCR the pulled analysis from the Mars and and the Anderson and Seville among other efforts to name uh but there there is also the tendency to discuss the omission of axillary surgery in those initially node uh negative that have a complete pathologic response the reductional is quite sound because we have the baron uh analysis the data set from the states that suggests that the discordance in these cases for the subset of triple negatives is 1.6 percent so there are only a few however Peter alluded to something that is very important so uh there is a good evidence among and in in these ones a patient living with analysis that Antonis did some years ago that shows that positive auxiliary status postnological and chemotherapy is probably the strongest prognosticator for how things will go so we will just need a way to refine identification and selection until we take this leap of faith of de-escalation and this is something that is particularly relevant in this subset of disease because the data that Antonio showed with regards to the metastatic breast cancer subtypes and how the triple negative has a much more dire prognosis than all the other subtypes should kind of keep us alert with regards to that but you know that this question I'll ask again now to another what will you do if you have somebody that had the same I had a small t122 T1 tumor for example you thought will be negative have a chemotherapy it was t1c you agreed to have chemotherapy in small breasts you have the t1c complete response in breast and you had an essential node biopsy complete responsibility on a node in the axillary what will you do locally in a new unit uh for the for the breast resection I mean we could it could be a breast conserving surgery after the new demand therapy right if even if it had complete response if I understood correctly your question yeah even if there was complete response of the tumor we would do still surgery we would not uh leave it and regarding the axilla we would do sentinel node biopsy no what I'm saying is that you've done the best conserving surgery there's complete response in the breast there's only tumor bed and you've done a sentiment biopsy in the excellent you found a negative node but that shows the pathology is telling you should respond to chemotherapy so so this node was positive before oh yeah in that context I think the medical oncologist would still go for adjuvant therapy and we would have a radiation therapy of the breast and the axilla and Antonio's when you give neaduate chemotherapy for a t1c tumor for example it's a small tumor it's not negative uh Andreas told you listen the state has an a compressed this one and a half centimeter grade three triple negative is big enough for her best we want to give him the argument chemotherapy up front will your chemotherapy be different it was a if it was not positive or if it was not negative will you de-escalate her chemotherapy when you give her the uh uh what you call it the new adjuvant chemotherapy if you think it was not negative upfront yes the difference would be that I would not give pembrolizum as an addition in a small tumor that I would like to give in a lot of chemotherapy because we don't have this kind of evidence so it would be different yes and the question here again to you so somebody had the complete responsive breast and completeness and you found that you thought was negative positive with complete response there what will you do will you change all the treatments and why will you change it has worked yes exactly completely sponsor complete response it doesn't matter how you started but here we we came with some kind of defensive on quality that's saying that we need to keep treating the patients as the initial stating for now we we hope that we're going to have the evidence to change that but for now we do so so we would give rather therapy to the axillary however I I have to be the devil's advocate here okay I usually do that I usually do that I know so so this is formally somebody that is clinically node negative at presentation and the only hint of possible metastasis is that you might have had is uh fibrosis in the node uh Professor dasuki is more of an expert than myself but from what I know fibrotic changes in the nodes are not highly specific of only previous metastases yes so this is a very good because fibrosis by itself I'm not going to consider this as a boost treatment effect but you have to have histiocytes we have to have reaction of this lymph nodes which show that there is previous metastasis because if we just have lymph nodes from normal populations you will find fibrosis in some of those lymph nodes and I see this sometimes some people consider this like fibrosis equivalent to boost the new therapy it is not the second point is that we just have crude evaluation of this we just say uh both development and your Maple size the size is very variable how to interpret this as I said if you have two cells one at the right and one in the left and the treatment effect true treatment effect in the middle you are going to measure the entire distance and and actually you have only few cells here and there so then we have to communicate this we have to to have certain other way to communicate what how much burden of metastatic disease in the and also in the primary site so this is one point again if you have multiple for PSI of metastatic disease and you have normal noodle tissue in between I'm not going to add those up you are going to go to the largest focus and then you measure this so the the volume of the disease should be reflected by certain other way I have to tell you this this is different from this and when I try those numbers on the any equation including the MD Anderson equation I try to put it three millimeter five millimeter six at the end of the day it will give me the same uh RCB number give me the same so sometimes those numbers very crude rcb1 RCB two three is still very uh narrow range of evaluation for this I I have a question for Antonis if I may so uh metastatic breast cancer patients are patients that surgeons do not see as a rule of thumb we do not meet them we are not aware of this reality however this is the reality for one fourth of all patients that get breast cancer in your talk you highlighted different treatment options per line and you alluded to the quality of life how does how do our current therapeutic options affect quality of life and what does this make uh what what is the weight of that when you are weighing in a decision there's always uh you know a kind of balance on what you get in terms of uh effectiveness of the treatment and and the several benefit and what will lose in terms of you know uh Adverse Events toxicity equality of Life issues uh so it's always a balance for us and for the patients um and our decisions are made after the discussion with our patients and we we need to see the context so that the disease as well so interlegated disease where we know that we have additional progresses we have uh you saw the median over survival we it might be so that we are maybe more in favor of choosing a treatment that might give a better benefit in terms of survival and we can accept maybe some more toxicity but this is something that we need to discuss with our patients um so so it's always a matter of discussion with our patients and the balance between what we can get with this in terms of benefit in terms of Adverse Events okay very sensible and one last very very practical question so neural patients treated with memorialismab should we routinely screen thyroid and adrenal before surgery for Antonis again well I hope that your uncle is already done that in terms of thyroid I mean it should be included in the in the you know in what we are doing before its treatment for for these patients the adrenal it's quite quite uncommon for just prevalisma so I would not do that just in in case of symptoms but for I wrote Of course absolutely but this is not something that you should consider is something that the encoders should consider so from a practical standpoint we should kind of demand that patients that come for to to plant surgery after completing new adjuvant chemotherapy including primary should have had recent screening hormonal screening yo I I absolutely think so and you can say to me if you don't have this in uppsala I need to talk with your you know your own qualities okay I think there's some common questions also that are being awesome I think one of them Santa has uh just one one practical question I agree look you know we know adrenal talks is about two percent three percent uh in this context I think if that's correct Antonis um and Sana I mean the Practical upshot is that when you give an anesthetic you give dexamethasone as the best antiemetic available for the anesthetics so that's a very pragmatic but sort of you know solution for the wrong reasons but a good solution should we say pragmatically to cover the surgery so just just to mention that and surgeons should be aware of that and uh should we go back to the question of the super negative cancer with pregnancy is there a certain trimesters that you operate on certain dinosaurs that you start with chemotherapy is there is the treatment strategy will be different for you anybody wants to take this so first trimester during during organogenesis it is surgery only there is no question about that everything else will be referred for new advent chemotherapy and the the obvious question also so early triple negative Will Do genetics on them we'll do the full panel here uh the gene positive lady so lady that has diagnosed with triple negative she's becoming Gene positive so sometimes we need to mention the obvious Peter any comments about that will you always consider mastectomies would you just discuss with them uh breast conservation uh will the biology gives you a different thing for example if it's a five centimeter not positive uh triple negative bracha one where you just want to do about mastectomies and reconstruction or will you consider that only if it was a small t1a or a t1b node negative that you just found on on a screening mammogram any any comments on that Peter yeah I'm not sure what you're asking exactly but I think that the point is that the the treatment um principles are the same first of all and if they need neurogent chemo that's going to be the best systemic treatment and they need that of course we can talk about adjuvant parp Inhibitors but first it's the treatment and then it's the prognosis because again one you know and we when we talk about treatment one of the other aspects apart from best conservation is that you want to know the response for these high-grade you know um triple negatives even if it's 15 millimeters it may still have adverse biology where you know you then want to know what what is the uh response is there residual disease what's the residual burden because that may change your adjuvant treatment and I think you know for the patients we haven't talked about patients who don't respond or progress during treatment it's rare maybe two percent but it's a complete disaster when that happens and I think as with any so coming back to your question about mastect risk reduction I think we have to weigh up the risk reduction according to Patient age risk of relapse from the the initial primary tumor and then talk look about you know timing and other morbidity issues in terms of how you're going to do that so I don't think it's a yes no answer um and you know it wouldn't be a sin to do a you know wide excision Central node uh say best conservation basically after neoagent chemo just to see what the response was uh and then plan you know later on depending on all the prognostic issues what not then plan a definitive mastectomy and reconstruction you know in whatever way you want because that's not a simple undertaking I mean you know presumably you've got the genetic specs sometime during the chemo maybe just before the end of chemotherapy uh and there's a lot of treatment algorithms to take that patient through risk reduction so I would still tend to push it into the background until we know the prognosis of this patient uh with a likely prognosis um sorry Zen what was the second question you asked all of that yeah right I agree with that I just wanted to I we need to point out two things with regards to a known positive mutation status in the setting of triple negative breast cancer so um I I will refer to a meta-analysis that I'm noticed in some years ago looking in the observational studies of patients with a positive mutation status that underwent breast conserving surgery and the interesting thing with that was that it it just comes to you know corroborate on the uh on the knowledge that we have these tumors do not have a worse prognosis because they are braca related or Gene positive in the mutation status what happens with these patients is that they have a higher risk for new primaries when compared to non-mutation carriers so this means that from a practical standpoint these patients have the risk to undergo the same Adventure some years later down the line if they survive their index cancer their index diagnosis as such I think that what Peter is saying is the way to go it a mastectomy a bilateral mastectomy is not the obligatory Next Step following a positive mutation status and we need to be open about that and realize why this is happening exactly what I think of it the way you think of it is that there's two problems here you need to treat the Gene and you need to treat the cancer and treating the cancer lumpectomy is enough if the cancer is poor prognosis cancer then there's no point in treating the gene because it's a longer term problem the gene thank you from another standpoint let's take it from another standpoint who would consider performing radical surgery in a lady with a locally Advanced triple negative breast cancer that has responded excellent to her treatment but still she's 52 and still has her over his own and you have not screened the ovaries for local malignancy because what you are doing by a mastectomy in the presence of early viral cancer in her first ovarial screening is a big nothing and NADA will you do anything differently in Serbia so somebody is triple negative pump to be held to positive what options will you discuss with them the the triple negative tumor that's after a neoagen Therapy Hair to positive right another bracha positive abraca positive okay so we don't test the bracha mutations in all triple negative patients unfortunately it's not available we have to stratify patients based on risk groups and then we refer them to genetic counselor and several of them are tested especially younger people and those who have triple negative cancers uh also we don't have any uh therapy for bracha positive patients so in this context I can only comment on the surgery and I agree with Peter what he said about the risk assessment and individual approach towards the patient and I don't see a special benefit in doing uh contralateral surgeries or prophylactic General mastectomies we should treat the disease and observe the risks in total and one of the common questions that we see on the Q a section somebody for example has at least centimeter node Negative they started with chemotherapy with Antonio's Antonio's out of the fourth cycle of chemotherapy is telling you it's five centimeters now it's not positive what will you do so will you just switch the chemotherapy will you operate on that patient yes in general we use as a question of treatment in our neural treatment so we we try one sweets and then if this and an early early uh you know early assessment of the tumor so we usually change once and then if we see that after maybe one one cycle of treatment we have still this is progression we go for a surgery I'm doing it would you would you stage a patient like that are presentation that that progresses during or is stationary during the Advent chemo yes and the question will you stage only with a pet with a CT and a bone scanner will do a pet and the other question is will you do a CT head for those triple negatives for or will you not all body pit okay uh well for for node negative we are not uh doing uh CT scan as an initial staging we do only for not positive uh for restaging in in case of progression we would do a CT scan in the first place we need to find the place of uh Pet City in breast cancer I know that we we do not have so so good evidence for that but we need to to find the place for that uh for for a more local Advance we would do pets yeah it's nearly Quarter Two now is there any final comments there's a couple of things I need to tell the participants before but any final comments before that Peter just a quick general statement because I think a lot of people watching as you say probably are surgeons we work in multidisciplinary teams and just a bit of a motherhood statement about Neo agent chemotherapy this is where surgeons shouldn't be lazy don't take a back step if if there's any risk of progression and I'm sure it happens in none of the institutions of any of the panelists ever but it can happen in some places that the medical oncologists don't routinely examine the patient with it we with each every two cycles say they might get some Imaging and imaging can be misleading so can I just say that so I think first of all there should be a clinical examination regularly and I think you know the very minimum a surgeon should see the patient heart at the halfway point but I think if the medical oncologist has any concern about progression and I and I I completely get yes you might uh you know go to the next line of therapy or sequence of therapy and alter drugs but please communicate with the surgeon the surgeon should be you know very there should be clear communication with the teams and and you know I think neogen team illustrates the epitome of the team approach in breast cancer it cannot work with people working isolated or not in a comprehensive unit because you really need all the players that includes Radiology pathology obviously but nowhere else really should surgeon and medical oncologists work more closely together and I completely agree with that and the scenario I mentioned like Antonio's also will change them with by changing the chemotherapy but at the same time with pencil in them in for surgery so if your chemo has failed then after that cycle they immediately go for theater otherwise you might lose that window and they become inoperable which will become a nightmare there was a question about what about the complete responders of excellent responders still surgery is the Mainstay we still cannot get rid of us so there's still some studies looking at uh with Peter for example in the Mars and they're doing a study also and and some other parts in the states are doing studies uh to look at omitting surgery and the excellent responders but still the the the the Mainstay the scenario is that even if you have completely response you need to do surgery so people that are online you'll get your certificates in about a week's time so I'll send all that I want to point out that the association of breast surgery the conferences open for abstract submission and this year the top five abstracts from low and medial income countries will be sponsored they'll be given 500 pounds to be able to come and attend the conference so please look at the website of the association of breast surgery and submit your abstracts we're trying to open this 40 good to come from all across the world so we'll have more International presence hopefully this year for the speakers I cannot thank you enough for this for giving up your time on this afternoon or morning or evening for you and for the panelists also the same and of course for everybody that has managed to join us today so for people in the states and South America have a lovely day for people in Europe have a lovely evening for people in the Middle East and further east also have a good evening and a good night thank you everybody for being with us tonight thank you thank you