Dr. Pérez, can you turn off the camera? Dr. Pérez and Dr. Victor, please can you turn off the camera to start? There we go. Okay, I will start the webinar, Dr. Vargas, and then give it just a minute for people to join, okay? Starting now. Good luck. Very good morning here in Mexico City. Good afternoon or good evening in any part of the world that is watching us. We are very grateful to the Mexican College of Gynecologists and we are very grateful to the International Society of Gynecological Cancer for being able to conclude with this third Saturday, this first international course on breast cancer. Only the active speaker can click the button to see. At the top of the screen and select, there is a view of the speaker to see all the panelists, to select the gallery view. When you have any technical difficulties, please contact the International Society of Cancer. If you want to learn the language, whatever you prefer, you have to click where it says Interpretation. On this occasion, we have excellent panelists who are going to give us their experience, both national and international, and from the site where they work. For this occasion, we are going to have, first of all, as coordinator of this event today, Dr. José Espinosa Gómez. He is a radiologist who graduated from the National Institute of Cancer in Mexico City, and apart from that, within the private sphere in our city, he is the founder and head of the radiotherapy unit of the ABC Medical Center in Mexico City. He belongs to ASTRO, and was a fellowship at the Methodist Hospital in Houston City, and is a board member of the Journal of Oncological Radiotherapy. Dr. José Espinosa, we give you the floor so that you can start with the panelists, and I leave the floor to you. Hello, thank you very much, Dr. Vargas. Good morning, everyone. It is an honor for me to be with you today, José Hinojosa, to serve you. And well, it is to be on the last Saturday in the closure of this important course, and that you have mentioned the most important aspects of breast cancer. It is actually a very good fact for all the attendees in the search for education, in the search for updates. So, welcome everyone. And we are going to start today with the topic of genetic signatures in breast cancer. The speaker is Dr. Victor Manuel Vargas Aguilar, from Oncological Gynecology. He is an expert in minimally invasive surgery. He is certified by both boards, the board and gynecology and obstetrics. And without a doubt, it is one of the most relevant topics today, where everything tends to evaluate, what can be predicted, what can be activated in a treatment, how it will affect the patients. So, welcome, Dr. Victor Manuel, and we look forward to your presentation. Good morning. Here, from the city of Tlaxcala, Mexico, we are also... You should get closer to the microphone, a little more, and speak in a loud voice. We are happy to be here participating. I hope you can hear me well, just to confirm. Well, we are going to touch on this topic of genetic signatures in breast cancer, the classification, a little of genetics, and I would like to start touching here some points on the agenda. The first detail, breast cancer. We are going to take some images that a friend shared with me, which I find very interesting, in relation to the history of breast cancer, and how it has existed throughout humanity. We are going to see the masks, because the molecular classification and the simplification that comes to be of the classes, and determine all this genetic complexity. Because we know that it is a disease that affects an organ, the prognostic behavior and risk, will be different. What has led us, to take therapy more and more individualized, and all based on the genetics that this same tumor is expressing. The scientific horizons, where the therapeutic alternatives of cancer have gone, and what we can currently find. I just start this talk with a very simple epidemiological aspect, of something that is already perfectly known, of the incidence of breast cancer, which represents it as the most common cancer in women. It has a causal importance, in comparison, nothing different from that of other countries. And this has shown over time, that it is a disease that has accompanied humanity. That is why in these images that a friend shared with me, and that I found quite attractive to present. Right now we show Diana and her nymphs, presented by Satiro and Madrid. In what the model in the foreground, you can realize that it has an umbilical and a retraction of the nipple. So, the same models that have been presented for the pictorial works, perhaps they had already begun to have the manifestations of breast cancer. This image of the two traces, the right breast is observed, a tumor in the upper external quadrant, with a retraction of the nipple towards the armpit. And then the volume of the breast, seems to be different with the contralateral, showing that there is a disease in the left exophytic breast. This image shows a retraction in the left breast. It has adenopathies and axillary disease on the same side. We can see that the model, who participated in this work, died of breast cancer. So, we started this image recognizing that the disease has been affecting humanity for a long time. And it was not until the genetics of cancer began to be elucidated, that it was possible to understand all this different theology, which makes the behavior, both prognostic and therapeutic, become clear again. If they are so kind, they can mute the microphones, to be able to listen only to the speaker. Here, the first one was the five subtypes. Luminal A and Luminal B with their positive or negative GERDOS variety. The amplified GERDOS, the basaloids of the negative triples. And even so, in the microchips it is shown that, although they have a morphological similarity, the genetics of each one behaves differently. We have seen the histological expressions of each of these classifications. And sometimes they can correlate with their immunohistochemistry, depending on the behavior. And this has divided us into those five, which was what was conventionally used as the therapeutic basis. The classification of this is dragging us an individualized genetic panel, according to the established groups. And this genetics is what begins to translate some certain behavior in the different tumors. However, the diseases in which there are no alternatives to hormonal treatment are exempt from some additional therapeutic alternative. We already know that the luminal tumors, we will start with Luminal A, which is the most frequent and has the expression of the receptors with a low replication potential, a low relapse rate, a favorable prognosis, with the possibility of bone metastasis disease, a very bad response to the assisting or non-assisting systemic treatment. Well, this type of tumors, that even the signs that are already established and validated, such as endopredic or zoncotype, show a certain benefit. But if we stay with the additional group, which does not have this hormonal expression, which can also give it some factor a little more aggressiveness, the low claudine, which has a low expression, with the expression of transitions in the epithelium, does not respond very well to treatments or acupuncture. They must turn off the microphones, please, in mute, to be able to listen to Dr. Victor. So, these groups are beginning to have a little more difficult horizons, because although the triple negative, which is a heterogeneous set, does not have the expression of hormonal receptors or of HER2, it has an accelerated growth, which represents around 10% of the cancers diagnosed. In the importance of this type of tumors, outside of the systemic treatment that can be offered, there is no longer any therapeutic alternative. When the genetics of each of these tumors begin to be defined a little, they begin to be divided into some subgroups, which begin to open the idea of ​​how their behaviors are going to be. The macular alterations and the strategies that are going to offer us the way for the treatment of these cancers, are rooted in a genetic expression. We have the pathological classification that is established, which can also have a certain impact, for example, the presence of intratumoral lymphocytes, which in turn may or may not have their molecular expression genetic, but even so, each of them will host a particular genetic alteration that will confer a different prognosis and behavior, which will begin to elucidate what additional therapeutic alternatives we can incorporate. Is there any discrepancy between the traditional histopathological criterion and the molecular criterion? You can see that some tumors could be reclassified and indicate that they will have a behavior like the luminal, which will confer a very good prognosis of patients with triple negatives. With these increments, you can see that the proliferation could be a little lower compared to tumors that have the same molecular panel, but with a slightly more aggressive expression and behavior. In this way, it is about having a precision in the treatment of breast cancer, already starting to sequence these genetic conditions. The first idea that we can find and that we know is that cancer is a multifactorial disease. Therefore, the genesis of this entire disease could establish different points of attack or therapeutic whites that guide us on what type of treatment. There are genetic ideas that are not even well defined yet and that may be the new future alternatives to establish treatments. Here in the image we can see this sequence, although we want to separate it into different points, it must be considered that it works globally, because all this genetic gap in which there is a proteic expression that can be inhibited or increased, will configure immortality to the cell, in which, identifying the different points of interaction, we can establish some therapeutic white in this genetic to favor the treatment. Then, taking into account this group of different alternations, treatments with growth factor inhibitors, cyclin-dependent inhibitors, immunological activation with lymphocytes, telomerase inhibitors, anti-inflammatories, growth factor inhibitors, vascular factors of PARP2, different routes that open these horizons a little more in those groups of tumors that may not be suitable for treatment. Therefore, the therapeutic whites that we find begin to demonstrate some genetic groups and in these data, as we can see in the graph on the right, these genes are identified, this proteic expression of these genes begin to be the possible therapeutic whites in the future. The scientific horizons that will be presented to us in relation to this goal is, first of all, and that much can impact the Mexican population, that if we drag all this metabolic risk related to obesity, insulin resistance, the role of adipose tissue as a pro-inflammatory marker, could show this primordial role in the recurrence of cancer. It is already established as a risk factor that the increases in the Mars index is an adverse prognosis and possibly some therapeutic whites in the relationship that exists in the metabolic conditions could be a therapeutic white in the elucidated genetics of metabolic activities. The tumor is part of what I may love about neurological disease, because it happens to be a fairly intelligent cell that although it is losing this differentiation, it is immortal, because in some way it evades all the immune response that the body could respond to. Here there is no selection and the tumors are invisible, the body cannot identify them, because within its genetic changes that immortalize it, they deceive the body so that it cannot have this immune activity against the same tumor. So, although the healthy body limits the growth of malignant cells, when there is this immunological suppression, the body cannot discriminate. That is why the intelligence of tumor cells, a little more philosophically speaking, can evade this immune response. But the new therapeutic alternatives will show that we can find, then try to activate this immune system, based on the established genetics, where the different points of attention are located so that all this response of antibodies can be activated, to ensure that the body itself cures cancer. There are immunological stimulators, reactions on lymphocytes, and make these visible tumor cells, and make the new therapeutic alternatives. Even the therapeutic objectives and the new drugs are already identified. This as an alternative to those tumors in which we cannot have. Reverting the sensitivity of the blockade to estrogen, inhibiting second messenger chains, increasing the effectiveness of therapy, inhibiting the ways of immortalization, are the horizons that will lead us to systemic treatments. Therefore, all our molecular classification, based on all the genetics that is well differentiated and that can be so vast, the key points are identified, to be able to incorporate current therapies, and give therapeutic benefit in those diseases in which we are going to have a bad control for the type of behavior. If we were on the path of the history of cancer, from the first descriptions, where the definition of neoplasia comes from, when systemic treatments were introduced, thanks to the nitrogen sample, when the first immunochemical determinations were identified, the GERDOS was established, which already began to differentiate tumors with hormonal receptors, those that had biological treatment, some were established that have the therapeutic object of promising the immune response, some signatures were incorporated to be able to establish the benefits or not, of the systemic treatments, because the last stage that came from the cytotoxic, we incommit the molecules, we will reach the immunological stage, where these genetic expressions will come, to have the therapeutic objectives, and the systemic treatment can promote self-cure by the body. In some conclusions, breast cancer, we have recognized that they are a heterogeneous group of diseases, it has many faces, it has many behaviors, and it is a very constant change. Genetic tests are increasingly bringing us closer to the correct prognosis of the disease, and they give us the opportunity of white therapies. We have some open microphones that are filtering background audios, they must mute the microphones if they are not presenting. The epigenetics, the changes that can present in the RNA, the modulation of cellular metabolism, but still you always have to consider that the best alternative that we can offer a patient is appropriate detection. Appropriate detection and risk reduction are going to be the main factors that will determine the best survival. Even so, advanced diseases are still a therapeutic challenge, and the best thing is the interventions, the appropriate taming. Good morning everyone, and thank you very much for listening to me. Thank you very much, Dr. Victor, for such an interesting presentation. Without a doubt, it is something of the most current that is being done around the world, and well, it opens a whole window of opportunity for the diagnosis of these patients, the treatment, and without a doubt there will be many questions at the end of the talks. So, if you have any comments, you can do it at the end, and we will continue then with our next speaker, which is Dr. Leni Gallardo. La doctora es clínica genetista clínica del Instituto Nacional de Cancerología. Ahí se encuentra en la División de Investigación Clínica, y también ampliamente reconocida por todos nosotros, y ella nos va a hablar de los factores hereditarios asociados a cáncer de mama. Entonces, bienvenida, doctora Leni. Adelante, por favor. I appreciate the invitation y la oportunidad de poder compartir con ustedes esta parte que creo que es muy importante para el tema como tal cáncer de mama. Vamos a hablar sobre los factores hereditarios asociados a estos. Sabemos que cuando empezamos a hablar de la herencia y el cáncer, siempre se nos viene como primer ejemplo el cáncer de mama, porque ha sido uno de los tumores donde principalmente se dan estos fenómenos. Como introducción, podemos ver que el cáncer de mama puede ser clasificado en tres tipos. Tenemos la gran mayoría de las mujeres que van a padecer cáncer de mama de manera esporádica, aproximadamente un 65 por ciento suffer from breast cancer sporadically, approximately 65%, but we have another 35% that we can divide into family and hereditary. What is the difference between the family and the hereditary? It is that we did some molecular testing for this group of patients for determination of hereditary predisposition to cancer, and this group, 20%, came out negative, but that does not take away their history. And by having family history of cancer and a personal history of cancer, they are in an intermediate risk group that we call family. This other group, which is 15%, in most of the books you will see that they are classified as 8 to 10%, with the latest advances in molecular biology and the expansion of molecular studies towards the population, it is being seen that this frequency is much higher and is now classified as 15%. Whenever we talk about breast cancer, we remember that the genes BRCA1 and BRCA2 are the ones that are most commonly associated with the hereditary predisposition to this tumor. However, from more than a decade, we know that these two genes, although they represent most of the predisposition syndromes associated with breast cancer, are no longer the only ones, and the advent of molecular biology techniques with the provision of multi-gene panels that not only evaluate these two genes, but another group of genes that may be associated with the development of tumors, has made it possible to identify another type of genes that are also related to this tumor. So, the new classification within the group of patients that have a hereditary predisposition to breast cancer, which is now between 10% and 15%, we know that more or less 60% of this group will be explained by mutations or alterations in BRCA1 and BRCA2 genes. However, we have a much wider group that will present alterations in other genes. What is the importance of being able to show this? That we are no longer limited to BRCA1 and BRCA2. We have to go beyond this. At the time of requesting a test for a patient that has characteristics and may have an alteration that predisposes it to breast cancer and cancers associated with these, it is important that we do not limit ourselves to BRCA1 and BRCA2. Knowing that we can have genetic alterations in other genes, but that these genes will also have expressions in other tissues outside the ovary, and then it will not be limited to a hereditary breast and ovary syndrome. As we can see here in the schematic presentation of the genes that will interact with BRCA1 and BRCA2, we have a group of genes that appear later as alterations in patients who have negative BRCA1 and BRCA2, and among them palbitude stands out, which is a gene that was discovered around 2004 and that there is an increasing frequency in the population of patients with breast cancer and alterations in this gene, which acts directly related to BRCA2. We have the families of RAT51, RAT51B, RAT51C, ATM, which is another gene that is altered in some patients whose molecular test for BRCA1 is negative, CK2 is another gene that is also related, and P53, which is a gene that we know is altered at the tumor level in many tumors, when it is altered in the germ line, that is, in healthy tissues, it can predispose us to a syndrome that is very rare, but that gives us many types of neoplasms, which are called lymphomas. We can also define here that BRCA1 will interact with many genes to be able to perform certain functions within the cell. The protein as such of BRCA1 and BRCA2 have functions within repair, within signaling to be able to attract certain molecules and be able to repair the DNA, functions in transcription, functions in chromatin remodeling, and specifically in repair. When we go to see the part of the repair, and this explains why certain directed therapies, such as PAP inhibitors, help us a lot, or certain drugs that are used in systemic chemotherapy can help us or give a greater response in this group of patients, it has to do with the activity of the proteins related to hereditary cancer. We know that BRCA1 will orchestrate a series of molecular-level signals to be able to repair the fractures of Dover's chain in a cell, and when this gene is altered, this repair is the one that is reduced. This is the result of a study where more than 8,000 patients were analyzed. These had not been selected by family history. The only requirement was that they had breast cancer. And as we can see here, the frequencies of the mutations are diverse and in different genes. In this case, it was much more frequent in BRCA2 than in BRCA1. If we look at it at the population level, BRCA1 is a little more frequent than BRCA2, but the intention of showing this is because I want, after this talk, to keep the idea that limiting ourselves to requesting BRCA1 and BRCA2 at this time is no longer something that should be considered as an indication. The classification of these genes can also be in three groups. The high-risk variants, where genes are found that are very rare in the population. However, when presented in a person, they acquire an importance due to the high risk of suffering not only breast cancer, but other tumors. Among them is BRCA1, BRCA2, PTEM, P53, among others. We have another group of genes that are a little more common within the population and have what we call intermediate risk and penetration. What do we mean by penetration? We mean the ability for this genetic alteration to cause a trait, in this case a disease, and we are talking about cancer. In the first case, the rare variants with a high risk, these variants give a higher risk of 60% to suffer some type of neoplasia. In the second case, in these intermediate risk variants, the risks range from 20% to 50%, and we have another group of genes. Then we have the common variants that can give a low risk in patients. However, this risk, when we add more than one, will be adding up. So, what is the use of studying other genes that are not BRCA1 and BRCA2? The importance is in the clinical decisions that we are going to make from this information. As you can see in this slide, I show you the classification of some genes related to breast cancer and the risks by age depending on the gene. If we can see here, the gene that apparently gives us a higher risk of breast cancer, which, however, in the population is very rare, is PITEN. PITEN is related to a syndrome called Cowden syndrome. And the risk accumulated at the age of 85 is 92% for breast cancer. However, we have to take into account that the risks accumulated at a certain age do not mean that they are constant over time. That is, calculated in the general population for 25 years, apparently there is no specific risk for breast cancer. In the case of having an alteration in this gene, which is called PITEN, the risk is a little less than 1%, but it already exists. And here, in women under 30, premenopausal women, the alterations in the gene TP53 are very important, which gives us a syndrome called Li-Fraumeni, where the risk of having breast cancer at the age of 25 is already 7%, compared to the general population, which is 0%, or compared to other genetic alterations, where the risk is a bit similar at 25 to that of the general population, such as ATM, NF1, etc. So, what is it for us to know that there are different risks depending on the age and depending on the gene? Because when identifying it, we have to personalize our intensive care follow-up plan, risk modification, depending on how high it is. From these alterations and from these numbers that we can see here, it is that the recommendations to be able to carry out risk-reducing surgeries in patients with mutations in BRCA1 and BRCA2 is that these could be carried out between the ages of 35 and 45, which is when the risk really begins to increase in this group of patients. As we can see here, in BRCA2, the risk at the age of 50 is calculated to suffer from breast cancer of 24%. Therefore, we can give ourselves a little space to be able to offer certain risk-reducing therapies, and in the meantime, be able to give the patient an accompaniment with intensive care follow-up and imaging studies that can help us detect appropriately. What happens with risk modification? We have many treatment options, from intensive care follow-up that helps us determine or detect certain tumors appropriately, but depending on the gene, we will know the expression in the tissues and, therefore, the risk of other neoplasms. In this case, since we are only talking about breast cancer, I allowed myself to show you here a theoretical approximation of what happens with the different modifications or with the different therapies that we can offer to patients, in this case, patients with a BRCA1 mutation. In the general population, the risk accumulated for the age of 85 for breast cancer, the mere fact of being a woman and having breasts, gives us a specific risk, and this is approximately 13%. In BRCA1, this risk can be as high as 69%. In the case that this patient with an alteration in BRCA1 is subjected to a risk-reducing bilateral salpingophorectomy, which we know is a preventive measure for ovarian cancer, this measure will affect the risk for breast cancer because we know that an important group of these patients will develop tumors that have positive receptors for estrogen and progesterone, which are directly related to hormonal activity. So, the mere fact that the patient is subjected to a risk-reducing bilateral salpingophorectomy makes this risk of 69% go down to 57% in premenopausal women. Offering patients or having patients subjected to a risk-reducing mastectomy lowers the risk of breast cancer by 6%. This risk, if you look at it, will never be 0% because the type of techniques used for the reduction of breast mastectomy always have to leave some tissue so that it can be reconstructed. And since we are biological beings, it is likely that some type of neoplasia can develop in this tissue. However, the probability of detecting it at an early stage is much higher because tissue remains on the surface where it can even be extracted with ultrasound. And this last approximation is that if the patient with BRCA1 is subjected to a bilateral salpingophorectomy plus a risk-reducing mastectomy, that is, these two measures together, the risk goes down even more, it becomes up to 3%. Demonstrating that these measures that can be offered to patients in the end will offer or confer to our patient with an increased risk, a much lower risk than that of the general population. In this graph I show you exactly the same, but with BRCA2. The intention of showing them separately is because we know that in BRCA1 between 75% and 80% of tumors will be triple negative, but that in BRCA2 they will behave more like the general population. They will be luminal A, luminal B, and triple positive. So, this action of the risk-reducing salpingophorectomy gives a little more risk reduction because these patients will have a higher percentage of tumors that have or overexpress progesterone and estrogen receptors. So, by applying a risk-reducing surgery with bilateral salpingophorectomy, the risk drops from 61%, which is the approximate for BRCA2, to 49%. A risk-reducing mastectomy will make this risk drop to 4.7%, and if we combine both, the final risk of this patient will be 1.6%, which if we compare with the general population, this patient will be much more protected in the end. Within the different analyses that have been done with patients in breast cancer, it has already been seen that those who do not have mutations in BRCA1 and BRCA2 may have some other mutation, and according to that, it has been possible to measure what is the survival of the disease, the specific survival, etc., depending on the mutation or alteration that these patients have, or mutations in other genes. As we can see here, the fact of not having any genetic alteration gives us a slightly higher probability of survival. This study was carried out or published in 2017. Currently, the trend is that, as we knew, as it was seen here, that patients who have alterations in BRCA1 and BRCA2 can be different, especially patients with BRCA2, because they have a higher percentage of triple negative tumors, because they are focusing on clinical trials to be able to intervene in this group of patients and be able to offer treatments that can improve or increase this expectation of free survival of disease or free survival of progression. Once we see that it is beyond BRCA1 and BRCA2, how do we get to the identification of these pathogenic variants related to breast cancer? To get to them, what needs to be done is a study through new generation sequencing in healthy tissues. Healthy tissues I mean everyone who has nucleic cells, except the tumor. The tumor, like cancer, is a purely genetic disease, because we know that it will be full of alterations or mutations as such that will not allow us to know if the person was already born with some predisposition or alteration or not. Therefore, doing this type of study in healthy tissues, mainly blood or saliva, is the method preferred to look for hereditary cancer predisposition. Within the new generation sequencing, panels of different number of genes are currently offered at the commercial level, from 23 genes to 84 genes. They all have pros and cons, but the probability of finding a genetic alteration, since the patient has this and that it is the cause of the disease he is suffering from, is above 99%. At the time of sending a molecular test, the important thing and what we have to know to be able to explain to our patient is what are the possible scenarios of the results and what are we going to do with them. They are patients who generally have characteristics that make us think and that it is a hereditary cancer predisposition syndrome. And the results of a molecular test of this type can be negative, variants of meaning uncertain, or pathogenic variants, or probably pathogenic. The pathogenic variants, unlike 10 years ago, where we only evaluated 3 genes, BRCA1, BRCA2 and TP53, in this case, since there are more than 25 genes and we can find alterations in any, the implication of this result is that the follow-up and treatment must be specific depending on the gene and mutation presented. In the case of negative tests, it is important that we know that a negative test will only rule out that the patient has a genetic alteration identifiable at this time. However, it is important to take into account the personal history and the family history that will help us take measures, because in many cases, patients with a negative test are not classified as sporadic cancers, but they are moved to the next classification, which are family cancers where no alteration has been found. The variables of meaning uncertain, this is something very important that I would like to make very clear for the moment of seeing a patient or having this type of result in our clinical practice. The variants of meaning uncertain are variants within a specific gene, that is, there is a change in the sequence of this gene, which is explained for two reasons. The main one is that this variable does not exist in the healthy population studied in the world, or it exists in very few individuals and cannot be classified as a polymorphism, which by definition refers to those variants within the genome that are found in more than 1% of the population. So, all the rarest ones that are in less than 1% of the population and that are found in individuals in which a certain type of predisposition is being studied, cannot be classified as benign. However, they cannot be classified as pathogenic either, because there is no information within the databases of data on variants that cause disease that this variant causes the disease as such. It is important that we handle it with tweezers, because the interpretation of this variable should never be pathogenic until it can be reclassified. As long as it is classified as meaning uncertain, it means that our patient does not have pathogenic variants and that the variant of meaning uncertain can be reclassified if we can support it to be reclassified, if we are sure that it can be explaining the clinical picture of our patient. Most of these variables are reclassified over time to negative or benign variables, and it is also important that we can analyze what type of gene is the one that is altered. If it is a gene that has nothing to do with the tumor that we are studying in our patient, it is most likely that it is a negative variant. If it is a gene that is related to the tumor that we are studying in our patient, we would have to look at the family history and even be able to study the rest of the families that have some neoplasia to see if they also have this alteration, which is one of the techniques used to reclassify the variables of meaning uncertain. As long as this cannot be done, the follow-up or implications of a variant of meaning uncertain is based on personal and family history and should never be taken into account as pathogenic. When we have a positive result, the treatment guides are no longer limited to BRCA1 and BRCA2. These are now individualized depending on the type of gene, and we have to take these guides into account because they refer to, as the name suggests, a guide, something that tells us how to follow our patients. However, it is important that we add the part of the patient's family and personal history to be able to offer them the best options for something personalized. So, both the NCCL and other groups, for example ESMO, TONG and GRAFEO, will issue their clinical guidelines or recommendations depending on the genes, and as we can see here, they vary from one to the other depending on the type of gene. For example, the start of intensive monitoring, which has to do with the clinical exam of the mothers, which has to do with implementing imaging studies such as magnetic resonance of the mother, or mastography with tomosynthesis. The age of initiation will change depending on the gene involved, but also depending on the family history. So, in BRCA1 and BRCA2, intensive monitoring is recommended at 25 years old or 5 or 10 years of the youngest case in the family. In the case of PITEN, the same thing happens, but in P53, as we know it is associated with tumors in very, very young women, it is recommended that the start is at 18 years old or 5 or 10 years before the youngest case in the family. In the case of other genes, such as ATM, PALVITU, etc., some are recommended to start together with the recommendations for the general population, which are at 40 years old, and another group of genes that will vary depending on the peak they have of risk to suffer from cancer. Within the surgical recommendations, there is enough evidence to recommend them in BRCA1, in BRCA2, in TP53. There is enough evidence to offer it in patients who have mutations or alterations in ATM, and this is the main reason why we should not stay with offering a patient a test in BRCA1 and BRCA2. We already have clinical recommendations for the other genes involved, and therefore, a panel of genes, offering the patient the opportunity to be evaluated with a panel of genes, I think is the most indicated at this time. Another important thing is the recommendations for clinical trials. Knowing what the implications are, we can see that PARP inhibitors work very well in patients who have mutations or alterations in BRCA1 and BRCA2. This is being used, and in fact, they are already part of the clinical guidelines for the use in ovarian cancer, but for breast cancer, they are also being tested in Phase III studies. So, it is important to be able to recognize these patients and offer them this type of trial, or at least that they are already aware that they have probabilities within clinical trials to be able to try this type of medication. In the case of CDH1 and in the case of PITEN, also trials with AKT inhibitors would be indicated, because within the molecular part, we know that mutations in PITEN or E-cadherin, which is the gene related to family gastric cancer, which is related to breast carcinoma and gastric cancer, are related to the activation of PI3K, and these are in the AKT pathway, which we know is a pathway that has to do with the inhibition of apoptosis and, therefore, the perennial cell multiplication of tumors. Within the genes that can respond to PARP inhibitors, there are BRCA1, BRCA2, PARV2, BRIP1, and, in theory, any gene that has to do with double-chain repair, because in the end we would be giving these cells an attack by two ways. The first is, we already have altered BRCA1, BRCA2, PARV2, BRIP1, or this pathway, and the alteration will make it impossible to repair the double-chain fractures, plus a PARP inhibitor, which is the one that inhibits the molecular pathway for the repair of a chain, because we come to cell death. When should we request a molecular genetic predisposition test? Well, if we have patients with breast cancer before the age of 45, triple negative breast cancer, breast cancer in males, more than one tumor in a patient, family history of breast cancer, ovarian, pancreas, prostate, melanoma, stomach, among others. The diagnosis or risk assessment must be individual. Family risk is different from individual evaluation. Risk assessment, there are many specific models to do it, depending on whether the patient has or does not have cancer, and the risk perception of the patient is very important for decision-making. These are certain risk assessment programs that we can use. Each one is used in different scenarios, if the patient has or does not have tumors, and most of these already have Hispanic representativeness to be able to make a more precise calculation. What do we do with the results? Well, we have to identify what type of gene, what type of mutation, if there are guides, what are the characteristics of the family and personal history, and to which relatives we are going to extend the test. We have already talked about the variants of uncertain significance, and the negative result, it is important that we know negative for what? What techniques were used so that in the future we can expand, if there is something familiar that is very heavy, that these studies can be complemented. Identification and close monitoring are directly influencing the love and mortality of this group of patients, and it also gives us a lot in the quality of life. Finally, I can tell you that early screening, more interventions will improve the quality of life of this group of patients and their families. Thank you for your attention. Thank you very much, Dr. Leni. Without a doubt, a review and a topic that gives for more. I think we could spend the whole morning talking about it. A presentation that has aroused multiple comments and questions, which we will see at the end. And now it is an honor for me to introduce the next speaker, without a doubt one of the pillars in the radiology of the whole world. He is Dr. Carlos Pérez, very well known by all of us, not only by Radio Oncologos, but by the entire Mexican and American oncology community and everywhere. He is currently a professor emeritus, previously director of the Department of Radio Oncology at the Zeitman Cancer Center at the University of Washington. And well, Dr. Pérez accompanies us today to present the topic, hypofractional schemes in breast cancer. They are always the first option. We know the whole boom that there has been to shorten the treatments of patients, the advantages that this implies. So we want to know much more about it. And who better than Dr. Pérez to talk to us about this. Thank you very much, Dr. Pérez, and go ahead. Thank you very much. Share the screen, Dr. Pérez. We still don't see your screen. Is it okay? Not yet. At the bottom, there is a green box with an arrow. Share screen. At the bottom. Yes, but, oh, I see it. Click there, and there you select the presentation. The rehearsal went very well, but... Do you see the slide? Not yet. Not yet. If you want, you can open it on another screen. Stop sharing. Yes, but... I had it on... On this one. No, I don't think so. Oh, no. I'm sharing the screen. No. I don't see it. You don't see it? Not yet, doctor. Stop sharing. Yes, stop sharing. If you want, you can open it without sharing, and then try to share again to select that window. Okay, perfect. There it is. Thank you very much for the technical assistance. It is a pleasure to be participating in this conference and presenting a current topic in oncological radiotherapy. With regard to irradiation effects in both tumors and normal tissues, there are a number of factors that are worth considering and that are important when talking about hypofractionation, especially the dose per fraction and the number of fractions. The most important thing is the total radiation dose that is administered to patients and, of course, the volumes, whether it is white or at-risk organs, normal tissues. And, of course, there are a number of biological factors that must be taken into consideration. In the practice of oncological radiotherapy, it is important to maintain a balance with the integration of both biological and physical factors in the treatment of these patients with cancer. When it comes to tumors and biology, of course, molecular and cellular kinetics are very important. The structure, function, and physiology of at-risk organs and also the tolerance of the patient. When it comes to physics, the distribution of the radiation dose and the optimization of that dose in both tumors and normal tissues play an important role in the results of therapy, which will influence the outcome. Guillermo, outcome is... Outcome and quality of life of the patients. To obtain the best treatment results, as has already been mentioned, it is important to integrate the volume, the total dose, the fractioning, and the time it takes to administer the treatments. The acute effects generally last about 2, 3, 4 weeks, and in general they are not very important. But normal tissues will be affected in what we call the late effects, which will depend, as you have already heard, on cellular kinetics, the cells that are being destroyed, and some alterations in the microvascular environment. In irradiation biology, the linear-square equation defines an equivalent biological dose that depends on the number of fractions, the dose, and the alphabetical proportion that has to do with the response of normal tissues to a certain dose of irradiation, and of course the administration time. Do you understand? In the studies that have been done, both in cell cultures, in animals, and in humans, the biological dose is greatly affected by the alphabetical proportion, and for mammals in general, values of 3 to 5 grays are used, that is, 300 to 500 centigrays, which are the RALs of a few years ago. As you can see here, the lower the alphabetical proportion, the greater the biological effects. Therefore, when we do hypofraction therapy, based on the experience of what we have called conventional fractioning, one can use this linear-square formula and determine the dose that must be administered when we change the fraction dose based on the alphabetical proportions. For example, if we give 50 grays, that is 5,000 centigrays, with conventional therapy, in general, the linear-square equation tells us that with hypofraction, the total dose is reduced to 39 grays. So, when a tissue with an alphabetical proportion of 3, more or less, like the thoracic wall, the ribs, compared to another tissue, like the skin, which has a fairly high alphabetical proportion of 10, the lower the alphabetical proportion, the greater the effect on normal tissues. So, small changes in the fraction dose will produce greater effects on these normal tissues. What are the advantages of hypofraction? It is possible that there is an increase in the therapeutic proportion, that is, between the dose and the morbidity, acquiring a greater probability of tumor control with fewer effects on normal tissues. Of course, it is convenient for patients, instead of coming 25 times to the oncology department, they come 13, 14, 15 visits. The efficiency of the radiation center is also increased, because more patients can be treated. And the cost-benefit has not yet been defined very well. However, there are some disadvantages, because it is feasible that a smaller number of fractions will not allow the tumor cells to reoxygenate, which occurs with a more fractional therapy. Or the transition of some of the cells from a more resistant phase to a more sensitive phase in the cellular cycle to irradiation. Also from a physical point of view and from the administration of treatments, errors in repositioning or changes in the position of normal organs, because there is some movement, will have a greater impact on tumor control or on morbidity. We already talked about the difference that exists with a lower alphabet, and therefore, if there are errors in the administration of the dose, in a fraction, this may result in more biological impact. And finally, the number of fractions, as you have seen, the more it decreases, the greater the effect on normal tissues, because the fraction dose has increased. Of course, we are going to talk only about total breast irradiation, not about other conditions. The most frequent fraction schemes that have been used are conventional therapy, as I have already told you, 50 grays or 5,000 centigrades in 25 fractions with daily doses five times a week of 2 grays or 200 centigrades. In the United Kingdom, there have been three doses that have been investigated. With different number of fractions, 39 grays in 13 fractions, 3 grays per fraction, 40 grays in 15 fractions, 266, or 42.5 grays in 16 fractions of 2.66 or 266 centigrades. Because it is easier to maintain the sum of these different doses, we have used 270 grays, 16 fractions, for a total dose of 43.2 or 4,320 centigrades. I am not going to talk about accelerated radiotherapy, which you will hear a presentation by Dr. Hinojosa Gómez later, which is what is used in partial breast irradiation. There are three or four very important studies that are worth exploring in more detail. In the United Kingdom, START-A, in which 2,236 patients were randomized, 749 were treated with conventional therapy, 50 grays, 750 with 13 fractions, 41.6 grays and 737 infections for a total of 39 grays. The results, fortunately, in these patients, which had T1 to T3 tumors, not ganglions or N1 ganglions, with an average follow-up of five years, the local-regional failure was very similar in the three groups, 3.6, 3.5, and 5.2. The alphabetical proportion for tumor control was 4.6, and for normal tissues it was 3.4 grays. As you can see, survival is similar, and the cumulative failure in the breast is also very similar. And the survival without disease was a little better in the patients who received the 39 grays, but the difference is not statistically different. Very few collateral effects, around 1%, very similar in terms of systemic disease, cardiac, or fractures, also around 1%, or pulmonary fibrosis, also around 1%. So, any of the three treatments are effective and have the same morbidity. The other clinical trial was in the UK, Start Bay, in which the patients were treated, and this is a total of 2,215 patients, with 50 grays in 25 fractions, or 40 grays in 15 fractions. More or less, 1,100 patients per group. Same, very little difference in local-regional residues, 3.3 with conventional, 2.2 with hypofractionation. But there was less morbidity in the group treated with hypofractionation, 40 grays in 15 fractions. And survival, also more or less the same thing, survival without disease, the same. And there was also no significant difference in terms of late effects, systemic disease, 1.7, 1.3. Rib fractures, 1.5, 1.4. And pulmonary fibrosis, 1.4 in both groups. So, very low morbidity. The other study, which is also very relevant, is the Canadian one, in which 1,234 patients were randomized, were treated in a random trial with 4,250 centigrade, or 42.5 grays, in 16 fractions, 2.65 per fraction, or the conventional therapy of 50 grays, 25 fractions, 2 grays per fraction. The results at 10 years, very similar. Hypofractionation, the failure was 6.2 in breast and ganglions, and the conventional therapy 6.7. Cosmetic results, which I did not show in other studies due to lack of time, very satisfactory, good or excellent in 70% of patients. And also, the morbidity, quite low, a little more in the hypofractionated group than in the conventional group. The results, there you can see them in the graphs. The morbidity was also quite low, and is similar in the conventional group, standard, or in the hypofractionation scheme. Skin reactions, either 2 or 3, 2.6, grade 2, 0.7, grade 3, equal in both. Subcutaneous tissue effects, more fibrosis, grade 2, 5.2, 3.8, and grade 3, less than 1%. Cosmetic results, quite good, very similar in both groups. This is another random study of patients treated with conventional therapy or hypofractionation. Very similar results for both groups of patients, either hypofractionation or conventional, and at 10 years, the mortality rate for breast cancer was 15% in the conventional group, and 11% in the hypofractionated group. This is a recent study, also in the United Kingdom, in 47 centers, and 50 hospitals. The patients were over 18 years old, breast cancer 1 to 3, NON1 ganglions, after conservation therapy or mastectomy, and were randomly distributed to receive 40 grades in 15 fractions, 27 grades in 5 fractions, or 26 grades also in 5 fractions. More or less, 1,300 patients in each group, which is a fairly respectable number, or 4,000 more or less. Local-regional failures, very similar, between 2% and distal failures, around 5%. No difference in the three groups. Mortality for breast cancer, very similar in the three groups, around 8%. And mortality for any cause, also quite comparable in the three groups, so there was no difference. I don't have results of research done in the United States on the acceptance that has been received in the community of oncologists, radiotherapists, when it comes to hypofractionation, but I did find this European study. 412 responses. In Europe, 54.7% of radiologists prefer total breast hydration, and more or less 29% in the lower group, hypofractional irradiation. And when it comes to post-blastectomy, minus 21% total breast hydration with conventional pressure, and 29% with hypofractionation. The factors that they mentioned that affect the decision to use hypofractionation, or conventional therapy, in general, hypofractionation is used more often in patients over 50 years of age. Regional ganglions, in 46.9% of patients, patients with ganglions, are treated with total breast, patients without ganglions are treated with hypofractionation. The same for patients with internal ganglion mammaries. The study is also important, because in general, radiologists in Europe, and the same in the United States, prefer to use hypofractionation in the smallest tumors, T1 or T2 of less than 3.5 centimeters. They also considered mammary reconstruction, 31.6%. Just like in the United States, patients treated in academic centers have a more frequent use of hypofractionation than in patients treated in private centers. It may be a philosophical attitude, but there may be an economic factor. I have already shown morbidity, but I want to mention in this study, of a significant number of patients, 2,300 patients, that morbidity is low. Pain in the breast, around 18% in the conventional group, 5% in hypofractionation, and a more intense pain, grade 3, very low, around less than 1%, 1.5%. Lymphedema, more or less 1% to 6%, and dermatitis is also very low. Induration of the skin, very low in both groups, 1.9%, 0.5%, for a grade 2. Pain in the thoracic wall, less than 1%, pericarditis, less than 1%, pericardial sprain, also less than 1%. Same for dyspnea, pleuritic pain, or pneumonitis, less than 1%. In this graph, you can see that the fraction dose is a factor that increases a little the incidence of morbidity or mortality, in this case, cardiac. Fractions of more than two grades, a little more, but it is very low, less than 5%, for patients in the right breast, and the same in the left breast. Same. This is a study using hypofraction in patients with ductal carcinoma in situ, 145 patients. The failure in the ipsilateral breast was around 4%, which is very low in both groups, and morbidity also quite low. Some grade 2, between 1% and 8%, and there is nothing more than angiectasis, grade 3. Cosmis is quite satisfactory in more than 90% of the patients. This has more to do with the conference that Dr. Hinojosa-Gomez will give, but it is a therapy meta-analysis which is actually a hypofraction scheme or conventional irradiation. And there was no difference in these two groups, with 10 randomized studies and more than 15,000 patients analyzed. These are the results. As you can see, there is no difference. Mastectomy, the same. Patients are being tested for thoracic palette, or thoracic palette and two ganglions, with hypofraction therapy. Several studies have shown that tumor control is quite high in all these studies, 96 to 100%, and with a fairly low morbidity, as you saw in other slides. Now, as far as mammary reconstruction is concerned, there is a tendency to use hypofraction in patients who have not had reconstruction, compared to those who have had reconstruction. The complication was 6.3% in patients who did not receive hypofraction, and 18% in those who received hypofraction therapy. To conclude, hypofraction is a fairly easy technique to treat. Tumor control and survival are equivalent to conventional therapy. Toxicity is also equivalent to standard or conventional hypofraction. For the highest dose per fraction administered, technical precision is very critical, because, as you saw, there may be more impact of these errors, which can rarely participate in the administration of patients. And finally, the equivalent biological dose and the optimal dose per fraction, as well as the total dose, are very important for both tumor control and acute and late morbidity. Thank you very much for your attention. On the contrary, Dr. Pérez, thank you very much for your complete review of this current topic, and that it is now the standard of treatment for early breast cancer. At least in Mexico, but it is increasing. Yes, yes. Here in Mexico it has become popular. And when they don't pay us per fraction, per treatment, we will use it more often. I know. Very well, doctor. Thank you very much for your participation. Without a doubt, many questions. We will see them a little later. We will also be forced to cut the recess a little so that you are aware. And now I am very pleased to welcome Dr. Albert Mena. He is a radiologist who is in Colombia, graduated and trained at the National Institute of Cancer of Mexico. Without a doubt, someone very bright and he will talk to us about the current state of radiation in breast cancer. Welcome, Dr. Albert. Thank you. Thank you very much, Dr. Hinojosa. Greetings to all. Good. Okay. Can we see it there? Yes? Can you hear me? Yes, we can see it. Thank you. Perfect. Thank you. Good morning. My name is Albert Mena. I am from Corredo, Colu. I am currently working at the Foscal Clinic in the city of Floridablanca, Santander, Colombia. To start, I wanted to thank the entire organized group for inviting me to this important event. At this time, we will talk about the current state of radiotherapy in breast cancer. It is a topic that can cover several topics, as we can see. Dr. Carlos Pérez already talked about extreme hyperflexion. Dr. Hinojosa will talk about accelerated breast hydration. I will focus on the last three topics, which are hyperflexion. It is interesting to talk about these topics. Hyperflexion with integrated BUS, SRP in oligometastatic disease, and corregional control in metastatic breast cancer. Starting with the premise that the trend of new radiotherapy treatments as objectives is to give treatments with a shorter radiotherapy time to achieve more efficient radiotherapy with low toxicity and improve both local control and global survival, thus reducing the mortality of patients. To begin with, hyperflexion with integrated BUS. Regarding BUS, we know that there are many randomized studies that have shown the benefit in local control of BUS after giving radiotherapy treatment to the entire breast. But we also know that administering a BUS implies perhaps worse aesthetic results at a higher cost in the treatment. There are several guidelines to determine who should receive a BUS, and this is already very clear. It should be patients ideally under 50 years of age with high-degree tumors or locally positive margins with an extensive intradoxal component, with negative estrogenic receptors and positive infovascular orientation. But there are still no guidelines in the consensus to administer a boost after a hypofractional treatment, or also in cases where the margins are not microscopically positive, but are narrow margins. Based on the lack of large controlled, electrolyzed trials that evaluate an adjuvant radiotherapy in an integrated boost for breast cancer, the American Society for Oncological Radiotherapy continues in the guidelines recommending that the administration of the boost be sequential. Therefore, there are no electrolyzed trials that support the non-inferiority of the integrated boost versus the sequential boost. Having said that, and knowing that there are few studies that talk about the integrated boost, Phase III studies, advanced studies, there are not many studies regarding the integrated boost in conventional fractionings. Only until this year, a new study was published, which is the IMRT-MC2, a study of non-inferiority, where 500 patients were included, and they compared patients who were going to a conventional fractioning treated with IMRT versus patients treated with conformational radiotherapy. The IMRT group was an integrated boost, the conformational ones were a sequential boost, and they managed to verify in this way, in their conclusions, that there were no significant differences in local control, nor in toxicity. However, there are no studies completed so far regarding fractioning, hypofractioning plus an integrated boost. And we start from something that Dr. Pérez had told us, there is a benefit of giving hypofractioned treatments, taking into account that the tumor of breast cancer has a low alpha beta, and with this we hope that there is a better radiobiological effect, that the hypofractionings are benefited, and that this also reduces the days of treatment, a more comfortable treatment with fewer days of treatment for patients. With this, two studies are being carried out at the moment, they are being updated, they are in progress, where they evaluate an integrated boost versus a sequential boost in women patients who receive radiotherapy treatment throughout the breast in a hypofractioned way. These two trials are the RTOG1005 and the HypoSyF, which are investigating whether to give treatment to the entire breast with an accelerated hypofractioning plus an integrated boost on the surgical bed in 15 fractions. In all patients who were previously taken to a breast cancer surgery, it is no less than giving treatment to the entire breast with a standard hypofractioning with a subsequent sequential boost. This study, which has already submitted its first results, is a randomized phase 3 study, two-arm, multicentric control, a non-inferiority study, which presents its first results and shows results regarding the safety and satisfaction of patients. The objective of this study is to determine whether the hypofractioned radiotherapy with an integrated boost compromised the oncological and cosmetic results versus the sequential boost. And what it is also looking for is to evaluate whether there is inferiority in free survival of disease at 5 years. Some secondary objectives are also to evaluate safety, adverse effects, acute chronic toxicity, free survival of recurrence, global survival, quality of life and cosmetic results. In this way, 2,324 patients were included in the study, which was carried out, recruited from 2015 to 2019, in 88 centers in Germany and Austria. These patients were taken to a conservative surgery and later to adjuvant radiotherapy with a boost in the surgical bed. The criteria for determining who was going to receive the boost were taken by the local researcher of each center. The group of patients who were included were all over 18 years old, with an ECOV-2, an invasive breast cancer, unilateral, unifocal, with a surgical bed that was identifiable in the planation tomography. In the exclusion criteria, patients who had been taken to mastectomy, bilateral breast cancer, who did not have a boost indication, who had a larger serum to postpone surgery, or who had a retherapy indication to ganglion chains, or who had serious comorbidities, or who had a previous cancer of the cell type or a cancer in situ of the cervix. In this study, the follow-up measure was 28 months, and in this way they randomized this group of patients into two groups, an integrated boost group and a control group. In the integrated boost group, the patients were treated with a hypo-fractional dose of 40 grays in 2.5 grays per day throughout the breast, plus the integrated boost, which reached up to 48 grays, with 3 grays per day in 16 fractions. In the control group, three subgroups were created, a group that went to conventional radiotherapy plus integrated boost, a conventional fraction plus sequential boost, and a group that went to hypo-fractional radiotherapy plus sequential boost. Most of the patients were included in the first group, conventional radiotherapy plus integrated boost. Then, the adverse events and acute cutaneous toxicity were analyzed, based on the terminology criteria for adverse events, in its version 4.03. The satisfaction of the patients was also analyzed, with the treatment and the quality of the attention. In these two pictures that we see here, we see the adverse events in the red curves, we see the standard treatment, the blue curves are the experimental treatment, hypo-fractional plus integrated boost, and we see that there are not many differences in terms of radiodermitis, these curves above correspond to acute cutaneous toxicity, a small decrease in the effects in terms of skin toxicity, in the experimental group. In the dotted curves that we see below, they are grade 2 toxicities, also in the group of hypo-fractional plus integrated boost, perhaps a little less toxicity compared to the standard treatment, but very few patients presented grade 3 toxicities. We see that the curves of grade 3 toxicity almost touch the baseline of the curves. And with respect to pain, there was no difference between the two groups, we see that the curves cross at different points, this with respect to grade 1 toxicity, grade 2 toxicity was very low, and in terms of pain, very few presented intense pain in grade 3, the line is almost flat. With respect to the satisfaction of the patients, an evaluation was carried out of the experience formed and measured by the patient, 120 questions were carried out, 120 patients, in which they could give a 0.9 rating to the experience they had. What was evaluated? The load generated by radiotherapy, by chemotherapy, by surgery, the intensity of individual symptoms, the satisfaction with medical information, or the satisfaction with regard to medical attention in consultation, with regard to radiotherapy, chemotherapy, surgery, or endocrine treatment. And we see here the results of those evaluations, we see in the first table the load generated with respect to the treatment, the scores that were generated with respect to the treatment in terms of the load were low, perhaps the one that generated more effects for the patient and more load was chemotherapy, but if we focus on radiotherapy, the effects by load, by side effects on the patient that they felt as effects, that is, they took it as something that deteriorated their health, because the experimental group had a lower percentage of these events with respect to the standard group. In terms of the satisfaction of the management of the disease, in the different specialties, radiotherapy and chemotherapy, they obtained a high score, they were all satisfied with respect to the management. As for the intensity of the symptoms, they were all low scores, they were few symptoms, with a predominance of fatigue, of asthenia, and perhaps the cutaneous manifestations, with a sensation of heat, there were manifestations of radiodermitis that were a little high, but all were low. As for the satisfaction with respect to the medical information that was provided in each consultation, we have all high scores, the highest generated in consultation were for surgery and for radiotherapy. Conclusions for this study, there is preliminary data that proves that hypofraction radiotherapy with integrated PUS can be administered with a low incidence of radiodermitis grade 2, with low numbers of adverse events, and without unexpected toxicity, grade 3. The cutaneous reactions, grade 2, were less pronounced in the group of hypofraction with integrated PUS, compared to the control group. The hypofractionated irradiation ended before the peak of cutaneous reaction was presented, which is something curious, and the satisfaction of the patients with respect to hypofractionated radiotherapy was generally high. In all cases, surgery and clinical oncology, but especially for radiotherapy. On the second topic, with respect to stereotactic radiotherapy in oligometastatic disease, we know that oligometastatic disease can be susceptible to ablative treatments, and thus achieve a prolonged disease-free interval or an improved survival. Both stereotactic radiotherapy and ablative radiotherapy can provide a non-invasive ablative treatment for oligometastasis. And speaking of oligometastasis, we know that the concept is to have less than 5 or 3 metastases, very well located, of small size. We know that with respect to this type of handling of SBRT or SBR in oligometastasis, we do not have much evidence in terms of advanced studies, authorized studies, phase 3, but at the moment an authorized study is being carried out for ablative treatments in oligometastatic breast cancer, which is the one we see on the screen. We do not have advanced studies for phase 3, but we have the Comet, which is a phase 2 study, in which it was demonstrated an improvement in global survival for patients who received ablative radiotherapy on metastatic mutations. In this study, it is not exclusive to breast cancer, although they included different primary tumors, such as colorectal, lung, prostate, and others, but 20% of the patients included in this study were breast cancer. The benefits in terms of global survival and free progression survival at 5 years, we already have the results, we see the curves of patients treated with ablative radiotherapy on metastatic lesions compared to those who did not, and these results at 5 years were statistically significant, both for global survival and for free progression survival. But we return to the same thing, there are few studies regarding breast and metastatic oligometastatic disease. Most of what we have at the moment are retrospective observational studies. This study, which is one of them, is an institutional retrospective study carried out in Germany, where the response of radiotherapy is evaluated, sterotoxic radiotherapy for extracranial lesions with a metastatic oligometastatic breast primary or progressive oligo. The objective was to evaluate the result and the prognostic factors and seek to understand the toxicities in this type of treatment. In this study, 43 patients were included, treated from 2002 to 2019, all with breast cancer, metastatic extracranial lesions, which were considered as inoperable, located in different places, bone, liver, lung and suprarenal gland. 70% of these lesions were metastatic oligometastatic, and 30% of the treated lesions were progressive oligometastatic. Most of the treatments, if we see that the study was carried out between 2002 and 2019, 58% of the treatments were carried out between 2017 and 2018. This has a special consideration, which we will see later. The toxicity was measured with the common terminology criteria, in its single version. These were the doses. The doses were measured between one, a maximum of 10 fractions. Minimum dose of 18 grays, maximum dose of 60 grays, with different fractions, some for lung, for bone lesions, as we can see here. The only interesting thing is that it was assumed that the alphabet for metastatic lesions was calculated in 10 grays. Here we see the results, in the curves for local control, for distance control, for free progression survival and for global survival. The results were that 4 out of 58 lesions occurred during the follow-up period, which was 2 years. Local control was achieved from 1 to 2 years, 92%, it went down 89% every 2 years. Distance control, 2 years, was 44%. Free progression survival was 17%. And global survival, 1 to 2 years, was 84% and it went down 62% every 2 years. Favorable prognostic factors were sought, and it was found that the positive hormonal receptors, predominantly bone-located lesions, and having one metastasis versus more than one metastasis, had a favorable prognostic benefit. And in the multivariate analysis, these factors were identified, of which we can highlight that patients older than 55 years or who had a PTB volume greater than 37 cubic centimeters, had better global survival, with statistically significant results. With respect to the location of the lesions, the bone metastatic lesions, which we have already seen in the curves, as having a metastasis, had a benefit for distance control and a benefit for free progression survival. Not so, if we refer here to local control. None of the factors in the multivariate analysis had a benefit to achieve local control. As conclusions, extracranial stereotoxic radiotherapy in patients with breast cancer or metastatic ligaments or progressive ligaments was well tolerated with excellent local control. There is an increase, that's what we saw at the beginning, although the study was from 2002 to 2019, the increase in the use of radiotherapy and radiotherapy surgery, from 2019, indicates that it has been a procedure that has led to an increasing acceptance for the management of oligometastases. This study that I present contributes to the body of literature that has been growing in the role of radiotherapy in treatment with radiotherapy for oligometastases in breast cancer. And future trials are necessary to consolidate the function of local relative treatment with radiotherapy in this type of patients. To conclude the last topic, which is to talk about local control in breast cancer and metastasis. We know that 6% of patients with breast cancer that are newly diagnosed, are presented as a disease of NOVOL, a clinical study 4 of NOVOL. Improvements in systemic treatment, including chemotherapy based on taxonomies, antigen-2 therapies, immunotherapy, have improved the prognosis and survival of these patients in advanced stages. Traditional treatment is to administer systemic chemotherapy. In some cases, very chosen, some go to additional surgery to achieve the control of the primary tumor. And in some less cases, they also go to radiotherapy treatment, all with the intention of controlling local-regional symptoms. Of this, we have 4 recent studies that investigated the prognosis of patients after being taken to surgery in metastatic cancer, clinical study 4 of NOVOL. Although in all studies it was possible to show that there was a benefit in local control, the results with respect to the benefits in terms of global survival were contradictory. Very well, in this way, we know that there are no studies, phase 3, that show the benefit in global survival. And this study appears, which is not a phase 3 study, it is a retrospective revision study that shows benefits in survival. There are several that show benefits in survival, but they have not been able to be taken to phase 3 to show us if this survival that the retrospective studies show is real. In this study, the existing information in the epidemiological surveillance program of final results was explored to evaluate the results of the different strategies with respect to the management of local control. So, the objective of the study was to investigate the effect of local radiotherapy on patients of MAMA, clinical study 4, diagnosed with NOVOL, who previously received chemotherapy. 5,374 patients were included between 2004 and 2012. All clinical studies 4, metastasis and chronic, 93% with invasive ductal carcinoma, 81% with positive changes, mostly under 65 years of age, with negative receptors, mostly non-Hispanic whites, little differentiated or undifferentiated diseases, and 50% of the patients were clinical studies T3 and T4. Patients who did not have a pathological diagnosis were excluded, that they were non-invasive ductal carcinomas, or invasive lobuli, and that they had not described in their history the ethnic origin, the degree, the size of the tumor, the state of the ankylosis, or the hormonal factors. Of this, 43% of the patients were taken to surgery alone, 17% to radiotherapy alone, and 39% to a combined treatment after chemo, surgery, and post-operative radiotherapy. These are the results with respect to cancer-specific survival at 3 years. We see that there was a benefit for surgery, for radiotherapy, but the greatest benefit was the patients who were taken to a combined treatment between surgery and radiotherapy, with also statistically significant results, but we see that the patients who were not operated and were taken to radiotherapy alone, the survival was less. And there is a benefit between these two groups, surgery and radiotherapy, that favors surgery. Combined treatment is one of the best results we have. So, for the percentage of local control, we see here the curves, which is practically what is on the table. So, here is the curve of radiotherapy alone, we have in green the combined treatment and in blue the surgery alone. And here we see the curves in terms of cancer-specific survival. Where we see the statistically significant result that benefits the combined treatment of surgery and radiotherapy, post-operative, after chemotherapy. As conclusions for this study, local therapy was an independent prognostic factor to improve cancer-specific survival. The comparison of radiotherapy alone and surgery can confer a benefit in survival. Post-operative radiotherapy improves the result after surgery, but more prospective studies are needed to identify what is the role of this type of treatment in the local management and in the survival of patients. The justification for continuing to do radiotherapy treatments in this type of patients is probably the possibility of increasing the efficacy of the chemotherapy, which is the treatment standard, reducing the total tumor load, eliminating the mother cells in breast cancer, the primary tumor, and reducing the probability that there is a resistant disease that can reduce the metastatic potential in case these patients do not achieve local control. As general conclusions of the talk, we know that hypofractionation has become the recommended approach for complete breast radiotherapy. It is an increasingly used treatment. The technical progress in terms of radiotherapy is already given by images, in terms of planning, the treatment equipment has allowed to develop new treatment techniques that are much more precise, that allow to give high doses such as stereotactic radiotherapy or radiotherapy with ablative intention, because they are more used, due to the precision that we can achieve with all the technological advances we have at the moment. And the consensus of the Third International Conference on Breast Cancer suggests that surgery can be considered on the primary site for selected patients and thus improve their quality of life. But retrospective studies have shown that radiotherapy also improves local control and that this could also perhaps improve the survival of patients. Thank you very much. Thank you very much, Dr. Albert. Without a doubt, a very interesting talk that summarizes the current state of radiotherapy in breast cancer. And well, we are approaching the questions and answers section. We appreciate that you remain connected. And now we go to the next talk, which is under my charge. And I am going to talk to you about accelerated partial radiotherapy in breast cancer, a topic within this First International Course on Breast Cancer. So, accelerated partial radiotherapy. Who, when and where? This is the agenda of the topics that we are going to see today. A brief introduction. The standard treatment of early breast cancer. How is it justified? The principles. We are going to review the evidence of four clinical guides and conclusions. So, as an introduction, the conservative treatment, as we have already seen, is the standard in early breast cancer. It has the same results in local control and survival, mastectomy, even superior in quality of life in the sexual and functional domains. And it has already been shown that radiotherapy, after conservative surgery, decreases recurrences and mortality in controlled studies and meta-analysis with a follow-up of 20 and 10 years. And traditional radiotherapy consists of giving the complete breast with a duration of 6 weeks, a duration that is not very attractive for both patients and doctors. And in recent decades, alternative schemes have been developed, such as perflected radiotherapy, which typically lasts 3 to 4 weeks, and partial radiotherapy, which can last less than a week. So, the treatment is conservative surgery. Patients must receive adjuvant radiotherapy, although we currently know that it is not always necessary. We are going to consider whether they have positive ganglions or not. And the options we can give are total breast radiotherapy plus ganglions, habitual hypoflexed radiotherapy if it has negative ganglions, or partial radiotherapy. And this can be with brachytherapy or with external radiotherapy. What is the justification? Giving partial treatment shortens the time of radiation and also the dose to the organs that are around, such as heart, lung, breast and skin. This is in a significant way. In the last 20 years, multiple techniques have been developed, which are already published, and it can be external radiotherapy with photons or protons, brachytherapy, which by way of administration can be intracavitary, interstitial or contact, or intraoperative radiotherapy with electrons or photons. How did all this originate? Well, almost more than 100 years ago, in England, interstitial radiotherapy was used in palliative and curative cases, and it was noticed that in those localized cases, a survival rate of 3 years of 85% was achieved. This is very surprising if we consider all the time that has passed. And this contradicts the theory of centrifugal permeation of breast cancer. Why is radiation necessary after surgery? There is already a meta-analysis of the collaborative group of early breast examiners, with more than 10,000 patients and 17 studies, which compared radiotherapy against non-radiotherapy in more than 7,000 patients with negative cancers. And so we have information that decreases the risk of recurrence at 10 years from 31% to 15%. This gives us an absolute reduction of 15%, and also decreases the risk of death at 15 years from 20% to 17%, with a reduction of 3%. This originates the rule of one in four. It means that a death from breast cancer is avoided if we prevent four local recurrences. What are the factors that influence local or digital recurrence at 10 years? They are age, degree, size and state of the receptors. All this in a significant way. And so we have, for example, women over 70 years of age have an 8% risk, while minors under 40 years 4 times more, 36%. The same happens with low degree, 11% against high, 28%, size T1 against T2, and the state of positive against negative receptors. Now we are going to start explaining the concept of partiality. You know that BUS is the additional dose that radiologists give to the site of greatest tumor risk, which is typically the surgical fact. So we are going to see two studies, the EORTC and the collaborative group, one that gave BUS and the other that did not give BUS, depending on age and degree. And so we have that women under 40 years of age have a risk of 13% with BUS compared to 36% without BUS. And the same with degree. Degree 3, 8% against 28% if they were not given BUS. This is the modern concept of partiality of Veronese, that BUS after total breast radiotherapy has a lower age and higher degree benefit. And this brings us to the next question. Is it always necessary to radiate the complete breast? And the answer is not always. Since 80% of these recurrences occur in the vicinity of the surgical fact, radiation can be directed in the area of greater risk, it avoids healthy tissues, this will reduce toxicity and improve patient evolution. For example, it reduces heart mortality. We are going to see partial radiotherapy in the modern era. Here the pioneers were the Orkney Clinic and the William B. Monde Hospital in the United States. This early experience of bikini with low rate and high rate brachytherapy gave us equivalent results in patients who had similar characteristics. And there was no significant difference in the local, distal and survival failure, only in the counter-lateral breast failure, 1 against 4%, favoring the complete breast group in this case. This is the controlled information that we are going to analyze today. This is the available evidence. At the beginning of this week, I was talking to the residents of INCAN, reviewing the subject of breast cancer. This is one of the few topics where there are more guides than evidence. But well, from this experience we know that it is recent. Brachytherapy and external radiotherapy have shown that local recurrence and survival make no difference. If we select the patients well, this can be interstitial or with an applicator, and radiotherapy that has low rates of local failure and lower survival than total breast. So this is the first guide that we are going to review, the consensus of the American Society of Brachytherapy. We are only going to review four guides, the four most important ones, and the ones that explain or justify why they came to this decision. Because there are guides that, even if you don't believe it, are in other guides. So, well, let's start with this one. In the age criteria, they tell us that they must be over 45 years old, a size less than 3 centimeters, any histological type, including ductal in situ, any state of the receptors, negative margins, and more than 2 millimeters for ductal in situ, that there is no lymphovascular invasion and that it has negative gains. We start with age. Although Hungary's studies reported major recurrences of 50 years, neither HEC-ESTRO nor that of the University of Florence, which included patients over 40 years old, being under 50, 15 and 18%, respectively, without differences in recurrences. They also found no difference in ductal in situ, and PROMIS also found no difference with a 45-year-old cut, so they come to the conclusion that the guide must be 45 years or older. Regarding the size, most studies included less than 2 centimeters, however, it seems that there is no difference between 2 and 3 centimeters, since if we treat older than 3 centimeters, not only the cavity is larger, but the tissue that will be irradiated, then the partiality benefit is already lost a little. It is also not recommended if the patient received chemo or adjuvant, since there may be microscopic disease in the original volume. Regarding histology, we already have information that ductal in situ does not have a higher rate of recurrences in all these studies. Regarding C. alovular invasor, it has been underrepresented in many of them. At first it was suggested that they would recur more, but more recent studies show us that this is not the case. Others have found a local recurrence at 10 years of 7%, with no difference in survival, and considering all this, the guide of the American Society of Brachy considers that it can be offered in both circumstances, ductal in situ and alovular invasor. Regarding the state of the receptors, we already know that they are of bad prognosis if they are negative, because they will recur more. In a subgroup of PROMIS, it was found that they recurred more, up to 13%, but here the condition was added, that they were under 50 years. In interstitial brachytherapy, Anderson also saw more recurrences in triple negative and HER2-neu positive, but this is not known. If the patient is going to recur more in full breast against partial, then they end up recommending them to be positive or negative. Regarding the margins, ASTRO tells us that there should be no tumor in ink, ASTRO-ASCO that in ductal in situ must be at least 2 mm, it is not known if it is close or if it is less than 2, the recommendation is that in invasor tumor there is no ink, and in ductal at least 2 mm. Regarding the ganglion state, although there have been small subgroups in the analyzed studies, we lack information. In those patients who have been included, 72 who had positive ganglions, they did not find a difference in local recurrence, but as expected, there was a greater metastasis to distal and less survival to specific cause, so they conclude that there is no need to give positive ganglions. Among other factors is lymphovascular invasion, which is controversial. There is a relationship between degree and axillary recurrence, also between multifacility and local recurrence, but this is insufficient. Regarding the extensive intraductal component, it is a recurrence factor by the University of Wisconsin, but not by the American BRACI, and they conclude that they are not candidates if they have lymphovascular invasion or multifacility, however, the degree and the extensive ductal component are not contraindications. There are special circumstances that for radiologists are quite a challenge, such as deep tumor beds, mumps with increased volume and oncoplastic surgery. Here, brachytherapy obtains better dosimetry or better dose distribution when compared to potomy. Regarding permanent implants, which many patients have despite breast cancer, brachytherapy is better because it reduces the risk of capsular contracture against total breast radiotherapy. And if we have very thin tissues around the implant, the best brachytherapy is the interstitial, and if the tumor bed is in the breast tail, in the central part, the intracavitary is better. And now we also have contact brachytherapy. This is not invasive. The iridium 192 is fixed by a mastogram, it is on the surface of the breast, and as a boost, it has shown very good cosmesis in 97% of patients, and it is already being used as partial radiotherapy, but there are no preliminary reports. As for new fractures, the typical partial is 7 to 10 fractures for a week on alternate days, and the University of Florence is using it every third day for two weeks, one implant a day for three weeks, William Behmond with a higher dose per session, with good tolerance, but there has been a little more of a costal fracture. Overnight, this study compared three courses in 30 patients, 7 x 4, 8 x 3, 9.5 x 2, with good results, but it was interrupted due to lack of support, and now it is running the try-on for T, which evaluates 7.5 x 3. Then they conclude that accelerated partial radiation can be standard in appropriately selected patients, which are the ones we have already seen. The techniques that have the greatest evidence are interstitial brachytherapy and IMRT. As for applied brachytherapy, the recommendation is moderate, and intraoperations are not recommended outside of the protocol. So that is the summary of these guides. Multicatheter interstitial brachytherapy has more follow-up in its favor, controlled information, it is cost-effective, but it is complex, and the recommendation is strong and it is recommended inside and outside the protocol. External radiotherapy with IMRT, there is also controlled information, of good evolution, little toxicity, but it is more expensive. Even so, it is recommended inside and outside the protocol. The applied brachytherapy has its favor, which is easy to use, there is prospective information, low toxicity, but it has against the cost, and that there is no controlled information, so the recommendation becomes moderate, although it can be used inside and outside the protocol. As for external radiotherapy, it is the least expensive technology, it is not invasive, but it has higher cosmetic toxicity and fibrosis. The recommendation is also moderate and can be used inside and outside the protocol. As for protons, it is not invasive, the updated results show little toxicity, however, few patients have been treated and at the beginning it was very toxic, so the recommendation is weak and they recommend it only within the protocol. And as for intraoperative radiotherapy, it has its favor, which is a unique treatment, but they use more, up to 20% will use total breast radiotherapy, and because it is low energy, there is a question of optimal volume coverage, so the recommendation is weak and only in protocol. As for brachytherapy, the types we can use are interstitial or intracavitary, interstitial, here you see it, intracavitary, which can be with a single catheter balloon or with multiple catheters. So we are going to briefly review the history of this, these were the initial studies, and if you see the type of patients treated, up to 4 cm of tumor, with positive results, more than 40 years, even so, using a high and low rate, the recurrence was low, less than 8%, and with good cosmetics. The criteria were polished, here we have the RTOG and the Austrian German group, where they already included smaller tumors, also with positive results, more than 35 years, they already cared about the margins, the state of the receptors, with high and low rate, the dose they gave, even lower recurrences, and good cosmetics. So, from the RTOG that we saw, they obtained better results, with high rate compared to low rate, and in the Austrian German group, they identified at the age of less than 50 years, as a local recurrence predictor, 92.5 against 98. And finally, thanks to the Hungarian studies of Polgar, we have the current indications, less than 3 cm, negative ganglions, more than 40 years, negative margin, at least 2 mm, that there is no ductal component, that there is no infovascular invasion, that it is a unicentric infocal, and thus they obtain partial comparisons against total mamma, low recurrences, less than 100%, and better cosmetics, compared with total mamma radiotherapy. So, here we obtained, at 5 years, a recurrence of 3 against 4%, and at 10 years, of 5 against 5.9%. As interstitial brachytherapy is something technically complex, to apply, there is already exposure to the radiologist who is granting it, this option was created, it is the mammocyte, at first with a single catheter, an alternative to the multi-catheter, it was approved by the FDA in 2002, a deflated balloon is placed in a second surgical time, here we see a current failure at 5 years, of 3.8%. However, it had fat necrosis and costal fracture, in the studies it carried out. Another alternative was the multi-catheter, approved by the FDA in 2006, here we have, using contour, a survival free of recurrence at 3 years, of 97%, very good, however, we see that they had high percentages of infection and seroma, this was related to the volume that was handled in this institution, and doing it in large volume centers, the survival improved and the infection decreased. Despite all this, the results are still better with interstitial brachytherapy. And this is how it is applied, the deflated balloon is applied, then it is expanded, radiotherapy is given, typically 2 times a day up to 5 days, and finally it is removed. This has already evolved, unique doses have been tested with good results and little toxicity, they have been altered both in time and in dose, and these short or unique courses are feasible, they have little toxicity, good cosmesis or excellent, but more monitoring is required. We also have new radisotopes, everything I have told you so far has been with Iridium-192 or Iodine-225, but there is already a new available source, it is Radio-224, which is an alpha diffuse emitter, so it has very little penetration, and it will also surely be used in very select cases. So, what do they conclude? That based on these controlled studies, there is no inferiority, neither of interstitial brachytherapy, nor of MRT. They have the same results, intraoperative radiotherapy, they have not shown an inferiority, conformed radiotherapy, it has a little more toxicity, so they support the use of multi-catheter interstitial brachytherapy, I do not know if it is because of the American society of brachy, but it is the one they want to use. The other options are external radiotherapy, which can be conformed with MRT, and here we basically see how the volume is restricted to the area of greatest risk. Here we have two examples, so instead of treating all the breast, it is only treated with high doses, the area of greatest risk, and this decreases the dose to the healthy tissues, as we can see. The next guide is that of EDEGRO, which to do it, it was only based on controlled studies with more than 15,000 patients. And here we see the same studies that we already mentioned at the beginning, the 7 plus 2, because we already included the intraoperative. So, we are going to analyze external radiotherapy, brachytherapy, and intraoperative radiotherapy. In all of them, there was no difference in local recurrence, except in intraoperative radiotherapy, both with electrons and with 50kb, no difference in survival, and also with a short follow-up in intraoperative cases, and long in the case of brachytherapy. This is the first study, the UK Import Law. So, this is phase 3 controlled with a 6-year control, which used EMRT radiotherapy field by field, with a local failure at 5 years, of 1.1, 0.2 and 0.5. So, the non-inferiority of partial radiotherapy is confirmed. Here we see how patients were distributed, and here we have when it was total mamma, reduced dose mamma with integrated bus, and partial mamma. So, basically, there is no difference in recurrence. The next study is RAPID. They have a very good follow-up of 8.6 years, in patients over 40 years, treating invasor or in situ cancer, less than 3 cm, which used conformed radiotherapy, and the local recurrence was 2.3 against 1.7 at 5 years, and 3 against 2.8 at 8 years. So, here we have the distribution of patients, and the same, this is survival, and this is recurrence. Here we have at 5 years, and here we have at 8 years. So, we see how there is no difference. The next study is NCBP. This is very interesting because it is phase 3. It has more than 4,000 patients. Here it compared conventional radiotherapy against basically all partial schemes. It used interstitial brachy, it used mammocyte, and it also used conformed radiotherapy. And the interesting thing is the same, speaking of recurrences, the partial radiotherapy, all together, 4.6 against 3.9 to total mamma, without differences in free survival of distal recurrence and global survival. Here we have the distribution of patients. Here we see that there is no difference between total breastfeeding and brachytherapy. And in the Forest Plot, we can see how the benefit is not clear in favor of either of the two arms. And here we have it graphically, neither in the free period of recurrence, nor in the free survival of disease, nor in global survival. The next study is the GEC-ESTRO, with more than 1,000 patients, against interstitial brachytherapy, with these criteria. And at 5 years, the local control was 1.4% in partial against 0.9% in total breastfeeding. Here we have the distribution of patients and the local recurrence curve without difference, the free survival of disease and global survival without difference. With regard to intraoperative radiotherapy, this can be done with electrons. Here we see the equipment in which it can be administered, or with intravim, using a low energy of 50 kb. This is the first study, the ELIOT, which was from 2000 to 2007, with more than 1,300 patients. It compared total breastfeeding against partial, using electrons, more than 600 patients in each arm. In a follow-up of 12 years, we see that 86 recurred, of which 70 were 11% in partial and 16 or 2%, which gave us an absolute excess of recurrence in the partial arm. In survival, there was no difference. Here we see some images of when it is being administered. This is also a bit technically complex. Here we have the distribution of patients. Here we see the significant difference between ELIOT, or those who received intraoperative electrons, and total breastfeeding radiotherapy, although there was no difference in survival. And here, unlike the previous one, in the FOREST PLOT, we see how this favors total breastfeeding. Analyzing, then, is what we already mentioned, greater lateral recurrence of 4% in partial electrons, against 0.4% in total breastfeeding. But the important findings is that a high-risk population was found, which were tumors larger than 2 cm, which had more than 4 ganglions. Grade 3, negative receptors. If there was a factor, a probability of 11.5% of recurrence, against 1.5% without any. This is similar to experiences in other centers, that if they use the strict criteria of the ASTRO, we see a recurrence similar to the other techniques, 1.5% of ASTRO 1.9 and 1.77. So what does it tell us? That there may be certain subgroups of patients, that if we are more strict, they could still benefit, and that they have to be very selective. This is the controversial TARGET, and I tell you that it is controversial because we are going to see. It is multicentric, including patients from 10 countries, with more than 2,000 patients, over 45 years of age, and also in smaller vessels of 3.5 cm, treated with conservative surgery. And here we start with the problems. It compared, according to adapted risk, intraoperative radiotherapy against external radiotherapy. Intraoperative was at the time of surgery, which was the only treatment in 80%, and if there were high-risk factors, they were sent to external radiotherapy. And here we have the results. This is very important. They defined as non-inferiority a margin of 2.5%. So in this period of time, more than 1,000 patients in each arm, with a local recurrence at 5 years, of 2.11% against 0.95%. So, as you can see, it is much higher in the intraoperative group than in external radiotherapy, but since the difference was 1.16, it is within what they described. In an update almost 9 years ago, they continued to report the same, that there was no difference in recurrence or survival, and they conclude that it is something effective and that it should be used. Here we have the spheres. These spheres are according to the size of the cavity. So the best candidate patients obviously have to use small spheres. Here we have the intravenous equipment, how the application is placed and when it is removed. Here we have the distribution of patients. And sorry for the size of all these graphs, but basically their only difference was the mortality, not associated with breast cancer, where they found greater mortality in the total breast arm, and this is the mortality in general. So, within the complexity of their study, there were pre- and post-pathological reports. The inferiority was only in the pre-pathological arm. Here we have a local recurrence at 5 years of 2 against 1%, and post-pathology, see how it increases, 5.4 against 1% to compensate for the first reports they made short, they made two cuts at 44 and 60 months to detect this absolute difference, and here they were also influenced by the state of the receptors. So the criticisms have been of all kinds, they made their first reports in very immature states, since it is expected that patients who have positive receptors are going to have breast recurrences. Their non-inferiority design was based on a local recurrence estimate at 6% at 5 years, and this 6% is very high, because we already saw what the expected recurrence is in the other studies. So, since they were based on this, then their 2.5 was not appropriate. And in their design it is 5 the same, they used binomial proportions instead of Kaplan-Meyer, but they did use Kaplan-Meyer for a recurrence estimate. And also the risk-adapted approach, which was up to 15% center discretion. So, for all this, many guides and IDEGRO coincide that it does not have to be used routinely, only within clinical trial, since it will explain to the patient, and if they can use it, patients over 70 years old, tumors less than 2 centimeters, margins greater than 2 millimeters, low degree, positive receptors, GERDOS of a negative, without infovascular invasion, or intraductal component. So, what is recommended? That the PBI be ideally within the first 6 to 10 weeks after surgery, or the first 4 weeks after chemo, and the same as level 1 of evidence for non-inferiority, only in external radiotherapy and BRAC. The criteria, what are the ones that are accepted, if they comply with everything, what are the contraindications, how to do the intraoperative, the basic rules of volume, the prescription of doses for external radiotherapy and BRAC therapy. And well, the third guide that we are going to review is that of ASTRO. They divide the groups by appropriate patients, with precaution or not candidates. In the first ones, that are women over 50 years old, negative margins, small tumors, the ductal incisor less than 2 centimeters or low risk, as precaution, if it is 40 to 49, but it has to comply with everything above, or more than 50 years, if there is a slightly larger tumor, close margin, lymphovascular invasion, limited focal, negative receptors, lobular or ductal a little larger, with risk factors, and definitely not candidates, younger, with risk factors, positive margin, or a ductal greater than 3 centimeters. The last one, that of the NSCN, tells us that after a conservative treatment, if the patient has negative ganglions, it can be treated with radiotherapy, either total breastfeeding, or depending on the positive or negative ganglions, partial, in selected cases, and that it could be omitted in those patients over 70 years old, with positive receptors, T1N0, who are going to receive hormone therapy. So, what are the criteria? The NSCN says that it accepts those of ASTRO, but it modifies them. It tells us that patients over 50 years old, if they have a ductal less than 2 centimeters, more than 2 millimeters margin, lymphobascular inundation, positive receptors, and negative BRCA. Also, low or intermediate risk ductal, less than 2.5 centimeters, with a margin of more than 3 millimeters, and it can be done with radiotherapy, with MRT, with interstitial glaucoma, or conformed radiotherapy. So, what to do with all that information we saw? What is the best technique for our patient? After conservative surgery, adjuvant radiotherapy, although we see that it is not necessary, in patients over 70 years old, with positive receptors, T1N0, who are going to receive hormone, if they have positive ganglions, amamatotal plus ganglionary regional, if they have negatives, it can be hypofractionated or partial, and the partial can be with external brachioradiotherapy, and if it is brachiotherapy, the best is interstitial, and if it is external, the same, the best is with MRT. So, this is the summary of the guides, where basically all agree that they are 50-year-old women, except for the American brachiotherapy, the size, all less than 3 centimeters, except for NCCN, which tells us that if it is invasive, less than 2 centimeters, and if it is ductile, less than 2.5 centimeters. Regarding histology, everyone accepts all, except for the Royal College of Radiology, which tells us that they should not be lobular and neither the estrus. Regarding ganglions, here they agree that all negative, of the estrogen receptors, the only one that accepts all is the American Society of Brachiotherapy, IDEGRO tells us that it is not triple negative, or HER2-neu positive, regarding the margins, all negative, at least 2 millimeters, depending on whether it is invasive or lobular, up to 5 millimeters, and the preferred modality, external radiotherapy or brachiotherapy, either with MRT or with interstitial or oval brachiotherapy. So, to the questions that we asked ourselves at the beginning, of accelerated partial radiotherapy, to whom, when and where, women with early breast cancer, after conservative surgery, that meet the criteria that we have already seen, that these are adapted to their country, according to the continent, that STEMI, the institutional protocol, and something very important, according to the modality available, that there is not in all our countries. So, the best brachiotherapy is interstitial, followed by multicatheter intracavitary, and the best external radiotherapy is MRT, but if there is not, it is with 3D radiotherapy. It has to be discussed with the patient within the therapeutic options, it has to be stipulated in the informed consent, the management expectations and the associated morbidity, and if it is intraoperative, it must be within the institutional protocol. More study follow-up is required and more recruitment within clinical trials, which must be promoted. So, if we want to treat with accelerated partial, we have to be very wise, like the old Yoda, not the baby Yoda, and choose well. That's all, and I thank you for your attention. So, we are already over time, basically we are out of time, so it is also a pleasure for me to introduce the next speaker, who is Dr. Gustavo Ferraris. Dr. Gustavo Ferraris is very well known by all of us, not only in Argentina, but in Latin America and in many places. He is the medical director of the Radio Oncology Service of the Infones Center of Radiotherapy in Cordoba, Argentina. Dr. Ferraris will talk to us today about adjuvant radiotherapy after adjuvancy and surgery. In locally advanced breast cancer. We already know that in an ideal situation all cases would be early, but unfortunately in all of our Latin American countries this does not happen. Advanced cases continue to arrive that benefit from chemo, and Dr. Gustavo will clarify all our doubts about it. Go ahead, Dr. Ferraris. Thank you. Thank you very much. I will share the screen. Does it look good? Perfect. Thank you. Well, before I start, I would like to thank this invitation to the Mexican College of Oncologists and, well, mainly Dr. José Hinojosa, whom I met a couple of years ago. So, well, we will try to give some tips about this disease that is increasingly being seen more and more precisely due to the rise of neoadjuvant therapy. Well, what is important here? When one talks about neoadjuvant chemotherapy, and later the indication of radiotherapy, two frames arise, which are, let's say, conceptual, which are competitive. Because, on the one hand, we have to evaluate what is the intensity and reach of our regional radiotherapy and whether it should only correspond to the initial clinical state of these patients who are derived. And, on the other hand, it is important to determine this indication if it should be mainly determined by the post-neoadjuvant state and, accordingly, the intensity of the subsequent treatment. The big drawback that we find to date is that there is no prospective study in this scenario that is evaluating post-mastectomy radiotherapy. Why does this happen? We will see later that some are being developed. So, what has been done is to see what happened with the patients who were irradiated post-mastectomy, as we will see next. Well, as we know, the meta-analysis of Oxford in 2014 did not give any idea. There were practically 1,100 patients where they evaluated that radiotherapy reduced the possibility of regional relapse from 21% to practically 5% in patients who did radiotherapy, which was highly effective and mainly reduced local and remote relapse. The issue is that all these studies are from the 70s and 80s with systemic agents that, as we know today, are no longer practically used. For example, there were no taxanos, there was no ectanide hormone therapy, there was no anti-GERDOS therapy. But they determined that the utility was mainly for positive asylum, more than 4 positive adenopathies, and it arises from 1 to 3 positive cancers. And that does prevent patients with negative asylum. There are also other publications, systematic revisions, where post-mastectomy radiotherapy in patients with negative asylum but with tumors of more than 5 cm we need to associate some factors, two or more, as we already know, age, if there is lymphovascular invasion, histological degree. And on the other hand, as we know, studies of some patients who have undergone mastectomy, such as the study of Dr. Pormans and the MA20 study of Dr. Wieland, also with negative asylum, showed that there was an important increase in the free period of disease and with a tendency to survival. So, well, this is a graph that I will use in different scenarios, mainly looking at the issue of relapse. Ideally, it should be less than 10%. Why? Because, according to the meta-analysis of Oxford, it is precisely the patients who benefit from survival from the age of 15. That is why this cut is made, precisely to determine which patients will have the probability of increasing their survival. Well, this is a small summary. We know not to carry out radiotherapy in the very early stages and later those patients with locally advanced disease, either at the level of the wall, such as axillary, their risk increases exponentially. Well, let's go with the retrospective work. There are several. One of the most important institutions, a cooperative group, was the study of NCAVP BB18B24. This study was elaborated by Dr. Mamounas. But what happens? 78% were early stages and they showed a local decline of 90%. What is important? None of these post-neoadjuvance studies indicated post-mastectomy radiotherapy. So, it was a study that allowed us to evaluate mainly which patients with a greater possibility of relapse so that they had indications. The B18 used ACE anticyclines and the B27 incorporated taxanos. What is important here? What they evaluated was, within their multivariate study, they already began to determine some predictors of local relapse. Mainly young patients, less than 40 years old, and then they evaluated what the response to this induction was. Mainly, to know the tumor size, the previous size, that is, tumors larger or smaller than 5 centimeters, and how that axilla was before neoadjuvant therapy. And then they evaluated how these patients responded to this systemic therapy. So, there were two scenarios. Those with residual disease, with pathological negative axilla, and on the other hand, what they evaluated was what happened to these patients with a complete axillary response, but with a pathological response in breast. So, we will see later how this influenced the results of local relapse. And other series, mainly of M.D. Anderson, who have really shown most of the series, but contrary to the NCBP studies, most of these patients, practically between 68 and 75%, were stage 3. So, what determined this series? Look at this study of patients with disease, stage 1 and 2, with a complete pathological response. Radiotherapy has no benefits in these patients. On the contrary, patients, regardless of their complete pathological response, but were stage 3 or 4 at the beginning, there is a significant tendency that they should receive post-mastectomy radiotherapy and practically with a significant P and with a CASA ratio of practically 1.12. Well, and later, Juan evaluated the predictive factors of local relapse at 10 years old. As we can see, they reported that it was a compromise of skin or areola, if there was supraclavicular disease, negative hormonal receptors, patients who have not used tamoxifen, and those with ganglion extracapsular infiltration. Well, what happens? In the modern era, we have to determine if this local relapse is impacted mainly by response and by the rise of biological subtypes, as they said at the beginning. Well, look at this study, which is the ACOSOC Z1071 study, which was a study where there were patients with positive axillary disease, where chemoneoxubant was done, and they wanted to mainly evaluate the possibility of false negatives after an evaluation with ganglion. So, well, these patients obviously received radiotherapy, all patients who received conservative radiotherapy, and those who had radiotherapy or mastectomy were at the discretion of the doctor. And here you start to see some data. Patients with residual disease, by this scheme known to you, which is called residual cancer burden, those with the higher possibility of relapsing of these patients. This was written in the Red Magazine by Dr. Hafty in 2016, but later he did another analysis to see some other factors. As I already mentioned, the indication of what radiotherapy is was at the discretion of the doctor. It was seen that when one irradiates these patients, the local relapse decreases. However, despite decreasing the local relapse, it had no impact on total survival, nor on the free period of disease, nor on specific cancer survival. Look at another data, that there was a lower local relapse in patients with residual axillary disease. There were no differences in patients with pathological response in the axilla, and here he begins to mention one of the first biological factors that is associated with relapse, and it is the triple N. Look here on the right, patients with triple N really decrease the local percentages, precisely because they relapse a lot. Unlike patients with hormonal disease and patients with HER2. Well, another study, also by Dr. Suiza, which is also by Ellen Anderson. These patients are in the Trastuzuma era, but what he wants to show is that these patients who did chemotherapy, neoadjuvant therapy, and later conservative surgery, in their multivariate analysis, they determine that triple N patients, patients with clinical disease at stage 3, and those who do not reach the complete pathological response, have a significant impact with an increase in local recurrence. When we add factors, notice how important it is. The more factors I add, the more likely it is to have a greater local recurrence of the disease. Let's go to clinical stage 3 of the NCABP study, as we saw, there were few patients. What is important here? Patients with clinical disease at the beginning, more than 5 centimeters, positive axilla, who later have negative axillary disease, but that can remain residual disease. Remember that they are patients that none of them got irradiated, they have a 10% local recurrence. On the contrary, the patients, the same stage, clinical disease T3N1, that the patients respond or not, partially in mammary tissue, but they are still positive with their axilla, that is, they did not have a complete response, the risk of disease is duplicated to 20% local recurrence. This study of MD Anderson, also when his group of these patients was studied, stage 3, when they were irradiated, the impact was significant among patients who received radiotherapy versus those who did not receive it. And this is a little to diagram it. So, the patients, as we saw earlier, with locally advanced disease, those who have pathological axillary response, have a risk of practically between 10 and 12%, so they should receive radiotherapy. And those, notice, while we add some biological factors, patients who remain with ganglion disease, but have positive hormonal receptors, have a better prognosis than those with terminal disease and with unfavorable histology. We are now going to study the early stages, which were the majority of those included in the study of MD Anderson. Look, patients who were early stages, who did neoadjuvancy and remained with negative axilla and with or without residual disease, look, at 10 years they have practically 6% local recurrence. And those patients with positive axillary disease, with a complete response or not, in MAMA the percentage is 10%. Remember, none received radiotherapy. This is a bit like, if I can diagram it, patients with residual disease, those who have a complete response, less than 10%, those patients who remain with residual disease, with neoadjuvancy, with positive receptors, have a percentage of 10%, on the contrary, those with patients who remain with that ganglion, sentinel, or with that emptying, after doing neoadjuvancy, and have unfavorable factors, such as negative estrogenic receptors, or that are GERDOS triple N, notice how it increases the incidence of an increased risk of local relapse. And look at the other scenario, those are patients with disease, a little more than the initial stages, patients with positive axilla, who do neoadjuvancy, those who reach a complete response, local risk of residual disease, less than 10%, and we are scaling according to the issue of hormonal receptors, or unfavorable biological profiles, such as negative receptors, triple N, and positive GERDOS. Well, how important, the previous one, this is the one that generates the greatest controversy today, because they are the stages 2, the study B51, which is in progress, they say that practically all patients are recruited, is the one that will give us information on these patients, with disease T1, T3, N1, who do neoadjuvancy, and they are patients who later reach a complete ganglion response. Two branches, one branch is going to be mastectomy, and later what is going to happen, certain patients receive post-mastectomy radiotherapy with or without ganglions, and other patients will not undergo any radiant treatment. Obviously, patients with conservative surgery, one branch will be radiotherapy only in the mammary, and the other branch will incorporate ganglion areas. So, the main objective is the free interval of recurrence, but it mainly tests what will be the benefit of irradiating the ganglion areas. The big drawback of all the detractors of this study is, although they are patients who can have a complete ganglion response, it is not specified what happens if these patients do not have a complete response, or a partial response at the level of the mammary. That seems to me to be a big drawback of this study. And on the other hand, in patients with the same situation, T1, T3, N1, who undergo neoadjuvant chemotherapy, but still have a positive sentinel ganglion. So, this study divides two branches. One is going to be a complete axillary dissection, and later radiotherapy on the mammary or on the costal wall with ganglion areas. And the other branch is simply going to irradiate the ganglion areas, avoiding the issue of axillary surgery, as already demonstrated by studies like the AMAROS study. So, the objective is similar to the other, which is the free interval of local invasive recurrence, and what it is, as I mentioned, it tests the benefit of ganglion dissection. Well, there are studies in progress. As you know, most of us do conventional fractures. Today, many post-neoadjuvant patients leave the operating room with a sponsor or a definitive prosthesis. And, as has already been mentioned here, the rise of hypofractionation. So, well, I leave that to the next speaker, Dr. Loria, who will surely talk about this topic, about what is oncoplastic radiotherapy, and everything that comes with hypofractionation. So, I'm not going to get into that topic. And, well, in 2018, Dr. Buchholz, in San Antonio, for me, he has left us some concepts until these studies come to light. Mainly, and what I suggest is that this is something that we can leave in our office so that it is a little easier for us, although not always, to discriminate which patient to receive. Well, one is this, patients with favorable clinical status, but with unfavorable biology. Look, patients with initial disease, patients with triple N, negative axilla, and another situation, patients with negative receptors, but with HER2. Well, chemo, neoadjuvant, they can do conservative surgery, mastectomy, and sentinella. And look, if the results are from these patients, that we get a negative axilla, these are patients who do not have to receive ganglion radiotherapy. On the other hand, if we have one or more sentinella ganglions, what they suggest is that these patients participate in the Alliance study, and if not, what they should do is a mammary volume radiotherapy, if they have conservative surgery, coastal wall radiotherapy, and irradiate all the axillary levels, the pit and the internal mammary chain, as I mentioned by the evidence of the principle. Then we have clinical status 2 with unfavorable biology. Look, patients with T1B, T2, N1, that is, the previous one was N0, this is N1, triple N, or those, as I mentioned before, negative receptor, but positive, the same scenario, neoadjuvant, conservative surgery, mastectomy, sentinella, then what they suggest. If the axilla is negative after this, enroll them in the B51 study, B51 because they are patients with positive axilla. If not, consider factors that we talked about, young age, high histological degree, lymphovascular infiltration, triple N, and those with tumor, residual, post neoadjuvant, greater than 2 centimeters. If everything is favorable, if we don't have any of this, we can avoid radiotherapy. And on the other hand, those who remain with axillary disease, with an adenopathy or more, well, these patients should be enrolled in the Alliance study, which I already mentioned, and in the case that is not, quite similar to the previous one, radiotherapy in mammary volume, in the coastal wall, and also include ganglion regions. Stage 3 is the simplest, because as we have already seen, all these patients with locally advanced disease are those who already have evidence that they really have benefits. Look, clinical stage 3, T3N positive or T4, or already with fixed or superclavicular adenopathy, is the same scenario, chemotherapy, neoadjuvant, surgery, dissection. So, well, in these patients, regardless of whether the answer leaves us with a negative or positive axillary, our conduct should be to irradiate the mammary volume with conservative surgery, radiotherapy on the wall, and comprehensive irradiation of all adjacent ganglion areas. And in ASTRO, from last year, they presented this study to me, which is really important to me, because they put together all the studies, the NSAVP, which I already mentioned, 18, 27, and two others that already incorporate more aggressive chemotherapy, anti-HER2, but in these two, 40, 41, they already allow to incorporate radiotherapy at the discretion of the treating doctor. Well, then, the patients who achieved the complete pathological response in the ganglion, we have two scenarios, those who have no disease at all, and those patients who have residual disease. This is important, which I already mentioned, this is not going to be contemplated in B51. So, the question is, if the patients who get a pathological response in the ganglion, but not in the breast, what happens? What are the results of these patients? So, the conclusion, not to make it so intense, remember, these patients did not receive radiotherapy, they did not have anti-HER2 therapy, and these patients, look, they have a worse survival, despite having a ganglion with a complete pathological response, and these patients had an increase in what was early local relapse. B40 and B41, as I mentioned, incorporate HER2 and optional radiotherapy, and these patients saw something similar, they had a longer free period of local relapse, precisely because of the use of more modern drugs, however, they had a worse survival and a possibility of increased metastasis at a distance. So, what I want to emphasize is that, despite the fact that the patients get a negative ganglion, it is important to irradiate them, to contemplate this, mainly because they are at high risk of relapse. So, as a conclusion, and to finish, number one, it is a paradigm of individualization. They are patients that must be discussed in a multidisciplinary way, and radiotherapists have to be part of that. So, precisely to evaluate which patient really has the benefit of being irradiated. There are these two studies that I mentioned, B51, the Palladians study, and finally, it is important to use appropriate techniques to irradiate both the breast and ganglion areas in this patient. And I say goodbye with this photo. We are in the middle of winter, and these are our Patagonian penguins, so I don't know if you know them, if you want to show them. Well, thank you very much for your attention. Thank you very much, Dr. Ferraris. Without a doubt, a very interesting and controversial topic, because here doing is bad and not doing is worse, I think. So, we thank you for your brilliant participation, and we are going to have a brief five-minute break, please, and then we will return with the last topic of radiotherapy. Thank you all. Hello, everyone. Hello, everyone. Thank you for staying with us. So, let's start with the last and very interesting presentation of today, closing the block of radiotherapy. This is the topic of radiotherapy and oncoplastic surgery by Dr. Rolando Loria. The doctor is Costa Rican, very well known in his country and abroad, and he has specialized in breast surgery. So, who better than him to address this topic of such relevance and relevance, which is oncoplastic surgery, and what role do we radiologists have in this? Thank you very much, Dr. Rolando, for joining us today. Well, thank you very much. Thank you very much for the invitation. I had the chance to speak in 20 minutes about radiotherapy oncology and oncoplastic surgery. This is a presentation that I have tried to focus more on the gynecologist, who will be more present in this audience, and I would also like to clarify that in 20 minutes it is very difficult for me to go into literature, which luckily has been extensively deepened prior to this talk. Well, as an introduction, these are my conflicts of interest. And, well, in terms of oncology, in terms of oncoplastic surgery, what is its purpose? What are its risk factors? And what is the timing after an oncoplastic surgery to start radiotherapy? Well, in terms of the goals of oncoplastic surgery, there is the local control of the disease, and it is basically based on reconstructing immediately or deferred, with good cosmetic results, without altering the oncological results. There are some contraindications for oncoplastic surgery that are shared with breast conservation surgery, such as inflammatory carcinomas, T4 lesions, multicentrality, and extensive microcalcifications. There are almost 40 oncoplastic surgery techniques described, but the most frequent ones that are carried out, at least here in San Jose de Costa Rica, and in some Latin American countries, are the glandular hangings, the hangings of the vicinity, such as the thoracoluminal fasciocutaneous, the hangings at a distance, such as the wide dorsal and the tran, which are very frequent, which were carried out here with a certain regularity prior to the pandemic. This has decreased. And well, in terms of safety, it is already widely known that early stages treated with conservative surgery, followed by external radiotherapy, give the same oncological results. We know this from several publications, at the beginning of the 2000s, which followed publications from the late 80s, especially those of Veronese and Fischer, where we can see that the surgical approach of conservative surgery plus external radiotherapy, which came to reduce the risk of local recurrence of 10 to 30%, is equivalent to mastectomy in early stages. Well, it has already been mentioned what are the risk factors of local recurrence in this conference, in this seminar today. And here I leave you just a literature where it compares the oncological results of conservative surgery versus oncoplastic surgery, where it is actually equivalent. So where there is indication of conservative breast surgery, there is indication of oncoplastic surgery. And also remember that perhaps one of the greatest risk factors of local recurrence in conservative surgery and oncoplastic surgery is the margin. Well, here is a summary of the main risk factors, but it is imperative that the margin is negative. It has also been said, and this was very widely explained in the morning hours, that there are molecular factors that can also influence recurrence. of this disease. Well, what happens in these times of COVID? And in Latin America, where sometimes the resources of the lineal accelerator equipment are not sufficient in some regions, and we want to do conservative surgery or oncoplastic surgery. What should the surgeon know? Well, the surgeon should know that radiotherapy, the ideal is to start between the sixth and eighth week after surgery. That is the ideal. After the eighth week, there are studies that have shown that it could increase the risk of recurrence by 1 to 1.3%. There is a lot of literature that indicates that it is acceptable to start external radiotherapy 12 weeks after that surgery. And there is even literature that has shown in series of less impact that up to 20 weeks has been the maximum time after a conservative surgery to start radiotherapy. These three timings are in the absence of assistance with systemic therapy. But what happens if that patient is finishing systemic therapy? Well, the ideal is to start radiotherapy between the fourth and sixth week. And this is important because depending on the region in Latin America where we are, we have to be aware of the waiting times, the starting opportunity of treatment of our users. There are also timings for conservative surgery in terms of those patients who require a risk reduction mastectomy or a mastectomy for merely cosmetic situations requested by the patient. In terms of when we can start radiotherapy treatments after a reconstructive surgery or an oncoplastic surgery. We even have timings also in terms of the use of expansors. When the surgeon has the opportunity to carry out an expansion and when they have to stop it so that we can apply the radiotherapy treatments. Basically, if we have the use of expansors in mastectomy, these expansors can gradually be filled during the adjuvant therapy with chemotherapy. And once the treatment is over, we could place the permanent implant four weeks later and four weeks later apply the radiotherapy. The next question would be, short or long-term radiotherapy? That is what we currently have together. And those who receive new adjuvant chemotherapy and then undergo mastectomy, the expansor must be manipulated by the surgeon or it can be manipulated by the surgeon during the first six weeks before starting the radiotherapy. And once that person receives the radiotherapy, they will ideally have a period of more than six months to place that permanent implant. Well, that's in terms of timing. Now, in the continuous practice between surgeons and radiotherapy oncologists, we have certain problems that I would like to remember. Perhaps one of the main problems we have is that LIM, in its JAMA publication in February of this year, indicates that it is a bad indication of risk-reducing mastectomy, those situations in which, without justification, by genetic advice, a bilateral mastectomy is performed. Well, that's a problem for us in radiotherapy oncology. Basically, if we want to pursue the cosmesis of oncoplastic surgery. And the problem lies in how we apply the radiation acids. We are going to place the patient in a supine position. We make a turn of the accelerator head, which is our gantry, so that the radiation acid passes tangentially and the heart and lung volume affected by this radiation acid is minimal. That's how things are. When a surgeon places an expander or an implant, what it does is prevent the natural fall of the disease. Here in the figure, with the letter A that you have on your left, you can see the natural fall of a breast. And how this fall is discreetly abolished when we have an implant or an expander. In this situation, in panel A, we don't have much of a problem. The problem is when bilateral reconstructions occur, because these natural falls of the breasts in women with supine position cause the radiation acid to involve the contralateral breast. And this goes against the cosmesis, which initially not only pursues the patient, but should also protect the surgeon. So it's something that, before the surgical procedure, I would recommend discussing with the radiotherapy oncologist to determine whether bilateral mastectomy is the most appropriate thing for the patient in absence of indication by the genetic counsel. And well, here we can see, reinforced in this line, where the radiation acid that comprises this contralateral breast is going to be sent. And you can tell me, well, but a solution to this could be to change the rotation of the gantry so that this lower edge of the breast does not contemplate the volume of the contralateral breast. Something like that. Well, it is a probable solution to avoid irradiating the contralateral breast. But this generates a problem of greater importance, which is the lung volume and the heart volume that we would be compromising if we made those changes. Therefore, in the risk-benefit balance, being this a cosmetic situation versus subjecting cardiovascular risks to the patient or risk of heart attack, we would generally apply the treatment as stipulated with the commitment to the contralateral breast. What other problems should the surgeon who may face his intention to maintain cosmesis in these patients? Well, radiodermatitis, which is going to be due to many variables. One may be inherently the genetic predisposition of women, as Dr. Garrido explained. These lesions have associations of genetic alterations with PTEN, P53, and ATM, which in the last instance are the proteins that are going to repair the damage of radiation. So, in the presence of certain known alterations, that also predisposes to complications in the repair of the damage, and therefore greater risk of having radiodermatitis or even radiation-induced tumors. The doses. Well, every time we use more hypofractic schemes, we are convinced that short schemes seem to be much less toxic than the conventional 50-gray scheme in 25 sessions. And that is something that empirically we are seeing in our daily practices here in San Jose, Costa Rica. And obviously, there are also factors that affect the team. How can the doses be conformed if we have linear accelerators or we are still in Latin American regions with cobalt equipment, where the risk of radiodermatitis, subcutaneous cirrhosis, appearance of telangiectasias is at greater risk. That is why with this intention of reducing radiodermatitis and also optimizing the time cycles in our teams, here in San Jose, we see with great pleasure the use of ultra-hypofractic schemes. What other complication can we have in patients? Well, the contracture of the mammary implant. Just by placing the mammary implant without receiving radiotherapy, that woman has a 15% risk of contracting the implant when the reconstruction is done with an implant. Initially, as it was exposed in the morning, there was a tendency to long radiotherapy schemes versus hypofractionals with the intention of reducing this risk of recurrence or commitment of the implant. It seems that when we apply treatments with external radiotherapy at 50 grays, the risk of the implant contracture could rise from 15% to 50%. However, recent literature published in the previous year with moderate hypofractional schemes, that is, with 15 sessions, seems to show that the risk is equivalent to conventional schemes. Therefore, we, who for many years here in San Jose have used the 25-session scheme with the intention of reducing the risk of implant contracture, in a couple of months, we have migrated to the use of moderate hypofractional of 15 sessions in women with implants. I also have to warn that there are certain risk factors that a mammary implant contracture and they are due to constitutional factors of the patient, surgical factors and those of the implant. Smoking patients will have a higher risk that this implant contracture. And also those who come from systemic therapy schemes. And the surgeon must warn that, indeed, with radiotherapy, the risk of contracture could increase. Also, the risk of implant contracture can increase due to late, acute or subclinical infections. As for the surgical parameters, well, if the surgical approach was made periodic, it predisposes to having more risk of implant contracture. The placement of the prosthesis in the glandular plane is a risk factor of contracture. Immediate complications of the intervention, such as skin necrosis, hematomas or seromas, could increase the risk of implant contracture. And also factors inherent to the implant that the surgeon is using or that the surgeon chooses to use, such as smooth prostheses or serum prostheses. The risks of the final cosmetic result that is perceived between both parties, the doctor and the patient, can be seen as damaged or compromised. What other problems do we have between oncoplastic surgeons and radiotherapy oncologists? Well, when certain factors inherent to the injury require that we apply a treatment bus in the tumor bed. This is a national consensus that we have made with radiotherapy oncologists here in San Jose, Costa Rica, on the indications of when a woman should receive a reinforcement after a breast treatment or during a breast treatment, because we have been using integrated bus schemes for these cases. And we have divided this into high indication criteria, which we have called major criteria and minor criteria, where we are going to give a bus to every woman under 50 years of age, when there are compromised margins or with carcinomas without sites less than two centimeters. And if there is an accumulation of more than two minor criteria, then we also apply the bus. Well, what is the daily problem of the bus? Well, that the oncoplastic surgeon, when performing an oncoplastic surgery, does not mark the surgical bed. And the other problem is when hangings are already made, such as TRAMP or FLAP, because then that bed is no longer where it should be. And in the absence of surgical markings, it compromises us a lot where to apply the treatment. I have to go before... Here we have an example of a patient of ours who does not mark the surgical bed. Please close the microphones. I don't know if... Please mute the microphones. It is difficult for us to locate in this situation, so the radiotherapy oncologist must return to the previous image studies to locate, based on mammography and ultrasound, where that tumoral bed was to be able to apply this bus. This is an example of a patient of ours treated in prone position by volumen 1 Mario. And here, in this particular case, we are using Fast Forward, 26 grays, followed by 5... I mean, followed by 10 grays, and to be used for two weeks only. And with these techniques, we can see that the risk to the organs is quite low. And for us, who have a limitation of equipment, it generates an impressive utility for the optimization of the use of our treatment machines. Well, these are just to name a few problems. But we could also mention some solutions that the oncoplastic surgeon could have in mind. One of the possible solutions to avoid spoiling the cosmetic results of his surgery could be to completely omit radiotherapy, which is already widely described in this course, such as the accelerated partial irradiation of the breast, or, eventually, only partial irradiation of the breast, and some co-adjuvants, which perhaps are not mentioned much in most of the conferences that we are going to talk about. As for the criteria for omitting radiotherapy, we have two major studies, CALP-9343 and PRINE-2. And here we can see that in the populations that they study, which are women over 70, 65 years old, who have early stages of breast cancer, luminal A, well, the risk of recurrence is quite low, so the guides of the NCCN, in their latest updates, recommend that those women with conservative surgery, with more than 70 years, and who have negative glands, could omit radiotherapy if their estrogen receptors are also negative. Well, another situation may be that at an early stage, you, as a surgeon, do not do conservative surgery, but proceed with a mastectomy, and that this mastectomy, which are stages T1, T2, with negative initial glands, does not need to be irradiated. However, there is literature that documents that there could be risks of local recurrence if the woman is less than 50 years old, in the stress histological degree, there is present vascular-lymphatic invasion and negative STRIP. There is still no Phase III evidence that tells us if only one of these criteria is enough to apply adjuvant radiotherapy to that coastal wall. We, by agreement, from Costa Rica, have said that if a patient with an astectomy T1, T2, N0 with two or more of these criteria that you have written down in these slides are present, then we will proceed with the treatment of adjuvant external radiotherapy. And that is something that we can also have present in the guides, where they tell us that without these risk factors, radiotherapy is not necessary. And if it presents the risk factors, which is the indication below, described in the S-incision of this NCCN slide, then proceed with radiotherapy. As for partial mammary irradiation, it was already widely explained in previous conversations. It is considerable to take into account negative N-tumorectomies in a select group of patients, which is basically a summary of this. Age over 50 years, less than 3 centimeters, N1. Without systemic neoadjuvant or by hormone therapy, the estrogen receptors should ideally be positive and the lymphatic vascular invasion is absent. Partial accelerated mammary irradiation treatments is also something very frequent that we do in San José de Costa Rica, because we have an intraoperative radiotherapy team that we use regularly. And in terms of social security, we basically use the criteria of the University of Florence to be able to use external radiotherapy teams to apply partial accelerated mammary irradiation. So this 2015 publication is very useful. We use it frequently. The target has already been discussed, but I would like to deepen the Elliot, which is what we use, because we have the electronic team here and as we can see, the risk of recurrence reported by them is adequate, it shows no inferiority. However, as I have also deepened, the risk of local recurrence with intraoperative radiotherapy may be due to the selection of the patient, in which it is super important to bear in mind that the risk of local recurrence is due to T2 tumors, osteological degree 3, negative estrogen receptors, and triple negative, so these patients are not candidates for this technique. The group that probably benefits from intraoperative radiotherapy are women between 50 and 70 years of age, because this technique shares almost the same criteria to be able to omit radiotherapy in women over 70 years of age. And well, what can be of co-adjuvant? Well, the surgeon and we could help each other a lot in eliminating the negative cosmetic events of both techniques, perhaps the use of hyperbaric oxygen, because hyperbaric oxygen brings irradiation, it is an effective tool to reduce the capsular reaction in the area that surrounds a mammary implant, for example. And in this experiment, it was an animal model where implants were placed on the back of mice, which then these implants were irradiated and through a microscope, once the species were sacrificed, it was possible to corroborate that the inflammatory process around the capsule was much smaller in those mice that received hyperbaric oxygen. As for the publication of the Red Magazine in 2001, one can say that hyperbaric oxygen therapy is considered a treatment option in patients with persistent symptoms after conservative surgery. It helps a lot in the healing processes, especially when adverse events such as skin necrosis or chronic inflammatory processes occur, which cause certain discomfort in patients. And well, in conclusion, to conclude, we agree on oncoplastic surgery, between oncoplastic surgery and radiotherapy oncology, which is safe. External radiotherapy in a select group is an adequate option, not only for current parameters of cosmesis, but to avoid exposure in centers where the patient may acquire the COVID-19 disease. Partial accelerated irradiation studies of the mother so far have shown no inferiority, a discreet but not significant risk of local recurrence, with much less toxic commitment, which explains that in the series that compare with external radiotherapy, those who receive accelerated partial irradiation of the mother have greater survival, possibly due to the fact that their hearts and lungs are not irradiated with the techniques of accelerated partial irradiation of the mother. Moderate hypofraction schemes are safe. We in San Jose de Costa Rica have used them since 2012, and now we have been using ultra hypofraction for a year. And hyperbaric oxygen seems to improve the cosmetic results of both surgery and radiotherapy. And well, with this, I hope I have clarified the daily doubts of surgeons. I am very grateful for the invitation by the organizers, and I am willing to clarify any questions. Thank you very much. Thank you very much, Dr. Rolando. This is also a very current topic, this of the oncoplastic surgery, which is being done more and more. And well, I think, fortunately, there are still a few minutes for questions and answers. So, taking advantage of the fact that you are on the line, one of the questions that have come out is implant versus expansion. Is there anything that you favor more? Well, possibly, if they use an expansion, it is less likely that they will have problems when placing the implant, that they contract, because that implant will not be subjected to radiotherapy. It is widely used. What needs to be known is that, obviously, the surgeon cannot manipulate the expansion once the simulation tag is made. I have no literature, nor is there a phase 3 study that has compared cosmetic results versus the expansion, versus the implant. This is also the reason why there are many brands in the market, and these risks are, as we have described, also in conditions inherent to the product that is being used. But we, in practice, prefer to use expansions. However, in the market, I must warn you, there are many types of expansions, and the drum that is used to be able to blow these expansions, depending on the brand, produces some artifacts in the simulation tag that could even alter the dosage calculations of up to 20% in our estimates. So, we recommend, in particular, a certain product that, due to security and confidentiality policies, is currently being tested, if I may say so, but we are doing clinical studies in expansions that are demonstrating to have less risk of producing alterations in our dosimetric calculations because these artifacts or these interferences that occur in the child are less. Perfect, doctor. Thank you very much. To the other panelists who are with us, Dr. Carlos Pérez, Dr. Ferraris, Dr. Albert, Dr. Victor, there are some questions that have also come out and have been left on the table. I don't know if any of you are here to join us. Dr. Pérez, talking about hypofractionated radiotherapy, you commented on it, but pointing out what is your position regarding ganglions and hypofractionated schemes, or post-mastectomy and hypofractionated schemes, because now, with this pandemic and COVID, we have medicine based on contingency instead of evidence, and we see that everything has been treated with hypofractionation. Is there anything you could tell us about it? Not much, because, as I showed you, in that questionnaire of European radiologists, they... Can you hear me? Yes, we can hear you. The Europeans in that questionnaire, as you saw, are not in favor of hypofractionation when it comes to treating regional ganglions. And I said the same thing. Here in the United States, we don't use hypofractionation to treat regional ganglions. And the reason is because the incidence of brachial plexopathy is higher with higher doses or with fractions with more doses. So, I don't advise it. Okay, doctor. Thank you very much. Dr. Ferraris, if the patient had a complete answer in breast, but not in ganglions, would you consider to stop irradiating the breast area and only irradiate ganglions? No, no, no. No, no, no. I irradiate everything. Perfect, doctor. I hope it was clear for our friends, gynecologists and surgeons who accompanied us. Because we, as radiologists, are very complex if something happens later. For Dr. Albert, costs are a whole issue in all our Latin American countries, not only Mexico, but Costa Rica, Argentina, Colombia. Hypofractionation is charged less. However, it cannot be used in all circumstances. And speaking of partial, it is not in all countries. And speaking of IMRT, it is not in all countries. How do you see the state of radiation regarding the geographic area, Albert? Well, here, what we found in the chat, we do not have so many problems in terms of the charge made by the institutions. Precisely because of the health system. We have a health system that covers all high-cost procedures. In that, an agreement was reached with the Colombian Society of Radiotherapy to create some codes together with the Ministry of Health to cover the procedure, not the number of sessions of administered treatments. So, we were also talking about this in the chat, that technology is needed to be able to do hypofractionated treatments with integrated BUS, which is the standard of treatment, and that we still need Phase III studies for it to be a generalized management. Not all patients would be candidates for this type of treatment, but also they have not been used in a generalized way because there was always a fear of using hypofractionated treatments because of the risk of presenting higher risk of complications, but with the new studies that are currently appearing, new hypofractionated treatments with much higher doses, and with all this situation of the pandemic, it forced us to use shorter treatments. So, the use of hypofractionated treatments has been generalizing in all centers. I think that in all Latin America the same thing has happened to us. I think that in time we will see what happens. Dr. Leni, talking about costs and tests, institution is one thing, private medium is another. What patients in institutions are being asked for this and who would you suggest to do it in the private medium and if you have any idea of costs? Regarding the costs, it has varied a lot in the last five years. Until around 2015 approximately $60,000, $70,000, there were some that cost more than $3,000. Lately, there is a trend for commercial laboratories to be able to offer studies at a low cost in a subsidized way, and we can find studies up to $350, which would be approximately $7,000. The results are also important. Before, it took up to three months. Even in institutions, we would spend a year because they were part of research protocols. And now we can have results in less than two weeks. Almost all commercial laboratories offer the possibility of delivering the result in approximately 10 days. In the institution, it is different because although the costs are much more accessible, they are public institutions where the patient does not pay, or, as in the case of the Secretariat of Health in Mexico City, they are patients of scarce resources. So in them, we try to include research protocols where there are other instances where these costs can be solved and the patient can benefit from the study. Thank you very much, doctor. Dr. Victor Jr., we already have the results of the tests. What is the approach of a surgeon, of a gynecologist, since they did this panel to the patients and we have positive results. How do you approach it? What do you suggest? Dr. Victor? Well, Dr. Leni, it's your turn. The results are already there, because this also involves a whole logistic as you showed us at the end. That is very important, and I would like to convey that to everyone. The management of a patient with breast cancer is multidisciplinary. So, being able to intervene in a patient with a positive test will depend on the patient's age, the clinical stage, what is the prognosis of the current disease, and also what are the patient's expectations regarding what we can offer. It is not the same for a patient with triple negative breast cancer that has an advanced stage where we know that in the next two years there is a very high possibility of recurrence. We will probably wait a while to offer some risk-reducing therapy and once we see that the prognosis is improving, we will intervene to prevent timely detection or risk modification of other tumors. Perfect, doctor. Thank you very much. Thank you all for your brilliant participation. I think we could not be happier to close with a golden brush. I give the floor to Dr. Victor Vargas. Dr. Victor Vargas, would you like to give any opinion, Junior? Well, I'm here with a mask, sorry. Well, within the tests, basically, if we consider the group of patients who have luminal treatment, those who have luminal profiles in a more therapeutic point of view, those will benefit with the signatures that endopredic can do and all in those T1, T2, as they are already established. And we must remember that luminal tumors have the benefit of hormone therapy. On the other hand, those patients in which immunohistochemistry is expressing the overexpression of GERDOS by the CRB gene, they have the benefit of biological therapy, Trastuzumab, Pertuzumab, Lapatinib. The approach that we were giving is in those genetic profiles that are not always applied in everyday practice, but are reserved for research protocols, in those that deal with differentiating the triple negative, since after cytotoxic chemotherapy no additional treatment can be offered that could compensate a little the survival or alter some recurrence. Although some negative triples could have a behavior of luminal A, as its genetics does show, in clinical practice it is not like that, until it is established that those therapeutic whites are already found in which benefits such as immunotherapy could give some therapeutic alternative. Good afternoon to all. Thank you, Dr. Vargas. Now, Dr. Vargas Padre, please. First of all, Dr. Jose Hinojosa, I would like to thank you for this magnificent and excellent coordination and excellent presentation you have given. As president of the Mexican College of Gynecologists and Oncologists, first of all, I would like to thank all the colleagues who participated both nationally and internationally and from all over the world for being able to be connected to this course. Mainly to the International Cancer Society for its organization to develop it together with our college. This achieved a successful realization and conclusion during these three Saturdays, each monthly. And that we contribute in this knowledge the latest advances in prevention, diagnosis and treatment of breast cancer. And this was a very important thing in a multidisciplinary way that allowed a better vision of breast cancer and particularly as here the present and the previous Saturdays with professors of great prestige, international trajectory and great knowledge. The evaluation will be done through a platform. It is a small exam, I simply request the advice to issue a statement to the assistants with 70% during all these three Saturdays. This course is endorsed by the Gynecology and Obstetrics Mexicans, Oncology and Radiotherapy. Again, I thank the team particularly Mary and Susan, who are part of the organizational direction of the academic aspects of the International Cancer Society for the brilliant and successful collaboration we have had. And we hope to see you again in these updates. A fraternal greeting to all. We hope that the next meeting we can shake hands. I wish you health, happiness and love. Thank you all very much. And we conclude this successful course of the International Cancer Society and the Mexican College of Gynecologists and Oncologists and our Latin academic Dr. René Pareja. Thank you. And a hug. Thank you. A hug to all. Thank you all. A hug. Happy weekend. Thank you. Congratulations. Bye. Bye, Dr. Pérez. Thank you for your participation. It was a pleasure. Thank you.

hypofractionation

breast cancer treatment

DCIS

tumor control

conventional fractionation

partial radiotherapy

brachytherapy

external radiotherapy

patient selection

oncoplastic surgery

cosmesis

surgical margins

oncological outcomes

radiotherapy timing

multidisciplinary collaboration