Susan. Oh, you got the recording. Perfect. All right, Susan, I'll let you do the countdown from when you start the webinar. Okay, Dr. Vargas, I'm going to start the countdown. I'll let you get to the start. I'm going to start the webinar and I'll give you a countdown. And then I would wait until several participants join. Okay. Okay, wonderful. Okay, I'm going to start in 5, 4, 3, 2, and 1. Hola, muy buenos dias. Es un gusto estar con ustedes conectados a los más lejanos lugares desde Iberoamérica y de México para el mundo. Le damos la bienvenida a todos los que están conectados a este primer curso en su segundo sábado, que está organizado por la Sociedad Internacional de Cáncer Ginecológico y el Colegio Mexicano de Ginecólogos o Oncólogos. Bueno, este grupo de expertos de Iberoamérica estará integrado en este primer bloque por la doctora Silvia Patricia Villarreal-Colin de México, la doctora Ana Lunsch de España, la doctora Paula Anel Cabrera de México y el doctor Marco Antonio García Hernández de México. Y quien hoy va a fungir como coordinador, nuestro panelista, el doctor David Cantú. Haciendo unas pequeñas notas, es que la vista, solo el operador activa hacer clip en el botón de ver en la parte superior de su pantalla y seleccionar vista del operador o del orador para ver todos los panelistas seleccionar vista de galería. Si tienen alguna dificultad técnica, pueden utilizar el soporte de la Sociedad Internacional y le damos la palabra al doctor David Cantú para que realice la presentación de cada uno de nuestros panelistas en este primer bloque. Buenos días. Hola, muy buenos días a todos. Sean ustedes bienvenidos a este curso. Vamos a tener un grupo importante de médicos que nos presentarán lo que está ocurriendo en cáncer de la mama. Nuestro primer ponente el día de hoy será la doctora Silvia Patricia Villarreal Colín. Ella es ginecóloga adscrita al Departamento de Tumores Mamarios del Instituto Nacional de Cancerología y nos hablará sobre la cirugía oncoplástica después del tratamiento neadjuvante en cáncer de mama. Muy buenos días, doctora Villarreal. Es un gusto tenerla por aquí. ¿Qué tal? Muy buenos días. Muchísimas gracias por la invitación. ¿Puede compartirnos su pantalla, por favor? Listo. Muy bien, pues te agradezco muchísimo. No, no te vemos. No vemos tu pantalla. ¿No? There we see it, if you can put it in presentation. ¿Ahí está bien? No. Esa es la copita a ti. Bajo, bajo. Bajo. Saliste. Ahí está. ¿Listo? Listo. Gracias, doctora. Perfecto, gracias. Muy bien. Es un honor estar en este segundo módulo del curso internacional de cáncer de mamá. El tema con el que yo participaré pues es la cirugía oncoplástica después del tratamiento en la adjuvante en cáncer de mamá. Sabemos que el manejo del cáncer de mamá es un tratamiento multidisciplinario donde el tratamiento local, básicamente representado por el manejo quirúrgico, pues es la piedra angular. Sin embargo, tenemos tratamiento multidisciplinario. that we can administer before the local treatment, called non-adjuvant treatments. Subsequently, surgical treatment is very frequent, we require treatment with adjuvant treatments. And finally, there is a group of patients who will require palliative treatment when the disease becomes in a metastatic environment. The benefits of chemotherapy treatment are multiple. On the one hand, it can facilitate the preservation of the mammary gland in patients with early disease, but that may show some degree of a malignant or limitrophic breast tumor relationship. It can also make operable inoperable tumors, like those cases with locally advanced cancers, inflammatory cancers. It gives us very important prognostic information, especially in the cases of women who have a complete pathological response, considering these patients with a better prognosis in terms of global survival. But it also identifies the need for adjuvant treatment in some cases. That is, it can help us to scale or de-scale the treatment, specifically women with triple negative cancers, because we know that they will benefit from the adjuvant treatment with capecitabine. It also allows us to wait for decision-making in women who still do not have a well-defined decision in terms of surgery, whether it is a conservative surgery or a mastectomy. It also gives us time to plan a mammary reconstruction in the cases in which the patient will require a mastectomy. And finally, it gives us the opportunity to save time to perform genetic tests in women who we consider candidates for this study group and who, in the case of being carriers of a genetic mutation that increases the risk of breast cancer, it will be suggested to do a risk-reducing mastectomy and we could do an oncological treatment at the same time. What are the candidates for treatment with adjuvant chemotherapy? Well, in early stages, it is said that the initial treatment should be with surgery. However, patients with early cancers or with operable disease can be candidates for receiving this adjuvant treatment. Like what? Those women who we know are sensitive to chemotherapy, like the group of women with over-expressed GERD2 tumors or patients with triple negative cancers. We know that they have a generally spectacular response to treatment and this can help improve surgical management. Also, patients with early cancers, but whose mammary-tumor relationship is unfavorable, or limitrophic and want a conservative surgery. It is a fact that all women with locally advanced disease should receive an adjuvant treatment. We are specifically talking about women with large tumors, with high tumor load at the ganglion level, inflammatory cancers. But there are patients who will not benefit from receiving this adjuvant treatment, such as those with extensive in situ component, where the invasive component cannot be identified or is very poor. Patients with poorly delimited tumors, in which it is perhaps not possible to define exactly the limits, non-palpable tumors or clinically non-evaluable tumors, and those tumors that we know in advance that will not respond to chemotherapy treatment, such as mucinous cancers. Adjuvant chemotherapy provides us with several opportunities. One of them is to be able to scale or de-scale surgical management, specifically in the management of patients with positive ganglions that are negativized after the treatment of an adjuvant, they could be candidates to perform only ganglions in TIN-ELAM. It also gives us the opportunity to modify treatments if the response we are obtaining is not optimal. It could help us limit the fields of radiotherapy in patients with positive ganglions if they were finally negativized after the adjuvant treatment. And of course, it gives us a platform for the research of new therapies and precise biomarkers in these patients, because we are evaluating the response of the treatment in the live tumor. We have to take some precautions to try to avoid over-treatment or under-treatment. And of course, one of the most important precautions or considerations is that we have the possibility of a tumor progression during treatment. It is well described that the benefits of global survival are practically the same with chemotherapy schemes administered pre- or post-operatively. The main objective is to try to obtain a complete pathological response, since it gives us a better prognosis in terms of global survival and free survival of the disease, especially when the treatment is administered in a complete way before surgical treatment. We have another non-adjuvant treatment option, which is hormone therapy in patients with tumors that are sensitive to estrogen and progesterone receptors. In other words, those patients with low-degree or low-risk ruminant cancers and who, due to some comorbidity, may not be considered candidates for chemotherapy. Within the treatment scheme with patients with overexpressed HER2, the treatment with trastuzumab and fatuzumab should be included. And again, be careful with the progression of the disease, which may require the change of a scheme. Finally, once the patient has undergone this non-adjuvant treatment, we can do two surgical treatments. On the one hand, we have the group of patients with mastectomy versus conservative surgery, combined with the treatment with radiotherapy. We know from publications with a long-term experience of more than 20 years that global survival is practically the same with these two treatment groups. So, there is no difference in global survival. And it is considered that most cases of local recurrence may be secondary to a bad surgical technique, that is, that we have left positive margins due to an inappropriate selection of the patient or that the same tumor aggressiveness may have been the cause of this recurrence. This new article was recently published, that is, last month, where it was found with a database of more than 100,000 patients how conservative surgery could be associated with an improvement in global survival when compared to mastectomy in patients with early breast cancer. Here we see how the curves are separated and when they are divided into clinical stages 1 and 2, this benefit is maintained in global survival with conservative surgery. So, it is a fact that conservative surgery is an extremely useful treatment strategy and applicable to many patients. There are several risks of conservative surgery. One of them is the possibility of leaving important deformities in the breast. This is one of the classifications of breast deformities. And well, that is why since the 1980s a series of procedures began to be carried out, considered as innovative procedures and included within a group of treatments that we call oncoplastic surgery. This is considered as the most advanced form of conservative surgery, where the objectives, on the one hand, are to preserve the mammary parenchyma, trying to achieve excellent cosmetic results, but importantly, maintain the oncological principles of radicality. It is considered as the third treatment route because the unacceptable or deficient cosmetic results can be as high as 30 or 40% of the cases. The objectives of this group of procedures are to improve the quality of surgical treatment, on the one hand, improve the local oncological control, since it allows us to make or give wider surgical margins, improve the preservation of the breast, which otherwise would probably have required a mastectomy, and also improve the cosmetic result by reducing this possibility of deformities in the breast treated with traditional conservative surgery. It also allows us to improve the flattening of radiotherapy fields, improve the conformation of the mammary structure, avoid assistive duplicity, and with this, reduce the costs of treatment. Within all the classifications that exist, I think this is one of the simplest and most consistent, where it is based on the amount of tissue, mammary tissue and the level of technical difficulty of the procedure. Within level 1, we have tumor resections or mammary volume less than 20%. Generally, a wide resection of the skin is not required, and it is accompanied by the centralization of the complex and the person. On the other hand, we have a group of procedures in level 2, where the mammary volume to be resected is much greater, which is calculated between 20% and 50%. Of course, this implies a greater complexity of technique. Generally, it is represented by reduction mammoplasty procedures, and it generally requires the resection and remodeling of the breast. Within the oncological indications, we have the need for large mammary volume resections of more than 20%. Obviously, the need to have free margins. Within the indications, we also have voluminous tumors, patients with extensive intraductal component or lobular histology, where a conventional conservative surgery may exclude them within its indications. Patients who are not eligible for mastectomy with reconstruction. And of course, the patient must be firmly convinced that they want the preservation of their breast. There are also some cosmetic indications, such as an unfavorable or limitrophic breast-tumor relationship, central tumors, the location of the tumor in risk sites, especially the middle quadrants, which are difficult to treat the upper internal quadrant. I will present a case later. Patients with mammary asymmetry or significant ptosis, where perhaps the retherapy fields can become difficult in their configuration. The same happens with patients with a need to reduce the mammary. And when we anticipate that the cosmetic result will not be the most appropriate, we do a conservative, traditional surgery or a tumorectomy. The steps, quickly, are the planning of the surgical approach, taking into account the size of the tumor, the location, the volume of the breast, the age of the patient. Next, the tumor resection with all the oncological principles, that is, to make a resection with microscopic margins, at least larger than one centimeter. To make the marking of the surgical piece in all its edges. To make the location of the tumor breast with staples. After this, the mobilization of the aeolapis complex. The mammary remodeling to achieve a satisfactory mammary contour. The handling of the axilla that each patient requires, either a ganglion-axillary dissection or the search for the gangliocentinella. And finally, the vast majority of patients will require to carry out a procedure of contralateral symmetrization. What are the disadvantages? Well, the difficulty of being able to make reexcisions when the margins were close or compromised. That is why the transoperative study in this type of procedure plays a very important role. Also, the disadvantage is that it gives us more surgical time because we generally have to do some contralateral breast treatment. For the same reason, there can also be a greater loss of hematoma. And well, the need to handle the healthy breast that some patients find difficult to accept. The complications can be fatty necrosi en una paciente con indicación de quimioterapia en adjuvante que estamos tratando de llevar una cirugía conservadora, no obtenemos una respuesta como la esperamos? Pues bueno, tenemos todavía una herramienta más. No todas las pacientes estarán, requerirán una mastectomía. Tenemos esta otra opción que es lo que llamamos la cirugía oncoplástica extrema, la cual podría ser definida como la conservación de la mama llevada al límite. El Dr. Silverstein publicó este artículo en donde introdujo este concepto de oncoplastía extrema, donde la conservación de la mama se realizaba en pacientes que necesitaban mastectomía, o que la mayoría de los médicos consideraba que se debería hacer una mastectomía. Dentro de su serie incluyó tumores mayores de 5 centímetros, multifocales o multicéntricos, la mayoría con ganglios positivos, y obviamente debido a estas características tumorales, pues bueno, la gran mayoría de las mujeres requerirían tratamiento de adjuvante con radioterapia, aún con procedimientos de mastectomía. Él presenta una serie de 66 pacientes con cánceres de mama multifocales, multicéntricos, mayores de 5 centímetros, o con enfermedad localmente avanzada. Se realizó una cirugía oncoplástica más simetrización contralateral. Todas las pacientes recibieron radioterapia posoperatoria, y se comparó con un grupo de 245 pacientes con enfermedad unifocal o multifocal, con volúmenes tumorales menores de 5 centímetros. ¿Qué encontró? Pues bueno, encontró que existieron diferencias significativas en varios ámbitos. Por un lado, el volumen y la extensión del tumor fue mayor en el grupo de la oncoplastía extrema. Hubo diferencias en cuanto a los márgenes quirúrgicos, obviamente porque estas pacientes con tumores localmente avanzados requirieron resecciones de tejido mamario más extensas, lo cual puede limitar o dificultar la obtención de un margen quirúrgico, pero si se fijan aquí, el margen libre fue de más del 83%. También, pues bueno, la necesidad de hacer una mastectomía se vio incrementada en estas pacientes, porque, pues bueno, esta era su última alternativa para conservar la mamá. Y algo importante es que no se encontraron diferencias significativas en cuanto a la recurrencia local, aunque el seguimiento fue corto. Él nos muestra algunos ejemplos, se los presento aquí. Este es un caso de una paciente de 48 años con un cáncer lobular infiltrante multicéntrico, y asociado a focos de hiperplasia ductal atípica. Esta paciente se le había propuesto una mastectomía. Sin embargo, la paciente solicitó considerar la preservación de la mamá. La enfermedad se extendía en un área de más de 8 centímetros. Y bueno, lo que se propuso fue hacer el marcaje de todas las lesiones, hacer una excisión amplia de los cuadrantes superiores donde estaba localizada la enfermedad. Se hizo una mamoplastía de reducción con patrón vertical de doble técnica, y estos son los resultados posoperatorios que muestra. Este es otro caso de una paciente de 65 años con un cáncer multifocal con una extensión hacia todo el cuadrante interino y cuadrantes externos, lo cual se extendía a más de 9 centímetros. También esta paciente se le sugirió una mastectomía por la extensión de la enfermedad. Sin embargo, la paciente solicitó la posibilidad de conservación mamaria. Nuevamente se colocaron marcaje con arpón en las lesiones. Esta es la pieza resecada. Y este es el resultado cosmético posoperatorio. El último caso es una mujer de 42 años con un cáncer localmente avanzado, con una enfermedad de 6 centímetros y con múltiples adenopatías, como podemos ver en la imagen, a nivel axilar. Ella recibió tratamiento en el yuvante, pero persistieron micro calcificaciones. Vemos las imágenes posoperatorias. Se hizo el marcaje de las lesiones. Y este fue el resultado cosmético después de una cirugía conservadora con patrón oncoplástico vertical de doble rama y la resección de toda la zona afectada. Yo les quiero mostrar algunos casos que tuve la oportunidad de realizar en el Instituto Nacional de Cancerología, también de casos seleccionados. Las pacientes con macromacia realmente representan un reto quirúrgico, un reto terapéutico también para el radioterapeuta, debido a que la conformación de los campos de radioterapia tiende a ser muy difícil con estos grandes volúmenes mamarios. El caso que les presento es una mujer de 56 años, con un cáncer de mama T3N0, un cáncer triple negativo, en la cual vemos que tiene enfermedad multicéntrica y se dio tratamiento en el yuvante con quimioterapia. Esta es la imagen de la mastografía, donde vemos las dos lesiones. La proyección medio lateral oblicua, donde también nuevamente se muestran las dos lesiones. Y bueno, lo que se propuso con ella fue realizar una mastografía de reducción, es decir, un patrón oncoplástico vertical de doble rama, con un pedículo superior, realizando el marcaje de las dos lesiones, como pueden ver aquí, la colocación de arpones indicando la localización de las lesiones, realizar ganglios en tinela y la simetrización contralateral. Esta es la imagen de la pieza quirúrgica con los dos arpones. Y este es el resultado separatorio. Esta paciente tiene un seguimiento de 6 años y 10 meses, en la cual se encuentra libre de enfermedad. Como lo dictan las guías de manejo, toda paciente menor de 60 años con tumores triple negativo, pues se sugiere hacer el estudio molecular en búsqueda de mutaciones genéticas, y esta paciente fue negativa para BRCA1 y BRCA2. Este es otro caso, una paciente con un cáncer de mama localmente avanzado, T3N1, con micro calcificaciones que se extendían hacia todo el cuadrante externo, HER2 sobreexpresado, y la conducta con ella fue administrar tratamiento en adjuvante, incluyendo HER7, y bueno, lo que esperamos es que la respuesta en el volumen tumoral fuera muy buena, lo cual se logró. Sin embargo, pues obviamente persistieron las zonas de micro calcificaciones difusas hacia todo el cuadrante. Entonces, a ella se le propuso realizar un patrono completo horizontal para la resección de todo el cuadrante, la intervención de los cuadrantes externos, y una disección de axila porque la enfermedad axilar no se negativizó con la quimioterapia en adjuvante, y se hizo la simetrización de la mama contralateral con el mismo patrón. Vemos aquí los resultados posoperatorios, los cuales son sumamente satisfactorios. Esta paciente tiene cinco años y nueve meses de seguimiento, también libre de enfermedad. Y el último caso que les quiero presentar es el caso de una mujer de 64 años con un sarcoma de la mama de alto grado, con área de producción de material osteoide, y triple negativo. Esta paciente, que aunque pudiera parecer que la lesión no es tan voluminosa, tratándose de un sarcoma, la recomendación es realizar márgenes quirúrgicos más amplios, de dos centímetros. El problema particular de esta mujer es que la localización de la lesión era hacia el cuadrante superior interno, que es el cuadrante más difícil de manejar quirúrgicamente para obtener un resultado cosmético adecuado. Esta paciente definitivamente no aceptaba la mastectomía, y entonces se le brindó la posibilidad de un tratamiento quirúrgico a base de un patrón con plástico romblo, con exisión amplia de márgenes y simetrización contralateral. Fue una pieza de 8.5 centímetros, que para este volumen mamario es bastante. El tumor fue de 5.8 centímetros, los márgenes quirúrgicos se encontraron libres, y esta paciente tiene un seguimiento de 4 años y 11 meses sin evidencia de enfermedad. Finalmente, quisiera concluir que, bueno, la ancoplastía extrema o la cirugía ancoplástica extrema, pues es un nuevo concepto que es prometedor en la conservación de la mamá y que es posible en cánceres localmente avanzados después de quimioterapia. Estas pacientes deben ser perfectamente seleccionadas, no todas las pacientes serán candidatas para este grupo de cirugías. Brinda una mejor opción en la calidad de vida comparada con pacientes realizando semastectomía, reconstrucción y radioterapia. Y bueno, lo que menciona el doctor en su artículo es que aún falta un seguimiento a largo plazo de este grupo de pacientes. Sin embargo, se estima que puede haber un ligero incremento en el riesgo de recurrencia local sin tener este impacto o teniendo un impacto muy leve en la supervivencia global. Como les mostré yo, tenemos pacientes con seguimientos de más de 5 años, las cuales afortunadamente se encuentran libres de enfermedad. Nuevamente, creo que lo más importante de este grupo de procedimientos es la selección adecuada de las pacientes. Y bueno, yo con esto termino agradeciendo a todos su atención y quedo al pendiente de comentarios y preguntas. Muchas gracias, doctora Villarreal. Excelente plática como siempre y muy puntual con sus comentarios y con su experiencia. Pues bueno, para seguir con nuestro módulo, los anuncios parroquiales. Pueden hacer las preguntas para la doctora Villarreal en la casilla de questions and answers. También la pueden mandar al chat donde estamos todos para que al final el doctor Canturre haga una recolección de todas aquellas preguntas y pues podamos tener nuestra mesa de discusión. Y bueno, pues para mí es un placer presentar a mi querida maestra, la doctora Ana Yu. Para los que no la conocen, la doctora es toda una personalidad en España. Premio Honoris Causa por la Universidad de Valencia. Investigadora reconocida por ESMO como la mejor investigadora del año. Pasionada del cáncer de mama y maestro de muchos de nuestros en México. Y pues quizá la parte más importante de su currículum es que participa y nos ayuda muchísimo en la creación del consenso de Colima en México. Bienvenida, maestra. Adelante. Nada, muchísimas gracias. Eso son presentaciones de amiga, de que nos queremos mucho, de que yo quiero mucho a México y que además cuando voy me encuentro como en mi casa. Lo tiro mucho de menos. Es de las cosas que más reconozco que me está costando en esta pandemia el no poder ver a todos ustedes y el poder estar ahí junto en las pláticas pudiendo discutir. Muchísimas gracias. Vamos a empezar. ¿Me escuchan? La escuchamos bien, pero no vemos su presentación. No ven la presentación. Estoy haciendo la... Yo creo que estoy compartiendo mi presentación, pero no me sale en las... A ver. Ahí ya podemos ver su pantalla, pero no su presentación. Es que cuando pongo compartir pantalla no sale mi presentación. A ver. Creo que tiene que abrir su presentación. Sí, está abierta. Entonces tiene que cerrar esa pantalla tal vez. Tengo que cerrar todo esto. Vamos a ver. Vemos su escritorio. ¿Cómo se está usted moviendo? No, es que no me sale la conexión. Perdonen. Sí, sí, sí. Lo tengo, lo tengo. Pero está compartiendo la pantalla, pero no me deja. A ver ahora. No, no me sale. Perdón, tendré que cerrar y volver a abrir. Es la única solución. Sí, sí, lo tengo, lo tengo claro. Vamos a ver. Perdónenme por el tiempo que no me gusta consumir. If I open the powerpoint, if I put it there in the powerpoint, it is low. But I give it to you and it doesn't take me to my powerpoint, but I'm going to open it again. Let's see. There it is. There it is. Yes, but can you see it? Yes. Can you see it? Yes, it looks very good. It looks perfect. It's a PDF presentation. Yes. No, no, no, mine is normal, but well, I can put the PDF. We are seeing the PDF without problem. Okay, perfect. We are going to open it completely. Now, can you see it well? Please. We see it much better. It's a shame. It is already showing us its conflicts of interest. If you want, we can start so as not to delay this any longer. Okay, okay. Yes, but I can't. It is moving forward and back and so on. But I can't do it. No. I'm sorry, I'm sorry. Let's see now. It's just that the screen doesn't pass me. I don't know if it's the technical team. Can you move it there, doctor? No, no, no. If you can say next slide and move it. Yes, yes, yes, I'm saying it with the next slide, but I can't. The people from GCF can make the movement of their presentation. When you say to pass the next one and pass the next one. No, but I prefer to pass the next one. But I'm going to do it. I think now it's going to open and we'll be able to see it. Can you see it, please? Can you see it? No, not yet. No. Do you want to send me your presentation by email? No, they have it there, but what I'm going to do is... Hey, I would like us to move on to the next speaker. Yes. And when we solve this issue, we'll be back with you. Okay, okay, it doesn't matter. Perfect. So, let's see, click on the PowerPoint icon below, please. Yes. There it is. Ready. Do you see it? There it is. Perfect. Perfect. It's done. Fantastic. We didn't need to scare you, I think. No, no, it's done. Immunotherapy, as the title says, has an impact on patients with triple negatives. These are my conflicts of interest. And we are going to see what is the evidence of the activity of immunology as an agent in triple negative. The effectiveness of the checkpoints, the three phases that we have at the moment, what we have in terms of safety of use of these checkpoints, if we have predictive biomarkers and what are the future directions. In the current state of triple negative, it is a challenge. Why? Because we have a great complexity for the dissection of biological heterogeneity. It is a disaster. It has been so far. At the moment we already have subgroups that will truly be able to help us choose the best treatment for each of them. But today there is no standard for metastatic disease. And we still have an average survival of 13 months. There are no approved diana treatments. At the moment we have approved the first treatment with immunotherapy by the FDA. They have identified their populations clinically relevant, but in clinical trials. And we do not have a clear strategy that integrates potentially relevant biomarkers to guide the choice of treatment. What we are clear about is that we have advanced in recent years in all subtypes because we have had better chemotherapy agents, better endocrine agents and the development of anti-herd therapies, above all. Here we see the years 86 to 92, how we had the relapse rates according to the different subtypes. All of them were high relapse rates in the years 2004 to 2008. Thanks to all this, to the new agents, to what we have seen in tumor biology, which is what guides us today in treatments, we see that the relapse rates are much lower. Therefore, we have advanced a little in what is the treatment of the disease by subtypes. But the metastatic disease, here they have it in a recent work, where we see that from 2008 to 2016 we have advanced in survival, in the average survival of the luminal group, 42 months of average survival, of the HER2, 44 months, but the negative triples in this period from 2008 to 2016, we have an average survival of 14 months, almost 15 months, but imagine the difference with the rest of their group of patients. What is clear is that the negative triple patients, which means that they do not express any receptor, we see that it is a percentage of patients from 15 to 20% of all breast tumors, usually have a high degree, a very pejorative prognosis. The only thing we had for them was chemotherapy, and as has already been said by Dr. Patricia previously, we see that patients, mostly negative triples, are carriers of BRCA1, BRCA2 at a high frequency. That is why it has given me joy, as Dr. Villarroel has said, that in Mexico BRCA1, BRCA2 is being done in those negative triple patients up to 60 years old. That is, that is very good, we do not reach 60, we do it to all those under 50 years old, who have negative triple tumors, although they do not meet the criteria to do BRCA1 and BRCA2 due to family characteristics. We are doing it to all those patients. It is a very aggressive disease, it is characterized by not overexpressing GER2 receptors and amplification. The truth is that they have a very pejorative prognosis and represent approximately 60% of cases with BRCA1 or 20% of BRCA2. Therefore, we have to be very clear about this when we have a negative triple patient, because today we already have treatment for those patients, their negative triple group with BRCA1 or BRCA2. Here we have, they are a very heterogeneous disease, it is a disease that has important mutational characteristics and we know that until now we did not have therapeutic guidelines, we did not have drivers to be able to select the treatment. This group of patients, through genomic platforms such as Nanostream, we also make that genomic platform and we know that it is a heterogeneous group, that is why I have told you. 47% can be Basal Light patients, 30% Claudine Long, 9% GER2, 5% and 6% Luminals. Therefore, there is a great heterogeneity and not always. Yesterday a colleague told me that a triple negative patient, already desperate to have given everything, was given a hormonal treatment with Abemaciclib and the patient responded. I say, that patient should have had a Nanostream to see if it was that subgroup of 11% of Luminals, or 9% of GER2. Therefore, we are going to see how triple negative patients, the average survival is, as we have seen currently, in 9-13 months of average survival. And we know that the duration of the treatment of the first, second or third line is much shorter than in any other subgroup. The average time to progress from the first line can be 12 weeks, to the second line 9 weeks, and to the third or more lines, very few weeks of response duration. Therefore, what do we have as a standard so far? Well, we had treatment in the initial disease, which, as Dr. Patricia has also said, we do neoadjuvant in most patients, even if they are not locally advanced, we do it in all patients, triple negative, greater than 1 cm. We are going to treat it with neoadjuvant therapy, because it will tell us, if the complete pathological response occurs, the prognosis of that patient will be much better. Today, for those who have a bad prognosis after neoadjuvant, we have nothing, but it is helping us to classify those that we can cure with our neoadjuvant therapy. And when we did not have any dyana therapy, the first line was taxanos, combinations of platinum salts with taxanos or bebacizumab, in the second line capecitabine or combinations with platinum salts, and in the third line eryboline. Today we already have some diana treatments for these patients, and we are going to see how, for the first line, we are going to have in a subgroup of patients, more or less 40-45% immunotherapy. What bases do we have to treat these patients with immunotherapy? Well, so far what we had was this, chemotherapy plus bebacizumab, chemotherapy plus other agents, but there was truly no clear selection and they were not effective. Today we know that we have different subtypes of patients within the triple negatives, such as basal-like, the immunological subtype, mesenchymals, positive androgen receptors, and with which we can have approximations for these patients. Today we are divided into subtypes of patients within that disaster box that we had before, which were only those that did not express receptors. But today the new therapeutic approaches that we have for this group of patients are PAR inhibitors, for those patients with BRCA1 or BRCA2, the immunocheckpoint inhibitors, that is, immune therapy, which is welcome, or we have conjugated antibodies, such as saccitocinib, which we know has been very effective in this group of patients, or emerging therapies of combination of dianas, such as the dianas in front of PI3K-KT in TOR, the androgen receptors as therapeutic diana, or combining various dianas. What is the potential of immunotherapy? Today we know that the triple negative patients within breast cancers have an immunogenic potential, not as much as melanoma or lung tumors, not as much as other types of head and neck cancers, but we do have a subtype, such as the triple negative, which has an amount of immunogenic therapies that we can apply. Imagine the number of mutations we have in those who are GR2. The TILs, which we already knew, which are a determination that is easy to do in our pathological anatomy laboratories, will also help us to select patients. We do not have them well cataloged in the triple negative disease, but they are of great help when they are positive, because they will impact the response to treatment with immunotherapy. Much of the therapeutic benefit will not be represented by the TILs, by direct damage, but by the reduction of the microenvironment of tumor immunosuppression. Therefore, this justification makes that the TILs can help us. We know that they will be associated with complete pathological response rates and with sensitivity to platinum salts. Here we have how they are a prognostic factor in breast cancer, and above all they are a prognostic factor in the triple negative patients and in the GR2, not in the luminal ones. Therefore, the TIL levels, which are easily performed in pathological anatomy services, are performed very well. And the other pathway that we know today, biomarker for the triple negative, is PD-1 or PD-L1, PD-1 for patients who are going to be treated with benzolizumab, PD-1 for patients who are going to be treated with atezolizumab. PD-1 is expressed, above all, in the immune cells of the tumor. They have high levels of PD-1, the negative triples, the inflammatory carcinomas, and are associated with the TILs, which are easily detectable. Therefore, we have that immunotherapy strategies in negative triple breast cancer cells are important, because, first of all, there is an antigen release, antigen presentation, activation, T-cell activation that mobilizes T-cells of the tumor, infiltration of T-cells of the tumor, recognition of these T-cells, and there we are going to apply what are the checkpoint inhibitors, because they are going to restore immunity against the tumor, revitalize the suppressed immune cells to attack and eliminate the tumor cells, and chemotherapy, assisted by chemotherapy, which induces the exposure of the antigens to increase the immunogenic action. Therefore, we have more than enough bases to treat our patients with immunotherapy. This was thanks to the two Nobel Prize in Medicine that we had in 2018, which told us that the failure of the immune cells not to attack the tumor cells was fundamentally in these receptors. If we, with checkpoint molecules, immune checkpoint, were able to make sure that there was no coupling of the immune cell receptor with the tumor cell, we would have partially won the battle and we would have done a specific immune treatment. This is how the immune drugs that you see here appeared. In MAMA, above all, we have Atezo and Pembrolizumab, which are the trials that we have done with these two drugs and with the determination of PD-L1 or PD-L1 for Pembrolizumab. We see that these checkpoints, alone, without chemotherapy, give answers, but very small answers. What we did see were answers like 23-26% unique drugs, but this was a poor answer without using chemotherapy as unique agents against checkpoint. But what we also saw when we used unique agents is that there could be very long-lasting answers, as occurs in melanoma, which for the first time we have seen a plateau of survival curves. Therefore, we saw that few answers as unique agents, but there were very long-lasting answers, so this encouraged us not to have to use immunotherapy, the anti-checkpoint, alone, but with a combination of chemotherapy, because chemotherapy induced immunomodulatory changes in the microenvironment and this caused antigens to be released to stimulate immunogenicity and T cells. Therefore, they made the microenvironment more favorable and made sure that there were much more important answers with chemotherapy, up to 32-38% with these immune treatments in combination with chemotherapy. Because when we use therapies in this group of patients, they have a short response duration, when we use immunotherapy alone, also, when we use TARCHET therapies alone, also, but when we use both therapies, chemotherapy, immunotherapy and possibly in the future TARCHET therapies, we will have, that this subgroup of patients can have treatments, as we already have, much more effective. Here I present the studies with Atezo-Lizumab Phase III that have been carried out. The IMPASSION 130, the IMPASSION 131, the IMPASSION 132, which has completed the inclusion in January of this year, the IMPASSION 131 in June 2021, we will have the definitive data. And with Pembrolizumab we have the KEYNOTES, the KEYNOTES also with chemotherapy, especially the KEYNOTE 355, which has given some results last year, presented in ASCO and ESMO, very important. The IMPASSION 130, Atezo-Lizumab plus NAPLA-Klitaxel as chemotherapy, compared to NAPLA-Klitaxel plus Placero. The primary endpoint was free survival of progression and global survival, but it also corresponded, the study had to be done in the subgroup of patients that overexpressed PD-L1. The PD-L1, each biomarker for immunotherapy must be used in the system, in the trial that has been carried out, and they are different for Atezo and for Pembrolizumab. For Atezo, the SP-142 antibody and the window trial must be used in a stoichimia. And so we have that triple negative patients that express PD-L1 are between 40 and 42%, as we see here. Almost half of the patients express PD-L1, and this is very important, because we see that truly the patients who benefit from immunotherapy with Atezo-Lizumab, both in free survival of progression and in global survival in triple negative, of more than 7 months of difference with respect to NAPLA-Klitaxel, only in an interim global survival analysis, we see that there are 7 months of difference, and that only those patients with PD-L1 expression benefited. Therefore, the patients of the global group did not benefit. Only that biomarker served to mark that benefit, and in ESMO it was seen that the patients who continued to benefit were those with PD-L1 expression. In ESMO 2020, the results of 3 years were presented. 36% of average survival compared to 22% after 3 years. Remember the average survival of the triple negative, which was 14 months. But like any drug, it has its side effects, but we have already been able to handle it in other tumors, immunotherapy, and it is truly not difficult. Epilepsy, vomiting, neutropenia, truly hypothyroidism or hyperthyroidism, this is what appears, just like lung cancer, just like melanoma. Therefore, this first study, IMPASSION-130, gave us the basis that immunotherapy in patients with PD-L1 expression of 1% can benefit from immunotherapy. The problem came when, in ESMO last year, the data of IMPASSION-131 were presented. IMPASSION was not with NAPA-Clitaxel, but with Paclitaxel, and these patients were given corticosteroids at the time of treatment with Paclitaxel. And this is thought, because this study was negative, it is thought that using Paclitaxel along with atezolizumab may be that this corticosteroid treatment that we add may be responsible, but it is not known, and it is a doubt that we have, that we will have to solve through other clinical trials. We now have IMPASSION-132 with carboplatinogencitabine plus atezolizumab, we will wait for results to see if these patients truly benefit from associating carbogencitabine instead of Paclitaxel. The study of pembrolizumab, this study, KEINO-355, the scheme similar to the previous study, pembro-maschimio versus placebo-maschimio, randomization 2 to 1, and truly here also the determination of PD-L1 positive is different, because here tumor cells and non-tumor cells are taken into account, and a quotient is made, but the determination has to be greater than 10, because it has been seen in greater than 1, and it is not as significant as in patients that the quotient is greater than 10, and we see that greater than 10 we have 38-40% of triple negative patients, and the patients who benefit from pembrolizumab are patients greater than 10, mostly in free-of-progress survival, those of greater than 1 also, but in lower frequency. Therefore, today it is accepted that those patients who benefit are those greater than 10, and here we also see it in terms of the response. Patients greater than 10 can achieve responses by looking at agents. Paclitaxel, here Paclitaxel did give positive results, and carboplatinum-gencitabine. When CPS, which is how it is measured, P-L1 greater than 10, CPS greater than 1, or intention to treat. The side effects, being similar immunotherapies, hypo and hyperthyroidism. But what is important, that is why I have brought here, and with this I finish, is that these side effects are temporary. These side effects are quickly resolved. The gastrointestinal very fast, those of the skin, the rascutaneus also, the pneumonia that can produce, the endocrine or liver or kidney defects take a little longer, but all of them are resolved. And these trials are being done in neoadjuvantia, with immunotherapy in triple negative, and with chemotherapy, also with Ateso and Pembrolizumab, also positive studies with increased complete pathological responses. And there are three studies that are being done for negative triples in adjuvantia, which today we only have chemotherapy. Biomarkers, we have many to study, but so far only the TILs and the P-L1 are the ones that have truly given us an effect of being more effective in these subgroups. The other biomarkers that have been studied, the somatic mutations, the mutational load, the TMB as an antigen, that is, others have not had a positive effect at all. We will have to continue studying, but we have some clinical factors that can be predictive, such as we have to treat patients in the first line, not over-treatment in time. First line or longer interval time of 12 months, low tumor load, normal LDH, lymphatic ganglions, low tumor load, and clinical factors of poor response, second or third lines, high tumor mass or hepatic metastasis. These are clinical factors that do not favor the response to immunotherapy. And this is what we are studying today in clinical trials with immunotherapy and other molecular treatments. PARP inhibitors along with checkpoint inhibitors, MEK inhibitors, chemotherapy types, AKT inhibitors. That is, today we are studying other therapeutic guidelines to associate them with immunotherapy. And these are my conclusions. The triple negative subtype is the most immunogenic with the highest expression of PD-L1 and TILS. The PD-L1 pathway is a common immune escape mechanism used by tumor cells. That is why, if we block them, it is when we have the beneficial effect. This block has become a therapeutic goal to enhance anti-tumor immunity. We have a security profile that we know how to handle. We need well-designed biomarker studies, because today we only have clinical data and PD-L1 and TILS, multiple biomarkers, gene expression signatures that we already have for immunotherapy. And truly, we are all still far from identifying a subsidiary population to adequately explore these therapies. We have to study much more and know that we have to achieve it. Thank you very much and nothing more. Thank you very much, Dr. Luch. Your presentation was very interesting. We hope that our audience has questions. Please use the Q&A section or send us your questions through the chat. We hope that you have many. Our next speaker is Dr. Paula Anel Cabrera-Galeana. She is a medical oncologist. She is the Head of Medical Oncology at the National Cancer Institute. Her topic is, When to use chemotherapy in patients with advanced breast cancer, positive hormone receptors, negative HER2. Paula. Hello, how are you? Thank you very much for the invitation. It is a pleasure for me to be with you today. We are going to do this journey of daily life. Surely, you have patients, as I present in this slide, those patients that it seems that the whole story is fine, but after probably more than 11 years of surveillance, they have a recurrence, or those patients who sadly, during their endocrine adjuvance, end up with a recurrence that is quite aggressive. As Dr. Yu said, today we have a sensational world of directed therapies, and in particular for this group of patients with mammary gland cancer, the question is whether chemotherapy still has a role in this. For this, we will answer the following questions. First, we will know if the use of this chemotherapy offers greater global survival versus endocrine therapy. This meta-analysis, although studies from the 90s and 2000 are included, it should be noted that it has a heterogeneity index of practically zero, and in it they compared the survival that treating a patient with endocrine therapy versus chemotherapy offered, and as you can see, there was no benefit in global survival with the use of chemotherapy. The retractors of this study could say that they are studies where hormonal receptors were mostly unknown. The second question we can ask ourselves is whether chemotherapy has higher response rates in these patients than endocrine therapy. Again, we have this meta-analysis, where, as you can see, the trend is that the responses with chemotherapy are higher. However, as we previously saw, this has no increase in global survival, and it is worth noting that this meta-analysis, compared to the previous one, has a higher heterogeneity index, so those who do not agree with this meta-analysis think that the impact of hormonal receptors being unknown and that many evaluation techniques were used in the end and that HER2 was not precisely separated, can have this bias in the results. But well, if we go to what has been published more recently, here I present a table of a series of studies, not with a direct comparison, but so that we can observe free-of-progress survival. So, you can see how with chemotherapy, even with duplets, there you have the number of months, and how, thanks to this selection of patients, through a better quality of the chemist, we have reached, with an aromatase inhibitor, to have up to 12 months, 13 months, 14 months of free-of-progress survival in the first line, even with full-vestran, up to 16, 18 months, and with second-generation therapies, which in this case would be the combination of an aromatase inhibitor or full-vestran with cyclin inhibitors, you can see how practically in all scenarios you get to gain 10 months more. If we talk about clinical benefit, you know that this represents the grouping of stable disease, partial response and complete response, and you can see that for these patients with CDK4 inhibitor, it reaches up to more than 83%, while for chemotherapy, from 25% to 68%, depending on what you check, so that it is not yet very clear when we have to use chemotherapy. I am going to present some results of these cyclin inhibitors in these patients. The first thing to put on the table is that today we have three molecules practically for the same indication, and sadly with the so-called Me Too Trials. What do I mean by these Me Too Trials? As you can see in this slide, it is practically the same design. The three studies, the three molecules, include post-menopausal patients in this concept called hormone-sensitive, that is, practically virgins to an endocrine therapy in the metastatic scenario, and a little bit of what Dr. June already commented, the endocrine therapy and a free period of illness of when less than 12 months, GECOC, etc. And the design in the three studies was the CDK4 inhibitor corresponding to each company plus the aromatase inhibitor versus the aromatase inhibitor. And well, all the studies are positive, with a free prevalence of progression, which practically increases in 10 or 12 months all these studies with significant P. And specifically for the case of pre-menopausal patients, we have this study that has practically the same design, with the difference that ovarian suppression was introduced together with the cyclin inhibitor and endocrine therapy. With the maturity of these results, finally in this recently published meta-analysis, today we know that all these molecules, regardless of the type, have managed to generate a global survival in these patients with advanced breast cancer, if they are used in the first or second line. And this has resulted in practically all the international guides, including the Consensus of Colima, being the standard of treatment today for patients. Let's see our last question, which is how the endocrine resistance is defined, and if this endocrine resistance is the niche where I could use chemotherapy. Here is a table where you can see the latest recommendations of the Advanced Breast Cancer Consensus, coordinated by Dr. Fátima Cardoso, and in the small squares you can see how they are included in each of the recommendations. In this second part, we will dedicate ourselves to reviewing the studies at the bottom of the slide, but we will make a summary, don't worry, we won't see them all. And we will also identify a concept where chemotherapy is still in force today, which is the so-called visceral crisis. And the problem is how I define visceral crisis, which I can tell you is the situation that compromises the patient's life, as such a Byzantine discussion that depends on the clinic and depends on the scenario for which each doctor is going to do a visceral crisis. Last week I had to listen to my colleague, Dr. Enrique Bargalló, who in a resident session commented, let's see, how are we going to define a visceral crisis? Obviously, all oncologists and doctors turn around and we are like, how not? And he put on the table two concepts that seemed pertinent to me. One, failure or claudication of a vital organ, and two, risk of death, imminent risk of death. So I think that's what we have to understand today because of the visceral crisis. Mother's cancer, the sensitive hormone, is also heterogeneous. Dr. Juke already commented on the negative triple, and even though we know some mutations that are related to phenotype B and phenotype A, sadly today we do not have any markers that can predict how our patients are going to do. So we have to take care of the clinic and see in which drawer we accommodate our patient. How do we do this? In this slide you can see how we have a highly sensitive profile to endocrine therapy and the visceral crisis profile that I already mentioned. All these elements that are in the middle, I think we can summarize them as follows. We are going to have 15% to 10% of patients with visceral crisis who are going to have an important load, where, as we already mentioned, their life is at imminent risk or they have a claudication of an organ, and where they are rapidly progressing to different lines of treatment. On the other hand, we are going to have that same percentage, maybe 5% more, of patients with disease and ailment, and you have seen them in your daily clinical practice. Many of them have low tumor load, it practically seems that they have no cancer, and they even have long-term responses to non-fashion drugs. I mean tamoxifen, capacitavine, or even aromatase inhibitors. But the reality is that 65% to 70% of our patients will be in this challenge or in this gray area where we have to take several things into account. Before going into the studies, I would like to tell you what this concept of endocrine resistance is like. Well, it is a concept that was arbitrary, a consensus was made, and the experts decided how this endocrine resistance was going to be defined. Trying to explain a little bit what you are going to see in the studies, those patients who are new, that is, not exposed to previous therapy, here I put in yellow what an endocrine resistance is, and I put this example at the bottom, where an endocrine resistance is that patient that I immediately give him the treatment, and he progresses to pregnancy in no less than 2 or 3 months. But that is another type of resistance that we have not been able to identify by biomarkers. So here we talk about primary and secondary, and that is what you are going to read in the articles. I would recommend that you interpret it exactly the other way around, if the patient is hormone-sensitive, that is going to mean an acquired resistance, and if it is hormone-resistant, it is a primary resistance, that is, it was the resistance first. It is a matter of time. And for those patients who have already had previous therapy, it is practically the same algorithm. And well, we can comment on the discussion table if we have any questions. So we go back to our management algorithm, and I want to show you how cancer of mammary hormones is also becoming personalized. We go back to the so-called Me Too Trials, where you can see that again these molecules, palvociclib, ribociclib, and abemaciclib, now in the second-line or patient-hormone-resistant scenario, that is, they have already progressed to a treatment line, either with chemotherapy or endocrine therapy, you can see how the control arm was full-vestran, and the arm studied was the CDK4 inhibitor plus the full-vestran. And our results confirm the benefit of the CDK4 inhibitors, now in combination with full-vestran, with a progression-free survival, which, as I mentioned previously, as the results mature, some of them have also documented global survival. Other molecules used are the inhibitors of Emetor, the famous Everolimus, and we have these three studies where it is finally demonstrated that a combination of endocrine therapy with Everolimus is better than endocrine therapy alone, more in combination. I would like to comment a little bit on the frequency of PI3K mutations, and here is another selection panorama of the third line, where today we know that the PEDLICYP combined with full-vestran, which is a PI3K inhibitor, versus full-vestran alone, for these patients who express the mutation, it is better to give them full-vestran alone. And probably this study is already one of those that begins to mark the therapeutic sequence, since in most cases these patients previously received these new molecules of CDK4 inhibitors, and it is being analyzed if the presence of the mutation in combination with the PI3K inhibitor gives a better prognosis, and so far the results are positive. Another thing that also exists, as the doctor mentioned, the PAP inhibitors, just remember that these PAP inhibitors can also be used in patients with specific hormonal receptors where we have this germinal mutation, and finally there is a benefit for these patients. In such a way that, as you can see, we are already in the third line or in the fourth, and there the disjunctive enters more frequently, if at what moment I am going to use chemotherapy, or at what moment it is futile that I continue to insist on this use of therapy endocrine. The reality is that I think it is a continuum, it will depend on the characteristics of the patients, we go and return frequently from one scenario to another, to analyze the case. And well, I would like to conclude by making certain reflections on where we stand. Despite everything I have told you, the reality is that in the United States, or even in high-income countries, only 60-70% will receive first-line patients with endocrine therapy, even though it is considered the standard. If they progress, only one in four will continue with endocrine therapy. And when an analysis is made of what characteristics patients have, you can see how we feel more comfortable in this indolent scenario, that is, we still have a lot of faith in chemotherapy. And what does this depend on? Well, probably access to these therapies is something that definitely makes a difference. Even in Germany, an economic power, the introduction of these new molecules has been gradual. You can see in the blue bar where the CDK4 inhibitors for this last cut were in 2017, already 40% of the patients, but look at the pink box, how still 36% of their patients continue to receive first-line chemotherapy. And well, we in Latin America, in particular the Institute, we are working on this study that coordinates the COG, to find out in Mexico and Latin America what our barriers are, if it is only our access or do we have other barriers that we want to explore. Well, I already took you through this film, where you can see that since the use of Tamoxifen in 1977, we practically had a great clinical experience with Tamoxifen, aromatase inhibitor and chemotherapy. And in 2012, when Everolimus came out, as I was telling you, and Fulvestran, and look at how now, practically from being a very important part of chemotherapy in our treatment, now it practically goes to the end and it will probably still remain after the directed therapies that continue to develop. Today the world is pink. I would not like to say goodbye without this reflection. Unfortunately, Latin America contributes with 70% of deaths, so our early detection work has to continue and continue to be able to reduce these numbers. Also remember that the objective for these breast cancer patients is, in the palliative scenario, to control their symptoms and for them it will be a marathon, because this group of patients will be those patients with 4, 5, 6 lines of treatment and today our goal is to delay the time for chemotherapy. Sadly, patients do not read the magazines or follow the guides and we have to find, day by day, where and how we accommodate our patient with what we have and how we can help him. In such a way that I conclude by saying that today, advanced breast cancer is a chronic disease. In its approach, we have to think in the long term, since today we have multiple alternatives and probably chemotherapy is the last one we should think about. Breast cancer is also directed to precision medicine. The world challenge is access in all countries, especially emerging ones, and if possible, a patient with advanced breast cancer or hormone sensitive, in its first line, must receive endocrine therapy, except in the visceral crisis. With this, I conclude. Thank you very much. Thank you very much, Dr. Cabrera. Very interesting, but from what we could see, it seems that if you are going to use a discipline inhibitor, take the one you want. Although everything that seemed very simple in my time as a resident, is already getting complicated and it is getting quite complicated. The directed therapy and the specific patient therapy, if you want to call it that, is where we have to go. And for this, Dr. Marco García, who is a medical oncologist from the National Cancer Institute and who is in the medical oncology service of the Hospital Estar Médica de Querétaro, will talk to us about early breast cancer treatment in GER2 positive patients. Marco, if you want to share your screen, please. Yes, good morning. I remind all the attendees to send their questions, put them in the questions and answers section so that we can present them at the time of the discussion. Marco, thank you very much. Hello, good morning to all. Thank you very much for the invitation. Today I am going to talk to you about early breast cancer, GER2 positive. As we know, the overexpression of GER2 positive is present in 15 to 20% of breast cancer clinical subtypes and represents an aggressive phenotype and poor results for patients. In this study, published in 2009, the study indicates the power as an independent prognosis that has the presence of GER2 positive receptors in patients with early clinical stages T1a, T1b, negative ganglions and its impact on free recurrence survival and free recurrence survival at a distance. Here we can see the lower rates when GER2 positive is present in patients with T1a. The addition of T1a to chemotherapy meant an improvement in free-of-progress survival and in global survival in the metastatic and early stage. However, despite the addition of Trastuzumab, a quarter of patients in the early stage have recurrences. This has led to looking for anti-HER2 strategies that allow us to reduce these recurrences. One of them is the scaling strategy, where we have tried to combine two anti-HER2 agents to try to reduce these recurrences or extend the duration of the anti-HER2 therapy. We have also learned that not all patients can be added to therapies. This type of strategy is called the scaling strategy, where basically the anticyclines are omitted. As we will see later, the results are quite interesting. The points that we are going to address are adjuvant treatment, post-adjuvant treatment, adjuvant treatment in high-risk and low-risk patients, and extended adjuvant therapy. Starting with the adjuvant treatment, in the past we know that this type of treatment was reserved for inoperable patients, locally advanced or inflammatory, and what it gave us was a better index and quality of surgery. However, this paradigm has changed. Currently, early breast cancer, tumors greater than 2 cm and with positive ganglions should receive adjuvant treatment. The first studies or pivotal studies using trastuzumab with chemotherapy are these, the NOAH study and the JEPAR-4 study. JEPAR-4. The NOAH study is a study that had as its primary objective the free survival of events. Here they report it with the combination of trastuzumab of 58% versus 43% with a rate of 0.6% and a significant rate. But the interesting thing was its secondary objective, the complete pathological responses, where they report for the treatment of the combination 38% versus 19% with chemotherapy. The JEPAR-4 study is a study that had as its primary objective to look for the complete pathological responses in adjuvant treatment, and here they report us with rates of pathological responses of 31% versus 15% in favor of the treatment with trastuzumab. So, these results are very forceful. And once the knowledge was given in the metastatic scenario of the double blockage, the horizontal blockage of the R2 pathway with trastuzumab, pertuzumab was tested in the adjuvant scenario. This study, the NOAH-SFER study, is a phase 2 study that had as its primary objective the complete pathological responses with the use of taxanos with trastuzumab or the double blockage. For this study, four arms were used, the first arm of 12-taxel trastuzumab, the second arm 12-taxel trastuzumab-pertuzumab, the third trastuzumab-pertuzumab only, and the fourth 12-taxel-pertuzumab. The complete pathological response rate with the use of taxano and the double blockage was 48.8%, something really very relevant. And when a 5-year follow-up was done of the progression-free survival, the B group, the taxano group, with the double blockage, had rates of 86% of progression-free survival at 5 years old with a rate of 0.69. Another pivotal study was the TRIFAENA study. TRIFAENA is a study that had as a primary objective cardiac tolerability. However, what is also interesting here was the complete pathological responses that are reported. The treatment arms were the following. It was to look for or know the effect that the use of anthracyclines had and the use with concomitant or sequential double hormonal blockage. The first arm of trastuzumab-pertuzumab with FEC followed by 12-taxel-trastuzumab-pertuzumab. The second arm with FEC followed in a sequential way with 12-taxel-trastuzumab-pertuzumab. And the third arm, very interesting, where they omit the use of anthracyclines and give 12-taxel-carboplatin-trastuzumab-pertuzumab. As we said, it was not the objective of this study, but here we see complete pathological responses, which are extremely important, ranging from 57.3% to 66.2%. And when a 3-year follow-up was done in free-of-progress survival, we see that there is no difference between the three treatment arms, nor was there when the 3-year follow-up was done in terms of global survival. Now, this... Well, I show you below this study, a randomized phase 3 study, where patients with hormonal receptors are evaluated, ER2 positive receptors, clinical stages 2-3, where two treatment arms are evaluated. A study that evaluates the absence of anthracyclines by giving paclitaxel-carboplatin-trastuzumab-pertuzumab for three cycles, followed by another six. And in the second arm, the use of epirugin-anthracycline for three cycles with comitant and with trastuzumab-pertuzumab, completing or adding six more cycles, evaluating for surgery and giving trastuzumab for a year. What is relevant is that when it is stratified by groups, the group that used anthracyclines had complete pathological responses of 67%, and in the group where the use of anthracyclines was absent, 68%. In progressive free survival, Dr. Vanderwood, born in 2020, reports the rates of free survival of disease at 3 years, 93 versus 92%. So, a very interesting fact to take into account. Now, with respect to the complete pathological responses, it is a very important marker that we look for after the chemo-activating treatment. It has always been a question if these complete pathological responses are a subrogate marker of long-term results. In this meta-analysis, two clinical trials were evaluated with 11,950 patients and were followed for three years. And here, what they graph us is that they report a correlation in the complete pathological responses rate and the free survival of disease and global survival regardless of the clinical subtype of breast cancer. When they are stratified by the subtype or clinical tumors, what they report is something we already know. The patients who have more complete pathological responses are the triple negatives and the CER2. And speaking specifically of the positive CER2 patients and stratified with the presence or absence of hormonal receptors, they report that there are complete pathological responses rates in 50.3% of patients with positive hormonal receptors versus 30.9% of those patients who have positive hormonal receptors. This response rate was found in a correlation in the free survival of events with positive CER2, as we see here graphed. And when we also stratify by the presence or absence of these receptors, we see that there is a benefit in those patients with positive hormonal receptors, but those who see a greater benefit are those who have negative hormonal receptors. Now, in the scenario of postnatal pregnancy, here we have the CATE study, which is a randomized phase 3 study that is stratified by negative positive hormonal receptors and complete pathological responses. An indispensable requirement in this study was that, after the meditative chemotherapy, there was residual disease, either in mothers or in exiles. Two groups of patients were evaluated, the first arm with emtansinatrastuzumab, the two that we already know, every three weeks for 14 cycles, and the usual arm, emtansinatrastuzumab, every three weeks for 14 cycles. The primary objective of this treatment was the free survival of invasive disease. Okay? I can't pass it on. I got stuck in the presentation. Why don't you try, Marco? If you leave and come back in, Marco. Or under the screen. There it is, sorry. Yes, great. As we said, the primary objective was the free survival of invasive disease, and here they report to us three years the results with rates in favor of emtansinatrastuzumab more than 83% versus 77% against emtansinatrastuzumab, and in the picture on the right, we see the events, where we see that the lower rates of emtansinatrastuzumab were for the experimental arm, and a lower rate of events in terms of recurrent disease at a distance, locoregional, and contralateral. When we stratify them by the state of the positive or negative hormonal receptors, there was benefit in these patients, even in those patients who only used emtansinatrastuzumab as a monodrug, there was also benefit, or the duplet, and regardless of the result of the ganglions after the surgery treatment. Moving on to the adjuvant treatment, the adjuvant treatment reduces the risk of recurrence by 40%, reduces the risk of death by 30%, and these benefits are independent of tumor size, ganglions, and the state of the receptors. However, we still have patients, 15 to 24% of patients have recurrence. In a scaling strategy, in the atepetrial study, patients with adjuvant paquitaxel and emtansinatrastuzumab in tumors smaller than 3 cm with negative ganglions, a single arm of treatment was used in this Phase II study, with the primary goal of survival free of disease. And in this, we see that the follow-up to 3, 5, and 7 years, the rates are really very even, 98%, 93%, and when it was stratified by the state of the receptors, both positive or negative, both groups of patients benefited. As for the affinity study, it evaluates the double blockage of LER2 versus the traditional one in patients with high risk of recurrence. Who are these patients with high risk of recurrence? Those patients who, after surgery, have had positive ganglions or negative nodules with a tumor size larger than 3 cm, or those patients who have negative ganglions with tumors between 5 mm and 1 mm with at least some of the following aspects, that they are grade III negative hormonal receptors or that the patients are less than 35 years old. And here we observe that in terms of survival free of invasive disease, there was a big difference compared to the population without negative ganglions, which was contrary to those patients where we had positive nodules with rates of 89% versus 76% and a HASA ratio of 0.77. And finally, the extended therapy. In this study, where meritinib and placebo were used after the auxiliary treatment with trastuzumab, a phase III study, also stratified in positive and negative hormonal receptors, patients were candidates for this trial, those who had completed the auxiliary treatment with trastuzumab before the age of 2 and were evaluated to give treatment with meritinib 240 mg per day versus placebo. And the primary result was survival free of invasive disease. And what they report to us in terms of survival free of invasive disease in the population with intention to treat, there are better rates in the group of meritinib of 80 versus 87.1% with a HASA ratio of 0.73. And when patients were stratified due to the absence of positive receptors, those who benefited the most were those patients with positive hormonal receptors. Well, as conclusions, neoadjuvant chemotherapy with trastuzumab and partuzumab should be given to those patients with early breast cancer, tumors larger than 2 cm or with positive ganglions, since it improves complete pathological responses and very likely these complete pathological responses have a correlation in survival free of disease. Patients with tumors smaller than 3 cm, negative nodules, we must consider paclitaxel trastuzumab as the ATP study in an effort of scaling therapy. In patients with adjuvant chemotherapy and high-risk patients, positive ganglions, the affinity study, partuzumab, trastuzumab. And in patients with residual tumor, we can use caterine in trastuzumab tanzine, after taxanos, in treatment based on trastuzumab, in those patients with residual disease, in mamma, waxilla. And meritinib in patients as an extension therapy, in patients with anti-ARDO treatment, in patients with positive hormonal factors. Finally, here I present you a treatment proposal from Dr. Bárcenas, which can encompass everything we just talked about. In those patients, T1a, T1b, without negative ganglions, patients can go to surgery and a treatment based on scaling, with taxano, erceptin, followed by erceptin for a year. In those patients that have some high-risk data, it must be evaluated. And in those patients where we already identify a high-risk factor, or those patients that are candidates in adjuvants, we can make use of the treatments, either by omitting the use of erubicin, altracyclines, or only using taxanos with the double hormone blocker. And depending on the results after the surgery, of the neoadjuvant treatment, in case of residual disease, in mamma, waxilla, using tantzina, trastuzuma, or extending the treatment in those positive CERDOS patients with meritinib. Thank you very much. Thank you very much, Dr. Marco Antonio García, for your detailed presentation, with the calmness you gave it, and thank you for taking the time to finish and complete with the recess. Thank you very much, doctor. The questions, I remind you, you can send them to the Q&A blog. To restart again with the course. And we ask you, that during this break, the recommendations do not leave the platform. If you can support us by keeping your microphones and cameras closed, we will thank you. I don't know if you want to add something, Dr. Vargas. I will ask everyone to keep their microphones off during the lectures. And I apologize for the inconveniences that have occurred. We hope that during this break we will not have any problems. Thank you very much, doctor, for that excellent coordination and Dr. Cantú for the questions and answers. This is normal in this new virtual life. See you at 10. Thank you for watching! Well, it's 10 o'clock in the morning. We give the floor to Dr. Paula to continue with this excellent coordination, doctor. Hello, how are you? Thank you very much. Welcome back here. Well, now we are going to enter the early disease module and we are going to close with the biomarkers that we can ask for in daily life. Well, for me it is a pleasure to introduce Dr. Iván Maldonado. He is a medical oncologist. He currently works in Quito, Ecuador. And well, with great pride, he did the high specialty in breast cancer with us at INCAN a little while ago. So, well, it was nice to see you again, Iván, and welcome. All yours. Thank you very much, Dr. Paula, for the presentation. Thank you for the invitation to the International Society of Gynecological Cancer and the Mexican College of Gynecologists and Oncologists. It is a pleasure to be able to share with you. And well, we are going to talk now about a totally different tumor. We are going to talk about neoadjuvant endocrine therapy, a topic that has really taken effect and will continue to take effect, especially in the context of the COVID-19 pandemic. The agenda that we are going to review briefly will be breast cancer, positive hormonal receptors, negative GERDOS. What types of neoadjuvant endocrine therapy can we use in this strategy? The comparison between endocrine therapy versus chemotherapy. How to evaluate the response and what biomarkers could we use to guide us for the treatment? The therapies directed along with endocrine therapy in the neoadjuvant scenario. And of course, to propose an algorithm to be able to make a selection of patients and to whom we could give endocrine therapy to neoadjuvant. When we talk about breast cancer, we know that it is a heterogeneous disease. And specifically, we will now talk about a different tumor. In the first part, the tumor with positive hormonal receptors, negative GERDOS or called luminal. A very representative group. We all know that within the classification, the luminal breast cancer, either A or B, corresponds to approximately 70 to 75% of the cases that we are going to see in clinical practice. It is the most frequent. And also of relevance to take into account that the disease in Latin America, as we had already mentioned, generally occurs in 2 and 3 locally advanced stages, up to 70% of the cases. That is why the neoadjuvant strategy is more relevant and even more so in disease with positive hormonal receptors. As for the neoadjuvant treatment, the neoadjuvant strategy has already been mentioned in previous talks, but remember that the main objectives of the neoadjuvant treatment are maintained, either with chemotherapy or endocrine therapy, which are the already known ones. The de-escalation of surgical treatment in patients who are inoperable, make them operable. Or in patients who need mastectomy, be able to do more conservative surgeries, raise the rates of conservative surgery instead of mastectomies. In the asylum, when it is also possible to de-escalate the treatment and be able to do a sentinel ganglion after neoadjuvance, when it is possible, by meeting certain parameters. And of course, the current objective for which we are now guided, especially in the systemic part, is this prognostic and predictive value that we can obtain by doing an in-life evaluation of the tumor, giving systemic treatment in the adjuvant. And of course, this complete pathological response has shown to have a prognostic value, as we see in the curves. It is better for the patients, they have better survival, who have a complete pathological response versus residual disease. And we can do something to rescue those patients, especially in tumors that are aggressive, aggressive phenotypes. This is already standardized in triple negative. We can rescue or save patients who do not have a pathological response with capecitabine based on the results of the CRADEX study, for example. In positive HER2 disease, which they just talked about, we can rescue those patients after neoadjuvance, who do not have a pathological response with TDM1 based on the results of the Catering study. However, in luminal disease, those who have positive lung receptors, I put a question mark on them, because it seems that this pathological response is not the best biomarker, it is not the best endpoint to pursue, and we are going to review it in the evaluation part of the answer. But this is the neoadjuvant strategy and it is well validated. As for the use of endocrine therapy in neoadjuvants, the prescription is really very low. It is a therapy that I think is underused. Generally and classically it has been reserved for elderly, fragile patients who have comorbidities, who do not want to receive chemotherapy. For example, in this study, which is a review of the National Cancer Data Base of the United States, only 3% of the patients who were candidates for a non-adjuvant systemic treatment received endocrine or hormone therapy, non-adjuvant. So the prescription is low, however, this will probably change. What information do we have about what medication we can use? What endocrine therapy should we use when we have a patient who is a candidate? Well, here are studies from 20 years ago that started already in phase 3, since 2001 with Dr. Mathew Ellis. We have the P24 study, IMPACT, PROAC, ACOSOC, Z1031, Part A and B, the STAGE. Most of the evidence is in post-menopausal patients. Uniquely, the STAGE study is in pre-menopausal patients. And as we can see here, tamoxifen was compared versus an aromatase inhibitor, either letrozole, anastrozole or exemestane. And these patients received an approximate treatment of 3 to 4 months. We see that the primary endpoints in these initial studies, in the studies of comparison between endocrine therapy, the objectives were the clinical response, generally measured by palpation only, by ultrasound, and also the rates of conservative surgery, how feasible it was to convert that patient and reduce the treatment to conservative surgery. As we can see here, most of the studies show that the aromatase inhibitor is higher than tamoxifen with clinical response rates, measured by ultrasound palpation, around 30, 50, up to 60% in some cases. The response to complete surgeries, however, remains very low, less than 2%. Just to highlight some of these studies, the P24 study, the oldest study that compared letrozole with tamoxifen before surgery in a non-adjuvant way, we can see that the clinical response rates were 55% versus 36% with tamoxifen, and also the rates of conservative surgery of the mother were higher, 45% with letrozole and 35% with tamoxifen. As for the Impact study, another study that also compared an aromatase inhibitor, in this case anastrozole versus tamoxifen, and versus the combination of the two drugs, tamoxifen plus anastrozole, we can see that anastrozole was also higher than tamoxifen and the combination. As for the rates of conservative surgery, the conversion of a mastectomy patient to conservative surgery. All these studies were put in a systematic review and a meta-analysis by Dr. Laura Spring, already well known for the meta-analyses, where the superiority of aromatase inhibitors over tamoxifen is confirmed, obviously in postmenopausal patients. We see that as for the clinical response, the Hazard Ratio reached 1.69 in favor of the aromatase inhibitor. As for the radiological response, the Hazard Ratio reached 1.49. As for the rates of conservative surgery, also in favor of the aromatase inhibitor with Hazard Ratio of 1.62. These were 20 studies, almost 3,500 patients, summarized all the studies that we reviewed previously. In the complete pathological response, however, there were no differences, they were low, both with tamoxifen and with aromatase inhibitor. We already know, then, that aromatase inhibitor is superior to tamoxifen and is what should be used. But which aromatase inhibitor should we use? Which would be the preferred? The favorite, well, we have the study ACOSOC Z1031, a study that compared the three available aromatase inhibitors, letrozole, anastrozole and hexamethane, in neoadjuvant form. And as we can see here, the bars, there was no statistically significant difference in terms of the clinical response between the three inhibitors and also in terms of suppression of the levels of KI-67. They were similar, so any of the three could be used in patients. Another option that could be considered and that could be thought of that perhaps works better, extrapolating from metastatic disease, is Fulvestran. However, there are not many studies. The CARMINA study and the ORGEN study were two studies that tried to compare Fulvestran versus aromatase inhibitor to see if it is superior, even in a dose of 500 mg, which proved to be superior to the dose of 250 mg. And well, here there really was no benefit of Fulvestran. In fact, numerically there was a benefit, rather, in favor of anastrozole versus Fulvestran in a neoadjuvant way. As for the duration of the treatment, there is no standard, but we are going to try to give a guideline here. Well, most studies, from P24 to all the most recent studies, have given an endocrine-neuroadjuvant treatment duration between 3 and 4 months at least. This is extrapolated a bit from the duration of the chemotherapy treatment to obtain response rates, as I had told you, between 40, 50, 60%. However, the response rates remain low. And as we are going to review here, we could give an approximate duration based on this study, the Lombard study, where the average time for the minimum objective response was 3.9 months. That is, patients take almost 4 months to have an objective response with endocrine-neuroadjuvant therapy. And in this study, the average time for the maximum response was 4.2 months. So I could tell you that the treatment should be given at least for 4 months to have an objective response and perhaps reach a maximum response. We have the study of Levi, where three periods of endocrine-neuroadjuvant therapy with aromatase injections were evaluated. Here the time of 4, 8 or 12 months of endocrine-neuroadjuvant therapy was evaluated. And we see that the longer the endocrine therapy is given, the clinical response rates generally increase and also the complete pathological response rates. That is, after 4 months, we had a 49.6% response rate, which rose to 95% if the patient received 12 months of endocrine treatment. The complete pathological response also rose from 2.5% to 17.5% in patients who received up to 12 months. You have to be a little cautious here. The longer it is true that it seems that the response increases, but there is also more risk of finding endocrine-resistant secondary. So we are going to see that the recommended time is between 4 and 8 months. But if the patient does not progress, there is no evidence of clinical or radiological progress, and the patient still does not have the conditions to have a conservative surgery, which would be the objective of endocrine-neuroadjuvant therapy, it could be continued until 12 months, having adequate control. As for the use of chemotherapy versus endocrine therapy, that is, the question is also why not use only chemo and endocrine therapy? Well, we have, there are not many studies, but at least 4 studies have compared, have evaluated chemotherapy with anticyclines and taxanos, the majority, versus endocrine therapy. In postmenopausal patients, the majority, and in the Spanish Geikan study, a subgroup had premenopausal patients, almost half of the patients were premenopausal, and the Kim study, which is of Korean origin exclusively, had only premenopausal patients. So, in postmenopausal patients, it is really comparable, there is no evidence that chemotherapy has better results than endocrine therapy in patients with luminal tumors. That is, the clinical response, for example, in the study of semiglasso, was identical, 64%, both with endocrine therapy and chemotherapy, with anticyclines and taxanos. The pathological response was slightly higher in chemotherapy, without statistical significance, and the rates of conservative surgery were even numerically higher in endocrine therapy, but it had no statistical significance. So, in postmenopausal patients, chemotherapy is similar to endocrine therapy. Here is a point of caution, if we must have, in the analysis of subgroups of the Spanish Geikan group and the Kim-Korean study, in premenopausal patients, there was a statistically significant difference in favor of chemotherapy in terms of clinical responses and also pathological responses. 75% vs. 44% with chemotherapy vs. endocrine therapy and 83% vs. 52%. That is, in premenopausal patients, we must be a little careful, because chemotherapy can be superior in terms of clinical responses in premenopausal patients. A meta-analysis was also analyzed, also by Dr. Laura Spring, where chemotherapy vs. endocrine therapy were compared, and here we can see that the HASA ratios, the confidence intervals and the PES are not statistically significant. There are no differences in clinical response, radiological response, conservative surgery rates, complete pathological response rates. It is really comparable to using chemotherapy with endocrine therapy. And going a little further, how would we evaluate the response to endocrine therapy? As we saw at the beginning, this new concept of evaluating the pathological response to be able to look for long-term links seems to be that it does not apply and that it is not the best biomarker in luminal disease. As you can see, triple negative disease, positive GERDOS disease, the curves are totally separated. The links are definitely higher than in patients who do pathological response. But if we look at luminal disease, in the group of positive low-degree hormonal receptors, especially 1 and 2, the curves are practically overlapped and do not reach a statistical significance in terms of the benefit of reaching a PCR. And if we evaluate it in an even finer way, a little more refined, as with the methodology of Dr. Simans through the Cancer Boarding Residual, the RCB, we can see that it is even a little striking and contradictory that those who have a complete pathological response, the arrow there with an RCB of 0, have a lower survival rate than those patients who have an RCB of 1, who have a residual disease, even if it is minimal. So it seems that other biomarkers are needed to be able to evaluate luminal disease in terms of the response. This is how some studies have been done, many of which have been participated by Dr. Elis, Mathew Elis, and publications where it has been sought, for example, the KI67 as a biomarker for the suppression of the proliferation of these tumors. Some validations have been made, one of them is in the study COSOC Z1031, in its Part B, where the free survival of recurrence was evaluated with a cut point of 10% of the KI67 performed in a biopsy, a new biopsy, during the non-adjuvant treatment at 2 or 4 weeks. It was seen that the cut point of 10% can discriminate in recurrence, more or less, according to the 10%. It was also identified not only the KI67 at 2 or 4 weeks after the non-adjuvant therapy, but also the basal. This was done in an equal perspective analysis, a validation of the POETIC study, where aromatase union was used in a perioperative way, two weeks before, two weeks after the surgery, and some groups could be made where, evaluating the basal KI67 and the KI67 at 2 weeks, we can know the absolute risk of recurrence or relapse at 5 years. For example, those patients who have a low risk of a low KI67, less than 10% basal, and at 2 weeks it is still low, the risk is less than 5% of relapse. On the other hand, the patients who have a high KI67, at first greater than 10%, and that remains high after 2 weeks of biopsy, those patients have a higher risk of relapse at 5 years of almost 20%. And those intermediate patients where the KI67 is high, but it can be suppressed at 2 weeks and it becomes low, less than 10%, they also have a good prognosis with a risk of less than 9%. All this has been put into context and Dr. Matthew Ellis first demonstrated it in the P24 study and then it was validated and finally in the Z1031 study is the famous PEPI score, which is the Endocrine Preoperative Prognosis Index, which can help us to discriminate the risk of recurrence and the survival of specific breast cancer in patients who reach or not a PEPI of 0. This PEPI index takes into account not only the KI67 as we saw, but also, for example, the size of patients who remain after endocrine like T1 or T2 have 0 points, who do not have positive ganglions have 0 points, who have a KI67 less than 2.7% have 0 points and who maintain the attention of estrogen receptors with an ALRES of 3 to 8 or that are positive have 0 points. Thus, the patient who remains with a PEPI of 0 in this validation we can see that they have an excellent survival, both free of recurrence and also of breast cancer, of survival of specific breast cancer. Most patients live more than 97% if they have a PEPI of 0, even without chemotherapy. As we will see, this will help us to avoid and de-escalate the treatment once the patient has finished endocrine therapy. As for the most recent times of the ALTERNATE TRIAL study, it was reported in ASCO 2020. This study is still in course, but it already had preliminary results. And here it is put precisely this way of treating endocrine therapy. It was evaluated as a primary endpoint, a residual endocrine sensitivity disease rate, the ESDR, which is nothing more than the sum of the PEPI 0, which I just explained, versus the complete pathological response. Adding those two, it is a residual endocrine sensitivity disease rate. And what was compared are three arms, anastrozole, which we already know is my favorite aromatase, fulvestran, by the FALCON study on metastatic disease, which proved to be superior, and the combination of anastrozole and fulvestran, as in the SWOV-226 study, where it was also superior to metastatic disease. And here it was about finding out which one was more effective to achieve this suppression. However, there was not, in the preliminary results presented, a statistically significant difference between anastrozole, fulvestran, or anastrozole plus fulvestran, in terms of this residual endocrine disease rate, which is the sum of PEPI 0, modified in this case because fulvestran is used, versus, and more the complete pathological response. As for the selection of patients, we have more and more information and we have more publications that you can use the genomic signatures, the genomic expression profiles, to select which patients could do better, with endocrine endocrine therapy or with chemotherapy, there are also reports. As for ALONCOTYPE, using the score of 21 genes, which has the most publications, we can see in this study, for example, that those patients who have a score of score records less than 18, these are scores from the previous Taylor X study, less than 18, reach a clinical response of 54% with endocrine therapy, which drops to 22% if the patient has a score record of more than 31. And likewise, the risk that the patient progresses, being in endocrine therapy, if we give him 18, is 1% versus the 17% risk that that patient progresses if we use endocrine therapy with a score record greater than 31. So ALONCOTYPE could, in fact, it can help us select these patients. Here we have evidence of a study that is much smaller, but with a design very similar to Taylor X in adjuvancy, but it is in adjuvancy, where ALONCOTYPE was also used, the score record of 21 genes, to select patients for endocrine therapy or chemotherapy. Those with less than 11 of the score records went directly to non-adjuvant endocrine treatment, those with more than 25 went directly to non-adjuvant chemotherapy, and those with an intermediate range between 11 and 25 were randomized for non-adjuvant endocrine treatment versus non-adjuvant chemotherapy. And these same clinical response and pathological response outlines were evaluated, and above all, the rates of conservative surgery with each of these groups. As we can see, the clinical response rates are always greater than 50-70% in all groups, obviously using chemotherapy in high-risk groups and endocrine therapy in low-risk groups. And what we can see is that there was a difference, which was statistically significant in terms of endocrine therapy in those patients with an intermediate score record of 11 to 25, versus chemotherapy, which was higher. However, in terms of conservative surgery rates, we can see that there was no difference, that is, they also had rates of 72% with non-adjuvant endocrine therapy versus even 63% with chemotherapy, which is usually the goal we look for in non-adjuvant therapy. As for targeted therapy or target therapy, the new drugs, cycline inhibitors 4-6, PI3K inhibitors, mTOR inhibitors, all of these drugs are already being tested and most Phase II studies have been published to be able to overcome endocrine resistance and be able to have better outcome. The problem is that most of these studies use different arms, some compare hormone therapy versus hormone therapy plus cycline inhibitors, others use hormone therapy plus cycline inhibitors versus chemotherapy, and above all, different treatment schemes, different durations of non-adjuvant treatment, and also different endpoints or different objectives. Some look for the suppression of KI67, others put it as an endpoint the RCV, the residual cancer burden, others, the complete pathology response, and some, the PEPI score, which is what we are talking about, and other genomic platforms, such as PAM50, which can be reported as low-risk after endocrine therapy. Just to mention, the main studies, Feline, which was recently reported, compared ribocycline plus letrozole versus just letrozole, both intermittently and continuously, before surgery, and the objective was to see if the PEPI 0 was mostly achieved with ribocycline and letrozole. However, here, the PEPI 0 rates were similar, with no statistically significant difference between letrozole alone and letrozole with ribocycline. However, the clinical response rates are higher than 70%. Another study that serves as an example for ataria therapy, the Coraline study, where hormone therapy was compared, not hormone therapy, with ribocycline versus hormones, but hormone therapy with ribocycline versus standard chemotherapy, four cycles of ACE, then weekly paclitaxel, PAM50 was evaluated in a molecular way, at the beginning there were luminal patients, B, and the endpoints were the complete response through RCV, the molecular platform of PAM50 with a low recurrence risk, and also the clinical response. As we can see here, the risk, the ROR, which is the PAM50 of low risk, was very similar between the two arms, between ribocycline and letrozole, and the other group. And well, the proposal to finish, what would be the proposal for optimal management of non-adjuvant treatment? Well, we have a postmenopausal patient, ideally stage 2 and 3, and the ideal is that we have the biopsy with all the information of KI67, a genomic signature, ideally oncotype, we can start a level of aromatase, evaluate the KI67 at 2 to 4 weeks, if it is greater than 10%, I would discuss the change to chemotherapy, if not, continue the treatment. We can downscale the treatment, yes, here we can evaluate the PP0, those patients do not need adjuvant chemotherapy, they have excellent links, and we can also evaluate the initial score record and the KI67 less than 10% based on the study, the ADAPT study, and those patients do not need chemotherapy in adjuvancy either. Here, just to mention and you can read it, this is a guide that Dr. Matthew Ellis and Dr. Mitch Donset proposed in times of COVID to be able to select these patients. As conclusions, already to finish being within the time, the non-adjuvant endocrine therapy is underused, but it will be more and more relevant in the context of the COVID-19 pandemic that we continue, and this treatment gives us many options. Is it less toxic than chemotherapy? Improves the rates of conservative HIV? Should it be administered between 4 and 8 months? Requires a dynamic monitoring strategy guided by biomarkers, Ki67, score records, PP score and Ki67 could help us select patients who do not go to chemotherapy after endocrine therapy. It is an excellent opportunity to evaluate endocrine sensitivity and is an effective, safe and reasonable alternative to chemotherapy in postmenopausal patients with illuminal tumors, especially. With that, I say goodbye and thank you very much. I am attentive to questions and comments. Thank you, Dr. Maldonado. As you can see, at least for neoadjuvant therapy, chemotherapy is a good alternative. Some of us would be anxious to have a patient 4 to 8 months without doing anything other than oral treatment, but the evidence seems to be strong. We can ask this in the section, when we have our discussion table. And now we have the same hormone therapy in the adjuvant scenario. And for this we have Dr. Leopoldo Lugo. He is a medical oncologist graduated from the National Cancer Institute and is currently at Regional Hospital No. 2 in Querétaro. Leopoldo, nice to meet you. Likewise. First of all, I would like to thank the International Society of Gynecology and the Mexican College of Gynecologists and Oncologists. And precisely the topic I want to discuss with you today will be about hormonal treatment in adjuvant breast cancer. This is a fairly broad topic, but I wanted to focus it precisely on what Dr. Paula had already commented on. We know that the hormonal disease is a heterogeneous disease. And many times we have all faced the decision in adjuvancy how much I am going to do more, that is, how much I am going to scale the treatment in a patient talking about hormone therapy, or how much I am going to de-scale the treatment in these same patients. Without that, I would like to focus the practice today. We are going to talk a little bit about introduction, some scaling strategies, and some de-scaling strategies. As you already mentioned, the hormonal disease is a heterogeneous disease. From histology, the expression of hormonal receptors is not the same when we have a high expression as when we have a low expression, or even one could be positive and negative. The KISS-67 is also a great predictor in terms of heterogeneity of this disease. And of course, the biological risk dictated by genomic signatures with a recurrence score, this will also give us differences in terms of the diagnosis of the disease. Historically, we have had great advances in what is hormonal treatment since the first description of the ophorectomy until now and more recently with the genomic tests and recently, last year, with some studies that have been published on incorporating inhibitors of cyclines in adjuvant treatment. However, this is the question that we all want to ask when deciding an hormonal adjuvant treatment. What benefit do I want to give to my patient? Global survival or a recurrence-free survival? And on the other side of the scale, do not forget the adverse effects that we are going to have, such as the risk of endometrial cancer, the risk of some traumatic events, the risk of osteoporosis, the deterioration in quality of life, which is very important for our patients. The adverse effects of chemotherapy, both short- and long-term. And finally, talking about the incorporation of inhibitors of cyclines, we know that they also have important adverse effects. But how are we going to understand the disease? We already said that it is a heterogeneous disease. Not all patients will behave the same. And when are we going to decide to scale and give our patient a double hormonal block? When are we going to decide to go beyond 5 years or recently it is valid to incorporate inhibitors of cyclines in the adjuvant part and in the part of de-scaling when we can stay calm in our patients with hormonal treatment. We are going to see these recent studies where patients with positive changes from 1 to 3 will surely be able to provide only endocrine therapy in some subgroups and be able to avoid the use of chemotherapy. To be able to understand this, we have to understand what are going to be our prognostic factors that are going to tell us when a patient has a higher probability of recurrence of the disease. On the one hand, we have the clinical stage. We know that the greater the presence of lymphatic ganglia, the greater the probability of recurrence. And on the other hand, we have the biological risk, this given by a high recurrence score where patients can also have this risk of recurrence. And not least, we also have to take into account the state of menopause. We know that the behavior of a pre-menopausal woman and a post-menopausal woman even compared by the same clinical stage and biological profile are different. As for the clinical stage, this slide is well known by all of you. We know that the greater the tumor size and the greater the presence of lymphatic ganglia, there is more risk of recurrence not only in the first years, but even a risk of recurrence up to 7.5 years later for this group of patients. We are going to talk a little about the scaling strategies in breast cancer and I would like to start with the part of the double hormone blockage. This is a study from here in Mexico where a different group is compared between women under the age of 40 and look, they were even compared by the same physiological level, by the same histological level, by the same clinical stage and the prognosis in these women will be more unfavorable than even in patients above 40 years both in free survival of disease and in global survival. Historically, we have these two studies already known by you, the TEX study and the SOFT study, both phase 3 studies, where pre-menopausal patients with breast cancer receive a tamoxifen treatment arm or more ovarian suppression and in the other arm give them exemestano, an aromatase inhibitor with ovarian suppression chosen by the researcher. Finally, I am going to talk about the joint analysis of both studies and we are going to see here the difference in terms of the primary objective, which was free survival of recurrence at a distance. We see a clear difference in the pre-menopausal patients who receive more exemestano for the pre-menopausal patients. This was not seen in global survival and this is something that we have to take into account that we are not going to benefit patients in global survival. Another thing that this study that is very important is that for the selected cohort of patients who had pathological clinical characteristics of low risk, such as the age above 40 years, such as negative changes or a smaller tumor size equal to 2 cm and a histological degree 1, patients generally and by tendency do not go to chemotherapy and are not seen either in this study benefited from a double hormonal blockage accompanied by an aromatase inhibitor. Not so for patients who had previously received chemotherapy and traditionally due to pathological characteristics, large tumor size or presence of positive changes, patients who had previously received chemotherapy and that finally this subgroup was also the one that benefited from giving this double blockage with an aromatase inhibitor such as exemestano. In the adjuvant part, and I have always talked about it, I think that something very important is the part of the adverse effects. We are going to improve free-of-recurrence survival, we must not forget that, but how are we going to affect our patient in quality of life? Many adverse effects can be related to the sexual part, such as the decrease of libido, vaginal dryness, and this implies other sociological and family aspects that can be affected in these patients. Something very important and associated with the aromatase inhibitor are the musculoskeletal symptoms, which is also important to take into account. Obviously, there was an early interruption in treatment for patients who had double blockage accompanied by an aromatase inhibitor, which was 16 against 11%. As conclusions, in favor, we have to increase free-of-recurrence survival, which has a greater benefit in young patients, with a 40-year age gap, with positive changes, and who had previously used chemotherapy. Against, which will not increase global survival, such as thrombosis, depression, and vasomotor symptoms. A strategy must be considered, and I think we always have to ask the patient, in young women, with high levels of tumor, with positive changes, and who had previously used chemotherapy. Another of the scaling strategies, and surely each of us has faced it, is when to decide to extend recurrence beyond 5 years. And this, the justification is that we know that in hormonal-sensitive patients, there is a subgroup of patients that can have recurrence beyond 5 years, continuously and constantly, between 5 and even 20 years. I think we all have in some of our files a patient who has recurred at 15 or 16 years of initial treatment. There are multiple trials that suggest that the risk of recurrence is reduced with extended therapy. It is always important to consider the real benefit against the cost of the increase of the cumulative side effects. And this is where we have to put the scale, and obviously more, ask the patient. In the same way, we have two studies already known to all of you, which is the ATLAS study and the ATOM study. I am going to talk about them together. Both are Phase III studies, where it was considered to authorize, in the case of the ATLAS study, to continue tamoxifen for 10 years, and the other was to suspend tamoxifen for years. In the ATOM study, it was also extended to 10 years or to stay only for 5 years. As for the results, the primary objective was the free survival of recurrence. There were benefits in favor of patients who had extended therapy above 5 years to 10 years. However, something very important to consider is the attachment to treatment, where we know that patients, for longer and with these adverse effects, it is more difficult for them to have a good attachment to treatment. Finally, the improvement of these two studies, plus other studies, showed that there is a benefit in reducing the risk of recurrence of extended therapy. The analysis of these two groups leaves us clear that extended therapy up to 10 years will make patients with positive gains. In the group of patients with negative gains, there was no such difference, and this lets us see again that the staging and the clinical stage played a very important role So, as conclusions of extended therapy, there is a significant benefit in terms of free survival of recurrence with extended therapy. Perhaps the subgroup that benefits the most from this treatment, would be patients with positive gains, and always consider this benefit against adverse effects, which will be accumulative over time. When we reach 5 years and face this decision, I think it is very important to take into account how our patient has been in the first 5 years in relation to adverse effects. Another scaling strategy that we recently saw last year is to incorporate cycline inhibitors in the treatment. We have important studies, one with positive results and another with negative results, although with some considerations that must be taken into account. We know that cycline inhibitors, such as vivocycline, valvocycline, and amebacycline, already have a demonstrated effectiveness in the metastatic field, however, we have always had the incognito in the adjuvant. In the same way, I am going to talk about the two studies together, the Monarch-E study, which is a phase 3 study that incorporated 5,637 patients with clinical characteristics of high risk that were characterized by the presence of 4 or more positive ganglions, or the patients who had 1 to 3 ganglions with some characteristics, a tumor size greater than or equal to 5 cm, a histological degree, degree 3, or a Ki-67 above 20%. In relation, they were randomized 1 to 1 to receive amebacycline. The Monarch-E study evaluated amebacycline, 150 mg every 12 hours plus standard endocrine therapy for 5 to 10 years, against the arm that we already knew, which was the comparator, which was standard endocrine therapy for 5 to 10 years. And finally, the PALAS study, which evaluated the incorporation of amebacycline in the adjuvant field, also evaluated high-risk patients clinically, and were randomized to receive amebacycline 25 mg 3 weeks for 1 week of rest for 2 years, plus standard endocrine therapy for the researcher, against standard endocrine therapy. Very important, before talking about the results, I would like to talk about the characteristics that differ a little in these two studies and that probably would have influenced the result of both studies, is that the Monarch-E study incorporated a little more patients in a slightly more advanced way, see, it incorporated about 60% with patients with more than 4 ganglions, unlike the PALAS study, that the patients with stage 3 and that could be given for this ganglionary trip, represented 48%. So, this is a difference that we can question in terms of the difference in both results. As for the results, the primary objective was free survival of invasive disease. There was a favorable response for the patients who received MEVACICLIP for 2 years, with an absolute difference in the benefit of free survival of disease, compared to the patients who received standard endocrine therapy. And as for the result of the PALAS study, you can see the curves are practically the same, there was no efficacy when incorporating PARVOCICLIP in the adjuvant terrain. As for adverse effects, and this is also important, we will not only have the adverse effects of endocrine therapy, but also those of a recycling inhibitor. In the case of the MONARCH study, one of the main toxicities that we already know was diarrhea, which was even presented in grade 3. And other toxicities presented that are of interest, although they were low, were neutropenic fever at 0.3%, interstitial pulmonary disease at 0.7%, and venous thromboembolic events at 2.3%. And in relation to the PALAS study with PARVOCICLIP, the most frequently presented toxicity was grade 3 neutropenia. However, as I told you a while ago, we have a positive and a negative study, and it is always important to take into account what could have been the characteristics that influenced the discrepancy between the two studies. And that is the high-risk disease, which had more patients in the MONARCH group than in PALAS. The discontinuation of the treatment, there was an early discontinuation with PARVOCICLIP at 42%, unlike AMEBACICLIP. And the median follow-up, which is something that has been criticized a lot in both studies, and especially in the Monarch study, is that it was a very early follow-up of 15.5 months. And another very important one, will be the pharmacokinetic and pharmacodynamic differences that both drugs may have. As conclusions in relation to Monarch, it was a positive study where an increase was shown in the survival rate of invasive disease against endocrine therapy only in patients who were in the category of disease. And in the PALAS study, the first year did not show significant benefits in increasing the survival rate of invasive disease. We have some studies pending, such as the NATALI study with ribocycline. And finally, something very important, and that we will all expect in the next months or years, will be the follow-up of both studies in the long term. We already talked about the fact that this disease is a heterogeneous disease with a risk of late relapse. And finally, I would like to talk to you about some of the strategies that we currently have for de-escalation in the hormonal adjuvant field, such as the RESPONDER study and the ADAPT study. We all already know the justification. The justification is given by the TAILOREX study, where patients with intermediate recurrence risk, cataloged between 11 and 25 points with negative axillary ganglions, it was enough to stay with endocrine treatment and chemotherapy did not increase the benefit in these patients. However, we always had the doubt in the patients who had 1 to 3 ganglions, and with this low or intermediate recurrence risk, it was also safe to stay only with endocrine therapy. Hence the justification of this study, which was also a phase 3 study, in which patients with positive 1 to 3 ganglions were incorporated, without metastasis at a distance, who were axillarily stratified by gangliosentinella or radical axillary dissection, and who had a recurrence score from 0 to 25. In total, 5,015 patients were enrolled and were allocated to receive follow-up chemotherapy of endocrine therapy against endocrine therapy. It should be mentioned that the basal characteristics of both arms were well balanced. And as for the free survival of invasive disease, which was the primary objective, we can see an important difference in favor of endocrine therapy, this in general in the population, with a follow-up average of 5.0 years. However, when evaluating some important characteristics, which at the beginning of the talk I had told you, that the state of menopause is a very important factor when deciding if my patient is going to scale or I am going to de-scale a hormonal treatment, this is made very clear to us by the RISPONDER study, where menopausal patients had an important benefit in continuing with chemotherapy. It should be mentioned that the basal characteristics were very similar for both groups of treatment. First, in the post-menopausal state, we can see that there is no difference in terms of adding chemotherapy to standard endocrine therapy. There was no difference in terms of free survival of invasive disease. But this was not the case in the group of pre-menopausal patients due to the characteristics that we already mentioned, where there is a clear benefit of incorporating chemotherapy in these patients, with a significant and extreme risk of invasive reduction of 46%. When talking about subgroups, in post-menopausal patients there was no difference, and in pre-menopausal patients, most of the subgroups are benefited when chemotherapy is incorporated into endocrine therapy. As for the menopausal state and the risk of recurrence, both in low risk from 0 to 13, and in intermediate risk from 14 to 25, there were no significant differences. And in pre-menopausal patients, from low risk from 0 to 13, and obviously in intermediate risk from 14 to 25, there is an important difference in terms of free survival of invasive disease. When comparing the menopausal state and the positive ganglions, we can see that in post-menopausal patients with a positive ganglion, or even with 2 to 3 positive ganglions, this difference is not seen either. And finally, in pre-menopausal patients, we can see this difference from the presence of a ganglion, even in 2 to 3 positive ganglions, incorporating chemotherapy into endocrine therapy. And in terms of global survival, we can see that in the case of post-menopausal patients there was no difference, and in the case of pre-menopausal patients, there was no absolute difference in favor of giving chemotherapy of 1.3%. And finally, the ADAPT study. Dr. Maldonado has already told us a little about this. This study values precisely the impact of the biological profile given by a recurrence risk less than 26, and this factor that Dr. Predictivo talked about, of X67, which could tell us a little about hormone sensitivity. Este estudio tuvo varios brazos. Me voy a enfocar únicamente en las pacientes que tomaron terapia endocrina adjuvante. Estas pacientes que habían recibido durante un periodo corto de tres semanas tratamiento hormonal. Después de este periodo de tres semanas eran evaluadas a través de la cirugía, y se evaluaba si las pacientes tenían un estadiaje ganglionar 2 o 3, o un riesgo de recurrencia mayor a 25, o 0, o un ganglio positivo, pero con un riesgo intermedio. Pero vean, sobre todo que no tuvieron una respuesta endocrina, y esto dado por un resultado de X67 mayor a 10, o el brazo continuaba a través de quimioterapia. Pero en el grupo de pacientes que tenían 0 o un ganglio, y que tenían un riesgo de recurrencia de 12 a 25, y que tuvieron este factor Predictivo menor al 10%, o las pacientes que ya conocíamos nosotros como de bajo riesgo por el score de recurrencia de 0 a 11, eran las pacientes que eran candidatas a continuar con el tratamiento endocrino. Aquí mostrarle un poquito... ¿Estamos sobre el tiempo? Sí, ya nada más les doy las conclusiones. Mencionarles que en estas pacientes de riesgo intermedio, y que tuvieron un kit como factor de respuesta menor al 10%, no hubo diferencia en términos generales, a excepción de las pacientes con presencia de más de 3 ganglios, donde sí hay diferencia, y que no serían las candidatas ideales para poder desescalar, y habría que brindarles quimioterapia. Finalmente, ya con esta última diapositiva, me gustaría concluir y volver a enfatizar que esta enfermedad es una enfermedad heterogénea, donde vamos a tener en cuenta estas tres características, el estado de la menopausia, la etapa clínica, y el riesgo biológico cuando podamos acceder a él, importante para poder decidir en qué momento voy a escalar o voy a desescalar. Y con esta diapositiva me despido. Muchas gracias. Muchas gracias, Dr. Lugo. Una muy interesante, y como siempre, usted muy puntual con sus comentarios para describirnos claramente dónde tenemos que poner énfasis al conocimiento. Y bueno, pues, las preguntas fueron muy nutridas. Las revisaremos al final en la sesión de preguntas y respuestas. Y para mí es un placer y un gusto muy querido presentar a la doctora Delia Pérez Montiel, investigadora y patóloga oncóloga del Instituto Nacional de Cancerología, quien nos va a poner, nos va a aterrizar a todo esto que hemos platicado, a como dice ella, a la realidad y la práctica clínica diaria. Doctora Delia, bienvenida. Creo que la tengo en mute. El micrófono, por favor. El micrófono. Creo que está... Todavía lo tiene apagado. ¿Ya me escuché? Buenísimo. Ahí ya la escuchamos. Si quiere poner su presentación en modo presentar, para que le quede más grande. Muchas gracias, Delia. Buenos días. Muchas gracias por la invitación. Y sobre todo, por la oportunidad de compartir con ustedes. Porque se han dado cuenta de que cada mañana hemos escuchado pláticas que se basan en los sectores positivos, los sectores negativos, los países del centro, el tráfico del virus, y todo esto que tiene que ver... Delia, no se te escucha bien. A ver. ¿Ya me escuché mejor? Acercate un poco más a tu micrófono. No, se escucha como mucho... Doctora, ¿si tiene a la mano algunos audífonos? Creo que podrían apoyarle. Sí, porque la mañana yo se la estaba con los audífonos. No lo escuchaba en ningún momento. Sí, pues ya ve que estas cosas de la tecnología... ¿Me escuchas mejor? No. ¿Qué puedo hacer? Yo creo que, como le mencionó el Doctor Cantú, lo más que puede estar cerca de su pantalla, y creo que eso ya ayudaría mucho con el micrófono que tiene directo la computadora. Voy a apagar la cámara. Sí. ¿Me escuchan mejor? Ya. Sí, mejor, doctora, gracias. Muy bien, gracias. Bueno, estuvimos escuchando toda la mañana conferencias acerca de cómo van a tratar ustedes a los pacientes, dependiendo del estatus general de la paciencia, si es de sectores positivos, si es de sectores negativos, etc. Pero esto tiene que ver principalmente con el resultado que les van a dar a ustedes del Departamento de Patrocinio. Entonces, vamos a evaluar cómo vamos nosotros, los patólogos... No puedo avanzar. No se te escucha. A ver, ¿ya me escucha? Sigue hablando. Vamos a dividir los marcadores en dos grupos. Los marcadores convencionales que lo vamos a realizar a todas las pacientes, y los marcadores en pacientes específicos. Vamos a dar un concepto de cómo es que los patólogos hacemos esto, cuáles son las limitaciones y los conceptos que ustedes deben conocer. Pero antes de empezar con esto, vamos a hablar de algo que tiene que ver con todos ustedes, que es el manejo de la biopsia antes de que llegue al laboratorio. Esto es muy importante porque este manejo lo va a hacer quien toma la muestra, el cirujano que está haciendo la cirugía, que es el directamente responsable de que este material llegue en forma bien al laboratorio. Entonces, la fijación de la muestra es fundamental. Y esto quiere decir que si ustedes no manejan de una manera adecuada, no vamos a tener todos estos resultados que son tan importantes para certificar a su paciente. Debemos de recordar que la penetración del formol en el tejido es de aproximadamente dos milímetros por hora. Entonces, en una biopsia está bien, pero imagínense un producto de mastectomía o un producto de un marcaje que no está seccionado para que llegue el formol al tejido van a pasar horas. Entonces, muchas veces cuando nosotros recibimos las muestras, recibimos la mastectomía que operaron ustedes el viernes en la tarde, se recibe en el laboratorio de patología el lunes, y cuando nosotros les decimos a ustedes tiene cambios por mala fijación, la respuesta es, pero es que estaba en formol. Sí, estaba en formol, pero sin cortar. Entonces, es muy importante que ustedes tomen en cuenta esto. En esta fotografía les muestro cómo los resultados de los receptores de estrógenos, vean ustedes a las ocho horas, son intensos. O sea, esta es una paciente que tiene receptores positivos. Pero si ustedes muestran, si ustedes ven esta fotografía con una fijación de apenas tres horas, vean cómo son negativos. Entonces, aquí también es muy importante el tiempo de fijación. En patología, cuando ustedes ven a los patólogos, dicen, no, pues es que ellos se la llevan muy a gusto, muy tranquilitos. No, lo que pasa es que hay tiempos. Y en patología, acuérdense, no hay urgencias. Si nosotros, por tratar de agilizar el procedimiento, no le damos el tiempo de fijación adecuado a las muestras, ya ustedes vamos a tener este desastre, que es una biopsia negativa cuando la paciente realmente es receptores positivos. Entonces, hay tiempos, por algo hay tiempos. Y necesitamos respetar esos tiempos. El tiempo mínimo de fijación en una biopsia es de seis horas. Así pasa lo mismo con los especímenes quirúrgicos, en los cuales los dejan fuera del... Cuando sale de la paciente, se empieza a contabilizar lo que llamamos isquemia fría. Entonces, el tiempo que transcurre en que ustedes retiran la pieza y la pieza se encuentra debidamente en formol y seccionada, es muy importante, no debe pasar más de una hora. Tenemos este caso, en el cual son casos que se han hecho de comunicaciones con el mismo tejido. Y vean la diferencia de la expresión de receptores en alguien que se... La misma pieza, en la cual un fragmento se puso inmediatamente en formol y el otro se quedó en el quirófano dos o tres horas. Entonces, vean cómo tenemos la pérdida de expresión en los receptores. Entonces, esto es realmente muy importante. Aquí podemos ver también la diferencia de diferentes tiempos de isquemia fría, o sea, el tiempo que tardaron en poner la muestra en formol, y podemos ver la diferencia entre 30 minutos y dos días. Entonces, esto es muy importante, porque si ustedes no tienen el cuidado de que ese material llegue al laboratorio de patología de manera adecuada, por más cirugía conservadora que hagan, por más experiencia que tengan en los tratamientos, por más que ustedes quieran categorizar a su paciente y vetarla hasta la frecuenciación masiva, no va a servir, porque su material está mal fijado y está mal conservado. Entonces, esto. Igual nos pasa con HER2. Vean la diferencia de isquemia fría entre una paciente correcta, que es el mismo tejido, y vean una paciente que tuvo el tejido tres horas afuera. Vean como se pierde completamente la expresión. Y no nada más la expresión. No podemos encontrar las proteínas, ni las de los cromosomas, cuando estamos haciendo los experimentos. Entonces, es fundamental que antes de cualquier cosa, por favor, manejen bien. Entonces, eso. Las biopsias, fijarlas inmediatamente en el hormonal 10% de lo que es el materializado. No dejar las piezas quirúrgicas más de una hora fuera del departamento de patología. Si ustedes no tienen departamento de patología en ese momento, tienen que ponerse de acuerdo con su patólogo y saber cómo van a seccionar esas muestras. Y otra cosa muy importante. Las biopsias no se deben de fijar más de 48 horas, porque si no, también pierden la expresión. Entonces, nos pasa lo que llamamos el síndrome del fin de semana. Pacientes que son biopsiadas el sábado en la mañana y llegan al laboratorio de patología el lunes en la tarde, o bien son operadas el sábado en la mañana, y la pieza quirúrgica se queda ahí en el quirófano hasta el lunes. Entonces, es muy importante tener eso en cuenta, porque ya vimos la importancia de poder seleccionar a estos pacientes para su tratamiento. Otra cosa que deben de saber es que el daño que se genera por una mala fijación es completamente irreversible. No hay forma en que nosotros podamos mejorar ni que podamos quitar ese daño. A veces podemos mejorar un poco algunos otros daños durante el proceso, pero por mala fijación es imposible. Entonces, ustedes en este momento están dando cuenta del gran impacto que esto tiene cuando nosotros hacemos receptores IFER2 porque vamos a tener entonces falsos negativos. Entonces, por favor, el manejo de la biopsia es fundamental. Y ahora sí, ya vamos a hablar cuando ya tenemos un material bien conservado, bien procesado, vamos a hablar sobre los marcadores. Hemos visto durante toda la mañana la importancia de los grupos basados en la expresión de receptores y de CAI-67, en el cual ya está de más ahorita decirles la importancia, pero sí vamos a hablar acerca de los marcadores más básicos, que es el grado histológico. El grado histológico fue el primer biomarcador que tuvimos, no nada más en cáncer de mamas, sino en diferentes cánceres, y nos basamos en la formación de tubulos, la formación, la presencia de mitosis, y el cremosismo. Dependiendo de eso, vamos a estratificar a las pacientes en grado 1, grado 2, o grado 3, o dependiendo del sistema que utilicemos, utilizamos el Scarlet-Richardson o el Novela. Entonces, cualquiera de estos que utilicemos, vamos a poder gradificar en 1, 2, y 3. Y esto es muy importante. ¿Por qué es importante? Porque generalmente el grado va a correlacionar con la expresión de marcadores. Y ahorita, vamos a ver esto, porque esta sería una de las causas por las cuales ustedes, y el patólogo también, tendría que repetir la realización de los estudios de búsqueda química si es que no tenemos correlación entre el grado y la expresión de marcadores. ¿Hay algunas recomendaciones para los patólogos que ustedes deben de conocer? ¿Cómo es que nosotros hacemos esto? Bueno, esto es un trabajo de control de calidad. Debemos de tener controles internos y controles externos para que estemos seguros de la tensión que estamos observando en el planeta. Como les mencionaba anteriormente, tenemos que tener confidencia con el grado histórico y, además de eso, debemos, según el CAP, debemos de tener los datos de isquemia y tiempo de infección. Porque ya vimos la importancia que es negamos estos datos porque si tenemos un tiempo de isquemia muy alargado, probablemente lo que estamos viendo es un falso negativo. ¿Cómo vamos a informar los receptores? Bueno, ustedes han visto muchos, muchos, muchos informes acerca de receptores y vemos, lo que hacemos nosotros es cuantificamos el porcentaje de células que son positivas y la intensidad de esta infección. Cuando el 1%, más del 1% de los prógenos son positivos, la infección se considera positiva. En cambio, en progestágenos, este número debe ser mayor del 5% para que lo consideramos positivo. ¿Cómo los vamos a ver? Cuando vemos los receptores, este es un ejemplo. Lo primero que vean es cómo esto, por ejemplo, sería tres cruces, 100%, en la que vemos cómo los núcleos son intensamente positivos en todas las células. En cambio, aquí vean este ejemplo, en el que los núcleos vean la heterogeneidad, tenemos núcleos negativos, tenemos núcleos positivos, dos cruces, dos cruces, entonces esto nos está hablando de una heterogeneidad negativa, que es un tema que ya hemos estado escuchando a lo largo del tiempo. Y esto sería un negativo cuando vemos prácticamente ningún núcleo expresando la tensión café. Y es importante que sepan que la expresión es exclusivamente neutra. Lo que vamos a hacer es, dependiendo del sistema que utilicemos para inform, whether it's HSPOR or ALRED, we're going to determine the percentage of positive cells, which is something visual. And after this, we're going to multiply it by the percentage of intensity, intensity per cell number, and we're going to have a sum of HSPOR, which goes from 0 to 300, and in the ALRED system, we're going to make a score that goes from 0 to 8, 0 negative, and 8 positive. And this is an example where we can observe the heterogeneity again. As you can see, we have negative nuclei, we have nuclei with one cross, nuclei with three crosses, and nuclei with two intensity crosses. What we do is an evaluation, and in a hypothetical example, we have 80% of the cells that are positive with two crosses, 10% with three crosses, and the other 10% are negative. We make a sum, and the total HSPOR in this patient is 100. So, this is how we evaluate. But there is one thing that is very important, that we must evaluate the heterogeneity of the nucleus. See how... This is a TAP report, in which we... It is practically the same, but here it is more specific, to say what percentage we have, the specificity, and we have the intensity of the tension, and if it is negative, if there are controls. We evaluate the K67 in a similar way, without the intensity. Here, all the nuclei are heterogeneous. The cutting point is controversial, we have already heard in previous talks, how it goes from 10% to 20%, it will depend on the patients, if they have received biographies, if they have not received, etc. But in the last cross-section, 20% is the point to distinguish between the A and B nuclei. And what I want you to see, is this diagram. In the same tumor, we have heterogeneity of K67 expression. This is very important, because many times, you have no idea, you see a little number, that says 20%, but you have to know that 20% is based on what? There are two ways that we can inform K67. One is the hotspot, in which we inform the area that has the highest expression of K67. In fact, in the report, it says K67, 30%, in parentheses. Or we do an evaluation of the sample, we take representative fields, and we make a percentage of expression. So, it is very important that you know that this will depend on the size of the sample. It is not the same to have six fragments, in which everyone has a tumor, than to have two fragments of one millimeter each, in which we will have only 100 or 200. So, it is very important also the quality of the sample, and how representative the sample is. So, imagine that you base your percentage on a small biopsy, in which in your biopsy this part, where K67 is, is representative. Instead, or you have a biopsy, in which your fragment only shows areas of K67, in which it is. So, it is very important that you have a biopsy, because it is not just the number that you see reflected in the report, but all the context behind that you must know when you are making this video. Now, when we are going to repeat, or we as pathologists, or you as chemists, you can tell the pathologist, you know what, I need you to repeat these receptors, because the nuclear degree does not correlate with what you are saying is negative. For example, a tubular carcinoma, or a carcinoma mucinosa, with negative receptors, which is true of some types, such as the tubular carcinoma, which we can see, the rest of the carcinomas with conventional pattern, we will not see this. So, it is important that we correlate the findings of both the degree and the histological with the receptors. If they are negative, it is probably worth repeating. It is true that there is a small percentage that is negative, but they are the same. When we have receptors of positive progestagen, but the dextrogens are negative, it is also worth repeating. If, repeating, the dextrogen markers are still negative, in any case, the patient is considered to be positive receptors, and the dextrogen is considered to be a false negative. There are some, we have to be very careful about the rest of the study, not just go to the receptors. and to see how we are going to deal with this crisis. Another indication to repeat the studies of this pandemic is the disease of the breast. We have to remember, again, the heterogeneity of the tumor. And in this, what we are going to do is repeat again, because probably the tumor that is more resistant is the one that is giving the disease of the breast. We already heard in the previous slides about the role of K177 as a prognosis in patients with previous treatment or patients with recurrence, which also leads us to repeat this. Now we are going to move on to HER2, in which HER2, what we expect, are three positive and determinative results. But to get to this result, there are several things that you should know. First, there have been changes in how we previously considered, especially the classification of the tumor, which has changed, the last modification was two years ago. But currently, what we consider to be positive is that this membrane tension is completely intense around the entire membrane of the brain. So what we evaluate is the intensity and that the entire membrane is positive. If this is not the case, then we are going to move on to the positive shadows. And here we also have a complete expression of the membrane, but if you compare the intensity of the expression of this expositive to this one, which is weaker, here we consider it indeterminate. If we have the complete tension of the membrane, weak or moderate, in more than 10% of the cell, we consider it indeterminate and it will go off. We can have tensions that are not as complete as these, in which if we have an incomplete and weak tension of the membrane, we can consider it a tumor. And there are some that, depending on the clinical characteristics of the patient, we can evaluate it in other ways. This is to show what we do. We have the negative, as I said, there are some cases where FISH should be evaluated, and those that are transpositive should be evaluated. But when it is indeterminate, FISH will be evaluated and we can see it. This is the number of copies that we have of these genes, but this is a more complicated thing. If you check the tab, you will see sheets and complete sheets about when it is considered positive or negative in an IVF study. This is a bit complicated, because remember that we are cutting cells. So, when we are cutting cells, if we modify our area, the tumor can change completely. So, it is very important that the person who is evaluating them knows what they are seeing, because sometimes in the same laboratory that is evaluating this, it is a tumor that does not have an idea of ​​what plastic cells are. For example, invasive and severe plastic. So, there always has to be a responsible pathologist to be able to evaluate the tumor. You see how in the indeterminate, we can have up to 5% of the tumor. So, it is important that you know what you are evaluating, and that in addition to this, there are some ways in which, when there is a lot of tumor, you have to go back to the studies of the Ministry of Health. And many times, these studies are indeterminate by FISH, indeterminate by the Ministry of Clinics. Clinically, there is a strong suspicion that people can benefit from the treatment. They can end up being diagnosed. Are we on time now? Perfect. Yes, it is very important that you know this. And just to finish, talk to you about PLL1. PLL1, you already saw it in the previous presentation, in the previous practices. And tell you that PLL1 is a marker for negative patients, which can be a pathogen. And what we do is, what you should be aware of is that it is with a very specific clone, which is the SNC. And unlike other types of markers, this is going to be evaluated in lymphocytes, not in the brain. And just to finish, tell you that liquid biopsies are not currently indicated as a standard. We are still investigating the prognosis and how to handle it. In conclusion, the correct management of the pathology is essential for all patients. You can have false negatives if you do not process the tissue. And tell you that in communication with the Department of Pathology, if you have any questions, or if you need to know what is going on with the patient, the best tool you have is the phone and call your doctor. Thank you. Thank you for the very interesting presentation. Before we finish, we have one more presentation from Dr. Andrés Pedro del Castillo on controversies in the surgical management of multifocal and multicentric tumors. Dr. Castillo is so kind. Dr. Castillo is a specialist in gynecology at the University of Cordoba, Argentina. He is a mastologist at the Rapson Provincial Hospital, also in Argentina. Good morning, everyone. It's a pleasure to be here. We already started with the presentation. Everything okay, right? It sounds perfect and looks perfect. Thank you. Thank you very much, doctor. Good morning, everyone. Here in Argentina, two more hours. It's a pleasure to be with you in this first international course. The second Saturday of this course was on March 27, 2024 and ends on May 29. First of all, we must thank Dr. Víctor Vargas Hernández, the board and coordinators for the invitation to organize this excellent course, the Mexican College of Gynecologists and Oncologists, and the International Gynecology Cancer Society, which is the one that supports this great course. This morning, we have been listening to different very good talks. They have complemented each other. Congratulations to the previous speakers. There are some topics that I will touch on that have already been touched on in other talks, but I will try to focus exclusively on the topic that is most relevant to us, which is about the controversy in the surgical management of the multifocal and multicentric tumors of the breast. To know where I come from, I come from Cordoba, Argentina. It is a province that is in the middle of Argentina. It is said to be the heart. And I live in Cordoba capital. It is the second most important city in Argentina, with almost 2 million inhabitants, very cosmopolitan, many universities, and, well, this city and this province are very strong. I work both in the public and in the private sector in several breast units. In the public sector, I work in a series of provincial hospitals that we have called the Oncological Breast Health Fund, and also in the private sector, in several places, and since last year also with the National Cancer Institute of Argentina. We have divided this talk into seven topics. We are going to make an introduction to the topic, what is definition and frequency of multifocal and multicentric tumors, talk about local recurrence and global survival in multifocal and multicentric tumors, pre-surgical management, we are going to emphasize, especially in the surgical part, remember that I am a surgeon, I am a master, so we will address, above all, that important part, the pre-surgical and surgical part of the multifocal and multicentric tumors. We will talk about mammary surgery, axillary surgery, and some final conclusions. To go deeper into the topic, the history of breast cancer treatment, you know that until 1970, the Husted hypothesis ruled, that it was a centrifugal and staggered dissemination, with a very aggressive local-regional management, hence the radical mastectomy of Husted, until with the Fischerian hypothesis, since 1970, that concept changes and more priority is given to systemic management, in which the local remains a little aside, and today we know that the Heldman hypothesis, in which both things are important, as we have seen this morning, both systemic, local and regional treatment, is very important for the treatment of our women and our patients, so there are different diseases, breast cancer is a very heterogeneous disease, and today a breast problem could not be treated if we did not have a working group on this concept of breast units. Those who speak of mastologists have spoken of pathologists, surgeons, oncologists, surely there will be specialists in imaging diagnosis, etc., so notice that today a treatment, the management and monitoring of a breast carcinoma, is really multidisciplinary. And emphasizing a little on the surgical part, because this is important, the surgeon or mastologist, as here we are in an auditorium of many gynecologists, the same thing happens in ovarian cancer, the same thing happens in neck cancer and endometrium, the specialty counts, right? It is not the same to be a specialist in surgery in something, that is not a specialist, the recurrence rates, the conservation rates, and the exhalation statification in this work, this is how they demonstrate it. And well, 2021 guides, both for in situ carcinoma and for basal carcinoma, in unifocal lesions, is quite concise, it is quite simple, you are all familiar with this, then do the diagnosis by function, mammography, echography, physical exam, we will have two major behaviors to follow from the surgical part, or conservative surgery plus radiotherapy, which is called conservative treatment, or if by some criteria it does not meet the requirements for a conservative treatment, more tectomy will be done, more or less radiotherapy. We know that these two surgical treatments have the same global survival, with similar local recurrence rates, therefore, every time it is possible, the standard goal would be surgery with observatory plus radiotherapy, which yesterday in the publication of Veronese in 1990, this was standardized. Now it always remained, after this publication, there were some doubts regarding what to do with central tumors, what to do with T3 tumors, locally advanced carcinomas, and a big question mark that was, and is to this day, what to do, what surgery to do regarding multifocal and multicentric tumors. Well, from 1980, which is the year I was born, to 2020, the truth is that there have been many changes, right? For good, luckily. There are better images, we have better studies of pre-surgical diagnosis, better pathological anatomy, better trials and protocols, we know more about biology, today several oncologist colleagues have spoken about the importance of the biology of breast tumors, there are new drugs, we have a whole concept of neoadjuvance, all the oncoplasty techniques, which the colleague earlier also spoke about, and the key concept of breast units, of working as a team. All this leads to what? We, all specialists, we began to move towards more conservative proposals, and this beautiful concept that we all share, which is de-escalation, to try to de-escalate in all types of treatment, and we are going to see what happens with multifocal and multisensory tumors. This is a slide from Dr. Nava, in which he sums it up very easily, right? Until 1980, breast cancer was mastectomy, thanks to the randomized work of Veronesi and Fischer, then it was either conservative treatment or mastectomy, and today, really, 2021, each breast cancer is a treatment, it is a very complex choice to follow. The optimal surgical treatment with multifocal and multisensory tumors, I can assure you that to this day there is a topical debate, one can stand on one side or the other, according to how to treat it, and the evidence is on both sides, to be more conservative or to continue with the classic mastectomy. There is no unanimous consensus, and why does this concept come from, that a multisensory tumor, above all, goes to mastectomy? Because it was thought, or it is thought, that they are more aggressive tumors, there is more risk of local recurrence, and there are doubts about global survival. And in turn, there would be a bad cosmetic result, added to the surgery, the surgical sequelae, and the double or triple boost that would have to be done in that breast if one tried a surgery or several conservative surgeries. However, many mastologists in the world and centers of work, in certain selected cases, despite not being standard, have done and do conservative surgeries. What is the reasoning? If two small multifocal or multisensory lesions with a good prognosis, mastectomy is performed, mastectomy must be done, while for an invasive cancer, perhaps much larger, or a large area of carcinoma autoin situ, we can be conservative. There is a discrepancy in the story, and there are two questions to be raised. Is the prognosis of multifocal or multifocal breast cancer really worse than unifocal? And if so, would we cure more with the most aggressive surgery? Would we modify that biology? Any concept of us in surgery, in mammary surgery, so that it is effective and we can apply a surgical technique, must meet four requirements. Have free margins. The local recurrence must be comparable to standard surgery. Global survival not less than the standard. And an acceptable cosmetic result. Very well. The second point is regarding the definition and frequency of focal and multisensory tumors. You know it well, but there are different definitions. Multifocal refers to the presence of two or more lesions in the same quadrant or less than five centimeters away. And the multisensory tumors refer to two or more lesions in different quadrants or in the same quadrant more than five centimeters away when they are very large breasts. Here is a summary of the incidence of multifocal and multisensory tumors. And look at the discrepancy there is, right? There are such low numbers, from 4 to 5%, up to 44%. It really is very discrepancy. There is a lot of variety, according to the literature. And we have to make a more precise analysis of all this literature, right? We have to see how they define the definition of multifocal and multisensory. What imaging technology did they use? Because there are very old studies from 1986 in which the resonance or mammography is of poor quality. How was the sample taken of a pathological atom? And did they also include the adult carcinoma in situ, the ananoplasia laboratoria or only the invasor carcinoma? So here, these works are very heterogeneous with each other. The guides in SCN 2021 warn that multifocal and multisensory will increase due to the best images we have, which before we did not see these focuses, because the pre-surgical magnetic resonance is increasingly used. Regarding the local recurrence and global survival of these tumors, traditionally it was thought that there was more local recurrence risk, more unfavorable survival rate, so the standard was more tectonics. Always talking about the surgical, exclusively, right? Since 1980, when more is known about conservative treatment, thanks to Veronese and other colleagues, conservative aneurysmal surgeries began to be done, and then, little by little, conservative treatment adapted to other tumors, such as multifocal and multicentric. Look at the publications there are, until 1993, now we are going to draw a line here, the local recurrence rates were really very high, very bad results, but we have three things to say there. There was poor image quality, bad mammography, poor mammography and echography quality, pathological studies, if you read the works, it is not entirely clear how they show the piece, and very few patients, look, 10 patients, 61 and 13. From then on, more serious work began to be done, with better studies, better pathological samples, and it is concluded that the local recurrence rates are increasingly comparable to unifocal tumors, with the same risk factors for local recurrence, than the unifocal ones, margins, histological and biological subtypes, and age. And here is a summary, I am not going to explain each one to you, but above all, there is a very good work by Wolters, published in 2013, in which there is no significant difference in local recurrence and survival in multifocal and multicentric tumors, treated with conservative surgery or mastectomy. So, we can leave this concept until now. Conservative surgery is safe, you have to select very well in which cases one can do for multifocal and multicentric tumors. Let's go a little to international literature and the Congress of St. Gallen, back in 2015, the panels and in the voting consensus, already spoke that in multifocal and multicentric tumors, the mother could be preserved, but always with negative margins and post-operative radiotherapy. And they went a little further, they also spoke about neojuvency, which could be feasible. That in 2015, in St. Gallen, in 2017, the same, they continue with the same, and they add one more thing, that we should have the criterion that non-inc in tumor, to see the issue of margins. 2019, the same, guides in SSN, the same, and now St. Gallen 2021, which was in March, recently in Austria, we continue with the same concept. International guides and international congresses endorse conservative surgery, but with highly selected patients. Let's go to pre-surgical management, and more to our pure surgical. Regarding pre-surgical management of multifocal and multicentric tumors, we have two scenarios, and we are going to stop at one. Especially in pre-operative diagnosis, when we have two or more injuries, either by palpation, by clinic or by images. And sometimes it can happen to us that there is a post-surgical histological diagnosis of multifocality or multicentricity that we did not know before. We are not going to touch that scenario. We are going to touch the pre-operative, in which we have a patient with two or more injuries, by clinic or by images. What should we do? Enhance the anamnesis, the physical exam, digital mammography or tomosynthesis, echomammary, if we can also apply the zone in the astrography and axillary, functions of all suspicious areas, and magnetic resonance. More and more in the world, this concept is imposed that, in the face of the suspicion of multifocality and multicentricity, magnetic resonance. Yes, we must warn. Well, what is all this for? To try to reduce the rate of positive margins and reduce the rate of re-operations. What do we have to keep in mind? That magnetic resonance can give us many false positives. So the guides tell us that all capture by magnetic resonance, suspicious or new, must have histological verification to take some conduct to follow. If not, we will be over-indicating surgeries and mastectomies. Let's go to our strong point, which is the surgical part. I have brought some photos or some videos so that the talk is a little more entertaining, since it is the last of the morning and we must be already all half saturated, right? What would be the algorithm to decide what type of surgery to continue in multifocal and multicentric tumors, once we know by clinical and by images? Several things follow. There will be three fundamental points. The oncological factors of decision, the aesthetic factors of decision, and the patients' comorbidities. Added to the experience that we have as surgeons, and the patient's preference. I'm not going to explain each of these concepts. For another opportunity, if there is another invitation, it will be a pleasure to perhaps deepen some of this. But look at the number of things that the mastectomist must take into account when defining what type of surgery to do, if it is a conservative or mastectomy, and then what conservative and what mastectomy. Therefore, the famous tumor-specific surgery is the one that measures the surgery adapted to the tumor. The idea is that we don't want this, right? To try that if we go to a mastectomy, to try to be able to do immediate mammary reconstruction. And if we go to a conservative, to try to make the sequel, the defect, be as small as possible. How can we mitigate the oncological control, the regional loco, with a good cosmetic result? How to mitigate the destructive with the reconstructive? The colleague spoke earlier about the issue of oncoplasty. You already know it by heart. But well, in 1996, this concept of specific surgery comes up. And oncoplasty surgery speaks of everything that is the prevention techniques for immediate conservative surgery in deferred, post-mastectomy, or in locally advanced tumors. Already in 1998, in Florence, oncoplasty is also included, that mammary reconstruction is an integral part of the treatment of breast cancer. Today, we, mastologists, whether we come from gynecology, whether we come from general surgery, wherever we come from, we should be as complete as possible, right? Manage the oncological part very well, and increasingly work on the aesthetic, reconstructive part, and if not, work together with plastic surgeon friends. There are many techniques. We are going to describe them with photos and videos, and it will be easier. In conservative surgery, we will see how we can de-escalate and try to minimize the sequelae, the incisions. And if we have to do mastectomy, we will see how we can reconstruct this patient. Some classic examples. This is a video from a few years ago, in which we no longer remove skin, but to make it a little more entertaining, this woman had two close multifocal tumors in the supra-external quadrant of the left breast. Years ago, we removed a piece of skin, not out of tumor commitment, but so that the pathologist had the previous margin. We no longer do this. We reference with sutures or with clips. The dye that comes there, for those who are not in the surgical part, I know that there are other colleagues, other specialties, is the patent blue that was injected. This is a classic tumorectomy or quarantectomy. It reaches the aponeurosis of the major pectoral. There is no need to dry it out if it is not committed. It advances in resection, as prolific as possible. And once the quarantectomy is done, or conservative surgery, or tumorectomy, whatever you want to call it, that is the pectoral muscle, we make references for the pathologist. The pathologist who spoke recently in her dissertation, will surely agree to reference the margins very well, in the upper part, the internal part. You will see how they will work with their work team, but always refer to conservative surgery if you have to expand margins, whether intraoperative or postoperative. Once the resection is done, that is the surgical fact of a standard quarantectomy in the supra-external quadrant of the left breast. Very important, and especially in multifocal and multicentric tumors, we always place five titanium clips, LT200 or LT300, where the tumor was, so that later the radiotherapists know more specifically where to do the boost. In multifocal and multicentricity, it is invaluable that each tumor bed is very well located for radiotherapy. And then the reconstructive part, in which here a level 1 oncoplasty has been done, in which the mammary gland is dissected and divorced, both from the pectoral muscle and from the skin. Glandular hangings are formed, in which the colleague spoke earlier, we are not going to get into this topic. Another example of multifocal tumors, in this post-neonatal patient, after marking the lesions before disappearing with clips, you can easily do a conservative surgery, either with ARPON technique, with CARBON, or with the SNOL technique, born there in Italy, in Milan. Some other examples, two multifocal tumors in the supra-external quadrant of the left breast, there comes the chat with respect to the only port, in this case we did so, from a low visibility periareolar incision, the resection of the quadrantectomy is done, and then by the same incision, what is called the only port, the biopsy of the sentinel ganglion is also done. Another example, also what is called the only port, take advantage of the incisions to do the double job, oncological in the breast, as we are seeing in the video, and then go to the armpit to do the sentinel ganglion, eventual armpit emptying. This woman had a prosthesis and was just marked in the upper collateral sulcus to be able to do the incision. There are different techniques when the incisions have to be larger, also the colleague has already talked about the subject, so I will not go into it, but we must know what other techniques we can use when talking about multifocal or multicentric tumors, because sometimes you have to do larger resections. Always placing CLIP in each surgical bed is key. And in extreme coplasty, the colleague also spoke earlier, when in cases where we have to do very large resections, in this case, this patient had two tumors, one in hour 6, one in hour 3, and some microcalcifications. In this surgical piece, 128 grams of breast were removed, and at the same time the other breast was symmetrized. So before, this patient may have had a mastectomy, or a, I don't know, mutilation, or a very important surgical aggression with a sequelae. Fortunately, today we have other techniques to be able to do it. Now, what about the BUST? This slide is from Dr. Zunino and all her team from the Córdoba Center for Radiotherapy in Argentina, in which it is known that the more BUST we do, there is more risk of fibrosis, of toxicity, and we must know that, and talk about it with the radiotherapists colleagues, because we have to see if it is on the left side, where are the tumors, if it was previously radiated, if it is possible to do a double BUST or a triple BUST. Also in conservative surgery, when there are large resections, what we are doing is immediate lipotransference, which is after doing the large mammary resection in these multifocal tumors, which is generally the largest excision, the fat is removed, it stops singing, it is processed and that purified fat, once the quadrantectomy and remodeling are done, is also injected to try to attenuate the sequelae of the surgery. These are all surgical tactics and techniques that one learns in Italy, in Spain, with Dr. Benigno Sanebril, with Dr. Eduardo González here in Argentina, in the ROFO, etc., etc. And well, enough conservative, and sometimes we have no choice but to do more tectomy, for multiple, diffuse lesions. Sometimes there is an impossibility of negative margins, and we have no choice but to do more tectomies. Sometimes it can be reconstructed at the same time, sometimes not. The most modern mastectomies that we like to do are the skin conservators, or the arioliposome skin. Here is an example of a patient with a relatively small breast, with three very distant foci, in which three conservative surgeries could not be feasible. In this case, a mastectomy was done in nipple sparing, there the gland is dissected, biopsy of the retroposome is done, and then, front and back, now I'm going to show you a video, and then in this case it was reconstructed with a prosthesis, immediately, with a complete muscular coverage. There are many techniques, we are not going to go into that topic. Here is a video so that the talk is a little more entertaining. This is a patient who came from us, from Bolivia, from Santa Cruz de la Sierra, in which he had, it is the patient that I showed you above, he had three tumors. An incision was made, in this case, in the supra-external quadrant. It could also have been due to the sulcosumamary, or by peripheral via. There are many techniques. The mammary gland is inserted, that tip you see there, it is called a tuxtenous tip, which is a material that does not heat the tissue, and therefore, we can conserve much more the vitality of the colgates of the mastectomy. By the same incision, returning to the only port, the biopsy of the sentinel ganglion is done, there is the colored ganglion, and with technetium, there is the gamma probe. In the case of mastectomy, we do not use blue to have clearer the cleavage planes, as you can see here, it becomes more difficult. It advances in surgery. Look at the blue here, how it makes the plane difficult, and one can run the risk of leaving either very thin the colgates, or very thick. Or it can leave tumors, or it can leave the mammary gland in an unnecessary way. One of the assistants is attracting to check the indemnity of the same, and that it can be left. Both the clinic and the images also help us. This is sent to the operating room with the pathologist, while we continue to work in the mastectomy. This is a small breast, so the smaller it is, the easier this type of surgery is. In very adipose breasts, with macromastia, we are advancing to the posterior face, we keep the pectoral fascia, since if it is not compromised, it makes no sense to leave it. This is the posterior face of the mammary gland. It advances with electrovisturation. There are different techniques, there are colleagues who go with cold visturi, or with scissors, that is very much in accordance with the surgeon. Our techniques, especially where we have learned, is from the European Institute of Oncology, with Dr. Veronese, Galimberti, Intra, and all his team, they work there. The external part of the tail of the breast is finished, and the breast is removed, which is what are called mastectomies. Here in this video you will see in detail how all the breast is removed. We no longer remove the skin as we did before. It is now marked 12, it is marked retro weight, and in this case it is also weighed, that is more than all to leave it registered in the surgical sheet, it makes no sense to weigh it, in this case it weighed 212 grams, which is the expansion of the prosthesis that we are going to put, but it is mere quality control, to see how our mastectomies are. In this case, an immediate breast reconstruction is done, with dual plane technique, that is the major pectoral, and then an anatomical retropectoral expansion is placed, there are the ribs, the cleavage plane, etc., etc. There are the ribs, we go ahead so as not to make it so long, we are already finishing. And well, we also have to do mastectomies in filotic tumors, sometimes multicentric, as in this case of a young girl, in which, look at the mastectomy, there are times when there is no choice but to do mastectomies when there are tumors throughout the breast, as in this case, and here it was reconstructed with an expander that has already finished its reconstruction and expansion, it still needs to be expanded. We in Argentina in 2013, there is a national law that the reconstruction coverage is done by the social works, or the state does it, the public part, we do a lot of mammary reconstruction since it is accessed for free. And we also have this, not everything is pink, there are complications, you have to be very careful not to overindicate oncoplasty and mammary reconstruction, there are hematomas, there is necrosis, there are extrusions, sometimes the expanders are in iatrogenic form, that is, by the remains that remain, they can deflate or puncture, this is something very strong, they are very far from the valve, but also notice that obviously you have to be very careful with this. With respect to axillary surgery, there are two diapos, it is the same, it is very simple, axillary statification in multifocal and multicentric tumors is the same as in unifocal tumors. If the axilla is clinically healthy and by images, the biopsy of the sentinel ganglion is accessed, either with blue or with tignesio, we routinely use the double method, and if the sentinel ganglion is positive, two or more, okay, and well, other things, but if there is a frankly positive axillary, it will be a standard axillary emptying. Two videos to show you, today the sentinel ganglion can be done in two ways, by a separate incision, this is a video that I want to show from the professor of the castle, who is my father, in which this video is a few years old, so the quality is different, but hey, it is a sentinel ganglion made by a very small axillary incision and it is about preserving the intercostal nerve that passes that level, usually it is the third, the ganglion is dried up, tignesio, etc. And today what we do the most is what is called a single port, which after the quadrantectomy we do the biopsy of the sentinel ganglion, all for the same incision and even the axillary emptying if necessary. Very well, and to finish and conclude and be strict with time, some messages to take home, summary after everything we talked about, the surgical treatment of breast cancer is in constant evolution, we have seen it this morning, we are going to see it in May, we have seen it in March and in all the congresses, until 1990 the multifocal and multicentric tumors were contraindicated to conservative surgery, the dogma and until today, especially in multicentrics, was and is mastectomy, but after more than 30 years of knowing the conservative treatment, there is more evidence, more images, there is a similar rate of local recurrence and global survival, than the unifocal tumors, regardless of the type of surgery, that according to where one stands with the literature can be in favor or against, I understand it and I invite you to read. The concept of multidiscipline in multifocal and multicentric tumors is very important to talk to imaging, pathologists, plastic surgeons if we do not do the reconstruction, radiotherapists, clinical oncologists and this all translates into breast units. Surgical analysis in multifocal and multicentric tumors as in the unifocals, negative margins, an acceptable cosmetic result, and that radiotherapy should be done later and that it can cover all the focuses with the appropriate boosts, if we would not be subtracting at the level of radiotherapy. We can do a surgery with classic preservatives or with the ocoplastic variants, always leave clips in all tumor beds and if we have to do a mastectomy, it can be a classic mastectomy, with a total mastectomy and with all its skin preservative variants, and with its variants in reconstructive techniques. Axillary stratification, we just saw it, is the same as in the unifocal tumors, ganglion, sentinella, or axillary emptying and with all the management according to positivity or negativity, the same as in the unifocals. There are two very good perspectives that I do not have time to develop, another time will be a pleasure if we have the opportunity to see each other again, in England and the ACOSOC 11.02 in which they are evaluating prospectively in multifocal and multicentric tumors conservative surgery versus mastectomy. There I leave the quotes in case you want to look for it. Last slide, honoring Professor Humberto Bronesi, that we all here in Latin America know him a lot, he started this conservation plan back in the 70s, scaling with mastectomy to conservative surgery, then he conserved the ganglions, many concepts of GAO regarding partial-operative radiotherapy, and also regarding conservative surgeries. Today, if Professor Bronesi was here, who unfortunately has passed away, he would perhaps put this concept of mammary surgery adapted to the tumor. Always what he says, we went from the maximum tolerable treatment to the minimum effective treatment, and try to cure, as he always said, with the best quality of life, which is what we treat in the surgical part, the chemical part, etc. I'll show you the work team, on the top right is my father, Professor del Castillo, I also work with my sister, a big team, all the people from the public hospital, also with Dr. Badran, we work in a cancer early detection program in Cordoba, also now with the National Cancer Institute, so I want to thank all the colleagues who help me to continue growing, I also invite you, I have a very important course next to the ROFO in Buenos Aires and San Juan, unfortunately the pandemic did not allow it, maybe we will do something virtual for the second semester, we will keep you informed, to be able to be a little more together. Thank you again to Dr. Victor Vargas, who has had the kindness and attention to invite me, together with the board and coordinators, to the Mexican School and the IGSS. I thank you very much, I am open to questions, thank you very much for everything. Thank you, Dr. del Castillo, very kind. We open the discussion of today's sessions. There are a good number of questions, possibly one of the ones we should take into account the most, and this would be for our pathologist, I don't see if she is connected, but in what she connects. One question, well, Dr. Mayadelia is already there, one of the questions they ask us is, how do I avoid overfixing in a trucut? Yes, can you hear me well now? No, but at least. I already moved, I don't know what it is. The overfixing is avoided by taking the biopsy immediately to the pathologist. That's all. There is no other thing? No. When some of us who are in a small center or in a small hospital that you do surgery and you don't have a pathology department there, what is the recommendation that you give us, especially for surgery, whether it is a wide resection or for mastectomy? Well, here is a lot of communication with the team. For example, I work with several surgeons who do breast resections, and we know, as Dr. del Castillo just said, that the edges are very important. So we have to dye before cutting. But if it is not possible for some reason, what is recommended is that the surgeon dyes. I know you don't like it, but there are dye kits for the surgeon to dye and he cuts the piece on the tube. The other thing they could do, if my pathologist colleagues hear me, they will burn me in green firewood, is to cut the piece, a single cut, on the tube so that the tube is fixed. And then we will try to rebuild that piece without the ink spreading to the inside. Because here the most difficult thing is that the ink, when you cut the piece, the ink gets in. And when the ink gets in, it will give us a false edge, a false positive, probably, when it is not real. The ink should not be there. In the cases of mastectomy, for example, what we want is for the tumor to be preserved, or the part of the tumor, to be able to evaluate the effectiveness of chemotherapy, is to cut over the tumor, over the part of the tumor. You have the skin and the anterior part, you are going to do the posterior part, and make a cut over the tumor so that the tumor enters. And obviously I will send that to the pathologist. The most important thing is that the tumor is in contact with the tumor, not the adipose tissue. Of course. And well, with what we have seen in the surgical part, both with Dr. Villarreal and with Dr. Andrés, it seems that mastectomy is no longer an alternative. And what recommendations could you make to the centers where more than 60 or 70% of our patients are in locally advanced stages? Because doing conservative surgery, liposuction, oncoplastic surgery, and others, sounds very nice, but for early stages, if I am in the right place. But for the locally advanced, what can be the most important recommendation in this regard? Why don't I remove the breast and rebuild it, and get rid of all these problems? Patti or Andrés? Yes, I believe that mastectomy still has its place. There are patients who really have an absolute contraindication to perform conservative surgery, such as cases with diffuse microcalcifications. So mastectomy surgery has its place. We try that all patients who are going to be taken to mastectomy can have some reconstructive procedure, especially immediate. In the cases of locally advanced cancers, what is our position? Well, in these patients, we try to give them all the rejuvenating treatment in order to reduce the residual tumor size to the maximum. Previously, before starting the treatment, we mark the tumor with clips. And in those patients that we know will have a very good response to rejuvenation, such as patients with triple negative cancers or overexpressed HER2, it is very important to mark the tumor before starting the treatment. And in these patients, well, if we expect a good response, they will surely be able to be taken to conservative surgery. Most of them may require some oncoplastic procedure, some oncoplastic technique, but I think they are excellent candidates, especially if they have responded to the treatment. Andrés? Yes, very good question, David. I also work in the public sector, in Mexico, Argentina, and I think that from Argentina to Mexico, everything happens to us the same, right? We also have patients with locally advanced carcinomas, large tumors, in which, as Patricia said, I consider rejuvenation to be the key, David. To start a downstaging and perhaps be able to preserve a little more, rejuvenation is key. Thanks to rejuvenation, we in the public sector, especially those that are more advanced tumors, have managed to increase the rate of conservative surgery. There is a disparity between the public and private sector. Patients arrive with other types of tumors, in which conservative surgery is much higher in percentage with respect to conservation. I agree, David, with you and with Patricia, that there are times when mastectomy is indicated, and obviously it will be seen if the possibilities of reconstruction can be immediate or differ according to many factors, but mastectomy has its place very well won, and to this day there are many patients who will have to be reconstructed. Obviously, reconstruction, whether immediate or deferred, with implants or hangings, is complex. Well, it has its things, so perhaps indicating it lightly is also complex. So, well, I think Dr. Victor wanted to speak. Yes, I will just give an opinion, because I worked 35 years in a public hospital and it was a national reference, which is the Juárez Hospital of Mexico. Really, at the beginning of three decades ago, in fact, we focused on the residence, when the conservative breast surgery was resident. However, apart from what my good friend David says, that locally advanced people arrive, at that time there was no neopuban chemistry, it was in its infancy, and there was difficulty in radiotherapy. However, with the passage of time, and speaking in the 21st century already in this, many patients no longer accept radiotherapy. So, as they have said in all their talks, the preference of the patient is fundamental, because sometimes it is said that they are aesthetically very accepted, and it is true, but many, when they get one from radiotherapy, although there are super specialized techniques where they do not have so many complications, they reject such. So, when a patient rejects such radiotherapy, it must also be discussed or contemplated within the treatment. As we have been able to see throughout the morning, the different scenarios, positive hormones, positive HER2, triple negative, even in the triple negative, there are differences. Dr. Luch, could you tell us how recommended it is to do this nanostring technique? Is it necessary? Is it accessible in any scenario? Or could we possibly do something different to a molecular technique like this? The nanostring is not essential, especially in the triple negative. In the triple negative and HER2, although we do not have access to a genomic platform, we do not do it either. We do it in the case, as I said, of a patient who does not respond because we have the nanostring at our disposal. We do the nanostring in patients with sensitive hormones, there we do it to indicate. And now, in those who have an axial affectation and are premenopausal, we do not do it either, because they are going to receive chemotherapy, yes or yes. In postmenopausal, we do it. And we do nanostring because it gives us the genomic profile and helps us more. And this in metastasis, we do it in research. This must not be forgotten. It is not essential to do it, but only when research is done and you need the nanostring to include a patient. For example, we know that HER2 rich will respond much better to a double block therapy and maybe without chemotherapy. But we do it in those cases. It is not essential. Okay? Okay, thank you. For medical oncologists, a question they ask us is, in neoadjuvant endocrine therapy, with positive ganglios initially, is it advisable to do gangliosentinella to avoid axillary dissection? That is one. And the other question, in that group of patients in which they had an injury and they have a complete image response, how is that injury located? To operate. Yes. For local control. We do, although it is for hormonal therapy, neoadjuvant, we do gangliosentinella. What we do is initial echography and biopsy. And if it is positive, we leave a mark, a mark in the ganglion and in the breast. And then, when the intervention is decided, which will never be before six months for hormonal therapy, we already know that it has to be long and prolonged, so when we do the surgery after neoadjuvant therapy, we do gangliosentinella again. If it is negative, we do not do axillary dissection. We have done our own study to have a validity and we are very calm with gangliosentinella and the previous marking if it is positive. We always do, we do not do only neoadjuvant to do conservative surgery. We, in a small tumor, triple negative or ER2 positive, even if it is small, it is 1.5 centimeters, 2 centimeters, that could be done conservative surgery at the beginning, we prefer to do neoadjuvant to know the prognosis and the prediction of the treatment. And in those cases, we always do ecography, biopsy, and if it is positive, marking, and then centinella. And with the marking, as the complete pathological response, in triple negative, small, with platen salts, with high KI, the complete response can reach 40-45% pathological response, we also need to mark the initial tumor, and we always mark it. And if it comes from a center that has not been marked, we do ecography and marking again, both breast and armpit, if it is positive. Thank you very much. I ask you to give your specific answers, because we are running out of time. Ivan, what do you think about this topic? Thank you very much. You can hear me, right? I agree with Dr. Luch. For example, the guides of NSSN do not distinguish the management of the armpit between neoadjuvant systemic therapy with chemo or hormone therapy. The data is really extrapolated from neoadjuvant chemotherapy, there is not much data with endocrine therapy in neoadjuvants. However, there is retrospective analysis, hospital experiences, which tell us that it is safe to perform, for example, sentinel ganglia after an armpit has been negativized with neoadjuvant treatment, and that there is even a tendency to make the management as if it were without neoadjuvant therapy. Patients who have up to one or two ganglions, there are some reports from Dr. Tarikín that these patients do not even go to emptying as if they went to COSOG Z011 despite the neoadjuvant endocrine therapy. It is a management proposal, however, it should be extrapolated a little from neoadjuvant chemotherapy. Specific question for Dr. Paula and Dr. Lugo. The double hormonal blockade, in which group of patients is it most suitable and what exactly do they refer to as double hormonal blockade? First, ladies, Paula, please, quickly. Okay. I think today we have a tool that was built from a sub-analysis of the Sofitex studies. You can look for it online, and right now I put it in the chat, it is the risk calculator of Dr. Regan. This calculator weighs all clinical risk factors associated with the benefit that is really going to be obtained by the double blockade. And the second, if you want, well, at least that's what I do in my practice. And what does a double blockade mean? It is a term that we use both in HER2 and in positive hormonal receptors. In HER2, give two anti-HER therapies, and in positive hormonal receptors, to a premenopausal patient, do an ovarian suppression plus the introduction of an aromatase inhibitor or a tamoxifen. Leopoldo? Yes, thank you. Practically, just like in institutional practice or in private practice, the double blockade, specifically at the hormonal level, we talk about this ovarian suppression, which generally, preferably, we do it with pharmacological inhibition. You have to remember that they are patients, according to the studies of Sofitex, under 35 years old. You have to weigh well if the patient benefits from a permanent suppression, but generally, in practice, it is with a pharmacological blockade, and remember that the benefit, in these studies, was with an aromatase inhibitor. So, that is precisely what we refer to, and the risks, according to the calculator or those we analyze during the talk, are based, above all, on the age part and the pathological clinical part of the patient. And within hormone therapy, in the adjuvant, Marco, it would give me a bit of stress to have a patient there for 6 months without doing anything to him, and giving him just a little bit of... Well, this treatment, it is clear to me, this treatment is approved, but how do I manage this part with the patients? How do you think I can handle it with them? I think the question was directed to me, doctor, of the adjuvant therapy. Yes or no? Well, to Marco Guadiván, I don't know if Marco wants to... Yes, yes, yes. Go ahead, Ivan. I think you explained it well. Well, really, as we saw in the studies, adjuvant endocrine therapy is an alternative because it is less toxic than chemotherapy. Studies really show that there is an equivalence according to the objective that is being sought. If it is about a mother's conservation and the patient is not a candidate for chemotherapy, and now I would dare to say, even in a larger population, not only elderly, fragile, with comorbidities, endocrine and adjuvant therapy can be used if the patient is post-menopausal, pre-menopausal, and a little cautious. And, well, just having a control, a clinical and ecological control that the patient does not progress, selecting the patient well, if it is an ideal world, with genomic signatures, with a low-risk cotype, with an initial K67 of low risk, those patients will have less than 2% or 1% of us progressing in endocrine and adjuvant therapy. So, it could give us security. And, of course, if you can do a control with biopsy to see the K67 at 4 weeks and less than 10% of those patients come out safe, they will do well and they will progress. So, we could be sure with that method. Well, precisely that is, I think, the most important point, right? The monitoring with K67 of these candidate patients to this type of management. I don't think I can say how I manage the patient. The first thing we have to do is to believe it ourselves. Neuadjuvant hormone therapy in a selected patient, as Ivan said, is exactly or more effective than chemotherapy. We did a study, Neuadjuvant in J-CAM, Neuadjuvant with hormone, Neuadjuvant with chemotherapy. And with what I said, at 4 weeks, doing a biopsy, if the K67 has gone down, we can be very calm that that patient is being controlled. Yes, thank you, doctor. Well, I think we are already in the time. Something they ask us, which I think is also important, how long will I give a patient double hormonal blockade? At least 6 months. At least 6 months? Double hormonal blockade? But in what scenario? Metastatic, adjuvant or neo? Well, we can talk quickly about the adjuvant and the metastatic. In the metastatic scenario. Possibly the adjuvant is not the most important point, but in the adjuvant and in the metastatic scenario. I say metastatic until the mental progression of the adjuvant. I was going to say, in the metastatic scenario, it is clear that we have to treat patients as menopausal patients. In the adjuvant scenario, the ideal would be to complete the hormonal treatment for 5 years. There is information between the lines that it seems that 2 years is enough. However, we also have to evaluate the patient's tolerance but the ideal would be to take her to the treatment of 5-year adjuvant. David? Ready? Yes, look, we are over time. I would ask Dr. David Cantu to write down all the questions and send them to each of the professors via email for the answer of the attendees. It is simply because the time is up and we invite you for the next Saturday, May 29, for the completion of this third let's say monthly Saturday. To Dr. Ana Luz, as always, very grateful to you for your kind availability for all academic events. Andres and all the Mexican colleagues, Dr. Ecuador, everyone, for their kind participation. I have nothing more to say, congratulations, they were excellent presentations, they have given us a light and still think more about breast cancer, which I never think will end up being studied in an adequate way. And see you on May 29. I am very grateful to the Mexican College of Gynecologists for all the benefits that it has given and facilitated to the Mexican College of Gynecologists and we end this second monthly Saturday of the three that are. Thank you very much, a kiss, a hug to everyone. Thank you. Thank you all. Thank you very much. Thank you, have a good afternoon.

multifocal breast tumors

multicentric breast tumors

management

multidisciplinary approach

breast cancer treatment

conservative surgery

recurrence

surgical techniques

neoadjuvant endocrine therapy

individualized treatment plans

follow-up monitoring

chemotherapy

endocrine therapies

tumor characteristics

personalized treatment approaches