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1 PowerPoint Slides English Spanish Translation Breast Cancer Survivorship: Identification of Highrisk Patients and Genetic Testing Video Transcript Transcripción del video Professional Oncology Education Breast Cancer Survivorship: Identification of Highrisk Patients and Genetic Testing Time: 16:00 Banu Arun, M.D. Professor Department of Breast Medical Oncology Co-Medical Director, Clinical Cancer Genetics The University of Texas MD Anderson Cancer Center Welcome to our lecture series. I m Banu Arun with the Department of Breast Medical Oncology and Clinical Cancer Genetics at The University of Texas MD Anderson Cancer Center. Today, we will be talking about Breast Cancer Survivorship: Identification of High-risk Patients and Genetic Testing. Supervivencia al cáncer de mama: Identificación de pacientes de alto riesgo y pruebas genéticas Educación Oncológica Profesional Supervivencia al cáncer de mama: Identificación de pacientes de alto riesgo y pruebas genéticas Duración: 16:00 Dra. Banu Arun Profesora Departamento de Oncología Médica Mamaria Codirectora Médica, Genética Clínica del Cáncer MD Anderson Cancer Center de la Universidad de Texas Bienvenidos a nuestra serie de disertaciones. Soy Banu Arun, del Departamento de Oncología Médica Mamaria y Genética Clínica del Cáncer en el MD Anderson Cancer Center de la Universidad de Texas. Hoy hablaremos de supervivencia al cáncer de mama y la identificación de pacientes de alto riesgo y pruebas genéticas. 1

2 The objec --- objectives today will be to understand Los objetivos son comprender la importancia de la the importance of family history; differentiate between historia familiar; diferenciar entre el cáncer hereditario y hereditary and sporadic breast cancer; increase esporádico; describir los genes BRCA1 y 2, y los knowledge about BRCA1 and BRCA2 genes and riesgos de cáncer asociados; e identificar a las associated cancer risks; and identify appropriate candidatas apropiadas para las pruebas genéticas. genetic testing candidates. The importance of and purpose of family history is La importancia y el propósito de la historia familiar es [that] it enables us to accurately perform high-risk que nos permite evaluar con precisión el alto riesgo de assessment regarding the likelihood of hereditary la probabilidad de un síndrome de cáncer hereditario cancer in the family. It also helps us identify other en la familia. También nos ayuda a identificar otros cancer risks and also helps us recommend riesgos de cáncer, recomendar su manejo adecuado e appropriate cancer risk management and also with the interpretar los resultados de las pruebas genéticas. interpretation of genetic test results. 2

3 Not all of the cancers are actually hereditary. In fact, No todos los cánceres son hereditarios, sino solo del 5 only 5-10% of breast cancers are hereditary. About al 10%. Entre el 15 y el 20% de los cánceres de mama 15-20% of breast cancers are familial. And the rest, son familiares. El resto, del 70 al 80%, son about 70-80% actually are sporadic breast cancers. esporádicos. This is an example --- actually two examples of a Estos son dos ejemplos de familias con cáncer de family with breast cancer. On the left hand side is an mama. A la izquierda tenemos cáncer de mama example of sporadic breast cancer. A patient with esporádico, en una paciente diagnosticada a los breast cancer diagnosed at age 60 with absolutely no 60 años sin historia familiar de cáncer de mama o de family history of breast or ovarian cancer. Whereas ovario. A la derecha, una paciente diagnosticada con on the right hand side we have a patient diagnosed cáncer de mama a los 45 años, una hermana con with breast cancer at age 45, a sister with ovarian cáncer de ovario a los 50 años, su madre con cáncer cancer at age 50, mother with breast cancer at age de mama a los 47 años y su abuela materna a los , and a maternal grandmother with breast cancer at Ciertamente, esta historia familiar induce a sospechar age 42. Certainly, this family history is very suspicious un síndrome hereditario. for hereditary breast and ovarian cancer syndrome. 3

4 What are the flags for hereditary breast and ovarian cancer syndrome? When, or in whom should we think about offering genetic counseling and testing? Certainly, if there is premenopausal or early onset of breast cancer, especially under the age of 50 or under the age of 60 with triple negative breast cancer; if there are several relatives with breast cancer or ovarian cancer on the same side of the family so either maternal or paternal side. If a person has breast and ovarian cancer, then the likelihood of carrying a BRCA mutation, for example, is pretty high. If there is an individual with bilateral breast cancer; or if there is a family history with male breast cancer; certainly, if there is a known mutation --- known BRCA mutation in the family, then the rest of the family members are at increased risk to carry a mutation and also if there is Ashkenazi Jewish ancestry in the family. In order to help us with referral and testing guidelines for genetic counseling and genetic testing, there are certain sites that are summarized here that can help us with the guidelines. There are guidelines by the National Comprehensive Cancer Network TM, the NCCN. There are guidelines defined by the American Society of Clinical Oncology. And there are also guidelines by the American Congress of Obstetricians and Gynecologists. And here we can see the websites for those guidelines. Cuáles son las señales de alerta del síndrome de cáncer hereditario de mama y ovario? A quién debemos ofrecer asesoramiento genético y pruebas? Si hay aparición premenopáusica o temprana de cáncer de mama, particularmente antes de los 50 años o antes de los 60 y es triple negativo; si tiene varios familiares con cáncer de mama o de ovario del mismo lado de la familia, materno o paterno. Si hay cáncer de mama y ovario, la probabilidad de mutación en los genes BRCA es bastante alta. Si hay cáncer de mama bilateral o antecedentes familiares de cáncer de mama masculino. Si existe en la familia una mutación conocida en estos genes, el resto de los familiares tienen mayor riesgo de mutación y también si son de ascendencia judía asquenazí. Como ayuda en cuanto a referidos y pautas para el asesoramiento genético y las pruebas genéticas, estos sitios pueden ser útiles. Tenemos pautas de la Red Nacional Integral de Cáncer o NCCN; las pautas de la Sociedad Americana de Oncología Clínica; y las pautas fijadas por el Colegio Americano de Obstetras y Ginecólogos, ACOG. Aquí figuran los sitios web para esas pautas. 4

5 Let s talk a little bit about the BRCA1 and 2 genes. Hablemos brevemente de los genes BRCA1 y 2, que These genes are responsible for the majority of son responsables de la mayoría de los cánceres hereditary breast and ovarian cancer. In fact, about hereditarios de mama y ovario. De hecho, del 80 al 80-90% of individuals who fall --- would fall into that 90% de las pacientes están en esa categoría. Son category. It s a large tumor suppressor gene which is importantes supresores tumorales que participan en la involved in DNA repair. One in 500 to one in 800 reparación del ADN. Se estima que una de cada 500 a individuals in the general population estimated to have 800 personas en la población general tienen una a BRCA1 or BRCA2 mutation. And one in 40 mutación BRCA1 o 2, pero que una de cada 40 individuals of Ashkenazi Jewish heritage may have personas de ascendencia judía asquenazí puede tener one of the three mutations. We call them founder una de tres mutaciones que denominamos mutaciones mutations. Specifically, they are 185delAG, 5382insC, fundadoras, más específicamente, 185 deleción AG, and 6174delT inserción C y 6174 deleción T. Now, what are the cancer risks that are associated Cuáles son los riesgos de cáncer asociados con las with BRCA1 mutations? On the left hand side, you mutaciones del gen BRCA1? A la izquierda, en rojo, see, which is in red, the risk of breast cancer for vemos el riesgo de cáncer de mama primario en la primary breast cancer in the general population that is población general, que es del 10 al 11%. Sin embargo, about 10-11%. However, an individual with the una persona con la mutación del gen BRCA1 tiene un BRCA1 mutation has a risk that is up to 80%. riesgo de hasta un 80%, pero también aumenta su Secondary breast cancer in these individuals are also riesgo de cáncer de mama secundario. En la población increased. Again, secondary breast cancer in the general, el riesgo de cáncer de mama secundario es general population is about 6-7% whereas individuals del 6 al 7%, pero con la mutación BRCA1 es de hasta with the BRCA1 mutation is up to 60, even 64% based un 60% e incluso del 64% según algunos estudios. El on some reported studies and very importantly ovarian riesgo de cáncer de ovario, esta barra roja, es muy cancer risk. As you can see here, in the red small bar bajo en la población general, menos del 5%, pero es is very low in the general population, less than 5%, but muy alto, hasta 45%, con mutaciones BRCA1. certainly it is very high up to 45% in individuals with Sabemos por algunos estudios que con mutaciones BRCA1 mutations. We also know from studies that in BRCA1, aumentan los riesgos de cáncer de mama individuals with BRCA1 mutations, male breast cancer masculino y de próstata, posiblemente el de cáncer risk is increased, prostate cancer risk is increased, as pancreático y tal vez algún otro cáncer gastrointestinal. well as possibly pancreatic and maybe some other GI cancer risk is increased as well. 5

6 What are the risks in BRCA2 mutation carriers? Cuáles son los riesgos en las portadoras de Again, starting with breast cancer risk compared to the mutaciones BRCA2? En comparación con la población average population the risk is again around 80%. promedio, el riesgo de cáncer de mama es de un 80%, Secondary breast cancer risk is a little bit less than el de cáncer de mama secundario es menos del 60%, 60%. Ovarian cancer risk is about 25-30%. Male el de cáncer de ovario es del 25 al 30%, y el de cáncer breast cancer risk is around 10%. Prostate cancer de mama masculino es de cerca del 10%. El riesgo de risk about 20% and pancreas cancer risk a little bit cáncer de próstata es de un 20% y el de cáncer de less than 5%. Studies have also shown that BRCA2 páncreas, de menos del 5%. Los estudios también han mutation carriers are at increased risk to develop demostrado que las portadoras de mutaciones BRCA2 some other cancers that include melanoma, colon tienen mayor riesgo de desarrollar otros cánceres cancer, larynx cancer, esophageal cancer, and gastric como melanoma, cáncer de colon, laringe, esófago y cancer. estómago. What are the risk models that we use to calculate the Qué modelos de riesgo utilizamos para calcular la probability of an individual carrying a BRCA1 or probabilidad de portar una mutación BRCA1 o 2 y por BRCA2 mutation and why do we have risk models at qué usarlos? Los actuales criterios de prueba no all? First of all, the current testing criteria does not cubren todas las situaciones clínicas que debemos cover all clinical situations that we face in the clinics. enfrentar a diario. Estos modelos ofrecen una manera And these models can also provide a way to quantify de cuantificar y a veces justificar pruebas genéticas and sometimes justify genetic testing for the patient as para la paciente y para algunas compañías de seguros, well as some insurance companies and also help además de ayudar a comprender el riesgo. patients understand their risk. 6

7 I would like to go over some of the risk models. The Repasemos algunos modelos de riesgo. La tabla de Myriad Genetic Laboratory s Prevalence Table is a prevalencia de Myriad Genetic Laboratories es un widely used model. It uses personal and family history modelo muy utilizado. Utiliza la historia personal y of cancer as reported on the test requisition forms that is sent to Myriad familiar de cáncer de la paciente, tal como aparece en. This is certainly a biased sample el formulario de solicitud de la prueba enviada a and may not be representative of the general population. However, Myriad updates the tables Myriad. Esta es una muestra sesgada y no siempre once in a while and the recent update happened in February representativa de la población general. Myriad actualiza las tablas ocasionalmente y la actualización más reciente es de febrero de Another model that is widely used is the BRCAPRO Otro modelo muy utilizado es el BRCAPRO, que está model. It is actually available as a part of the disponible como parte del programa CancerGene y CancerGene program that can be found on this puede encontrarse en este sitio web. Para un patrón de website. And what this model does, it says, Given familiares afectados y no afectados, el modelo define la this pattern of affected and unaffected relatives what is probabilidad de que una persona sea portadora de una the probability that this individual carries a mutation in mutación en uno de los genes BRCA. Incluye los one of the BRCA genes? This model includes antecedentes personales y familiares de cáncer de personal and family history of breast and ovarian mama y ovario en parientes de primer y segundo cancer in first and second degree relatives. However, grado. Sin embargo, como en muchos modelos, este as in many models, there are limitations to using this tiene limitaciones. Por ejemplo, no considera el risk model. For example, it does not account for carcinoma ductal in situ, la cirugía profiláctica de mama ductal carcinoma in situ, prophylactic breast surgery, u otros cánceres asociados. En estos casos, no se or other associated cancers. So you cannot model puede usar el modelo ni ingresar información para that in, give that information to calculate the probability calcular la probabilidad de portar una mutación. of carrying a mutation. 7

8 Now, there are also other risk models that we use in Hay otros modelos de riesgo que utilizamos en our clinics. For example, some other models that nuestras clínicas. Algunos estiman la probabilidad de estimate the likelihood of having a BRCA mutation una mutación BRCA, como el BOADICEA. Otros such as the BOADICEA model. There are also estiman el riesgo de desarrollar cáncer de mama, models that estimate the risk of developing breast como el Gail y el Claus. Afortunadamente, también hay cancer, such as the Gail and Claus models. And modelos que calculan los riesgos de mutación y de luckily, there are also models that calculate both the cáncer de mama, como el de Tyrer-Cuzick. Debo risk of carrying a mutation but also [the] risk of breast señalar que en el entorno clínico nos recomiendan cancer such as the Tyrer-Cuzick model. And I would utilizar todos los modelos, por lo que a veces debemos like to point out that in the clinical setting it is informar a las pacientes rangos de porcentajes. recommended that we use all of the models and sometimes we end up giving ranges to patients of carrying the mutation. So the other important question in our clinics is, Who Otra pregunta importante es quién debe hacerse should be tested first for a genetic mutation? We primero una prueba de mutación genética. Las pruebas know that genetic testing is most informative when first genéticas son muy informativas cuando se realizan por performed on someone diagnosed with breast or primera vez en una persona diagnosticada con cáncer ovarian cancer so we are trying to test the affected de mama u ovario, así que tratamos de analizar a las person. If a gene mutation is identified, then personas afectadas. Si se identifica una mutación, esto hereditary cancer has been confirmed in the family confirma el cáncer hereditario en la familia y otras and other family members can receive targeted, what familiares pueden hacerse análisis selectivos, lo que we call predictive genetic testing. Also, a negative test llamamos pruebas genéticas predictivas. En una result in someone without cancer can offer false persona sin cáncer, un resultado negativo puede reassurance and does not rule out hereditary cancer ofrecer una falsa seguridad y no descarta el cáncer in the family because we really didn t test the affected hereditario familiar, ya que no hemos analizado a una person and perhaps that person has a mutation and persona afectada que tal vez porte una mutación, sino we test[ed] the unaffected person and she does not a una persona no afectada que no la porta. Eso no have a mutation. But that does not rule out that the significa que la familia no tenga un mayor riesgo. family is not at increased risk. 8

9 So for example, here, if this patient age 24 is Por ejemplo, esta paciente de 24 años está concerned because she has a mother with ovarian preocupada porque su madre tiene cáncer de ovario, y cancer, she has a maternal aunt with breast cancer, una tía, una prima y su abuela maternas tienen cáncer and maternal cousin with breast cancer, and a de mama. No es aconsejable ofrecerle pruebas maternal grandmother with breast cancer. While it genéticas, por no estar afectada, pero sí a su familiar would be advisable that we do not offer this unaffected de primer grado. En este caso su madre, diagnosticada person genetic testing but go with the alive first degree con cáncer de ovario a los 48 años, sería la persona relative first. That would be her mother diagnosed más apropiada para ello. Si tales pruebas dan with ovarian cancer at age 48. So she would be a resultados positivos, podemos ofrecerlas a la paciente more appropriate person to be tested. And if she is no afectada, que tiene un 50% de probabilidad de found to be positive, then we would offer testing to the portar una mutación. unaffected individual who then would have [a] 50% likelihood of carrying a mutation. What are the types of BRCA testing? Certainly Cuáles son los tipos de pruebas de BRCA? Las comprehensive testing includes full sequencing of the pruebas integrales incluyen una secuenciación BRCA1 and BRCA2 gene that was developed in 1996 completa de los genes BRCA1 y 2 desarrollada en and then further improved by doing BRCA 5-site 1996 y luego optimizada con un panel de rearrangement panel that was added to the testing in reordenamiento de 5 sitios para genes BRCA, que se We also offer Multisite 3 testing for the three incorporó a las pruebas en También ofrecemos founder mutations seen commonly in individuals who pruebas multisitio 3 para las tres mutaciones are Ashkenazi Jewish as I discussed previously. fundadoras que por lo general se ven en judíos Once we have information about a mutation in the asquenazí. Una vez que tenemos información sobre family then we would not offer comprehensive testing una mutación familiar, ya no ofrecemos pruebas to the whole family but rather single site testing for a completas a todo el grupo familiar sino pruebas de sitio known familial mutation. Because know we know único para una mutación familiar conocida. Una vez where the mutation is so we would be offering identificada la mutación, ofrecemos pruebas predictive testing. And very recently another predictivas. Muy recientemente se incluyó otra methodology was included into the BRCA analysis. It metodología en el análisis BRCA, que se denomina is called BRACAnalysis Rearrangement Test or prueba de reordenamiento BRACAnalysis o prueba BART TM testing that was first available in August BART, disponible desde agosto de

10 What are the possible test results? Certainly, we Cuáles son los posibles resultados de las pruebas? Si might be able to find the deleterious mutation in the encontramos la mutación deletérea en el gen BRCA1 o BRCA1 or 2 gene that is called a positive result. Then 2, es un resultado positivo. Si no encontramos ninguna we might not find any mutation in the BRCA1 or 2 mutación, el resultado puede ser negativo verdadero o gene. That is called a negative result which can be a negativo no concluyente, que luego describiré. true negative or inconclusive that I will discuss in a También podemos encontrar otra mutación en el gen minute. Then we might find a mutation in the BRCA1 BRCA1 o 2, pero desconocer su significado clínico. or 2 gene. However, we don t know what the clinical Estas mutaciones se denominan variantes de significance of that mutation is. And these mutations significado clínico incierto o mutaciones VUS. are called variant of uncertain clinical significance or VUS mutations. So let s talk about the positive results. Certainly if we find a deleterious mutation in the BRCA1 or BRCA2 gene, we now can explain the cancer in the family. We can tell the individuals, the carriers, of this mutation that they are at increased risk for breast, ovarian, and possibly other cancers as I have discussed. We also can offer testing to first degree relatives. And as I mentioned, each first degree relative has a 50% likelihood of carrying the mutation. And we certainly have to and offer patients risk reductive management for breast and/or ovarian cancer. Hablemos de los resultados positivos. Si encontramos una mutación deletérea en el gen BRCA1 o 2, podemos explicar el cáncer en la familia. Podemos informar a los portadores de esta mutación que tienen mayor riesgo de cáncer de mama, de ovario y posiblemente de otros cánceres. También podemos ofrecer pruebas genéticas a los familiares de primer grado. Cada familiar de primer grado tiene un 50% de probabilidad de portar la mutación. Nuestro centro cuenta con un sistema de reducción de riesgos de cáncer de mama y ovario. 10

11 Now, the other result could be a inconclusive negative Si el resultado es negativo no concluyente, no hemos result. That means that we did not find a mutation, the encontrado una mutación en el gen BRCA1 o 2. La BRCA1 or BRCA2 gene. The interpretation of that is a interpretación es más compleja, ya que depende de la little bit more complex because the interpretation historia familiar, de que las pruebas se hayan realizado depends on the family history, whether the most a la persona más indicada y del tipo de pruebas appropriate person was tested, or what type of testing realizadas. Por ejemplo, si no se hacen pruebas a la was performed. For example, if you do not test the persona con cáncer, podríamos no detectar la person with cancer, you might miss the mutation. mutación, y el resultado tal vez no sea un negativo And, therefore, that negative might not be a true verdadero. El riesgo restante depende de la historia negative. And the remaining risk really depends on familiar. Si no existe ninguna mutación pero muchas the family history. If there is no mutation, but many familiares tienen cáncer de mama, un resultado individuals still have breast cancer, then the person negativo no significa el mismo riesgo que el resto de la that tested negative is certainly not at population risk población de desarrollar cáncer de mama. for development of breast cancer. Also, if the result is not what we expect we might need Si el resultado es inesperado, es posible que debamos to do some more testing. So let s say we did hacer más pruebas, por ejemplo si la secuenciación dio sequencing and it s negative. But there is something negativa. Cuando hay indicios, la historia familiar es going on, the family history is very significant. significativa. Tal vez debamos hacer pruebas BART Perhaps we should be doing BART TM testing or if we o si hicimos pruebas multisitio, hacer pruebas did multisite, we should be --- do comprehensive integrales. Podemos inscribir a las pacientes en testing. We also should consider enrolling patients in ensayos clínicos o estudios de investigación y tal vez clinical trials or research studies. And perhaps offer ofrecer almacenamiento de ADN, en caso de que en el DNA banking, in case in the future, some genes were futuro se identifiquen otros genes, para repetir las identified and we want to go back and test that pruebas en esa persona o familia. Un resultado individual or family. And also, as I just mentioned negativo, especialmente si la paciente se somete a las having a negative test result, especially if the person pruebas debido a su historia familiar, no significa que underwent testing because of a significant family tenga un riesgo normal. Si hay indicios en la familia, history does not rule out --- does not rule out that the debemos personalizar el manejo del riesgo para la person is at normal risk. So something is going on in paciente. the family. Therefore, we have to individualize risk management for this patient. 11

12 Now, let s talk about true negative. This is only possible when the exact gene mutation in the family is known. So let s say we have a young breast cancer patient who has now --- no mutation, then we know which gene to look for. And the other family members can be offered this testing. And if the first degree relative tests negative then we can call it reassuring or true negative and not inconclusive because we know the sister has the gene, but the other sister doesn t have it. If there s a true negative result then that individual s cancer risk is similar to that of the general population. And general population screening is recommended. And the individual s children are not at increased risk to inherit the mutation because that person doesn t have it. Hablemos ahora del negativo verdadero. Esto solo es posible cuando se conoce exactamente la mutación genética de la familia. Si tenemos una paciente joven con cáncer de mama que no porta ninguna mutación, ahora sabemos qué gen buscar. Además, podemos ofrecer esta prueba a los otras familiares. Si las pruebas de una familiar de primer grado arrojan un resultado negativo, podemos llamarlo alentador o negativo verdadero y no concluyente, ya que sabemos que la hermana porta el gen, pero no esta otra hermana. Si hay un resultado negativo verdadero, el riesgo de cáncer es similar al de la población general, para quienes se recomiendan exámenes de detección. Los hijos de esa persona no tienen mayor riesgo de heredar la mutación porque esa persona no la tiene. So now let s talk a little bit about the variant of Hablemos ahora de la variante de significado incierto o uncertain significance, the VUSs. A gene change is VUS. Se ha determinado que un cambio en el gen found that could be associated with increased risk for podría estar asociado con un mayor riesgo de cáncer o cancer or could be a change that doesn t affect the ser un cambio que no afecta en absoluto la función del gene function at all. Testing other affected family gen. Puede ser útil realizar pruebas a otras familiares members or parents could be helpful, but testing afectadas, pero no se recomiendan en familiares no unaffected family members is not recommended. afectados. 12

13 In these cases, we again must work with the patient to create [an] individualized management plan based on personal and family history. And these people should have annual follow-up with their providers to update status of the variant. Likelihood of variant depends on the ethnicity also. And Myriad is actually offering a variant reclassification program so you might consider that as well. En estos casos, debemos trabajar con la paciente para crear un plan de control individual, basado en su historia personal y familiar paciente. Deben hacerse seguimientos anuales con sus proveedores para actualizar el estado de las variantes. La probabilidad de tener variantes también depende del origen étnico. Myriad ofrece un programa de reclasificación de variantes, que también se puede considerar. So in summary, a majority of cancer is not inherited. En resumen, la mayoría de los cánceres no son Approximately 10% of breast and ovarian cancers are hereditarios. Cerca del 10% de los cánceres de mama the result of mutations in the BRCA1 and BRCA2 y ovario son resultado de mutaciones en los genes gene. The red flags are used to identify individuals BRCA1 y 2. Hay signos de advertencia para identificar and families at increased risk for hereditary breast and a personas y familias en situación de riesgo de cáncer ovarian cancer and guide recommendations regarding hereditario de mama y ovario, y recomendaciones y genetic testing. pautas para las pruebas genéticas. 13

14 Family history is an important tool in genetic risk La historia familiar es una herramienta importante assessment providing accurate risk assessment, risk para evaluar el riesgo genético, aplicar estrategias de management strategies, and interpreting genetic test manejo de riesgos e interpretar los resultados de las results. Appropriately identifying the ideal testing pruebas genéticas. El identificar a la candidata ideal candidate is most informative for the patient and family para las pruebas es sumamente informativo para la members and enables a more accurate interpretation paciente y sus familiares, y permite una of genetic test results. This concludes our session. interpretación más precisa de sus resultados. Con Thank you very much for your attention. Please send esto concluye nuestra sesión. Muchas gracias por su us your feedback. atención. No dude en enviarnos sus comentarios. 14

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