PowerPoint Slides English Text Spanish Translation Cancer Genetic Risk Assessment VideoTranscript

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1 PowerPoint Slides English Text Spanish Translation VideoTranscript Evaluación de riesgos genéticos del cáncer Transcripción del video Professional Oncology Education Time: 24:32 Educación Oncológica Profesional Evaluación de riesgos genéticos del cáncer Duración: 24:32 Thuy Vu, M.S. Genetic Counselor Clinical Cancer Genetics The University of Texas, MD Anderson Cancer Center Hi, my name is Thuy Vu. I am a Genetic Counselor in a Clinical Cancer Genetics Program at MD Anderson Cancer Center. This lesson will focus on cancer genetic risk assessment. M.C. Thuy Vu Asesora Genética Genética Clínica del Cáncer Universidad de Texas, MD Anderson Cancer Center Hola. Me llamo Thuy Vu y soy asesora genética del Programa de Genética Clínica del Cáncer en el MD Anderson Cancer Center. Esta lección se centrará en la evaluación del riesgo genético del cáncer. Cancer Genetic Risk Assessment Thuy Vu, M.S. Genetic Counselor Clinical Cancer Genetics 1

2 Objectives Upon completion of this lesson, participants will be able to: Identify family history features suggestive for hereditary cancer syndromes Understand the implications of hereditary cancer Understand the benefits, limitations and risks of genetic testing for hereditary cancer At the end of this lesson, I hope that you should be able to identify some family history features suggestive for hereditary cancer syndromes; to understand what it means for an individual and their family to have hereditary cancer; and also to understand the benefits, limitations, and risks of genetic testing for hereditary cancer. Espero que al finalizar esta lección usted pueda identificar algunas de las características de los antecedentes familiares que sugieren síndromes de cáncer hereditario, pueda comprender qué significa para una persona y su familia tener cáncer hereditario, y también pueda comprender las ventajas, limitaciones y riesgos de las pruebas genéticas de cáncer hereditario. How Much of Cancer is Hereditary? With hereditary cancers, I actually focus on a very small subset of all individuals who develop cancer. That is because the majority of individuals who develop cancer, it is due to sporadic causes or due to personal risk factors, and that accounts for about 70% to 80% of cancers. There are about 15% to 20% of cancers that are attributed to multifactorial inheritance, which is also called familial clustering. In these families, we see that there are multiple --- several individuals with cancer; however, they are diagnosed at later more typical ages of onset and there is really no clear pattern of inheritance in these families. With multifactorial cancers, it is due to a combination of environmental factors as well as some low penetrance or more subtle acting genetic factors. Finally, only 5% to 10% of cancers are actually attributed to inherited or genetic causes. In these families, we see that there are very young ages of cancer onset in the family, they occur in multiple family members, and it can have quite a significant impact on these families. So this is what the talk will focus on today. Para los cánceres hereditarios, me concentro en un subconjunto muy pequeño de personas que desarrollan cáncer, dado que en su mayoría obedece a causas esporádicas o a factores personales de riesgo, lo que representa alrededor del 70% al 80% de los cánceres. Alrededor del 15% al 20% de los cánceres son atribuidos a la herencia multifactorial, también llamada agrupación familiar. En estas familias, hay una pluralidad de personas que desarrollan cáncer; sin embargo, son diagnosticados posteriormente, a edades de inicio más características. En estas familias no existe realmente un claro patrón de herencia. En los cánceres multifactoriales, esto se debe a una combinación de factores ambientales, así como a algunos factores genéticos de baja penetrancia o de acción más sutil. Por último, sólo del 5% al 10% de los cánceres son atribuidos a causas hereditarias o genéticas. En estas familias, vemos que la aparición del cáncer ocurre a edades más tempranas y en varios miembros de la familia, y que puede tener un impacto significativo en ella. Este será el tema de nuestra charla de hoy. 2

3 Risk Assessment With the discovery of hereditary cancer genes, genetic testing is available as a tool to identify patients at high risk for certain cancers Role of health care providers Inquire about family cancer history Identify red flags in family history Refer to genetic counseling With the discovery of hereditary cancer genes, genetic testing has become a valuable tool to identify patients at high risk for certain types of cancers. Therefore, as health care providers, it is your job to inquire about family cancer history, to identify red flags within the family history, and finally to refer these individuals and their families to genetic counseling and testing. Con el descubrimiento de los genes del cáncer hereditario, las pruebas genéticas se han convertido en una herramienta valiosa para identificar a los pacientes con un alto riesgo de padecer ciertos tipos de cáncer. Por ello, como proveedores de cuidado de la salud, debemos preguntar sobre los antecedentes familiares de cáncer, identificar los signos de advertencia, y referir a estas personas y sus familias a servicios de asesoramiento y pruebas genéticas. Inquire About Family History We will first talk about identifying the family history features. Comencemos con la identificación de características en los antecedentes familiares. Paternal Grandfather Paternal Grandmother Maternal Grandfather Maternal Grandmother Paternal Aunt Paternal Aunt Paternal Uncle Paternal Uncle Father Mother Maternal Aunt Maternal Aunt Maternal Uncle Maternal Uncle Sister Sister Brother You Brother Your Partner Daughter Daughter Son Son 3

4 Cancer Focused Family History 3 generations Maternal and paternal families Cancer history Type of cancer Age at onset Personal risk factors Unaffected relatives Ages at death or current ages As providers, it is important to take a cancer focused family history. This entails asking questions about three generations of the family, to focus on both the maternal and paternal side of the family. And for all individuals diagnosed with cancer it is important to ask about the type of cancers these individuals were diagnosed with, their ages at onset as well as any personal risk factors that may have contributed to that cancer. And for unaffected relatives, it is important to know the ages at death or the current ages of these individuals. Como proveedores, es importante considerar los antecedentes familiares centrados en el cáncer. Esto requiere hacer preguntas sobre tres generaciones de la familia, centrándose tanto en el lado materno como en el paterno. Y para todas las personas diagnosticadas con cáncer es importante preguntar sobre el tipo de cáncer que se diagnosticó, la edad de inicio y los factores de riesgo personal que puedan haber contribuido. Para los familiares no afectados, es importante saber la edad de fallecimiento o su edad actual. Autosomal Dominant Inheritance with Incomplete Penetrance Normal Susceptible carrier Carrier, affected with cancer Sporadic cancer Penetrance is often incomplete May appear to skip generations Individuals inherit altered cancer susceptibility genes, not cancer ASCO The majority of hereditary cancer syndromes are inherited in a family in an autosomal dominant manner with incomplete penetrance. With autosomal-dominant inheritance, we see that there are multiple generations affected and that the gene mutation that occurs within the family is passed out in a manner. Men and women are equally affected, or at risk to inherit the mutation, and they are at equal risk to pass on the mutation to their sons or their daughters. The gene mutation does not skip generations, but due to incomplete penetrance, the cancer risk don't always occur in each individual who carries a genetic mutation. You can see here that the individuals shaded in orange have cancer history and have the gene mutation; whereas these individuals in the white and with the blue line down the middle, these individuals have the genetic mutation, but have not inherited cancer risk. So this individual here has not developed cancer, but several of their children have developed cancer and you can understand that this is an autosomal-dominant inheritance of this cancer genetic gene. En una familia, la mayoría de los síndromes de cáncer hereditario se transmiten de una manera autosómica dominante, con penetrancia incompleta. Con la herencia autosómica dominante, vemos que hay varias generaciones afectadas y que la mutación genética dentro de la familia se transmite por partes iguales. Los hombres y las mujeres son igualmente afectados, o tienen el mismo riesgo de heredar la mutación y transmitirla a su descendencia. La mutación genética no omite generaciones, pero debido a la penetrancia incompleta, el riesgo de cáncer no siempre ocurre en cada individuo con una mutación genética. Vemos aquí que las personas de color naranja tienen antecedentes de cáncer y la mutación del gen, mientras que las personas de color blanco con una línea azul tienen la mutación genética, pero no han heredado el riesgo de cáncer. Esta persona no ha desarrollado cáncer, pero varios de sus hijos sí, de lo que se deduce que se trata de una herencia autosómica dominante de este gen del cáncer. 4

5 The Two-Hit Hypothesis First Hit First Hit in Germline of Child Second Hit (Tumor) Jorde LB, Carey JC, White RL, Medical Genetics 2 nd ed. St. Louis: Mosby; 2000 Knudson AG. Proc Natl Acad Sci USA. 1971;68: ASCO Red Flags for Hereditary Cancer Clustering of the same cancer in close relatives (on the same side of the family) Early age of cancer onset 2+ primary cancers in a single individual Bilateral or multifocal cancers Evidence of autosomal dominant inheritance Successive generations affected Family pattern consistent with a known cancer predisposition syndrome Alfred Knudson in 1971 described this Two-Hit Hypotheses in families with heritable retinoblastoma. The Two-Hit Hypothesis is the premise behind hereditary cancers in the sense that individuals with hereditary cancers inherit their first genetic mutation from a parent or through the germline and then the second mutation occurs in the normal allele is a somatic hit or is an acquired mutation. This is in contrast to individuals who have sporadic cancers. These individuals are born with two normal copies of the gene and acquire a somatic hit within one of the genes. And, therefore, individuals with sporadic cancers tend to develop their cancers at later ages of onset compared to families or individuals with hereditary cancers. After you have taken the family history of cancer, these are some of the red flags that you should look for to identify families that might be suspicious or concerning to have a hereditary cancer syndrome. In these families, we would see that there are close relatives with a same type or related types of cancers and they all occur on the same side of the family. The majority of these individuals are diagnosed with cancers at much younger ages than you would expect to see that cancer occurring. You may see individuals with two or more primary cancers. In organs, where there are paired organs, there may be bilateral cancer involvement or multifocal tumors. Also autosomal-dominant inheritance is seen in these family histories. And if you are familiar with some of the cancer genetic syndromes, you may recognize that the family pattern is consistent with that particular genetic syndrome. En 1971, Alfred Knudson presentó su hipótesis de doble mutación en las familias con retinoblastoma hereditario. Esta hipótesis es la premisa que yace detrás de los cánceres hereditarios, en el sentido de que las personas con estos cánceres heredan su primera mutación genética de uno de sus padres o a través de la línea germinal, y luego se produce la segunda mutación en el alelo normal, un efecto somático o mutación adquirida. Esto contrasta con las personas que tienen cánceres esporádicos. Nacen con dos copias normales del gen y adquieren una mutación somática en uno de sus genes. Por eso, las personas con cánceres esporádicos tienden a desarrollarlos a edades más tardías que las familias o personas con cánceres hereditarios. Después de compilar los antecedentes familiares de cáncer, hay ciertos signos de advertencia que permiten identificar a las familias con el potencial de tener un síndrome de cáncer hereditario. En estas familias, veremos que hay parientes cercanos con cánceres de un mismo tipo o relacionados, y que todos han ocurrido en el mismo lado de la familia. La mayoría de ellos son diagnosticados con cáncer a una edad mucho más temprana de lo que cabría esperar para la enfermedad. Posiblemente haya personas con dos o más cánceres primarios. En los órganos pares, puede ocurrir cáncer bilateral o tumores multifocales. En estas familias también veremos antecedentes de herencia autosómica dominante. Si usted está familiarizado con algunos síndromes de cáncer genético, reconocerá que el patrón familiar es coherente con ese síndrome genético particular. 5

6 So now we will review some of the common hereditary cancer syndromes. Ahora veremos los síndromes de cáncer hereditario más comunes. Implications of Hereditary Cancer: Overview of Common Syndromes Implications of Hereditary Cancer Hereditary breast cancer syndromes - Hereditary breast and ovarian cancer (BRCA1 and BRCA2 genes) Hereditary colorectal cancer syndromes - Lynch syndrome (DNA mismatch repair genes) - Familial adenomatous polyposis (APC gene) Other hereditary cancer syndromes There are over two dozen hereditary cancer predisposition syndromes, but the three that I have listed on this page here are the ones that occur most commonly and the ones that some of you may be more familiar with. Amongst the hereditary breast cancer syndromes, the one that most people are familiar with is called Hereditary Breast and Ovarian Cancer Syndrome and this condition is associated with mutations within the BRCA1 and BRCA2 genes. For hereditary colorectal cancer syndromes, most individuals are familiar with two particular conditions. One is called Lynch syndrome, which was previously known as Hereditary Nonpolyposis Colorectal Cancer or HNPCC, and this condition is associated with mutations in the DNA mismatch repair genes. And the second hereditary colorectal cancer syndrome is called Familial Adenomatous Polyposis or FAP in short and this condition is associated with mutations in the APC gene. There are numerous other hereditary cancer syndromes as well, but we will not focus on that. Hay más de veinte síndromes de predisposición al cáncer hereditario, pero los tres que he listado en esta página ocurren con mayor frecuencia y posiblemente le resulten conocidos. Entre los síndromes hereditarios de cáncer de mama, el más conocido es el de cáncer hereditario de mama y ovario, una condición asociada con mutaciones en los genes BRCA1 y BRCA2. Para los síndromes hereditarios de cáncer colorrectal, la mayoría de las personas conocen dos condiciones particulares: uno es el síndrome de Lynch, anteriormente denominado cáncer colorrectal hereditario sin poliposis o HNPCC, una condición asociada con mutaciones en los genes de reparación de mal apareamiento del ADN. El otro síndrome hereditario de cáncer colorrectal es la poliposis adenomatosa familiar o FAP, y esta condición está asociada con mutaciones en el gen de la poliposis adenomatosa del colon, o APC. Hay muchos otros síndromes de cáncer hereditario, pero no podemos cubrirlos aquí. 6

7 Hereditary Breast and Ovarian Cancer Causative for the majority of hereditary breast cancers Germline mutations in the BRCA1 and BRCA2 genes We will focus mostly on one particular hereditary form of cancer and that is called Hereditary Breast and Ovarian Cancer Syndrome. This condition accounts for the majority of hereditary breast cancers that occur and the condition is associated with mutations within the BRCA1 and BRCA2 genes. Nos centraremos principalmente en una forma particular de cáncer hereditario: el síndrome de cáncer hereditario de mama y ovario, que corresponde a la mayoría de los cánceres de mama hereditarios y que está asociado con mutaciones en los genes BRCA1 y BRCA2. Ford D., et al, Am J Hum Genet 1998 BRCA1 & BRCA2 Lifetime Cancer Risks Breast: 50-85% Second primary breast: 40-60% Ovarian: 15-45% Includes fallopian tube and primary peritoneal cancers Others: Male breast cancer Prostate cancer Pancreatic cancer (BRCA2) For individuals, who carry a mutation in either one of these genes, the cancer risks are very high. For a woman who has a mutation with an either BRCA1 or BRCA2 genes, her lifetime risk to develop breast cancer increases up to 50% to 85%. And once the woman has developed a breast cancer, she has a high risk to develop a second primary breast cancer and that risk is 40% to 60% lifetime risk. This condition is also associated with ovarian cancer, which can include a fallopian tube and primary peritoneal cancers; and the lifetime risk is approximately 15% to 45% risk. We do see other cancers are associated with this condition and that includes men having breast cancer, prostate cancer as well as pancreas cancer En el caso de personas con una mutación en estos genes, el riesgo de cáncer es muy alto. Si una mujer tiene esta mutación, su riesgo de por vida de desarrollar cáncer de mama aumenta de un 50% a un 85%. Y una vez que ha desarrollado cáncer de mama, tiene un alto riesgo de desarrollar un segundo cáncer de mama primario, con un riesgo de por vida del 40% al 60%. Esta condición también está asociada con el cáncer de ovario, que puede incluir cáncer de trompa de Falopio y cáncer peritoneal primario; y el riesgo de por vida es del 15% al 45%. También vemos otros tipos de cáncer asociados con esta condición, que incluyen a hombres con cáncer de mama, próstata y páncreas. 7

8 Red Flags for Hereditary Breast/Ovarian Cancer Multiple family members with ovarian cancer or breast cancer Age of onset of breast cancer: under 50 (pre-menopausal) Bilateral breast cancer Both breast and ovarian cancer in same patient Ashkenazi Jewish ancestry Male breast cancer Family history features that are concerning for Hereditary Breast and Ovarian Cancer Syndrome include multiple family members with ovarian or breast cancer. And typically these breast cancers occur at younger age of onset, so you would see many women with premenopausal onset of breast cancer. Women may also have bilateral breast cancer within their lifetime or you may see a woman with both bilateral and ovarian cancer within her lifetime. Individuals of Ashkenazi Jewish descent are considered to have a higher chance of having a mutation in one of these genes than non-ashkenazi Jewish Caucasians. And male breast cancer is quite rare, but it is common in this particular condition Los antecedentes familiares de interés para el síndrome de cáncer hereditario de mama y ovario son los familiares con este tipo de cáncer. Por lo general, este cáncer de mama ocurre a edades más tempranas, de modo que habrá muchas mujeres con inicio premenopáusico del cáncer de mama. Las mujeres también pueden tener cáncer de mama bilateral, y habrá otras con cáncer bilateral y cáncer de ovario. Se considera que las personas de ascendencia judía asquenazí tienen mayor probabilidad de mutación en uno de estos genes que las personas caucásicas de ascendencia judía no ashkenazí. El cáncer de mama masculino es bastante raro, pero es común en esta condición particular. 73 Family History of Hereditary Breast/Ovarian Cancer 92 Br Ca, dx Br Ca, dx 36 Br Ca = Breast cancer Ov Ca = Ovarian cancer d Br Ca, dx 45 TAH/BSO, d Br Ca, dx 40 Br Ca, dx 59 Ov Ca, dx 45 Deceased Noncarrier of mutation BRCA 1 mutation carrier, unaffected BRCA 1 mutation carrier with cancer ASCO This is a family history that exemplifies a typical family that may have a BRCA1 or BRCA2 gene. So you can see here in this first generation there are several women affected with breast cancer and ovarian cancer. This particular woman here, she has a BRCA1 mutation, but she has never developed cancer in her lifetime. And that may be due to the fact that she had a complete abdominal hysterectomy and oophorectomy when she was 46 years old. But we will presume that she has the mutation because her daughter was diagnosed with breast cancer at age 59 and does have the BRCA1 mutation. So this is an example of incomplete penetrance for hereditary cancer. You can see here this woman was diagnosed with breast cancer at age 52. She passed the mutation onto her son, who has not developed any cancer history. But his daughter developed breast cancer when she was 36 years old; and this man s sister had both breast cancer and ovarian cancer. So this family exemplifies some of the typical family history features that we would see commonly in this condition. Estos son los antecedentes familiares de una familia típica que puede tener un gen BRCA1 o BRCA2. Aquí vemos que en la primera generación hay varias mujeres afectadas con cáncer de mama y ovario. Esta mujer en particular tiene una mutación BRCA1, pero nunca ha desarrollado cáncer. Eso puede deberse a que tuvo una histerectomía abdominal total y una ooforectomía a los 46 años, pero podemos suponer que tiene la mutación porque su hija fue diagnosticada con cáncer de mama a los 59 años y no tiene la mutación BRCA1. Este es un ejemplo de penetrancia incompleta del cáncer hereditario. Vemos aquí que esta mujer fue diagnosticada con cáncer de mama a los 52 años. Pasó la mutación a su hijo, quien no desarrolló ningún historial de cáncer; sin embargo, su hija tuvo cáncer de mama a los 36 años, y la hermana de ese hombre tuvo cáncer de mama y ovario. Esta familia es un ejemplo de las características típicas de antecedentes familiares que comúnmente se ven en esta condición. 8

9 Management Options for HBOC Breast Cancer Increased surveillance mammogram plus breast MRI every 12 months, clinical breast exams every 6 months, beginning at age 25 Chemoprevention tamoxifen Risk reducing bilateral mastectomy Ovarian Cancer Surveillance no proven benefit transvaginal ultrasound and CA-125 blood test every 6 months, beginning at age 35 Chemoprevention oral contraceptives Risk reducing bilateral salpingo-oophorectomy NCCN v Implications of Hereditary Cancer: Summary Unique family history features Increased cancer surveillance and management Begin at younger ages Increased frequency Range of management options High-risk cancer management clinics often available For families that have this condition, we do recommend that they follow with high-risk cancer surveillance and management options. And these recommendations that I am discussing here are based on the National Comprehensive Cancer Network. For breast cancer, we recommend that women undergo increased surveillance. This would include mammogram plus breast MRI every 12 months, a clinical breast exam every six months and that the screening begins at age 25 years. Women may also consider tamoxifen chemoprevention as well as riskreducing bilateral mastectomy. For ovarian cancer risk, although the surveillance has no proven benefit, we do recommend that women consider a transvaginal ultrasound and a CA125 blood serum marker performed every six months beginning at age 35. Oral contraceptives may be a chemopreventative option and some women may also consider risk-reducing bilateral salpingo-oophorectomy. In summary, for families that have hereditary cancer, we do recognize that there are very unique family history features and they do follow the red flags for hereditary cancer that we previously discussed. These family members are recommended to undergo increased cancer surveillance and management. And typically this begins at younger ages and at much increased frequency compared to the general population and there is a range of management options for these family members. And often within the United States, there are high-risk cancer management clinics available to coordinate all of these high-risk screening. Para las familias que la presentan, recomendamos una vigilancia del cáncer de alto riesgo y las opciones de tratamiento. Estas recomendaciones se basan en la Red Nacional Integral de Cáncer, o NCCN. Para el cáncer de mama, recomendamos a las mujeres que se sometan a una mayor vigilancia. Esto incluye una mamografía y una resonancia magnética de mama cada 12 meses, un examen clínico de mama cada 6 meses, y exámenes de detección desde los 25 años. Las mujeres también pueden considerar la quimioprevención con tamoxifeno, y la mastectomía bilateral para reducir el riesgo. Para mujeres con riesgo de cáncer de ovario, si bien la vigilancia no tiene ningún beneficio comprobado, recomendamos que consideren una ecografía transvaginal y un análisis del marcador CA125 de suero en sangre cada seis meses a partir de los 35 años. Los anticonceptivos orales pueden ser una opción quimiopreventiva y también puede considerarse una salpingo-ooforectomía bilateral para reducir el riesgo. En resumen, para las familias con cáncer hereditario existen antecedentes familiares muy singulares con los signos de advertencia ya mencionados. Se recomienda a estos familiares someterse a mayor vigilancia y control del cáncer. Esto suele comenzar a edades más tempranas y con una frecuencia mucho mayor que en la población general, y se dispone de una serie de opciones de tratamiento. En los Estados Unidos, contamos con clínicas para el tratamiento del cáncer de alto riesgo que coordinan todos estos exámenes de detección. 9

10 Finally, we will review the genetic counseling and testing process. Por último, nos referiremos al asesoramiento genético y el proceso de pruebas. Genetic Counseling & Testing Process Genetic Counseling A process of: Providing information about an inherited condition to an individual or family Providing supportive counseling to families Providing families with resources Genetic counseling is a process of providing information about an inherited condition to an individual or their family, of also providing supportive counseling to the families and providing these families with resources. El asesoramiento genético es un proceso que proporciona información a una persona y su familia sobre una condición hereditaria, e incluye asesoramiento de apoyo y acceso a recursos. 10

11 Genetic Counseling Process Risk assessment Multi-generation pedigree Clarification/documentation of reported cancer family history Identification of appropriate family member to test Interpretation of genetic test results Psychosocial and insurance issues Individualized screening recommendations Genetic Testing Process Not all patients seen for risk assessment are offered genetic testing So once you have done your part in identifying the appropriate family history features that are concerning for hereditary cancer and have recommended a referral to genetic counseling for these families, they do see us for the genetic counseling and that includes a risk assessment of their family history. We will take a three-generation family history, focus on clarifying the reported cancer histories, as well as looking at all the individuals who have not developed cancer. From the risk assessment, we will identify whether genetic testing is appropriate for the family to consider, and importantly identifying who in the family is the most important person to initiate the genetic testing process. If genetic testing is pursued in the family, we will discuss interpretation of the genetic test results and also we will discuss psychosocial and insurance issues surrounding the genetic counseling and genetic testing process. And whether testing is pursued or not, we discuss individualized screening recommendations based on the family history. The genetic testing process is a multistep process. The first step is that we need to identify who is at risk for having --- potentially having this hereditary cancer syndrome. Now not all patients seen for the genetic risk assessment are actually offered genetic testing. It is important to identify the most informative family member. Once genetic testing is discussed with the family, we want to provide very detailed pre-test information --- pretest counseling providing informed consent to the family or the individual undergoing testing. And then once the results are disclosed to the patient, provide detailed post test counseling and followup regarding management. Una vez que hemos identificado los antecedentes familiares relevantes para el cáncer hereditario y hemos recomendado asesoramiento genético a estas familias, nos consultan sobre el asesoramiento genético, que incluye una evaluación de los riesgos de sus antecedentes familiares. Tomamos los antecedentes familiares de tres generaciones, aclaramos las historias de cáncer informadas y consideramos a los individuos que no han desarrollado cáncer. Con la evaluación de riesgos, determinamos si las pruebas genéticas son apropiadas para la familia, a fin de identificar en quién es más importante iniciarlas. Si las pruebas se llevan a cabo en una familia, discutimos la interpretación de sus resultados y los problemas psicosociales y de seguro médico que rodean el proceso de asesoramiento genético y pruebas genéticas. Y aunque las pruebas no se realicen, hacemos recomendaciones de detección individuales basadas en los antecedentes familiares. El proceso de pruebas genéticas tiene varios pasos. El primero es identificar quién está en riesgo de tener el síndrome de cáncer hereditario. Las pruebas genéticas no se ofrecen a todos los pacientes de evaluación de riesgo genético. Es importante identificar al miembro de la familia más informativo. Una vez que se habla con la familia de las pruebas genéticas, antes de realizarlas brindamos información muy detallada, con asesoramiento sobre el consentimiento informado para la familia o la persona que se hará las pruebas. Una vez que los resultados se informan al paciente, ofrecemos asesoramiento detallado y seguimiento sobre el control. Geller G et al. JAMA. 1997;277: Offit K.Clinical Cancer Genetics: Risk Counseling and Management. New York: Wiley-Liss; 1998 Schneider K. Counseling about Cancer: Strategies for Genetic Counseling. 2 nd ed New York: John Wiley & Sons 2001 ASCO 11

12 American Society of Clinical Oncology: Policy Statement Indications for genetic testing for cancer susceptibility Personal/family history features suggestive of hereditary cancer syndrome Test can be adequately interpreted Results will aid in diagnosis or medical management Genetic testing should be done in setting of preand post-counseling The American Society of Clinical Oncology has issued a policy statement back in 2003 based on recommending indications for genetic testing for cancer susceptibility and there are three premises to their recommendation. The first is that the personal or family history actually is suggestive for a particular hereditary cancer syndrome; that the tests being offered can be adequately interpreted; and that the results of the testing will actually aid in the diagnosis or medical management for that individual or their family. An important emphasis is that the genetic testing should always be done in the setting of post- [I am sorry] --- in the setting of pre- and post-test counseling En 2003, la Sociedad Americana de Oncología Clínica publicó una declaración de política para recomendar pruebas genéticas de susceptibilidad al cáncer, la cual tiene tres premisas. La primera es que los antecedentes personales o familiares indican determinados síndromes de cáncer hereditario; la segunda, que las pruebas puedan interpretarse correctamente; la tercera, que los resultados de las pruebas permitan diagnosticar o tratar a una persona o su familia. Se destaca la importancia de que las pruebas genéticas se hagan en un contexto de asesoramiento brindado antes y después de las pruebas. J Clin Oncol 2003; 21(12): Genetic Testing: Other Considerations Wide range of possible emotional reactions How will the patient and their family use this information? Sharing genetic test results with family members May change cancer screening and health management Cost of genetic testing Concerns of genetic discrimination Other considerations regarding genetic testing that families consider is that there is quite a wide range of possible emotional reactions for the patient as well as members of their family. It is important to ask the family, "How do they intend on using this information?" The patient or the person undergoing the genetic testing. "How do they intend to share this information with the rest of their family members?" And to focus on how the genetic test results may change their cancer screening and health management. So this will provide a lot of useful information for their health care team. Many patients also want to know the more logistical aspects of genetic testing such as the costs involved, the timeframe to receive the results, and the majority of patients do express concerns about genetic discrimination and we have a lot of resources that we can share with the families Otra consideración respecto a estas pruebas es tener en cuenta que existe una amplia gama de posibles reacciones emocionales del paciente y su familia. Es importante preguntar a la familia cómo utilizará esa información, y a la persona que se hizo las pruebas genéticas cómo compartirá esa información con otros miembros de su familia. También es importante centrarse en cómo los resultados pueden cambiar los métodos de detección del cáncer y el control de la salud. Todo esto proporciona una gran cantidad de información a su equipo médico. Muchos pacientes también quieren conocer aspectos más logísticos de las pruebas genéticas, como costos y plazos para recibir los resultados. La mayoría expresa preocupaciones sobre discriminación genética, y tenemos una gran cantidad de recursos para compartir con las familias. 12

13 Benefits of Genetic Testing Provides information about one s cancer risk Helps determine the cancer risk for family members May assist in making decisions about cancer screening or management May provide relief from uncertainty May identify individuals who are not at risk in families with known mutations Some of the benefits of genetic testing include the ability to provide information to clarify one s cancer risk, to help determine the cancer risk for their family members. And this is a big motivation for many individuals to undergo genetic testing and counseling. The genetic test results may also aid in making decisions about cancer screening or management. Many families, they experience a sense of relief from uncertainty once the hereditary syndrome has actually been identified in the family or the genetic testing has ruled out that they have not inherited this cancer susceptibility gene. And finally, genetic testing may identify individuals who are not at high risk in families with no mutations and this definitely provides a great sense of relief from knowing that they are not at high risk for certain types of cancers. Algunos beneficios de estas pruebas son su capacidad para definir los riesgos de cáncer y ayudar a determinarlos para los miembros de la familia. Para muchos, esta es una gran motivación para recibir pruebas genéticas y asesoramiento. Sus resultados también ayudan a tomar decisiones sobre exámenes de detección y control. Muchas familias sienten alivio respecto a la incertidumbre una vez que el síndrome hereditario es identificado en la familia o las pruebas genéticas descartan la herencia del gen de susceptibilidad al cáncer. Por último, las pruebas pueden identificar a las personas que no están en alto riesgo en familias con mutaciones, y esto sin duda constituye un gran alivio al saber que no están en alto riesgo de ciertos tipos de cáncer. Limitations of Genetic Testing Cannot determine with certainty if or when a cancer will develop A negative result cannot rule out an increased cancer risk Screening and prevention measures are not 100% effective All individuals have a background risk for cancer Unfortunately, there are some limitations to genetic testing. The testing cannot determine with certainty if or when a cancer will develop and this goes back to the incomplete penetrance that we discussed earlier. A negative genetic test result cannot actually rule out an increased cancer risk. And we will talk about the implications and interpretation of genetic test results in a bit. Screening and prevention measures are not 100% effective and all individuals must be reminded that we all have a background risk for cancer development. Desafortunadamente, estas pruebas tienen limitaciones. No permiten determinar con certeza si el cáncer se desarrollará o cuándo, lo cual está relacionado con la penetrancia incompleta ya mencionada. Un resultado negativo no permite descartar un mayor riesgo de cáncer. Más adelante hablaremos de la repercusión e interpretación de estos resultados. Las medidas de detección y prevención no son 100% eficaces y debemos tener en cuenta que todos tenemos un riesgo subyacente de desarrollar cáncer. 13

14 Basics of Genetic Testing Type of Test Full Gene Analysis Analyzes entire gene for mutations Known Mutations Testing Testing for mutation previously identified in family Multi-site Testing Testing for panel of specific mutations Comments May not identify all mutations May identify uncertain variants Best method once family mutation is found 100% accuracy for family members Testing for population-specific founder mutations So, some of the basic concepts of genetic testing include the type of genetic test that would be offered to the family. There are several types including full gene analysis, known mutation testing, and Multi-Site testing. For full gene analysis, this involves analyzing the entire gene for mutations. Some of the limitations of this are that not all mutations are identifiable with today s current genetic testing technology. And also we may identify variants or genetic alterations that have uncertain clinical significance. And this can be quite frustrating for the genetic provider as well as the patient and their family. However, once the mutation has been identified in the family, then at-risk relatives can undergo what is called known mutation testing and this is testing for a mutation that has previously been identified in the family. This is actually the best method once the mutation is found in the family because it provides 100% accuracy whether an individual has inherited the genetic susceptibility gene or not. For some genetic testing, we actually initiate the testing process with what is called Multi-Site testing and this is testing for a panel of specific mutations. I mentioned earlier that one of the red flags for Hereditary Breast and Ovarian Cancer Syndrome is that an individual of Ashkenazi Jewish descent may have a high risk of having a BRCA1 and BRCA2 gene change. For these individuals, we would actually offer Multi-Site testing for the three Ashkenazi Jewish founder mutations. Una parte de los conceptos básicos es qué tipo de pruebas genéticas ofrecer a una familia. Existen varios tipos, como el análisis de gen completo, las pruebas de mutación conocida y las de sitios múltiples. Para el análisis de gen completo, se analizan las mutaciones en todo un gen. Una limitación es que no todas las mutaciones son identificables con la actual tecnología genética. También pueden identificarse variantes o alteraciones genéticas de significado clínico incierto. Esto puede causar frustración al laboratorio genético, al paciente y a su familia; sin embargo, una vez identificada la mutación en la familia, los familiares en riesgo pueden hacerse una prueba de la mutación conocida, es decir, la que ya ha sido identificada en la familia. Este es el mejor método cuando se encuentra una mutación en la familia, ya que determina con una exactitud del 100% si una persona ha heredado el gen de susceptibilidad genética. Para algunas pruebas genéticas, iniciamos el proceso con una prueba de sitios múltiples, que es un panel de mutaciones específicas. Ya mencionamos que uno de los signos de advertencia del síndrome hereditario de cáncer de mama y ovario es la ascendencia judía asquenazí, que conlleva un alto riesgo de cambios en los genes BRCA1 y BRCA2. En estas personas, ofrecemos pruebas de sitios múltiples para tres mutaciones fundadoras de esta ascendencia. 14

15 Possible Genetic Test Results Test Result Positive Deleterious mutation identified True Negative No mutation detected Family mutation known Comments Confirms diagnosis of cancer syndrome Family members can definitively clarify their risk to inherit syndrome Reassuring that individual has not inherited the cancer syndrome Cancer risks return to general population Possible Genetic Test Results Test Result Uninformative Negative No mutation detected No mutation previously identified in the family Uncertain Variant DNA change identified but clinical significance is unknown Comments Familial mutation cannot be ruled out Consider testing another affected family member Cancer risk management based on family history Testing affected family members (only) can also help determine segregation with cancer Cancer risk management based on family history Once an individual pursues genetic testing, there are several types of results that can be anticipated. The first type of result is called a positive result. This means that a deleterious or disease-causing mutation has been identified in the family. This really means that -- this confirms the diagnosis that the family has this particular hereditary cancer syndrome. And having a positive result allows family members to definitively clarify whether they have inherited the condition or not and they can then pursue the known mutation testing. Another type of result we can expect to receive is called a true negative result. True negative results can be anticipated in individuals who pursue known mutation testing. This is because they are testing only for that mutation that has already been identified in the family and they have tested negative for this. So, we know that they have truly not inherited this gene for cancer susceptibility and this is a very reassuring result for the individual. And these individuals have the same cancer risk as anyone else in the general population now. These two types of results have a little bit more ambiguity in interpretation and it is important to return to the family history to help interpret these results. An uninformative negative result can be received when --- [I am sorry] --- full gene mutation testing is pursued. With uninformed negative results, it means that no mutation has previously been identified in the family and this person has tested also negative for any mutations in that gene. So in these cases the family mutation still cannot be ruled out. Oftentimes, we return to the family history to see if there is a better, more informative test candidate or a family member that could undergo the same genetic testing. And the cancer risk management is based back on the family history and the pattern of cancers that we see. The last type of result we may anticipate receiving is called an uncertain variant. This means that a DNA change or alteration was identified from the genetic Una vez que una persona se hace una prueba genética, cabe esperar varios tipos de resultados. El primero es el resultado positivo, cuando se identifica en la familia una mutación deletérea o causante de enfermedad. Esto confirma el diagnóstico de que la familia tiene un síndrome particular de cáncer hereditario. Un resultado positivo permite a los miembros de la familia determinar si han heredado la condición y continuar con las pruebas de la mutación conocida. Otro resultado posible es el negativo verdadero. Estos resultados pueden anticiparse en individuos que se hacen pruebas de mutación conocida. Esto obedece a que solamente se ha buscado una mutación que ya ha sido identificada en la familia, con resultado negativo. Así sabemos que no han heredado ese gen de susceptibilidad al cáncer, un resultado muy reconfortante para el individuo, pues tiene entonces el mismo riesgo de cáncer que cualquier otra persona en la población general. Estos dos tipos de resultados tienen una interpretación un poco más ambigua y requieren volver a considerar los antecedentes familiares. Con las pruebas genéticas de mutación de gen completo es posible recibir un resultado negativo no informativo. En estos casos, no se ha identificado ninguna mutación en la familia y la persona también ha dado negativo para mutaciones de ese gen. Por ello, la mutación en la familia aún no puede descartarse. A menudo retomamos los antecedentes familiares para ver si hay un mejor candidato de prueba o uno más informativo, o un pariente que pueda hacerse las mismas pruebas genéticas. El control del riesgo de cáncer se basa en los antecedentes familiares y el patrón de cánceres detectado. El último tipo de resultado que cabe esperar es una variante incierta, donde las pruebas identifican un cambio o alteración del ADN cuya relevancia clínica se desconoce. En tal caso, las pruebas 15

16 Risk Management Regardless if patient pursues genetic testing, we discuss: Individualized cancer screening Prevention Medical management options, including referrals to appropriate specialists Recommendations based on either positive genetic test results or family history testing, but the clinical significance is unknown. In this case, testing affected family members only, can help determine whether the gene mutation or gene alteration is segregating with cancer. But there is no utility in testing unaffected family members because we do not know how to interpret these results. The cancer risk management is, therefore, based on the family history of cancer Regardless of whether the patient pursues genetic testing, risk management options for cancer are always discussed. We provided detailed individualized cancer screening and a prevention plan based on review of the three-generation family history and we discuss medical management options including referrals to appropriate specialists. So, while some families may not actually have a gene mutation identified in the family, the family history features may be still concerning for hereditary cancer and a referral to high-risk screening clinics may still be indicated for the family. realizadas sólo a los familiares afectados ayudan a determinar si la mutación o alteración del gen produce segregación del cáncer. No es útil analizar a los parientes no afectados pues no sabríamos interpretar los resultados. El control del riesgo de cáncer se basa, por lo tanto, en los antecedentes familiares de la enfermedad. Independientemente de que el paciente se haga o no pruebas genéticas, siempre analizamos las opciones para controlar el riesgo de cáncer. Realizamos exámenes de detección detallados e individualizados y un plan de prevención basado en los antecedentes de tres generaciones, y brindamos opciones de control médico, con referidos a los especialistas apropiados. Si bien en algunas familias no es posible identificar una mutación genética, sus antecedentes pueden ser motivo de preocupación de cáncer hereditario y posiblemente debamos referirlas a una clínica de detección de alto riesgo. 16

17 Genetic Information Discrimination Act of 2008 (GINA 2008) Federal legislation signed into law on May 21, 2008 Prohibits discrimination in health coverage and employment based on genetic information Genetic information An individual or family member s genetic tests Family history Genetic testing, counseling or education by an individual or family member National Human Genome Research Institute State Laws on Genetic Discrimination 47 states have laws pertaining to genetic discrimination Variable protections for requirement of genetic test/information, eligibility and risk classification by insurers States with less protection than GINA will need to comply to minimum protections of GINA National Conference of State Legislatures Issues & Research > health > genetic nondiscrimination in health insurance laws Many families are very concerned about the possibility of genetic discrimination. In 2008, Congress passed a law called Genetic Information Nondiscrimination Act. This is also known as GINA. And GINA prohibits discrimination in health coverage and employment based on genetic information. Genetic information is defined as an individual or their family members genetic test results, their family history alone, and information obtained from the genetic testing, counseling, or education process by a family member. To learn more about GINA, you can go to this link listed at the bottom of the page. Prior to the passage of GINA in 2008, approximately 47 states have passed laws pertaining to genetic discrimination. These states had variable protections for the requirement of genetic test and information, eligibility and risk classification by health --- group health insurers. And states --- now with the passage of GINA, states that had less protection than GINA will actually need to comply with minimum protections of GINA. So this can be good news for families in which you have family members scattered all across the United States because GINA provides a blanket law regardless of where you live in or if you plan on moving to other states. To actually learn about your specific state laws, you can to go the National Conference of State Legislatures and look up more information on that. Muchas familias sienten preocupación ante la posibilidad de una discriminación genética. En 2008, el Congreso aprobó la Ley de no Discriminación por Información Genética, o GINA, que prohíbe la discriminación en la cobertura de salud y el empleo basada en información genética. Esta se define como los resultados de las pruebas genéticas de una persona o sus familiares, sus antecedentes familiares o información obtenida de un proceso de pruebas genéticas, asesoramiento y educación por un miembro de la familia. Para obtener más detalles, visite el enlace indicado al pie de esta página. Antes de aprobarse esta ley en 2008, 47 estados ya habían aprobado leyes contra la discriminación genética que establecían diversas protecciones para las pruebas e información genética, la elegibilidad y la clasificación de riesgo de las aseguradoras de planes grupales. Con la ley GINA, los estados que tenían menos protección deberán ahora fijar ciertas protecciones mínimas. Esto es una buena noticia para las familias con miembros dispersos por todo el país, porque esta es una ley general, independientemente del lugar de residencia actual o futuro. Para obtener más información sobre leyes estatales específicas, visite la página Web de la Conferencia Nacional de Legislaturas Estatales en NCSL.org. 17

18 Genetic Counseling & Testing: Summary Not everyone who presents for risk assessment will be offered genetic testing Emphasis on pre- and post-test counseling Not all genetic test results are unequivocal Cancer risk management based on positive test results or family history Consider emotional and psychological impact on family Federal and state legislation for genetic discrimination Summary Concerning family histories warrant referral to genetic consultation Young onset cancer, multiple affected relatives, successive generations, bilateral/multifocal cancers Genetic consultation is a risk assessment of personal, medical and family histories for hereditary cancer syndromes Genetic testing not appropriate for everyone Implications for increased surveillance and cancer management for families with hereditary cancer susceptibility syndromes In summary, not everyone who presents for genetic counseling will actually be offered genetic testing. The genetic counseling process focuses on providing both pre- and post-test genetic counseling. Not all genetic test results are considered unequivocal. We often have to return to the family history for interpretation of these results and also make cancer risk management recommendations based on either the family history or whether a positive genetic test result has been identified in the family. With the genetic counseling and genetic testing process, it is very important to consider the emotional and psychological impacts on the family; as different family members will perceive these results in very different ways. And finally there are federal and state legislation for genetic discrimination. In summary, there are many concerning family histories that we have discussed today. And if you have identified a family that meets any of these red flags for hereditary cancer, please make a referral for genetic counseling for these individuals. This will include families with young onset of cancer, multiple affected family members occurring in multiple generations, and individuals with bilateral multifocal or multiple primary cancers. The genetic consultation visit is a risk assessment of an individual s personal, medical, and family histories for hereditary cancer syndrome. And although patients may undergo genetic counseling, genetic testing may not always be recommended for that individual or their family and, therefore, it may not be appropriate for everyone. Whether testing is discussed or pursued by the patient, implications for increased screening and cancer risk management are always discussed based on the family cancer pattern. This concludes my presentation. Thank you for your time. Resumiendo, no todos los que solicitan asesoramiento genético reciben pruebas genéticas. El proceso de asesoramiento genético brinda orientación tanto antes como después de las pruebas. No todos los resultados de las pruebas genéticas se consideran inequívocos. Con frecuencia debemos retomar los antecedentes familiares para interpretar los resultados y hacer recomendaciones para controlar el riesgo de cáncer, de acuerdo con esos antecedentes o con los resultados positivos de las pruebas genéticas en la familia. En el proceso de asesoramiento genético y pruebas genéticas, es muy importante tener en cuenta el impacto emocional y psicológico en la familia, pues cada familiar percibirá los resultados de una manera muy diferente. Por último, tenemos leyes federales y estatales contra la discriminación genética. Hoy hemos analizado numerosos antecedentes familiares relevantes. Si usted identifica a una familia que tiene alguno de estos signos de advertencia de cáncer hereditario, refiéralos a un servicio de asesoramiento genético. Esto incluye familias con una manifestación temprana de cáncer, varios familiares afectados en varias generaciones, y personas con cáncer primario multifocal bilateral o múltiple. La visita de consulta genética es una evaluación del riesgo de los antecedentes personales, médicos y familiares para el síndrome de cáncer hereditario. Aunque un paciente reciba asesoramiento genético, no siempre se le recomiendan pruebas genéticas individuales o familiares, pues no son apropiadas para todos. Si un paciente pide información o solicita pruebas, siempre deben analizarse los exámenes de detección y el control del riesgo de cáncer según el patrón familiar. Con esto concluye mi presentación. Gracias por su tiempo. 18