Cirugía de reducción de riesgo en mujeres portadoras de mutaciones BRCA 1 o 2 / Risk reducing surgery in BRCA1 or 2 mutation carriers

INTRODUCCIÓN: Los genes de susceptibilidad al cáncer de mama tipo 1/2 (BRCA1/2) pueden sufrir mutaciones deletéreas que conllevan un aumento significativo del riesgo de cáncer comparado con la población general (cáncer de mama 50-85% versus 11%, cáncer de ovario mayor al 20% versus 1,5%). En la población general la frecuencia de las mutaciones perjudiciales es menor al 1%, pero es mayor al 8% en aquellas mujeres con alto riesgo por antecedentes familiares. Existe consenso internacional en que la determinación de los genes BRCA se debería recomendar sólo en las mujeres de alto riesgo de acuerdo a criterios predefinidos. Distintas estrategias terapéuticas se plantean para la reducción del riesgo asociado a estas mutaciones: quimioprevención, rastreo intensivo y cirugía. Se postula la mastectomía bilateral (MBRR) y la salpingo-ooforectomia (SORR), ambas conocidas como cirugías reductoras de riesgo, como opción terapéutica en estas pacientes. TECNOLOGÍA: Para la cirugía de reducción de riesgo la mastectomía puede ser simple (total) o subcutánea, mientras que la salpingo-ooforectomia requiere la extracción de las trompas de Falopio, así como ambos ovarios. OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de cirugía de reducción del riesgo en portadores de mutaciones BRCA1/2. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas DARE, NHS EED en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias y económicas, guías de práctica clínica y políticas de cobertura de otros sistemas de salud. RESULTADOS: Se seleccionaron dos revisiones sistemáticas, cuatro estudios de cohorte prospectivos, cinco guías de práctica clínica, un documento de evaluación de tecnología sanitaria, dos evaluaciones económicas y ocho políticas de cobertura. Mortalidad: La cohorte PROSE (n=2482 mujeres portadoras de mutaciones) asoció la realización de la SORR con una disminución del riesgo de muerte por todas las causas (3,1% versus 9,8%; HR= 0,40; IC 95%: 0,26-0,61) luego de una mediana de seguimiento de 3,7 años. También hubo menor mortalidad por cáncer de mama (2,1% versus 5,7%; HR= 0,44; IC 95%, 0,26 - 0,76) y ovario (0,04% versus 2,5%HR= 0,21; IC 95%: 0,06-0,80). Políticas de Cobertura: Existe concordancia entre las aseguradoras de los Estados Unidos consultadas en brindar cobertura a la MBRR y la SORR en mujeres portadoras de mutaciones en los genes BRCA 1/2. Incidencia Cáncer de Mama: El estudio PROSE evidencio la asociación de la MBRR con un menor riesgo de cáncer de mama (n=1619), al no detectarse ningún evento durante los tres años de seguimiento en las mujeres que se sometieron a MBRR (0/247), frente al 7,14% (98/1372) en el grupo que optó por la rastreo intensivo. En este mismo estudio la SORR también se asoció a una disminución del riesgo de cáncer de mama primario (HR=0,54; IC 95%: 0,37 - 0,69). En un meta-análisis (n=5703) publicado previamente, la SORR también se asoció con una reducción significativa en el riesgo de cáncer de mama (HR=0,49; IC 95%:0,37 - 0,65). El estudio EMBRACE (cohorte de 1639 mujeres portadoras de mutaciones) confirmo estos resultados, pero solo cuando la SORR fue llevada a cabo antes de los 45 años (HR: 0,39; IC 95%: 0,17 ­0,87; p=0,02). Otros dos estudios de cohorte prospectivos arrojaron resultados similares sobre la MBRR. Incidencia Cáncer de Ovario: Un meta-análisis de tres estudios (n=2840) reportó una reducción significativa en el riesgo de cáncer de ovario o trompa de Falopio en aquellas pacientes sometidas a SORR (HR=0,21; IC 95%:0,12 ­ 0,39). El estudio PROSE reportó resultados similares (HR: 0,28; IC 95%: 0,12 - 0,69). Guías de Práctica Clínica: La Red Nacional de Cáncer de los Estados Unidos y la Sociedad Europea de Oncología recomiendan la SORR en aquellas mujeres portadoras de una mutación deletérea en los genes BRCA1/2, idealmente entre los 35 y 40 años de edad o al término de la procreación. Recomienda la MBRR como una opción terapéutica que debe ser discutida caso por caso. El Grupo de Trabajo de Servicios Preventivos de los Estados Unidos concluye que hay pruebas razonables de que la cirugía profiláctica disminuye la incidencia de cáncer mama y de ovario en estas mujeres y que las complicaciones asociadas son de escasa magnitud al compararlas con los beneficios esperados. En Canadá el Grupo Nacional de Trabajo sobre Cáncer Hereditario considera que tanto la MBRR como la SORR deben ser discutidas con todas las mujeres con mutaciones conocidas de los genes BRCA1/2. CONCLUSIONES: La calidad de la evidencia encontrada es baja. La MBRR y la SORR como estrategias reductoras de riesgo mostraron una disminución en la incidencia de cáncer en mujeres portadoras de mutaciones deletéreas, aunque solo en el caso de la SORR este beneficio estuvo asociado a una menor mortalidad. Si bien la evidencia es todavía escasa y de baja calidad, existe consenso a nivel internacional en recomendar a la SORR, sobre todo en mujeres menores de 40 años, y en considerar y discutir de manera detallada los riesgos y beneficios de la MBRR. Debido a que el riesgo individual puede ser muy diferente entre personas portadoras, así como también el beneficio esperado por las distintas estrategias terapéuticas, la consulta de asesoramiento genético se considera esencial en el proceso de toma de decisiones.(AU)

INTRODUCTION: Breast cancer type 1/2 (BRCA1/2) susceptibility genes may undergo deleterious mutations leading to a significant increase in the risk of cancer if compared with that of the general population (50-85% breast cancer versus 11%; ovarian cancer above 20% versus 1.5%). In the general population, the frequency of harmful mutations is less than 1%, but above 8% in those women at high risk due to family history. There is international consensus on the fact that BRCA gene identification should be recommended only in women at high risk as stated by predefined criteria. Different therapeutic strategies are proposed to reduce the risk associated with these mutations: Preventive chemotherapy, intensive screening and surgery. Bilateral mastectomy (RRBM) and salpingo oophorectomy (RRSO), both known as risk-reducing surgeries are proposed as therapeutic options in these patients. TECHNOLOGY: For risk-reducing surgery, mastectomy may be simple (complete) or subcutaneous, while salpingo oophorectomy require resection of fallopian tubes as well as both ovaries. PURPOSE: To assess the available evidence on the efficacy, safety and coverage related aspect regarding the use of risk-reducing surgery in BRCA1/2 mutation female carriers. METHODS: A bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems. RESULTS: Two systematic reviews, four prospective cohort studies, five clinical practice guidelines, one health technology assessment, two economic evaluations and eight coverage policies were selected. Mortality: The PROSE cohort (n=2,482 mutation female carriers) associated RRSO with a decrease in the risk of death due to all causes (3.1% versus 9.8%; HR= 0.40; 95% CI: 0.26-0.61) after a median follow up of 3.7 years. There was also lower mortality due to breast cancer (2.1% versus 5.7%; HR= 0.44; 95% CI, 0.26 - 0.76) and ovarian cancer (0.04% versus 2.5%, HR= 0.21; 95% CI: 0.06-0.80). Incidence of Breast Cancer: The PROSE study evidenced the association of RRBM with a lower risk of breast cancer (n=1,619), since no event was detected during the three-year follow up in women undergoing RRBM (0/247), versus 7.14% (98/1,372) in the group choosing intensive screening. In this very same study, the RRSO was also associated to a decrease in the risk of primary breast cancer (HR=0.54; 95% CI: 0.37 - 0.69). One meta-analysis (n=5,703) published earlier showed that the RRSO was also associated to a significant reduction in the risk of breast cancer (HR=0.49; 95% CI: 0.37 - 0.65). The EMBRACE study (a cohort of 1,639 mutation female carriers) confirmed these results but only when the RRSO was performed before the age of 45 (HR: 0.39; 95% CI: 0.17 ­0.87; p=0.02). Other two cohort prospective studies showed similar results about RRBM. Incidence of Ovarian Cancer: One three-study meta-analysis (n=2,840) reported a significant reduction in the risk of ovarian or fallopian tube cancer in those patients undergoing RRSO (HR= 0.21; 95%:CI 0.12 ­ 0.39). The PROSE study showed similar results (HR: 0.28; 95% CI: 0.12 - 0.69). Clinical Practice Guidelines: The United States National Cancer Network and the European Oncology Society recommend RRSO in female carriers of a deleterious mutation of BRCA1/2 genes, ideally 35 to 40 years old or after the child-bearing period. They recommend RRBM as a therapeutic option that should be considered case by case. The United States Preventive Service Taskforce concludes that there is reasonable evidence that prophylactic surgery decreases the incidence of breast and ovarian cancer in these women and that the related complications are non significant when compared with the expected benefits. In Canada, the National Hereditary Cancer Taskforce considers that both RRBM and RRSO should be considered in all women with known BRCA1/2 gene mutations. Coverage Policies: There is agreement among the United States health insurance companies consulted in providing coverage of RRBM and RRSO in female BRCA 1/2 gene mutation carriers. CONCLUSIONS: The quality of the evidence found is poor. RRBM and RRSO as risk-reducing strategies showed a decrease in the incidence of cancer in deleterious mutation female carriers, although only in the case of RRSO, this benefit was associated with a lower mortality. Even though the evidence is still poor and low quality, there is an international consensus to recommend RRSO, specially in women under 40, and in considering and discussing in detail the risks and benefits of RRBM. Since the individual risk may differ among carriers, as well as the benefit expected from the different therapeutic strategies, a genetic consultation is considered key to the decision making process.(AU)

INTRODUÇÃO: Os genes de suscetibilidade ao câncer de mama tipo 1/2 (BRCA 1/2) podem sofrer mutações deletérias que levam a um aumento significativo do risco de câncer comparado com a população geral (câncer de mama 50-85% versus 11%, câncer de ovário maior a 20% versus 1,5%). Na população geral a frequência das mutações prejudiciais é menor que 1%, mas é maior a 8% naquelas mulheres com alto risco de acordo a critérios pré-definidos. Distintas estratégias terapêuticas se sugerem para a redução do risco associado a estas mutações: quimio-prevenção, rastreio intensivo e cirurgia. Postula-se a mastectomia bilateral (MBRR) e a salpingo-ooforectomia (SORR), ambas conhecidas como cirurgias redutoras de risco, como opção terapêutica nestas pacientes. TECNOLOGIA: Para a cirurgia de redução de risco a mastectomia pode ser simples (total) ou subcutânea, enquanto a salpingo-ooforectomia requer a extração das trompas de Falópio, bem como ambos os ovários. OBJETIVO: Avaliar a evidencia disponível sobre a eficácia, segurança e aspectos relacionados às políticas de cobertura do uso de cirurgia para redução de risco em portadores de mutações BRCA1/2. MÉTODOS: Realizou-se uma busca nas principais bases de dados bibliográficos DARE, NHS EED, em buscadores genéricos de Internet, agências de avaliação de tecnologias sanitárias e financiadores de saúde. Priorizou-se a inclusão de revisões sistemáticas, ensaios clínicos controlados aleatorizados (ECAs), avaliações de tecnologias sanitárias e econômicas, guias de práticas clínica e políticas de cobertura de outros sistemas de saúde. RESULTADOS: Selecionaram-se duas revisões sistemáticas, quatro estudos de cohorte prospectivos, cinco guias de prática clinica, um documento de avaliação de tecnologia em saúde, duas avaliações econômicas e oito políticas de cobertura. Mortalidade: A cohorte PROSE (n=2482 mulheres portadoras de mutações) associou a realização da SORR com uma diminuição do risco de morte por todas as causas (3,1% versus 9,8%; HR=0,40; IC95% 0,26 a 0,61) depois de uma mediana de seguimento de 3,7 anos. Também houve menor mortalidade por câncer de mama (2,1% versus 5,7%;HR=0,44; IC95% 0,26 a 0,76) e ovário (0,04% versus 2,5%; HR=0,21; IC95% 0,06 a 0,80). Incidência Câncer de Mama: O estudo PROSE evidenciou a associação da MBRR com um menor risco de câncer de mama (n=1619), ao não detectar-se nenhum evento durante os três anos de seguimento nas mulheres que se submeteram a MBRR (0/247), frente a 7,14% (98/1372) no grupo que optou por rastreio intensivo. Neste mesmo estudo a SORR também se associou a diminuição de risco de câncer de mama primário (HR=0,54, IC95% 0,37 a 0,69). Numa meta-análise (n=5703) publicada previamente, a SORR também se associou com uma redução significativa no risco de câncer de mama (HR=0,49; IC95% 0,37 a 0,65). O estudo EMBRACE (cohorte de 1639 mulheres portadoras de mutações) confirmou esses resultados, mas somente quando a SORR foi realizada antes dos 45 anos (HR=0,39; IC95% 0,17 a 0,87; p=0,02). Outros estudos de cohorte prospectivos mostraram resultados similares sobre a MBRR. Incidência Câncer de Ovário: Uma meta-análise de três estudos (n=2840) reportou uma redução significativa do risco de câncer de ovário ou trompa de Falópio naquelas pacientes submetidas a SORR (HR=0,21; IC95% 0,12 a 0,39). O estudo PROSE reportou resultados similares (HR=0,28; IC95% 0,12 a 0,69). Guias de Prática Clínica: A Rede Nacional de Câncer dos Estados Unidos e a Sociedade Europeia de Oncologia recomendam a SORR naquelas mulheres portadoras de uma mutação deletéria nos genes BRCA1/2, idealmente entre os 35 e 40 anos ou ao término da procriação. Recomenda-se a MBRR como uma opção terapêutica que deve ser discutida caso a caso. O Grupo de Trabalho de Serviços Preventivos dos estados Unidos conclui que há provas razoáveis de que a cirurgia profilática diminui a incidência de câncer de mama e de ovário nestas mulheres e que as complicações associadas são de magnitudes escassas comparadas aos benefícios esperados. No Canadá o Grupo Nacional de Trabalho sobre Câncer Hereditário considera que tanto a MBRR como a SORR devem ser discutidas com todas as mulheres com mutações conhecidas dos genes BRCA1/2. Políticas de Cobertura: Existe concordância entre as seguradoras dos Estados Unidos consultadas em brindar cobertura a MBRR e a SORR em mulheres portadoras de mutações nos genes BRCA1/2. CONCLUSÕES: A qualidade da evidencia encontrada é baixa. A MBRR e a SORR como estratégias redutoras de risco mostraram uma diminuição na incidência de câncer em mulheres portadoras de mutações deletérias, ainda que somente no caso da SORR este benefício esteve associado a uma menor mortalidade. Se bem a evidência ainda é escassa e de baixa qualidade, existe consenso em nível internacional em recomendar a SORR, sobretudo em mulheres menores de 40 anos, e em considerar e discutir de maneira detalhada os riscos e benefícios da MBRR. Devido que o risco individual pode ser muito diferente entre pessoas portadoras, assim como também o benefício esperado pelas distintas estratégias terapêuticas, a consulta de assessoramento genético se considera essencial no processo para a tomada de decisões.(AU)

Contribution of BRCA1/2 mutation testing to risk assessment for susceptibility to breast and ovarian cancer: summary report

INTRODUCTION: For both breast and ovarian cancer the strongest known risk factor, after adjusting for age, is family history. The figure most often cited is that approximately 1/3 of breast cancer is familial, where family history is defined by the presence of at least two cases of breast cancer, at any age, in fi rst- or second-degree relatives. Approximately 5% of all breast cancer cases are currently thought to be hereditary, that is, related to the transmission of mutations in a single gene. Clustering of cancer cases in families does not imply that genetic susceptibility is always present, since environmental factors and chance can also play a role. Conversely, the presence of a genetic susceptibility will not always translate into the occurrence of multiple cancer cases within one family. However, persons considered to be at highest risk of carrying a mutation in a breast or ovarian cancer susceptibility gene are those displaying the characteristics of a hereditary breast and ovarian cancer syndrome, HBOC. The HBOC syndrome is characterized by a pattern of occurrence of cancers in a family, involving multiple relatives affected by breast and/or ovarian cancer, and by early age at diagnosis. Currently, there is no consensus as to the minimal set of criteria defining an HBOC family. METHODS: A comprehensive search strategy using key words was designed in order to identify published, 'grey', and unpublished literature for each topic. The search was limited to human studies, and there were no language restrictions. A draft set of key words was tested for its precision before finalization. Databases of published literature were searched through December 2004. The reference lists of primary research studies, review articles, and reports were searched to identify other relevant articles. The detailed literature search strategies and study selection criteria used for the assessment are presented in Appendix A. Two reviewers independently made the final selection of studies to be included in the review based on the selection criteria. Study selection forms were developed and pilot tested for this purpose. The decision to order an article was based on the title and abstract, where available. In cases where these offered insufficient information, the article was ordered for further information. The degree of agreement between reviewers was noted, and any persisting differences were resolved by consensus. For articles containing quantitative data, forms that were specifically developed and pilot tested for this project were used to extract data. Various procedures were put in place to ensure quality control, including checking of extracted data by a second reviewer, discussion of all particularly complex articles by several reviewers, and reading of text and tables by a scientific reviewer not directly involved in data extraction. CONCLUSION: In the process of reviewing the literature for this report, important limitations in the evidence have been found. Major problems are the lack of a consensual definition of HBOC and the quality of the study designs and reporting of data, which are not up to epidemiological standards for molecular test evaluation studies. The variability in the study population selection criteria and in the testing protocols for molecular testing complicates the synthesis of the evidence. This variability is particularly striking in the literature on prevalence, penetrance and clinical validity. Current knowledge in areas such as the distribution of BRCA1/2 mutations is dependent on the evolution of molecular techniques and testing criteria. Both prevalence and penetrance have been studied more thoroughly in high-risk families and in some founder populations than in families at moderate or low risk. Residual uncertainties and gaps in current knowledge have implications regarding decision making for individuals and families, for health-care providers and for policy makers. Among the conditions put forward by the American Society of Clinical Oncology for molecular testing in cancer genetics in general, the evidence was reviewed with respect to the assessment of prior (pre-test) risk based on family history and on the informativeness of test results for the post-test updating of the risk assessment. As far as current practices are concerned, the majority of families considered eligible for testing in cancer genetics clinics (typically families with two or three affected individuals) are not found to carry a BRCA1/2 mutation. Such a result is considered inconclusive and the residual risk of cancer remains higher than that of the general population. Providing precise post-test probabilities to these families is, however, difficult because good data on clinical negative predictive value are lacking. Another inconclusive test result which represents a challenging task for geneticists and genetic counsellors and does not substantially alleviate a family's anxiety, is the discovery of a variant of unknown clinical significance. This situation is relatively frequent, possibly almost as frequent as a positive test finding, but may be resolved over time as new knowledge about these variants accrues. In practice, for the very high risk families, the pre-test (prior) risk will not be substantially modified by an inconclusive test result. Testing primarily benefits families in which a BRCA1/2 mutation has been discovered. For unaffected relatives who undergo testing and are found not to carry the mutation present in the family, breast cancer risk drops from a high prior probability to a post-test risk comparable to that in the general population. Unaffected relatives in whom a mutation is identified, on the other hand, have a substantially higher cancer risk than that of the general population. In addition, individuals with breast or ovarian cancer in whom a BRCA1/2 mutation is identified are at increased risk of developing a second cancer. For families in which a BRCA1/2 mutation is identified, both positive and negative test results have implications for clinical management, either in the sense of a 'demedicalization' or of increased requirements for surveillance, prevention or prophylactic measures. A review of the effectiveness of these interventions did not fall within the purview of this report. Consequently, a balanced view of benefits and risks, and formal recommendations with respect to the use of BRCA1/2 mutation testing, cannot be presented at this time. It is, however, already apparent that the balance of benefits and risks will be heavily dependent on the prior risk assessment and that the knowledge base to derive decisions is stronger for high-risk families than for populations at lower risk. In the subsequent AETMIS report, the forthcoming evidence from other systematic reviews on issues such as the analytical validity of molecular tests, the psychosocial consequences of testing, and the effectiveness of available interventions will be integrated with our further analysis of the economic and organizational issues surrounding cancer genetic services.

Validez diagnóstica de las pruebas genéticas BRCA1 y BRCA2 / Validade diagnóstica dos testes genéticos BRCA1 e BRCA2

INTRODUCCIÓN: La causa más común de cáncer de seno hereditario es una mutación hereditaria en los genes BRCA1 y 2. De todas las mujeres con cáncer de mama, entre 5 y 10% pueden tener una mutación de la línea germinal de los genes BRCA1 y 2. El cálculo de riesgo vitalicio de presentar cáncer de mama para las mujeres con mutaciones del BRCA1 y 2 oscila entre 40 y 85%. Por ello en casos específicos (Criterios Adelaida) de acuerdo a la edad y a la historia de cáncer de mama u ovario en la familia, en casos de cáncer de mama en hombre y en personas que tienen ancestros Judíos Ashkenazi, según criterio médico se pueden llevar a cabo las pruebas genéticas BRCA1 y 2. Esta prueba genética, a través del análisis de una muestra de sangre, identifica mutaciones en el cromosoma 17 o 13. Un resultado positivo en esta prueba de mutación genética, permite identificar estrategias de manejo (mastectomía bilateral profiláctica, ooforectomía, o quimioprevención con un modulador selectivo de receptores estrogénicos) tendientes a disminuir la probabilidad de padecer cáncer de mama. GRAVEDAD DE LA ENFERMEDAD: El cáncer de mama es un crecimiento anormal e incontrolable de las células mamarias usualmente como resultado de mutaciones en genes que controlan la proliferación y muerte celular. En la mayoría de los casos, estas mutaciones ocurren debido a eventos aún no plenamente entendidos con efectos acumulativos durante el tiempo de vida de la persona. El tumor resultante tiene la característica de invadir localmente los Tejidos sanos vecinos así como enviar células tumorales a órganos a distancia, con una destrucción progresiva de los mismos. CONCLUSIONES: -Efectividad: la GPC de diagnóstico y tratamiento del cáncer de mama no evalúa las características validez diagnóstica de esta prueba, y por ende no hay una recomendación específica para su realización rutinaria. La GPC presenta algunos criterios que podrían soportar la pertinencia de la solicitud del estudio para la detección genética de BRCA1 y BRCA2, basados en los criterios de Adelaida. -Seguridad: no hay un pronunciamiento explícito en el texto de la GPC sobre aspectos de seguridad de la prueba genética. -Costo-efectividad: No se identificaron estudios de costo-efectividad para Colombia.