Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

 

Source:  http://jnci.oxfordjournals.org/content/early/2013/04/26/jnci.djt095

Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

1. Nasim Mavaddat,
2. Susan Peock,
3. Debra Frost,
4. Steve Ellis,
5. Radka Platte,
6. Elena Fineberg,
7. D. Gareth Evans,
8. Louise Izatt,
9. Rosalind A. Eeles,
10. Julian Adlard,
11. Rosemarie Davidson,
12. Diana Eccles,
13. Trevor Cole,
14. Jackie Cook,
15. Carole Brewer,
16. Marc Tischkowitz,
17. Fiona Douglas,
18. Shirley Hodgson,
19. Lisa Walker,
20. Mary E. Porteous,
21. Patrick J. Morrison,
22. Lucy E. Side,
23. M. John Kennedy,
24. Catherine Houghton,
25. Alan Donaldson,
26. Mark T. Rogers,
27. Huw Dorkins,
28. Zosia Miedzybrodzka,
29. Helen Gregory,
30. Jacqueline Eason,
31. Julian Barwell,
32. Emma McCann,
33. Alex Murray,
34. Antonis C. Antoniou,
35. Douglas F. Easton,
36. on behalf of EMBRACE

+ Author Affiliations

1. Affiliations of authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care (NM, SP, DF, SE, RP, EF, ACA, DFE); Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK (DGE); South East Thames Regional Genetics Service, Guy’s Hospital, London, UK (LI); Oncogenetics Team, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK (RAE); Yorkshire Regional Genetics Service, Leeds, UK (JA); Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK (RD); Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK (DE); West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK (TC); Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield, UK (JC); Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK (CB); Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK (MT); Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK (FD); Clinical Genetics Department, St.Georges University of London, Tooting, London, UK (SH); Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK (LW); South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK (MEP); Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK (PJM); North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK (LES); Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James’s Hospital, Dublin, Ireland (MJK); Cheshire & Merseyside Clinical Genetics Service, Liverpool Women’s NHS Foundation Trust, Liverpool, UK (CH); South West Regional Genetics Service, Bristol, UK (AD); All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK (MTR); North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK (HD); North of Scotland Regional Genetics Service, NHS Grampian & University of Aberdeen, Foresterhill, Aberdeen, UK (ZM, HG); Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, UK (JE); Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK (JB); All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK (EM, AM).

1. Correspondence to: Nasim Mavaddat, MBBS, PhD, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK (e-mail: nasim@srl.cam.ac.uk).

• Received July 24, 2012.
• Revision received March 20, 2013.
• Accepted March 22, 2013.

Abstract

Background Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles.

Methods Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan–Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided.

Results The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02).

Conclusions Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

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Management of hereditary breast and ovarian cancer syndrome and patients with BRCA mutations

Ovarian and breast cancer patients in a pedigree chart of a family (Photo credit: Wikipedia)

Via: Alfonso Casi en grupo https://www.facebook.com/groups/informacionmedica/

Salud Juntos  RIESGO FAMILIAR DEL CANCER DE MAMA, el primer paso es conocer, en mujeres con intensa historia familiar de cáncer de mama, su situación de portadora o no de la mutación BRCA.

Sólo alrededor del 5% al 10% de los cánceres de mama que se diagnostican son causados por mutaciones BRCA 1 y 2; la mayoría son causados por otros factores.
Ciertas características señalan a las mujeres que tienen mayor riesgo de ser portadoras de la mutación, como una menor edad en el momento del diagnóstico, una intensa historia familiar y ciertos grupos étnicos. En estos casos se recomienda un asesoramiento genético para las mutaciones BRCA 1 y 2.
Las portadoras de la mutación BRCA tienen un 80% a 90% riesgo de cáncer de mama durante su vida (estudio retrospectivo), así como un 40% a 50% riesgo de cáncer de ovario. (Riesgo prospectivo de 1/200 aproximadamente).
Las principales opciones para el riesgo de cáncer de mama son la vigilancia, el tratamiento médico preventivo con tamoxifeno u otros agentes quimioterapéuticos, o la doble mastectomía profiláctica - la forma más eficaz de prevención pero con importantes implicaciones.
Para información exhaustiva ->http://ow.ly/lbr4s
http://ow.ly/lbrck

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Bandolier: Genewatch: BRCA genes - potential and problems

Ovarian and breast cancer patients in a pedigree chart of a family (Photo credit: Wikipedia)

Genewatch: BRCA genes - potential and problems

Potential and Problems Statistical prophecies Inappropriate optimism Implication for screening BRCA1 gene Statistical prediction Potential and Problems The New England Journal of Medicine had a headline back in May of which Bandolier would be proud - "BRCA genes - Bookmaking, Fortunetelling, and Medical care" [1]. It pulled together information in four papers in that issue which examined new research on these genes involved with breast and ovarian cancer. The correspondence published in September is also interesting for those contemplating how to make the best use of new genetic information. Statistical prophecies The discovery of the so-called breast cancer genes, BRCA 1 in 1994 and BRCA 2 in the following year, were clearly landmarks in the study of breast cancer. It was naturally hoped, indeed almost assumed, that such important discoveries would quickly be followed by rationally designed improvements in prevention and treatment of this dread disease. The message that a woman with a strong family history of breast and/or ovarian cancer who carries a germ line mutation in one of these genes carries a lifetime risk of breast cancer of about 85%, and about 60% for ovarian cancer, is a very frightening one. Not surprisingly the pressure created for the practical application of these discoveries was almost immediate and very great. The situation was further complicated by the potential economic returns of genetic testing and the speed with which commercial companies were able to offer their services. Although the ethical and socio-economic problems raised by this were quickly appreciated, ongoing discussions between well informed representatives of the public, patient groups and the relevant professions will be required before any consensus can be reached. It is at least of some comfort to note that government regards the situation as sufficiently important to have set up (even if only after severe pressure from the professions!) both a Human Genetic Commission and a Genetics Testing Advisory Group. Although the emerging information is of great scientific value and interest, it does have a great potential for misunderstanding and misapplication. The editorial [1] refers to the making of gene-based statistical prophecies - but not necessarily with all the evidence yet in. Inappropriate optimism One of the papers in the NEJM issue was a study of the prevalence of BRCA1 mutations in a population of women with breast cancer. Clinical information, family histories and blood was given by 263 women, and DNA sequencing was used to identify BRCA1 mutations. Women were consecutive referrals who were referred either because there was a strong familial risk factor for breast cancer (169 women) or breast cancer was diagnosed before 40 years of age (94 women). There was an average of 4 breast cancers per family and 1.5 cases of ovarian cancer in the women with a family history.

BRCA 1 mutations were identified in 9/124 (7%) women where there was a family history of breast cancer without ovarian cancer, 10/57 (18%) where family members had bilateral breast cancer, 28/60 (47%) with family members with both breast and ovarian cancer or a single member with both cancers. Implication for screening This suggests that even when subjects are selected from families with a strong history of breast cancer only about 7 in 100 will be found to have BRCA 1 mutations. So more than 9 out of 10 tests would be negative, with 10% or fewer positive, if screening for BRCA1 mutations were instituted. The implication is that BRCA1 mutations may account for fewer than half of hereditary cases of breast cancer, not much higher figures suggested previously (see Bandolier 18 ). Routine screening, even where there is a family history, will be wasteful in that it will require enormous back up, both scientific and medical, including counselling, to undertake responsibly. Furthermore, women who do not have a mutation have to be cautioned to prevent a false sense of security, because, in the striking words of the article, "negative tests are not truly negative". That is, women with negative results for BRCA1 mutation are still at risk of cancer. BRCA1 gene Scientists have already identified more than 200 different mutations in the two BRCA genes. But we do not know how these different mutations differ in their relative contributions to breast, ovarian and other cancers. Clearly some mutations are responsible for the very high risks identified in some families, but others are likely to be within the normal variations found in many genes (polymorphisms) and not be relevant to cancer. It is also likely that different mutations will determine different types of cancers with different pathologies and different outcomes. There are some very preliminary indications that mutations towards one end of the BRCA1 gene are more likely to lead to breast cancer while those towards the other end of the gene are more likely to give ovarian cancer. It is also suggested that mutations in the BRCA2 gene are less likely to be found in early onset breast cancer than are BRCA1 mutations. Moreover the same mutations may behave differently in different populations of women. This emphasises the importance of modifying factors in determining the final outcome (eg, reproductive history, hormone therapy, diet, smoking and other genes which, for example, control the metabolism of hormones). We must not forget that all cancers are ultimately determined by a combination of genetic and environmental factors and the interplay of these is one of our most urgent subjects for research. Statistical prediction The problem of statistical prediction becomes especially worrying when irreversible decisions are based on it. The question of whether to have prophylactic mastectomies or oophorectomies for carriers of BRCA mutations is a particularly difficult one. A theoretical model [3], based on a number of statistical assumptions, estimated that prophylactic mastectomies would add 2.9 to 5.3 years of life expectancy for a 30 year old carrier of a mutation and an oophorectomy would add 0.3 to 1.7 years. Estimated gains in life expectancy decline with age, however. Gains would be minimal for a 60 year old, less than one year on average, very little more than the estimated gain in life expectancy of 8 months for a woman without a mutation. But as correspondence suggests [4], even this reported gain in life expectancy may overstate the benefit of prophylactic surgery to the patients for several reasons: The effects of surgery on quality of life are ignored. Risks associated with surgery are immediate. Benefits (prevention of cancer) accrue over time. The reported gain in life expectancy applies only to women who already know they have the gene mutations. Screening to find the mutation would carry its own demerits - not least those of false positive or false negative results in circumstances where prevalence may not be high. So this information should encourage a conservative approach to prophylactic surgery. But patients are individuals rather than units of a statistical study and each needs to be given individual consideration. Where this involves changes in genes which predispose to breast cancer this means access to experts who themselves are in possession of the latest information and are able to communicate this in a digestible form to worried people who do not understand the science or statistics. References: B Healy. BRCA genes - Bookmaking, Fortunetelling, and Medical Care. New England Journal of Medicine 1997 336: 1449-9. FJ Couch, ML DeShano, A Blackwood et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. New England Journal of Medicine 1997 336: 1409-15. D Schrag, KM Kuntz, JE Garber, JC Weeks. Decision analysis - effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. New England Journal of Medicine 1997 336: 1465-71. JD Birkmeyer, HG Welch. Risk of breast cancer in carriers of BRCA gene mutations. New England Journal of Medicine 1997 337: 787.

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La doble mastectomía de Angelina Jolie impulsa las acciones del fabricante de pruebas genéticas Myriad Genetics

Angelina Jolie at the premiere of Alexander in Cologne. Español: Angelina Jolie en el estreno de Alejandro Magno en Colonia. Français : Angelina Jolie à la première du film Alexandre à Cologne. Italiano: Angelina Jolie alla prima del film Alexander a Colonia. Português: Angelina Jolie na estréia do filme Alexandre Magno em Colônia. (Photo credit: Wikipedia)

Via: Martin Cañas

el Economista, 14/05/2013


Las acciones del fabricante de pruebas genéticas Myriad Genetics llegaron a dispararse hasta un 4 por ciento después de que la actriz Angelina Jolie detallase su decisión de someterse a una mastectomía doble. La decisión se produjo tras las pruebas que mostraban que es portadora del gen BRCA, que potencia el cáncer de mama.

Jolie detalló su decisión en un artículo de opinión publicado en The New York Times donde dijo tener "un gen defectuoso", el BRCA1, que aumenta bruscamente el riesgo de desarrollar cáncer de mama y cáncer de ovario. Jolie, cuya madre murió de cáncer de mama, dijo que eligió someterse a esta cirugía agresiva para reducir el riesgo de padecer cáncer de mama.

Myriad Genetics es la compañía encargada de hacer la prueba predictiva del cáncer de mama y ovario hereditarios que contienen los genes BRCA1 y BCRA2. Las acciones de esta compañía se han revalorizado más de un 19 por ciento desde que comenzase el año.

En un comunicado, un portavoz de Myriad animó a los pacientes a hablar con sus proveedores de atención médica acerca del riesgo hereditario de cáncer. "Creemos firmemente el uso apropiado de muchas de nuestras pruebas de diagnóstico puede ayudar a reducir las enfermedades, hospitalizaciones y otras intervenciones costosas, y potencialmente reducir los costes de atención médica", aseguró.

El portavoz explicó que bajo la Ley de Cuidado de Salud Asequible, popularmente conocido como Obamacare, las pruebas genéticas BRACA serán totalmente cubiertas. Así, los pacientes de riesgo no serán responsable de los copagos para la detección del cáncer. Es decir, aquellos que están en riesgo podrían librarse de pagar una prueba cuyo coste asciende a los 3.000 dólares.

Si bien la eficacia de esta prueba está más que probada, la patente de Myriad sobre los genes BRCA es el centro de atención de un caso que debate el Supremo de EEUU, donde se cuestiona si se puede patentar un gen. El caso está siendo seguido de cerca por la industria de biotecnología y el sector farmacéutico.

Myriad tiene los derechos exclusivos de mas de dos docenas de patentes en todo el mundo sobre los genes BRCA. La compañía patentó su descubrimiento después de aislar los genes en la década de 1990 y desarrollar una prueba para generar un marcador genético. El fabricante sostiene que el aislamiento de las moléculas llevado a cabo, y su aplicación, son comparables al desarrollo de un nuevo producto químico ya que el gen por sí mismo no detecta el cáncer.

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