Rebecca Doherty

Optimal Selection of Individuals for BRCA Mutation Testing: A Comparison of Available Methods

PURPOSE Several methods have been described that estimate the likelihood that a family history of cancer is a result of a mutation in the BRCA1 or BRCA2 genes. We examined the performance of six different methods with the aim of identifying an optimal strategy for selecting individuals for mutation testing in clinical practice. PATIENTS AND METHODS Two hundred fifty-seven families who had completed BRCA1 and BRCA2 mutation screening were assessed by six models representing the major methodologies used to assess the likelihood of a pathogenic mutation. The performance of each method as a selection criterion was compared with the result of mutation testing to produce sensitivity, specificity, and receiver operating curve data. The impact of incorporating breast cancer pathology data in the assessment was also analyzed. RESULTS The highest accuracy was achieved by the Bayesian probabilistic model (BRCAPRO). The formal probabilistic methods were significantly more accurate than clinical scoring methods. The methods were further improved by the incorporation of information on breast cancer pathology (tumor grade and estrogen receptor/progesterone receptor status). The resulting combined probability figure was highly accurate when selecting individuals for BRCA1 testing. Some BRCA2 mutation carriers were missed by all of the models examined. CONCLUSION Formal probabilistic models provide significantly greater accuracy in the selection of families for gene testing than the use of clinical criteria or scoring methods. The accuracy is further enhanced by incorporating information on the pathology of breast cancers occurring in the families.

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype

There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P=0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial.

Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives.

BackgroundWomen from families with a high risk of breast or ovarian cancer in which genetic testing for mutations in the BRCA1/2 genes is inconclusive are a vulnerable and understudied group. Furthermore, there are no studies of the professional specialists who treat them - geneticists, genetic counsellors/nurses, oncologists, gynaecologists and breast surgeons.MethodsWe conducted a small qualitative study that investigated women who had developed breast cancer under the age of 45 and who had an inconclusive BRCA1/2 genetic diagnostic test (where no mutations or unclassified variants were identified). We arranged three focus groups for affected women and their close female relatives - 13 women took part. We also interviewed 12 health professionals who were involved in the care of these women.ResultsThe majority of the women had a good grasp of the meaning of their own or a family members inconclusive result, but a few indicated some misunderstanding. Most of the women in this study underwent the test for the benefit of others in the family and none mentioned that they were having the test purely for themselves. A difficult issue for sisters of affected women was whether or not to undertake prophylactic breast surgery. The professionals were sensitive to the difficulties in explaining an inconclusive result. Some felt frustrated that technology had not as yet provided them with a better tool for prediction of risk.ConclusionsSome of the women were left with the dilemma of what decision to make regarding medical management of their cancer risk. For the most part, the professionals believed that the women should be supported in whatever management decisions they considered best, provided these decisions were based on a complete and accurate understanding of the genetic test that had taken place in the family.

A population-based audit of ethnicity and breast cancer risk in one general practice catchment area in North London, UK: implications for practice

ObjectivesTo conduct a pilot population-based study within a general practice catchment area to determine whether the incidence of breast cancer was increased in the Ashkenazi population.DesignPopulation-based cohort study.SettingA single general practice catchment area in North London.Participants1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer.Main outcome measuresIncidence of breast cancer, ethnicity.ResultsThis study showed a 1.5-fold (95% CI 0.93–2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10–1.89). Results were adjusted for other risk factors for breast cancer.ConclusionThis study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community.

Short report. The AIDIT and IMPACT conference 2006: Outcomes and future directions.

IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international collaboration investigating the utility of targeted prostate-specific antigen (PSA) screening for men at increased risk of prostate cancer due to inherited predisposition. Although the majority of prostate cancer occurs sporadically, it is recognized that family history plays a role in a significant number of cases: a family history either of prostate cancer alone [1], or of other cancers including breast and ovarian cancer [2]. Evidence of the link between single genes and prostate cancer risk is strongest for the BRCA1 and BRCA2 genes [3-5], with BRCA2 in particular thought to lead to a relative risk of 4.65 (95% CI 3.48-6.22). This relative risk may be as high as 7.33 in men under the age of 65 years. Population prostate cancer screening remains controversial because of the potential for detection of clinically insignificant disease in young men and the risk of over-treatment. There is increasing interest and concern in European countries about whether prostate cancer screening should be offered to the general population and whether this would lead to a reduction in mortality from prostate cancer. IMPACT raises the hypothesis that targeting screening at the men in the population who are known to have an increased risk of the disease might improve the effectiveness of prostate cancer screening. Beginning with a pilot of 100 patients, the IMPACT study ultimately aims to recruit a total of 850 carriers of mutations in BRCA1 and BRCA2 and 850 controls (men shown not to carry familial BRCA1/2 mutations by predictive genetic testing). Recruitment will be open for five years, followed by five years of follow-up. In 2005, a project known as AIDIT (Advancing International co-operation and Developing Infrastructure for Targeted screening of prostate cancer in men with genetic predisposition) was awarded funding through the EC Framework 6 Programme as part of an endeavour to reduce research fragmentation and duplication, and to facilitate research collaboration across Europe. IMPACT currently includes collaborators from 24 countries. AIDITs aim is to expand the IMPACT consortium within the associated candidate countries (ACCs) and new member states of the EU. The expansion of IMPACT is likely to benefit both the study and the research teams: a higher number of collaborating centres will allow access to a larger number of men at risk, making it possible to recruit as many carriers as are needed for the study, particularly in populations likely to harbour founder mutations; and for all collaborators - both new and existing - it is hoped that participation in AIDIT and IMPACT will foster an environment of ongoing interaction and learning.

The contribution of LARGE genomic rearrangements of BRCA1 and BRCA2 gene mutations in breast and ovarian cancer families in a clinical cohort

Background The use of multiplex ligation-dependent probe amplification (MLPA) to detect large scale rearrangements is now a standard component of BRCA1 and BRCA2 gene testing in the clinical setting. With the cost of full Sanger sequencing up to 4 times higher than the cost of MLPA, it is important not only to determine the prevalence of these mutations but to ascertain the probability that a family may harbour a large deletion or rearrangement in the BRCA1 and BRCA2 genes. Here we examine the incidence and clinical associations of genomic rearrangements in the BRCA1 and BRCA2 genes in a cohort of index cases from high risk breast and ovarian cancer families recruited from familial cancer centres (FCC).

Optimal selection of individuals for BRCA1 and BRCA2 gene testing

1009 Background: Targeting BRCA1 and BRCA2 mutation analysis to those most likely to carry a mutation is desirable. We examined the performance of 6 different methods of selecting individuals for BRCA gene testing with the aim of identifying the optimal strategy. METHODS 266 families who were seen at a single Familial Cancer Centre between 1997 and 2003 where at least one affected family member had completed full BRCA1 and 2 mutation screening were included in this retrospective study. 68 individuals (25.5%) carried a gene mutation (33(12.5%) BRCA1, 35(13%) BRCA2). Each family was assessed using the BRCAPRO computer program, the models published by Couch et al (1997), Frank et al(2002), as well as the Family History Assessment Tool ( Gilpin et al 2000), the Australian National Breast Cancer Centre guidelines, and an assessment tool developed by the South Australian Family Cancer Centre. The performance of each method as a selection criterion was compared with the result of the gene test to produce sensitivity, specificity, predictive values and receiver operating curve data. The effect of using different levels of pre-test probability as a cut-off for gene testing, as well as the impact of breast pathology data on the assessment were analysed. RESULTS Use of the probability data generated by the BRCAPRO program produced the highest area under the receiver operated curve ( 0.78) compared with the other methods. Applying a cut-off of 10% or higher probability for testing gave a sensitivity of 79% and a specificity of 61% for BRCA mutation detection. These data were further improved by the incorporation of breast cancer pathology information ( tumour grade and ER/PR status). The probability generated by BRCAPRO was adjusted on the basis of the pathology of the breast cancers in the families using Bayes theorem. A cut-off of 10% or more for testing resulted in further improvements in both sensitivity and specificity in comparison to the BRCAPRO score alone. CONCLUSIONS The BRCAPRO score with a Bayesian adjustment incorporating breast cancer pathology data, with a cut-off of 10% or greater, was the optimal method for selecting individuals for BRCA1 and 2 mutation analysis. No significant financial relationships to disclose.