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In Reply

Familial Cancer Centre, Peter MacCallum Cancer Centre; and Genetic Health Services Victoria, Murdoch Children's Research Institute, Melbourne, Australia

Rebecca Doherty

Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Australia

Marion Harris

Familial Cancer Centre, Peter MacCallum Cancer Centre; and Genetic Health Services Victoria, Murdoch Children's Research Institute, Melbourne, Australia

Mary-Anne Young, Clare Scott

Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Australia

In Reply:

In our recent study¹ of 257 families (including 67 families in which pathogenic mutations in BRCA1 or BRCA2 were found), we performed an independent comparison of six previously described methods that can be used to select families for mutation screening of the BRCA1 and BRCA2 genes, representing a cross-section of the different methodologies that have been employed. The aim of the study was to achieve optimal performance with each of the methods and to compare them in the setting of the standard practice of a Family Cancer Clinic. As we discussed, each of the methods has both advantages and limitations. The scoring method described by Evans et al,² performed well in direct comparison with the other methods, and we were impressed by how simple it was to learn and the speed with which it could be employed. We noted, as do Evans et al,² that the Manchester score was developed using only non-Ashkenazi Jewish families and consequently our complete analysis was repeated in 209 families (including 51 with BRCA mutations), with the 37 families of Jewish ancestry (15% of the probands) excluded as they suggest. Additional data for this comparison are given in Table 1. As reported in our article, the Manchester score (along with the Family History Assessment Tool) showed improved performance in this analysis, although the changes in accuracy (as measured by the area under the receiver operator curve) are not large and the overall rank order of the methods remains the same. Evans et al, are correct in noting that in the smaller group of non-Jewish families the differences between the methods no longer reach statistical significance, however, neither these data nor the findings of the recent study by Barcenas et al,³ are consistent with the conclusion that the Manchester score outperforms other existing methods as has been suggested.² Overall, the difference between the accuracy of the least accurate methods in our comparison and the highest levels of selection accuracy achieved, which were observed with the probabilistic methods when an adjustment was made to incorporate the pathology findings of the proband's tumor, could not be described as marginal. We have emphasized that the accuracy of a method is only one component that needs to be considered when selecting a family for BRCA gene testing. The experience and clinical expertise of local clinicians and counselors, the ethnic composition of the population, and the available resources all need to be taken into account when designing a testing strategy. However, in services where clinical, financial, or laboratory resources are limited, accurate selection of those families at genuinely increased risk is critical to achieving effective patient care.

The authors indicated no potential conflicts of interest.

REFERENCES

1. James PA, Doherty R, Harris M, et al: Optimal selection of individuals for BRCA mutation testing: A comparison of available methods. J Clin Oncol 24:707-714, 2006[Abstract/Free Full Text]

2. Evans DGR, Eccles DM, Rahman N, et al: A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41:474-480, 2004[Abstract/Free Full Text]

3. Barcenas CH, Hosain M, Arun B, et al: Assessing BRCA carrier probabilities in extended families. J Clin Oncol 24:354-360, 2006[Abstract/Free Full Text]

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