We have undertaken the largest analysis of BRCA1 in TN breast cancer to date, and showed that the frequency of BRCA1 mutations in unselected individuals with TN breast cancer is ~10%, increasing to ~19% of individuals diagnosed below 50 years. The latter is similar to the frequency of BRCA1 mutations (23%) in individuals diagnosed before 50 years that were selected for inclusion because of a family history of breast cancer and/or young age at diagnosis. Our study included samples from four different sources and more precise figures would be obtainable from larger, prospective studies. Nevertheless, our results are similar to those previously reported and we believe that they are likely to be broadly accurate (refs in ).
We estimated the proportion of individuals included in this study that would currently qualify for a clinical BRCA test. Our analysis suggests that over a third of the BRCA1 mutation-positive individuals we identified would not have been eligible for clinical genetic testing in departments that use a 10% mutation detection threshold calculated without consideration of histological parameters.
Taken together, these data strongly indicate that histological parameters should be included in deciding which individuals should be offered BRCA testing. There have been efforts to incorporate histological parameters into existing BRCA-testing selection systems, such as BOADICEA and the Manchester system, (Evans et al, 2009
; Mavaddat et al, 2010
). Additionally, studies to define testing criteria in individuals that are not eligible for testing using current systems (e.g., individuals with TN breast cancer but without a family history) have been undertaken (Young et al, 2009
; Evans et al, 2011
). We believe a drawback to these approaches is that complex evaluation by specialist practitioners is typically required for most cases, but is unnecessary in the sizeable proportion eligible for testing on the basis of age alone.
A simpler approach, which would be readily comprehensible by clinicians and patients, would be to define a BRCA testing eligibility criteria for women with TN breast cancer based on age. Only individuals above the age threshold would require the more detailed, specialist review incorporating family history and scoring algorithms to decide whether they were eligible for BRCA testing.
Our data suggests that diagnosis of TN cancer below 50 years would be a suitable age threshold for BRCA testing. It is also consistent with recent simulation data, suggesting that this testing threshold would be a cost-effective strategy and would result in substantial reduction in subsequent breast and ovarian cancer in mutation-positive women (Kwon et al, 2010
). However, implementation of routine BRCA testing in all TN breast cancers diagnosed before 50 years would increase the logistical and financial burdens on genetic departments. We estimate that it would lead to ~1200 extra tests in England each year, which may be challenging for some departments to immediately implement with current resources and procedures. However, new sequencing technologies are leading us into an era of fast, affordable gene testing. Together with procedural reorganisation to allow BRCA testing in affected individuals to be undertaken though oncology services (with support from genetics as required), this should enable genetic services to introduce BRCA testing to women with TN breast cancer diagnosed below 50 years of age, within the next few years.