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Background Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX®, a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test. Methods The results of Ki67, uPA/PAI-1 and OncotypeDX® were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed. Results With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p  = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 ( p  < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values. Conclusion A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised).

Breast cancer treatment has advanced enormously in the last decade. Most of this is due to advances reached in the knowledge regarding tumor biology, mainly in the field of diagnosis and treatment. This review brings information about how the genomics-based information contributed to advances in breast cancer diagnosis and prognosis perspective, as well as presents how tumor biology discoveries fostered the main therapeutic approaches available to treat such patients, based on a personalized point of view.

Concerted evolution is a consequence of processes that convert copies of a gene in a multigene family into the same copy. Here we ask whether this homogenization may be adaptive. Analysis of a modifier of homogenization reveals (1) that the trait is most likely to spread if interactions between deleterious mutations are not strongly synergistic; (2) that selection on the modifier is of the order of the mutation rate, hence the modifier is most likely to be favoured by selection when the species has a large effective population size and/or if the modifier affects many genes simultaneously; and (3) that linkage between the genes in the family, and between these genes and the modifier, makes invasion of the modifier easier, suggesting that selection may favour multigene families being in clustered arrays. It follows from the first conclusion that genes for which mutations may often be dominant or semi-dominant should undergo concerted evolution more commonly than others. By analysis of the mouse knockout database, we show that mutations affecting growth-related genes are more commonly associated with dominant lethality than expected by chance. We predict then that selection will favour homogenization of such genes, and possibly others that are significantly dosage dependent, more often than it favours homogenization in other genes. The first condition is almost the opposite of that required for the maintenance of sexual reproduction according to the mutation-deterministic theory. The analysis here therefore suggests that sexual organisms can simultaneously minimize both the effects of deleterious, strongly synergistically, interacting mutations and those that interact either weakly synergistically, multiplicatively, or antagonistically, assuming the latter class belong to a multicopy gene family. Recombination and an absence of homogenization are efficient in purging deleterious mutations in the former class, homogenization and an absence of recombination are efficient at minimizing the costs imposed by the latter classes.