Acknowledgements

regulation of ER [129, 134]. On the other hand, breast cancer originated in BRCA2 mutation carriers are typically much more similar to sporadic cases, despite with higher grading, higher

Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers is still controversial, and if some authors describe a worse prognosis even in classically low-risk node-negative disease [136], other exclude any significant difference if compared to the general breast cancer population [137]. Furthermore, BRCA1 and BRCA2 mutation carriers result to have an increased

New drugs have been purposed as a promising therapeutic strategy in BRCA defective tumor cells, such as the inhibitors of the poly(adenosine diphosphate-ribose) polymerase-1 (PARP1), which is an enzyme involved in the single-stranded DNA repair that use base excision repair. Other breast cancer susceptibility genes have been described, which can be divided into three categories in terms of mutation risk and the frequency of mutation. Along with BRCA1 and BRCA2 gene mutation, the first category includes PTEN and TP53 gene mutations, which are classified as high-penetrance, low-frequency predisposition genes, and the occurrence of even one of these mutations can increase the risk of breast cancer to 25% [139, 140]. The second category includes the CHEK2, ATM, PALB and BRIP1 2 genes, which are moderate-penetrance, low-frequency predisposition genes, and lead to an increased risk of cancer of twofold to fourfold [110]. Finally, the third category consists of the FGFR2, MAP3K1,and TGFB1 gene

In the last decades, many genomic and molecular classification have been described with a prognostic intent. The most famous divides breast cancers into the following subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like [142]. Luminal subtypes express high levels of ER, they usually have an indolent clinical course, with a low distant recurrence rate, which anyway persists even up to 15 years after the diagnosis. Luminal B subtypes express fewer ER-related genes, have a higher proliferation rate and may overexpress HER2/neu, so that they usually require to be treated with both hormonal therapy and chemotherapy. HER2 enriched subtype exhibits HER2/neu gene amplification but does not express ER-related genes, they have an aggressive natural clinical course but fortunately respond very well to HER2 targeted therapy. The basal-like or triple-negative subtype does not express ER, PR, and HER2/ neu but expresses basal cytokeratins 5/6 and 17, they have a poor prognosis and a high

The first molecular signature of breast cancer was determined in 2000 by the expression of a set of genes within the tumor, which were able to predict the clinical outcome [143]. The main limitations of gene signature profiling include difficulties in reproducing the specific gene sets, testing expense, and reporting standardization. However, gene signature cannot be substituted

by IHC surrogates which have significant discordances with genetic profiling [144].

frequency of ER-positivity and lower frequency of HER2/neu overexpression [135].

mutations, which are low-penetrance, high-frequency predisposition genes [141].

risk of contralateral breast cancer occurrence [138].

14 Biomarker - Indicator of Abnormal Physiological Process

5.2. Multigene signatures

recurrence rate.

The authors would like to thank the whole collaborating staff of the Universitât dal Friûl, and the support from Ennergi research non-profit association.
