Biological Subtypes of Triple-Negative Breast Cancer

Michael Hubalek, Theresa Czech, Hannes Müller
2017 Breast Care  
is further highlighted by the high prevalence of rare histopathological subtypes, such as metaplastic (90%), medullary (95%), adenoid cystic (90-100%), and apocrine (40-60%) carcinomas. Some common markers have been identified, such as basal cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) [4] . On the other hand, the molecular differentiation shows also a wide range of heterogeneity. New studies have now refined the understanding of TNBCs. The basal-like subtype was discovered
more » ... ore than a decade ago by first-generation cDNA microarrays [5] . These tumors are often referred to as TNBCs because most basal-like tumors are typically negative for ER, PR, and HER2. This subtype of breast cancer is characterized by a gene expression profile that is similar to that of the basal-myoepithelial layer of the normal breast [5] . However, approximately 75% of TNBCs are basal-like, with the other 25% comprising all other mRNA subtypes [6]. These subtypes include mostly HER2+ breast cancer ( fig. 1 ). 25% of all TNBCs lack ER, PR, and HER2 in IHC but do not exhibit the features of the basallike subtype. The Cancer Genome Atlas (TCGA) Research Network analyzed primary breast cancers using 6 platforms, including genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing, and reverse phase protein arrays [7] . By integrating information across platforms, the authors were able to examine the genomic heterogeneity of tumors. The TCGA analysis revealed that the most frequent loss-of-function and gain-of-function alterations in TNBC involve genes associated with DNA damage repair and phosphatidylinositol 3-kinase (PI3K) signaling pathways, respectively. Alterations in DNA damage repair genes include loss of TP53, RB1, and BRCA1 function. Aberrant activation of the PI3K pathway occurs due to loss of negative regulators such as the lipid phosphatases PTEN or INPP4B [8, 9] or activating mutations in PIK3CA, along with other genes in the PI3K/TOR signaling network [10, 11 ]. Another study sequenced and analyzed 104 TNBC tumors at the time of diagnosis and confirmed the high rate of TP53 mutations; however, they showed that 12% of cases did not have somatic mutations in any established 'driver' genes, suggesting that primary TNBCs are mutationally heterogeneous from the outset [12] . Summary Triple-negative breast cancers (TNBCs) are defined as tumors that are negative for estrogen, progesterone and HER-2 receptor. At a percentage of 10-20% TNBCs represent a minority in all breast cancers. However, because of the poor prognosis this particular subtype, triple negative disease accounts for a disproportionate number of metastatic cases and breast cancer deaths. Identification of its subtypes is essential for understanding the biological characteristics and clinical behavior of TNBC, as well as for developing personalized treatments. This review will focus on the great progress that has been made in the past few years on identifying new targets in TNBC subtypes and a variety of new treatment options that are on the verge of routine clinical application.
doi:10.1159/000455820 pmid:28611535 pmcid:PMC5465739 fatcat:n2lwvxc6enb77ea5fhyn4lweja