Triple Negative Breast Cancer: Updates on Classification and Treatment in 2021

Abstract

Breast cancer (BC) is the most common malignancy affecting women. It is a highly heterogeneous disease broadly defined by the differential expression of cell surface receptors. In the United States, triple negative breast cancer (TNBC) represents 15 to 20% of all BC. When compared with other subtypes of BC, TNBC tends to present in younger women, and has a higher mortality rate of 40% in advanced stages within the first 5 years after diagnosis. TNBC has historically had limited treatment options when compared to other types of BC. The mainstay of treatment for TNBC remains cytotoxic chemotherapy despite the emergence of new biologic and targeted agents. Defining the specific tumor molecular profile including PDL-1 and androgen receptor testing is expanding treatment options in the clinical setting. Identifying more targetable, novel biomarkers that may better define therapeutic targets or prognostic markers is currently underway. TNBC nomenclature is expected to be updated in favor of other nomenclature which would help direct therapy, and further redefine TNBC’s heterogeneity. Given the continuous advances in the field of TNBC, this review assesses the latest developments in basic characterization, subtyping, and treatment of TNBC, including novel drug developments with antibody-drug conjugates, immune checkpoint inhibitors, PARP inhibitors and androgen receptor targeted agents. Future trials are necessary in the face of these innovations to further support the use of new therapies in TNBC and the detection of the appropriate biomarkers.

Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype

“…In a recent study performed on PDX-established cell lines from triple negative breast tumors we demonstrated that Vav1 promotes the expression of miR-29b exclusively in cells showing relatively high levels of CEBPα [ 24 ], the main transcription factor for the miR-29b1/a cluster [ 36 ], whose activity is strongly dependent on Vav1 levels [ 24 ]. Here we demonstrated that, in PDX-derived cell lines belonging to the most frequent TNBC molecular subtypes identified by Lehmann [ 2 ], one of the most studied classifications as it recognized tumors that differ in histopathology, response to neoadjuvant chemotherapy [ 37 , 38 , 39 ] and disease progression, forcedly expressed Vav1 significantly down-modulates Akt2 only in cells in which it up-modulates miR-29b. This occurrence does not appear to correlate with specific Lehmann subtype/s, and contributes to further increase the intrinsic variability of breast tumors with a triple negative phenotype.…”

“…Despite the advent of new sequencing technologies and of advanced computing systems allowed to increase the number of data to be used for cataloging, TNBC subtypes identified with the different methods are often overlapped, and however they fail to precisely classify every single tumor [ 38 , 39 ]. This, on one hand, confirms that specific profiles can define the response to therapy and, ultimately, the prognosis of TNBC [ 2 , 4 , 5 ].…”

Contribution of n-3 Long-Chain Polyunsaturated Fatty Acids to the Prevention of Breast Cancer Risk Factors

“…TNBCs are lacking the three biomarkers, i.e., HER2, Erα, and progesterone receptors, and do not respond to hormone therapy for instance. Not all TNBCs are basal-like subtypes, and they can be divided into six subtypes: (i) basal-like-1 (BL1), (ii) BL2, (iii) immunomodulatory subtype, (iv) mesenchymal subtype, (v) mesenchymal stem-like subtype, and (vi) luminal androgen receptor subtype, each of which has distinct gene expressions and ontologies [8]. Therefore, the existence of different subtypes might suggest a differential response to a given 2 of 19 treatment, such as chemotherapy, radiotherapy, hormone therapy, or surgery.…”

Redox Mechanisms in Cisplatin Resistance of Cancer Cells: The Twofold Role of Gamma-Glutamyltransferase 1 (GGT1)

“…Major difficulties are however represented by the frequent occurrence of CDDP resistance and the considerable heterogeneity of TNBC, leading to a wide variability in patients’ response to the drug. Several potential biomarkers are under investigation in order to identify patients most likely to benefit from CDDP, including homologous recombination repair deficiency, tumor infiltrating lymphocytes, TP53, cyclin-dependent kinase 2 expression, vascular endothelial growth factor and matrix metalloproteinase-9 ( 4 – 6 ).…”

“…In conclusion, the expression of GGT1 represents an important biomarker of CDDP resistance, and studies are warranted in order to investigate its ability to prevent ferroptosis in other malignant neoplasias besides TNBC. The development of CDDP resistance was observed to correlate with the activation of Keap1/Nrf2 transduction pathway in a series of solid tumors ( 6 ) and signalling through the Keap1/Nrf2 axis is indeed involved in GGT1 expression ( 17 ), raising the possibility that this may be the case in at least some patients. The finding of GGT1 expression should be anyway interpreted as a biomarker of CDDP resistance and an indication towards alternative treatments.…”