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Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer

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Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer cancers Review Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer Silvia Mezi 1 , Andrea Botticelli 2, Giulia Pomati 3,*, Bruna Cerbelli 1, Simone Scagnoli 4 , Sasan Amirhassankhani 5, Giulia d’Amati 1 and Paolo Marchetti 2 1 Department of Radiological, Oncological and Pathological Science, University of Rome “Sapienza”, 00185 Rome, Italy; [email protected] (S.M.); [email protected] (B.C.); [email protected] (G.d.) 2 Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, 00185 Rome, Italy; [email protected] (A.B.); [email protected] (P.M.) 3 Department of Molecular Medicine, University of Rome “Sapienza”, 00185 Rome, Italy 4 Department of Medical and Surgical Sciences and Translational Medicine, University of Rome “Sapienza”, 00185 Rome, Italy; [email protected] 5 Department of Plastic Surgery, Guy’s & St Thomas’ NHS Foundation Trust, London SE1 7EH, UK; [email protected] * Correspondence: [email protected]; Tel.: +39-340-348-7850 Simple Summary: Mesenchymal triple negative breast cancer subtype expresses genes involved in proliferation, epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, this subgroup is characterized by an immunosuppressive microenvironment. This review focuses on the intracellular pathways involved in tumorigenesis and cancer progression, as well as in the immune evasion mechanisms. Furthermore, we provide an overview of current clinical trials investigating the efficacy and safety of different therapeutic molecules for this aggressive subtype Citation: Mezi, S.; Botticelli, A.; of triple negative breast cancer. The challenge is to restore immunocompetence by overcoming the Pomati, G.; Cerbelli, B.; Scagnoli, S.; chemo and immune-resistance profile of mesenchymal triple negative breast cancer to achieve a Amirhassankhani, S.; d’Amati, G.; lasting response to therapy. Marchetti, P. Standard of Care and Promising New Agents for the Abstract: The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of ex- Treatment of Mesenchymal pression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished Triple-Negative Breast Cancer. by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the Cancers 2021, 13, 1080. https:// mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal doi.org/10.3390/cancers13051080 transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes in- volved in proliferation and an immune-suppressive microenvironment. Several molecular alterations Received: 7 January 2021 Accepted: 25 February 2021 along different pathways activated during carcinogenesis and tumor progression have been outlined Published: 3 March 2021 and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mes- enchymal transition process could lead to the overcoming of immune-resistance. This paper reviews Publisher’s Note: MDPI stays neutral the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional with regard to jurisdictional claims in therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. published maps and institutional affil- The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order iations. to restore immunocompetence in mesenchymal breast cancer patients. Keywords: triple negative; breast cancer; mesenchymal subtype; immunotherapy; target therapy Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and The management of breast cancer (BC), the most common tumor in women [1] has conditions of the Creative Commons improved since its sub-classification based on the expression of estrogen (ER), progesterone Attribution (CC BY) license (https:// receptors (PR) [2] and human epidermal growth factor receptor-2 (HER2) [3]. Four main creativecommons.org/licenses/by/ molecular subtypes of BC have been identified so far, based on the analysis of its global 4.0/). Cancers 2021, 13, 1080. https://doi.org/10.3390/cancers13051080 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 24 Cancers 2021, 13, 1080 2 of 24 main molecular subtypes of BC have been identified so far, based on the analysis of its global gene expression: Luminal A, luminal B, HER2, basal-like, and the more recently geneidentified expression: claudin-lo Luminalw tumor A, luminal subtype B, [4,5]. HER2, basal-like, and the more recently identified claudin-lowTriple negative tumor subtype breast cancer [4,5]. (TNBC) is defined by the lack of expression of ER, PR and HER2Triple and negative accounts breast for cancer about (TNBC)10–20% of is definedBCs [6]. byThis the definition lack of expression of TNBC is, of howev- ER, PR ander, limiting HER2and and accounts does not for allow about for 10–20% understa ofnding BCs [ 6its]. Thisheterogeneou definitions ofclinical TNBC behavior. is, how- ever,Based limiting on gene and expression does not profiling, allow for TNBCs understanding were originally its heterogeneous divided by Lehmann clinical behavior. into six Baseddifferent on subtypes: gene expression Basal-like profiling, 1 (BL1), TNBCs basal-like were 2 (BL2), originally immunomodulatory divided by Lehmann (IM), mes- into sixenchymal-like different subtypes: (M), mesenchymal Basal-like 1stem (BL1), cell-l basal-likeike (MSL) 2 (BL2), and luminal immunomodulatory androgen receptor (IM), mesenchymal-like(LAR). Both M and (M), MSL mesenchymal subtypes express stem cell-like genes (MSL)involved and in luminal the epithelial androgen to receptor mesen- (LAR).chymal Both transition M and (ETM), MSL subtypes stromal express interact genesion and involved cell motility. in the epithelial Moreover, to mesenchymal the M sub- transitiongroup displays (ETM), a stromalhigher interactionexpression andof genes cell motility. involved Moreover, in proliferation, the M subgroup while the displays MSL amore higher frequently expression shows of genesexpression involved of genes in proliferation, associated with while cell the stemness MSL more [5,7]. frequently Further showsstudies expression revealed that of genes the IM associated and MSL with subtypes cell stemness were strongly [5,7]. Further influenced studies by revealed the contri- that thebution IM andof transcripts MSL subtypes from were normal strongly stroma influenced and immune by the cells contribution of the tumor of transcripts microenviron- from normalment, respectively. stroma and immuneThus, the cells classification of the tumor hasmicroenvironment, been refined in therespectively. following 4 Thus,subtypes: the classificationBL1, BL2, M and has beenLAR refined[7–9]. The in thecomplexity following of 4 the subtypes: TNBC BL1,classification BL2, M and is also LAR determined [7–9]. The complexityby the possibility of the TNBCof identification classification of more is also than determined one subgroup by the in possibility some histological of identification types: ofFor more example, than onemetaplastic subgroup breast in some carcinoma histological could types: belong For to example, either the metaplastic BL2 or the breast M sub- car- cinomatype of couldBCs. Predominantly, belong to either themetaplastic BL2 or the tu Mmor subtype cells ofare BCs. pleomorphic Predominantly, and arranged metaplastic in tumor cells are pleomorphic and arranged in solid nests (Figure1A). The epithelial cells solid nests (Figure 1A). The epithelial cells shows a diffuse positivity for the mesenchy- shows a diffuse positivity for the mesenchymal marker vimentin on immunohistochemical mal marker vimentin on immunohistochemical staining (Figure 1B) staining (Figure1B). FigureFigure 1.1.Metaplastic Metaplastic breast breast carcinoma. carcinoma. (A ()A Tumor) Tumor cells cells are are highly highly pleomorphic pleomorphic and and arranged arranged in solid in solid nests. nests. (B) Immuno- (B) Im- histochemistrymunohistochemistry shows shows a diffuse a diffuse positivity positivity of neoplastic of neoplastic cells for cells the for mesenchymal the mesenchymal marker marker vimentin. vimentin. For the last two decadesdecades chemotherapy has been the onlyonly therapeutictherapeutic option,option, inin thethe absence ofof aa druggable druggable target. target. It playedIt played a central a central role inrole the in treatment the treatment of TNBC of inTNBC all disease in all settings,disease settings, even though even eachthough TNBC each subtype TNBC hassubt aype different has a different response response pattern to pattern the available to the chemotherapyavailable chemotherapy regimens [10regime]. Genens expression[10]. Gene analysis expression may an alsoalysis influence may chemotherapyalso influence treatmentchemotherapy choices; treatment a randomized choices; phase a randomiz III trial wased phase performed III trial comparing was performed use of carboplatincomparing vs.use docetaxelof carboplatin in unselected vs. docetaxel advanced in unselected TNBC and advanced in a priori TNBC specified and in biomarker a priori specified defined sub-populationsbiomarker defined [11 ].sub-populati In the unselectedons [11]. TNBC In patientthe unselected population, TNBC carboplatin patient was population, not more activecarboplatin compared
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